Breast cancer

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• Regimens for HER2 positive breast cancer are here.
• Regimens for Triple negative breast cancer (TNBC) are here.
• Regimens for BRCA-mutated breast cancer are here.
• Because docetaxel and paclitaxel are both often abbreviated as "T," we try to always make clear in the regimen name which agent is being used.

144 regimens on this page 333 variants on this page

Guidelines

ASCO

• 2016: Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology guideline PubMed
• 2016: Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline
• 2014: Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update

ASCO/CCO

• 2017: Role of bone-modifying agents in metastatic breast cancer: an American Society of Clinical Oncology–Cancer Care Ontario focused guideline update PubMed

ESMO

• 2015: Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

ESO/ESMO

• 2017: 3rd ESO-ESMO international consensus guidelines for advanced breast cancer (ABC3) PubMed

Older

• 2014: ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2) PubMed

NCCN

• NCCN Guidelines - Breast Cancer

Neoadjuvant chemotherapy

AC

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AC: Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen #1, 4 cycles

Study	Evidence	Comparator	Efficacy
Bear et al. 2012 (NSABP B-40)	Phase III	See link	See link
Robidoux et al. 2013 (NSABP B-41)	Non-randomized portion of RCT
Park et al. 2016 (I-SPY 2)	Non-randomized portion of RCT

Note: patients in NSABP B-41 and I-SPY 2 were HER2-positive.

Preceding treatment

• NSABP B-40: T (Taxotere) x 4 versus TX x 4 versus TG x 4
• I-SPY 2: Neratinib & Paclitaxel x 12 wk versus TH x 12 wk

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• NSABP B-40: Surgery
• NSABP B-41: TH versus THL versus TL, then surgery
• I-SPY 2: Surgery

Regimen #2, 5 cycles

Study	Evidence	Comparator	Efficacy
Ellis et al. 2011 (SWOG 0012)	Phase III (C)	Weekly doxorubicin & daily paclitaxel	Seems not superior

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 5 cycles

Subsequent treatment

• Paclitaxel x 12, then surgery

References

1. Ellis GK, Barlow WE, Gralow JR, Hortobagyi GN, Russell CA, Royce ME, Perez EA, Lew D, Livingston RB. Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012. J Clin Oncol. 2011 Mar 10;29(8):1014-21. Epub 2011 Jan 10. link to original article contains verified protocol link to PMC article PubMed
2. Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article PubMed
   1. Update: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article link to PMC article PubMed
3. Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. link to original article contains protocol PubMed
4. Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. link to original article contains verified protocol link to PMC article PubMed

AC+Bev

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AC+Bev: Adriamycin (Doxorubicin), Cyclophosphamide, Bevacizumab

Regimen

Study	Evidence	Comparator	Efficacy
Bear et al. 2012 (NSABP B-40)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• T+Bev x 4 versus TX+Bev x 4 versus TG+Bev x 4

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1
• Bevacizumab (Avastin) as follows:
  • Cycles 1 & 2: 15 mg/kg IV once on day 1
  • Cycles 3 & 4: none

21-day cycle for 4 cycles

Subsequent treatment

• Surgery, then adjuvant bevacizumab

References

1. Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article PubMed
   1. Update: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article link to PMC article PubMed

ddAC

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ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide

Regimen

Study	Evidence
Burstein et al. 2005	Non-randomized
Park et al. 2016 (I-SPY 2)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients in I-SPY 2 were HER2-positive.

Preceding treatment

• I-SPY 2: Neratinib & Paclitaxel x 12 wk versus TH x 12 wk

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive medications

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy
• Burstein et al. 2005: Darbepoetin alfa (Aranesp) 200 mcg SC once on day 1 for patients with Hb 10 to 12 g/dL; see paper for additional dose adjustments

14-day cycle for 4 cycles

Subsequent treatment

• Burstein et al. 2005: Optional Neoaduvant paclitaxel, then surgery or surgery, then adjuvant paclitaxel; this was not a randomization
• I-SPY 2: Surgery

References

1. Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains verified protocol PubMed
2. Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. link to original article contains verified protocol link to PMC article PubMed

Docetaxel monotherapy

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D: Docetaxel
T: Taxotere (Docetaxel)

Regimen #1, 75 mg/m² x 4

Study	Evidence	Comparator	Efficacy
Bear et al. 2012 (NSABP B-40)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• AC x 4, then surgery

Regimen #2, 100 mg/m² x 3

Study	Evidence	Comparator	Efficacy
Earl et al. 2015 (ARTemis)	Phase III	Docetaxel & Bevacizumab	Seems to have inferior pCR rate

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• FEC

Regimen #3, 100 mg/m² x 4

Study	Evidence	Comparator	Efficacy
von Minckwitz et al. 2012 (GeparQuinto)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• EC x 4

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Müller BM, Denkert C, Loibl S, Nekljudova V, Untch M; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Groups. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012 Jan 26;366(4):299-309. link to original article contains verified protocol PubMed
2. Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article PubMed
   1. Update: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article link to PMC article PubMed
3. Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Abraham J, Thomas J, Provenzano E, Hughes-Davies L, Gounaris I, McAdam K, Chan S, Ahmad R, Hickish T, Houston S, Rea D, Bartlett J, Caldas C, Cameron DA, Hayward L; ARTemis Investigators. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):656-66. Epub 2015 May 11. link to original article contains verified protocol PubMed

Docetaxel & Bevacizumab

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Bev+D: Bevacizumab & Docetaxel
T+Bev: Taxotere (Docetaxel) & Bevacizumab

Regimen #1, docetaxel 75 mg/m²

Study	Evidence	Comparator	Efficacy
Bear et al. 2012 (NSABP B-40)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• AC+Bev x 4, then surgery

Regimen #2, docetaxel 100 mg/m²

Study	Evidence	Comparator	Efficacy
Earl et al. 2015 (ARTemis)	Phase III	Docetaxel	Seems to have superior pCR rate

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. A total of four bevacizumab doses are given, with the fourth given with the first cycle of FEC.

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• FEC

References

1. Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article PubMed
   1. Update: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article link to PMC article PubMed
2. Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Abraham J, Thomas J, Provenzano E, Hughes-Davies L, Gounaris I, McAdam K, Chan S, Ahmad R, Hickish T, Houston S, Rea D, Bartlett J, Caldas C, Cameron DA, Hayward L; ARTemis Investigators. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):656-66. Epub 2015 May 11. link to original article contains verified protocol PubMed

EC

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EC: Epirubicin & Cyclophosphamide

Regimen

Study	Evidence	Comparator	Efficacy
von Minckwitz et al. 2012 (GeparQuinto)	Phase III	See link	See link
Untch et al. 2016 (GBG 69)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• GBG 69: nab-Paclitaxel x 4 versus Paclitaxel x 4

Chemotherapy

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• GeparQuinto: Docetaxel, then surgery
• GBG 69: Surgery

References

1. von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Müller BM, Denkert C, Loibl S, Nekljudova V, Untch M; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Groups. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012 Jan 26;366(4):299-309. link to original article contains verified protocol PubMed
2. Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group (GBG).; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. Epub 2016 Feb 8. 2016 Mar;17(3):345-56. link to original article contains verified protocol PubMed

FEC

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FEC: Fluorouracil, Epirubicin, Cyclophosphamide

Regimen #1, 500/75/500 ("FEC-75")

Study	Evidence	Comparator	Efficacy
Buzdar et al. 2013 (ACOSOG Z1041)	Phase III	See link	See link

Note that patients in this trial had HER2-positive breast cancer. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• TH (Taxol) x 12 wk, then surgery

Regimen #2, 500/100/500

Study	Evidence
Earl et al. 2015 (ARTemis)	Non-randomized portion of RCT

Note that for the patients randomized to the bevacizumab arm, a fourth dose was given with the first cycle of FEC. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Docetaxel & Bevacizumab x 3 versus Docetaxel x 3

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Surgery

References

1. Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005 Jun 1;23(16):3676-85. Epub 2005 Feb 28. link to original article PubMed
   1. Update: Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, Sahin AA, Esteva F, Symmans WF, Ewer MS, Buchholz TA, Hortobagyi GN. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007 Jan 1;13(1):228-33. link to original article PubMed
2. Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig G, Royce M, McCall LM, Ewer MS, Hunt KK; American College of Surgeons Oncology Group investigators. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1317-25. Epub 2013 Nov 13. link to original article link to PMC article contains verified protocol PubMed
3. Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Abraham J, Thomas J, Provenzano E, Hughes-Davies L, Gounaris I, McAdam K, Chan S, Ahmad R, Hickish T, Houston S, Rea D, Bartlett J, Caldas C, Cameron DA, Hayward L; ARTemis Investigators. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):656-66. Epub 2015 May 11. link to original article contains verified protocol PubMed

Paclitaxel monotherapy

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T: Taxol (Paclitaxel)

Regimen #1, weekly paclitaxel

Study	Evidence	Comparator	Efficacy
Ellis et al. 2011 (SWOG 0012)	Non-randomized portion of RCT
Untch et al. 2016 (GBG 69)	Phase III	nab-Paclitaxel	Inferior pCR rate

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• SWOG 0012: AC x 5 versus weekly doxorubicin & daily cyclophosphamide

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per week

12-week course

Subsequent treatment

• SWOG 0012: Surgery
• GBG 69: EC x 4, then surgery

Regimen #2, bi-weekly paclitaxel

Study	Evidence	Comparator	Efficacy
Burstein et al. 2005	Non-randomized
Earl et al. 2013 (Neo-tAnGo)	Phase III	EC, then T EC, then TG	Seems to have superior pCR rate
		TG	Seems not superior

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Burstein et al. 2005: ddAC x 4

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

14-day cycle for 4 cycles

Subsequent treatment

• Burstein et al. 2005: Surgery
• Neo-tAnGo: EC

References

1. Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005 Jun 1;23(16):3676-85. Epub 2005 Feb 28. link to original article PubMed
   1. Update: Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, Sahin AA, Esteva F, Symmans WF, Ewer MS, Buchholz TA, Hortobagyi GN. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007 Jan 1;13(1):228-33. link to original article PubMed
2. Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains verified protocol PubMed
3. Ellis GK, Barlow WE, Gralow JR, Hortobagyi GN, Russell CA, Royce ME, Perez EA, Lew D, Livingston RB. Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012. J Clin Oncol. 2011 Mar 10;29(8):1014-21. Epub 2011 Jan 10. link to original article contains verified protocol link to PMC article PubMed
4. Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):201-12. Epub 2013 Dec 19. link to original article contains verified protocol PubMed
5. Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group (GBG).; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. Epub 2016 Feb 8. 2016 Mar;17(3):345-56. link to original article contains verified protocol PubMed

Paclitaxel, nanoparticle albumin-bound monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Untch et al. 2016 (GBG 69)	Phase III	Paclitaxel	Superior pCR rate

Note: this is the dose after study amendment due to increased treatment discontinuation and sensory neuropathy. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m² IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Subsequent treatment

• EC

References

1. Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group (GBG).; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. Epub 2016 Feb 8. 2016 Mar;17(3):345-56. link to original article contains verified protocol PubMed

Neoadjuvant endocrine therapy

Anastrozole monotherapy

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Regimen

Study	Evidence	Efficacy
Ellis et al. 2011 (ACOSOG Z1031)	Screening Phase II	cRR: 69% (95% CI, 60-77)

Note: ACOSOG Z1031 was randomized but with the intent to select candidates for phase III trials; efficacy comparisons were not made.

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day

16- to 18-week course

Subsequent treatment

• Surgery

References

1. Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K, Allred DC, Esserman LJ, Unzeitig GW, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Watson MA, Leitch M, Hunt K, Olson JA. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol. 2011 Jun 10;29(17):2342-9. Epub 2011 May 9. link to original article link to PMC article contains verified protocol PubMed

Anastrozole & Goserelin

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Regimen

Study	Evidence	Comparator	Efficacy
Masuda et al. 2012 (STAGE)	Phase III	Goserelin & Tamoxifen	Superior RR

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day
• Goserelin (Zoladex) 3.6 mg IM depot once per month

24-week course

Subsequent treatment

• Surgery

References

1. Masuda N, Sagara Y, Kinoshita T, Iwata H, Nakamura S, Yanagita Y, Nishimura R, Iwase H, Kamigaki S, Takei H, Noguchi S. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial. Lancet Oncol. 2012 Apr;13(4):345-52. Epub 2012 Jan 20. link to original article contains protocol PubMed

Goserelin & Tamoxifen

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Regimen

Study	Evidence	Comparator	Efficacy
Masuda et al. 2012 (STAGE)	Phase III	Goserelin & Tamoxifen	Inferior RR

Endocrine therapy

• Goserelin (Zoladex) 3.6 mg IM depot once per month
• Tamoxifen (Nolvadex) 20 mg PO once per day

24-week course

Subsequent treatment

• Surgery

References

1. Masuda N, Sagara Y, Kinoshita T, Iwata H, Nakamura S, Yanagita Y, Nishimura R, Iwase H, Kamigaki S, Takei H, Noguchi S. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial. Lancet Oncol. 2012 Apr;13(4):345-52. Epub 2012 Jan 20. link to original article contains protocol PubMed

Letrozole monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Eiermann et al. 2001 (P024))	Phase III	Tamoxifen	Superior ORR
Ellis et al. 2011 (ACOSOG Z1031)	Screening Phase II		cRR: 75% (95% CI, 66-82)

Note: ACOSOG Z1031 gave a total treatment duration of 16 to 18 weeks, which is approximately 4 months. Also, this trial was randomized but with the intent to select candidates for phase III trials; efficacy comparisons were not made.

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

4-month course

Subsequent treatment

• Surgery

References

1. Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J, Mauriac L, Ellis M, Lassus M, Chaudri-Ross HA, Dugan M, Borgs M; Letrozole Neo-Adjuvant Breast Cancer Study Group. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol. 2001 Nov;12(11):1527-32. link to original article contains protocol PubMed
2. Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K, Allred DC, Esserman LJ, Unzeitig GW, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Watson MA, Leitch M, Hunt K, Olson JA. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol. 2011 Jun 10;29(17):2342-9. Epub 2011 May 9. link to original article link to PMC article contains verified protocol PubMed

Neoadjuvant response criteria

Clinical response rate (cRR)

Although fairly dated, some trials such as ACOSOG Z1031 make use of the WHO criteria for response to neoadjuvant therapy. Included here primarily for historical purposes.

References

1. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981 Jan 1;47(1):207-14. link to original article PubMed

Miller-Payne scoring system

• Grade 1: No change or some changes to individual malignant cells, but no reduction in overall cellularity
• Grade 2: Minor loss of tumor cells (up to 30%), but overall cellularity still high
• Grade 3: An estimated 30 to 90% reduction in the number of tumor cells
• Grade 4: Marked disappearance of tumor cells such that only small clusters or widely dispersed individual cells remain (loss of greater than 90% of tumor cells)
• Grade 5: No invasive cancer cells identifiable in sections from the site of the tumor (carcinoma in situ may be present)

References

1. Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003 Oct;12(5):320-7. link to original article PubMed

Residual cancer burden (RCB)

• The RCB is calculated as follows: RCB = 1.4 (f_inv*d_prim)^0.17 + [4(1 - 0.75^LN)d_met]^0.17
  • where d_prim is derived from the bidimensional diameters of the primary tumor bed in the resected specimen, f_inv is the proportion of the primary tumor bed that contains invasive carcinoma, LN is the number of axillary lymph nodes containing metastatic carcinoma, and d_met is the diameter of the largest metastasis in an axillary lymph node.
  • The cut-off points are 1.36 and 3.28.

References

1. Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007 Oct 1;25(28):4414-22. Epub 2007 Sep 4. link to original article PubMed

Residual disease in breast and nodes (RDBN)

• Level 1: pCR in breast and nodes with or without in situ carcinoma
• Levels 2 to 4: Residual disease, calculated as 0.2 (residual breast tumor size in cm) + index of involved nodes (0 for no positive nodes, 1 for 1 to 4 positive nodes, 2 for 5 to 7 positive nodes, and 3 for 8 positive nodes) + the Scarff–Bloom–Richardson grade (1, 2, or 3). The cut-off points are 3 and 4.3.

References

1. Chollet P, Abrial C, Durando X, Thivat E, Tacca O, Mouret-Reynier MA, Leheurteur M, Kwiatkowski F, Dauplat J, Penault-Llorca F. A new prognostic classification after primary chemotherapy for breast cancer: residual disease in breast and nodes (RDBN). Cancer J. 2008 Mar-Apr;14(2):128-32. link to original article PubMed

Sataloff's classification

• Breast:
  • T-A: Total or nearly total therapeutic effect
  • T-B: Greater than 50% therapeutic effect
  • T-C: Less than 50% therapeutic effect
  • T-D: No therapeutic effect
• Lymph node:
  • N-A: Therapeutic effect but no metastasis
  • N-B: No metastasis, no therapeutic effect
  • N-C: Therapeutic effect but metastasis
  • N-D: Metastasis, no therapeutic effect

References

1. Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg. 1995 Mar;180(3):297-306. PubMed

Tumor response ratio

Calculated as follows: Residual breast disease observed upon pathologic examination divided by the size of the tumor on the pre-neoadjuvant therapy image.

• TRR = 0: pathologic complete response (pCR)
• TRR greater than 0 up to 0.4: strong partial response
• TRR greater than 0.4 up to 1.0: weak partial response (WPR)
• TRR greater than 1.0: tumor growth

References

1. Miller M, Ottesen RA, Niland JC, Kruper L, Chen SL, Vito C. Tumor response ratio predicts overall survival in breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol. 2014 Oct;21(10):3317-23. Epub 2014 Jul 25. link to original article PubMed

ypTNM staging

This system is proprietary to the AJCC. Please visit their site or consult the AJCC Manual for further details.

Adjuvant chemotherapy

AC

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AC: Adriamycin (Doxorubicin) and Cyclophosphamide
CA: Cyclophosphamide and Adriamycin (Doxorubicin)

Regimen #1

Study	Evidence	Comparator	Efficacy
Fisher et al. 2001 (NSABP B-23)	Phase III	CMF	Seems not superior
Henderson et al. 2003 (INT 0148/CALGB 9344)	Phase III	High-dose AC Very-high-dose AC	Seems not superior
Citron et al. 2003 (CALGB 9741)	Phase III	A ddA ddAC	See link
Van Pelt et al. 2003	Phase II
Mamounas et al. 2005 (NSABP B-28)	Non-randomized portion of RCT
Romond et al. 2005 (NSABP B-31/NCCTG N9831)	Non-randomized portion of RCT
Jones et al. 2006 (US Oncology Trial 9735)	Phase III	TC	Seems to have inferior OS
Sparano et al. 2008 (ECOG E1199)	Non-randomized portion of RCT
Eiermann et al. 2011 (BCIRG-005)	Phase III	See link	See link
Slamon et al. 2011 (BCIRG 006)	Phase III	See link	See link

Patients in Van Pelt et al. 2003, NSABP B-31, NCCTG N9831, and BCIRG 006 were HER2-positive.

Preceding treatment

• Van Pelt et al. 2003: Neoadjuvant TH, then surgery
• INT 0148/CALGB 9344: Surgery, within 84 days

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• NSABP B-23: Tamoxifen versus placebo
• Van Pelt et al. 2003: H
• INT 0148/CALGB 9344 and NSABP B-28: T (Taxol) versus no further therapy
• CALGB 9741: T (Taxol)
• NSABP B-31: T (Taxol) versus TH (Taxol)
• NCCTG N9831: T (Taxol) versus T (Taxol), then H versus TH (Taxol)
• ECOG E1199: Docetaxel q3wk versus Docetaxel weekly versus Paclitaxel q3wk versus Paclitaxel weekly
• BCIRG-005: T (Taxotere)
• BCIRG 006: T (Taxol) versus TH (Taxol)

Regimen #2, with range

Study	Evidence
von Minckwitz et al. 2017 (APHINITY)	Non-randomized portion of RCT

Patients in APHINITY had HER2-positive breast cancer. Note that ranges for AC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• TH (Taxol) versus THP (Taxol) or TH (Taxotere) versus THP (Taxotere)

References

1. Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article PubMed
2. Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. link to original article contains verified protocol PubMed
3. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains verified protocol PubMed
4. Van Pelt AE, Mohsin S, Elledge RM, Hilsenbeck SG, Gutierrez MC, Lucci A Jr, Kalidas M, Granchi T, Scott BG, Allred DC, Chang JC. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer. 2003 Dec;4(5):348-53. PubMed
5. Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. link to original article PubMed
6. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. link to original article PubMed
   1. Update: Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. Epub 2011 Oct 31. link to original article link to PMC article PubMed
   2. Update: Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. link to original article link to PMC article PubMed
   3. Update and HRQoL analysis: Ganz PA, Romond EH, Cecchini RS, Rastogi P, Geyer CE Jr, Swain SM, Jeong JH, Fehrenbacher L, Gross HM, Brufsky AM, Flynn PJ, Wahl TA, Seay TE, Wade JL 3rd, Biggs DD, Atkins JN, Polikoff J, Zapas JL, Mamounas EP, Wolmark N. Long-term follow-up of cardiac function and quality of life for patients in NSABP protocol B-31/NRG Oncology: a randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel and trastuzumab in patients with node-positive breast cancer with tumors overexpressing human epidermal growth factor receptor 2. J Clin Oncol. 2017 Dec 10;35(35):3942-3948. Epub 2017 Oct 26. link to original article link to PMC article PubMed
7. Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Anthony SP, Mennel RG, Boehm KA, Meyer WG, Asmar L. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006 Dec 1;24(34):5381-7. Erratum in: J Clin Oncol. 2007 May 1;25(13):1819. link to original article PubMed
   1. Update: Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. Epub 2009 Feb 9. link to original article PubMed
8. Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. link to original article link to PMC article PubMed
   1. Update: Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. link to original article link to PMC article PubMed
9. Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martin M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press M, Sauter G, Lindsay MA, Riva A, Buyse M, Drevot P, Taupin H, Mackey JR. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011 Oct 10;29(29):3877-84. Epub 2011 Sep 12. link to original article contains verified protocol PubMed
   1. Update: Mackey JR, Pieńkowski T, Crown J, Sadeghi S, Martin M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press MF, Sauter G, Lindsay M, Houé V, Buyse M, Drevot P, Hitier S, Bensfia S, Eiermann W; Translational Research In Oncology (TRIO)/ Breast Cancer International Research Group (BCIRG)-005 investigators. Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. Ann Oncol. 2016 Jun;27(6):1041-7. Epub 2016 Mar 2. link to original article PubMed
10. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. link to original article link to PMC article PubMed
11. Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: Final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article PubMed
12. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed

Bevacizumab monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Bear et al. 2012 (NSABP B-40)	Phase III	See link	See link

Preceding treatment

• Neoadjuvant AC+Bev x 4, then surgery

Chemotherapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for 10 cycles

References

1. Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article PubMed
   1. Update: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article link to PMC article PubMed

Capecitabine monotherapy

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Regimen #1, 4 cycles

Study	Evidence	Comparator	Efficacy
Cameron et al. 2017 (TACT2)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• ddE x 4 versus Epirubicin x 4

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO BID on days 1 to 14

21-day cycle for 4 cycles

Regimen #2, 6 to 8 cycles

Study	Evidence	Comparator	Efficacy
Masuda et al. 2017	Phase III	Standard therapy	Superior OS

All patients in this study had residual disease at time of surgical resection. Concomitant endocrine therapy was allowed.

Preceding treatment

• Neoadjuvant chemotherapy containing anthracycline, taxane, or both, then surgery

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO BID on days 1 to 14

21-day cycle for 6 to 8 cycles

References

1. Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, Park BW, Kim SB, Yanagita Y, Ohno S, Takao S, Aogi K, Iwata H, Jeong J, Kim A, Park KH, Sasano H, Ohashi Y, Toi M. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017 Jun 1;376(22):2147-2159. link to original article contains verified protocol PubMed
2. Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. link to original article link to PMC article contains verified protocol PubMed

CMF

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CMF: Cyclophosphamide, Methotrexate, Fluorouracil

Regimen #1, IV cyclophosphamide

Study	Evidence	Comparator	Efficacy
Schmid et al. 2007 (TABLE)	Phase III	Leuprolide	Inferior OS

Preceding treatment

• Surgery, within 6 weeks

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days 1 & 8
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/m² IV once per day on days 1 & 8

28-day cycle for 6 cycles

Regimen #2, classic CMF (IV) x 6

Study	Evidence	Comparator	Efficacy
Poole et al. 2006 (NEAT)	Phase III	Epirubicin, then CMF x 4	Inferior OS

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 600 mg/m² IV once per day on days 1 & 8
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/m² IV once per day on days 1 & 8

28-day cycle for 6 cycles

Regimen #3, classic CMF (PO) x 6

Study	Evidence	Comparator	Efficacy
Levine et al. 1998 (NCIC CTG MA5)	Phase III	CEF	Inferior RFS
Fisher et al. 2001 (NSABP B-23)	Phase III	AC	Seems not superior
Piccart et al. 2001	Phase III	Full-dose EC	Seems not superior
		Moderate-dose EC	Not reported
Hutchins et al. 2005 (INT-0102)	Phase III	CAF	Seems to have inferior OS
Poole et al. 2006 (NEAT)	Phase III	Epirubicin, then CMF x 4	Inferior OS

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/m² IV once per day on days 1 & 8

28-day cycle for 6 cycles

Subsequent treatment

• NSABP B-23 and INT-0102: tamoxifen x 5 years versus placebo

Regimen #4, classic CMF (PO) x 4

Study	Evidence	Comparator	Efficacy
Poole et al. 2006 (NEAT)	Phase III	See link	See link
Cameron et al. 2017 (TACT2)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Epirubicin x 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/m² IV once per day on days 1 & 8

28-day cycle for 4 cycles

Regimen #5, classic CMF (IV) x 4

Study	Evidence	Comparator	Efficacy
Poole et al. 2006 (NEAT)	Phase III	See link	See link
Cameron et al. 2017 (TACT2)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Epirubicin x 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 600 mg/m² IV once per day on days 1 & 8
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/m² IV once per day on days 1 & 8

28-day cycle for 4 cycles

Regimen #6, modified CMF x 4

Study	Evidence	Comparator	Efficacy
Poole et al. 2006 (BR9601)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Epirubicin x 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Methotrexate (MTX) 50 mg/m² IV once on day 1
• Fluorouracil (5-FU) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Regimen #7, modified CMF x 8

Study	Evidence	Comparator	Efficacy
Poole et al. 2006 (BR9601)	Phase III	Epirubicin, then CMF x 4	Inferior OS

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Methotrexate (MTX) 50 mg/m² IV once on day 1
• Fluorouracil (5-FU) 600 mg/m² IV once on day 1

21-day cycle for 8 cycles

Regimen #8, classic CMF x 12

Study	Evidence	Comparator	Efficacy
Bonadonna et al. 1976	Phase III	Observation	Superior RFS

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/m² IV once per day on days 1 & 8

28-day cycle for 12 cycles

References

1. Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini G, Bajetta E, Musumeci R, Veronesi U. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976 Feb 19;294(8):405-10. link to original article contains verified protocol PubMed
   1. Update: Bonadonna G, Rossi A, Valagussa P, Banfi A, Veronesi U. The CMF program for operable breast cancer with positive axillary nodes. Updated analysis on the disease-free interval, site of relapse and drug tolerance. Cancer. 1977 Jun;39(6 Suppl):2904-15. link to original article PubMed
   2. Update: Bonadonna G, Valagussa P, Rossi A, Tancini G, Brambilla C, Zambetti M, Veronesi U. Ten-year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat. 1985;5(2):95-115. PubMed
   3. Update: Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995 Apr 6;332(14):901-6. link to original article PubMed
2. Brincker H, Mouridsen HT, Andersen KW. Adjuvant chemotherapy with cyclophosphamide or CMF in premenopausal women with stage II breast cancer. Breast Cancer Res Treat. 1983;3(1):91-5. PubMed
   1. Update: Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Andersson M, Kamby C, Knoop AS; Danish Breast Cancer Cooperative Group. Cyclophosphamide, methotrexate, and fluorouracil; oral cyclophosphamide; levamisole; or no adjuvant therapy for patients with high-risk, premenopausal breast cancer. Cancer. 2010 May 1;116(9):2081-9. link to original article PubMed
3. Tormey DC, Gray R, Gilchrist K, Grage T, Carbone PP, Wolter J, Woll JE, Cummings FJ. Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients. An Eastern Cooperative Oncology Group trial. Cancer. 1990 Jan 15;65(2):200-6. link to original article PubMed
4. Coombes RC, Bliss JM, Wils J, Morvan F, Espié M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A, McArdle C, Pérez-López FR, Vassilopoulos P, Ferreira EP, Chilvers CE, Coombes G, Woods EM, Marty M. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. The International Collaborative Cancer Group. J Clin Oncol. 1996 Jan;14(1):35-45. link to original article PubMed
5. Review: Goldhirsch A, Colleoni M, Coates AS, Castiglione-Gertsch M, Gelber RD. Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike? The International Breast Cancer Study Group (IBCSG). Ann Oncol. 1998 May;9(5):489-93. link to original article contains protocol PubMed
6. Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CK, Tu D. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1998 Aug;16(8):2651-8. link to original article PubMed
   1. Update: Levine MN, Pritchard KI, Bramwell VH, Shepherd LE, Tu D, Paul N; National Cancer Institute of Canada Clinical Trials Group. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol. 2005 Aug 1;23(22):5166-70. link to original article PubMed
7. Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article PubMed
8. Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. link to original article PubMed
9. Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article PubMed
10. Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article PubMed
11. Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Cold S, Edlund P, Ewertz M, Jensen BB, Kamby C, Nordenskjold B, Bergh J. Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer. Eur J Cancer. 2007 Mar;43(5):877-84. Epub 2007 Feb 16. link to original article PubMed
12. Schmid P, Untch M, Kossé V, Bondar G, Vassiljev L, Tarutinov V, Lehmann U, Maubach L, Meurer J, Wallwiener D, Possinger K. Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol. 2007 Jun 20;25(18):2509-15. link to original article contains verified protocol PubMed
13. Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article PubMed

CMFT

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CMFT: Cyclophosphamide, Methotrexate, Fluorouracil, Tamoxifen

Regimen

Study	Evidence	Comparator	Efficacy
Eljertsen et al. 2013 (DBCG 82C)	Phase III	Tamoxifen	Superior DFS
		Tamoxifen & RT	Not reported

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1
• Methotrexate (MTX) 40 mg/m² IV once on day 1
• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Tamoxifen (Nolvadex) 30 mg PO once per day

28-day cycle for 9 cycles (tamoxifen continued for one year total)

References

1. Ejlertsen B, Jensen MB, Elversang J, Rasmussen BB, Andersson M, Andersen J, Nielsen DL, Cold S, Mouridsen HT. One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer. Eur J Cancer. 2013 Sep;49(14):2986-94. Epub 2013 Jun 8. link to original article contains verified protocol PubMed

DC

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DC: Docetaxel and Cyclophosphamide

Regimen

Study	Evidence	Comparator	Efficacy
Ejlertsen et al. 2017 (DBCG 07-READ)	Phase III	EC, then D	Seems not superior

Patients were TOP2A normal as determined by FISH.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles

References

1. Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. link to original article contains verified protocol PubMed

ddA

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ddA: dose-dense Adriamycin (Doxorubicin)

Regimen

Study	Evidence	Comparator	Efficacy
Citron et al. 2003 (CALGB 9741)	Phase III	See link	See link
Kahan et al. 2005	Phase II

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

Supportive medications

• Filgrastim (Neupogen)

14-day cycle for 4 cycles

Subsequent treatment

• ddT

References

1. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains verified protocol PubMed
2. Kahan Z, Uhercsak G, Hajnal-Papp R, Boda K, Thurzo L. Dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy is well tolerated and safe in high-risk early breast cancer. Oncology. 2005;68(4-6):446-53. Epub 2005 Jul 13. link to original article PubMed
   1. Update: Kelemen G, Uhercsák G, Ormándi K, Eller J, Thurzó L, Kahán Z. Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer. Oncology. 2010;78(3-4):271-3. Epub 2010 Jun 7. link to original article PubMed

ddAC

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ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide

Regimen

Study	Evidence	Comparator	Efficacy
Citron et al. 2003 (CALGB 9741)	Phase III	See link	See link
Burstein et al. 2005	Non-randomized
Dang et al. 2008	Phase II
Shulman et al. 2012 (CALGB 40101)	Phase III	ddAC x 6	Seems not superior
		Paclitaxel x 4	Seems not superior
		Paclitaxel x 6	Seems not superior
Swain et al. 2013 (NSABP B-38)	Phase III	See link	See link

Note: CALGB 40101 originally specified 21-day cycles but was amended to 14-day cycles after results of CALGB 9741 were available. Patients in Dang et al. 2008 had HER2-positive breast cancer.

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive medications

• (varies depending on reference):
• CALGB 9741:
  • Filgrastim (Neupogen) 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
    • Note: Citron et al. 2003 says the schedule was "filgrastim days 3 to 10 of each cycle (a total of seven doses)," so it is unclear whether 7 or 8 doses was actually used).
• Burstein et al. 2005 and Dang et al. 2008:
  • Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy
• Burstein et al. 2005:
  • Darbepoetin alfa (Aranesp) 200 mcg SC once on day 1 for patients with Hb 10 to 12 g/dL; see Burstein et al. 2005 for additional dose adjustments
• CALGB 40101: one of the following:
  • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
  • Sargramostim (Leukine) 250 to 500 mcg/m² SC on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
  • Pegfilgrastim (Neulasta) 6 mg SC, administered once 24 to 36 hours after chemotherapy

14-day cycle for 4 cycles

Subsequent treatment

• CALGB 9741 and Burstein et al. 2005: Paclitaxel x 4
• Dang et al. 2008: ddTH (Taxol)
• NSABP B-38: dose-dense paclitaxel x 4 versus ddPG x 4

Regimen #2, with range

Study	Evidence
von Minckwitz et al. 2017 (APHINITY)	Non-randomized portion of RCT

Patients in APHINITY had HER2-positive breast cancer. Note that ranges for ddAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive medications

• G-CSF support (drug/dose/schedule not specified)

14-day cycle for 4 cycles

Subsequent treatment

• TH (Taxol) versus THP (Taxol) or TH (Taxotere) versus THP (Taxotere)

References

1. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains verified protocol PubMed
2. Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains verified protocol PubMed
3. Dang C, Fornier M, Sugarman S, Troso-Sandoval T, Lake D, D'Andrea G, Seidman A, Sklarin N, Dickler M, Currie V, Gilewski T, Moynahan ME, Drullinsky P, Robson M, Wasserheit-Leiblich C, Mills N, Steingart R, Panageas K, Norton L, Hudis C. The safety of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer. J Clin Oncol. 2008 Mar 10;26(8):1216-22. link to original article contains verified protocol PubMed
4. Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains verified protocol link to study protocol PDF link to PMC article PubMed
   1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to PMC article PubMed
5. Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. link to original article link to PMC article contains verified protocol PubMed
6. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed

ddC

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ddC: dose-dense Cyclophosphamide

Regimen #1, 600 mg/m²

Study	Evidence	Comparator	Efficacy
Citron et al. 2003 (CALGB 9741)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• ddT x 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive medications

• Filgrastim (Neupogen) 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
  • Note: Citron et al. 2003 says the schedule was "filgrastim days 3 to 10 of each cycle (a total of seven doses)," so it is unclear whether 7 or 8 doses was actually used).

14-day cycle for 4 cycles

Regimen #2, 800 mg/m²

Study	Evidence
Kahan et al. 2005	Phase II

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• ddT x 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once on day 1

Supportive medications

• Filgrastim (Neupogen)

14-day cycle for 4 cycles

References

1. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains verified protocol PubMed
2. Kahan Z, Uhercsak G, Hajnal-Papp R, Boda K, Thurzo L. Dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy is well tolerated and safe in high-risk early breast cancer. Oncology. 2005;68(4-6):446-53. Epub 2005 Jul 13. link to original article PubMed
   1. Update: Kelemen G, Uhercsák G, Ormándi K, Eller J, Thurzó L, Kahán Z. Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer. Oncology. 2010;78(3-4):271-3. Epub 2010 Jun 7. link to original article PubMed

ddEC

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ddEC: dose-dense Epirubicin and Cyclophosphamide

Regimen #1, with range

Study	Evidence
von Minckwitz et al. 2017 (APHINITY)	Non-randomized portion of RCT

Patients in APHINITY had HER2-positive breast cancer. Note that ranges for ddEC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive medications

• G-CSF support (drug/dose/schedule not specified)

14-day cycle for 4 cycles

Subsequent treatment

• TH (Taxol) versus THP (Taxol) or TH (Taxotere) versus THP (Taxotere)

Regimen #2

Study	Evidence	Comparator	Efficacy
Del Mastro et al. 2015 (GIM2)	Phase III	ddFEC	Seems not superior
		EC FEC	Superior OS

To be completed; insufficient details in abstract for dosing.

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence)
• Cyclophosphamide (Cytoxan)

Supportive medications

• Pegfilgrastim (Neulasta)

Subsequent treatment

• Paclitaxel

References

1. Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella (GIM) investigators. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article PubMed
2. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed

ddFEC

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ddFEC: dose-dense Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study	Evidence	Comparator	Efficacy
Mavroudis et al. 2016 (HORG CT/07.17)	Phase III	See link	See link

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

Supportive medications

• Filgrastim or Pegfilgrastim support (drug/dose/schedule not specified)

14-day cycle for 4 cycles

Subsequent treatment

• Docetaxel

References

1. Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; Breast Cancer Investigators of the Hellenic Oncology Research Group (HORG), Athens, Greece. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article contains verified protocol PubMed

ddT (Taxol)

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ddT: dose-dense Taxol (Paclitaxel)
ddP: dose-dense Paclitaxel

Regimen #1, 175 mg/m²

Study	Evidence	Comparator	Efficacy
Citron et al. 2003 (CALGB 9741)	Phase III	See link	See link
Burstein et al. 2005	Non-randomized
Shulman et al. 2012 (CALGB 40101)	Phase III	ddAC x 4	Seems not superior
		ddAC x 6	Seems not superior
		ddT x 6	Seems not superior
Swain et al. 2013 (NSABP B-38)	Phase III	See link	See link

Note: in CALGB 40101, this is the dosing after a mid-protocol amendment in 2003.

Preceding treatment

• CALGB 9741: ddA x 4 or ddAC x 4
• Burstein et al. 2005: Neoadjuvant ddAC and surgery or adjuvant ddAC
• CALGB 40101: Surgery, within 90 days
• NSABP B-38: ddAC x 4

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

Supportive medications

• Diphenhydramine (Benadryl) 12.5 to 50 mg IV 30 to 60 minutes prior to paclitaxel
• One of the following H2 blockers:
  • Ranitidine (Zantac) 50 mg IV 30 to 60 minutes prior to paclitaxel
  • Cimetidine (Tagamet) 300 mg IV 30 to 60 minutes prior to paclitaxel
  • Famotidine (Pepcid) 20 mg IV 30 to 60 minutes prior to paclitaxel
• One of the following dexamethasone choices:
  • Dexamethasone (Decadron) 10 mg IV less than 60 minutes prior to paclitaxel
  • Dexamethasone (Decadron) 10 mg PO greater than 60 minutes prior to paclitaxel
  • Dexamethasone (Decadron) 20 mg PO 6 hours and 12 hour prior to paclitaxel
• Recommended growth factor support with one of the following:
  • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
  • Sargramostim (Leukine) 250 to 500 mcg/m² SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
  • Pegfilgrastim (Neulasta) 6 mg SC, administered once 24 to 36 hours after chemotherapy

14-day cycle for 4 cycles

Subsequent treatment

• CALGB 9741: ddC x 4 (if preceded by ddA)

Regimen #2, 200 mg/m²

Study	Evidence
Kahan et al. 2005	Phase II

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• ddA x 4

Chemotherapy

• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours day 1

Supportive medications

• Filgrastim (Neupogen)

14-day cycle for 4 cycles

Subsequent treatment

• ddC

References

1. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains verified protocol PubMed
2. Kahan Z, Uhercsak G, Hajnal-Papp R, Boda K, Thurzo L. Dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy is well tolerated and safe in high-risk early breast cancer. Oncology. 2005;68(4-6):446-53. Epub 2005 Jul 13. link to original article PubMed
   1. Update: Kelemen G, Uhercsák G, Ormándi K, Eller J, Thurzó L, Kahán Z. Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer. Oncology. 2010;78(3-4):271-3. Epub 2010 Jun 7. link to original article PubMed
3. Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains verified protocol PubMed
4. Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains verified protocol link to study protocol PDF link to PMC article PubMed
   1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to PMC article PubMed
5. Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. link to original article link to PMC article contains verified protocol PubMed

ddT (Taxotere)

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ddT: dose-dense Taxotere (Docetaxel)
ddD: dose-dense Docetaxel

Regimen

Study	Evidence	Comparator	Efficacy
Mavroudis et al. 2016 (HORG CT/07.17)	Phase III	See link	See link

Preceding treatment

• ddFEC x 4

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Supportive medications

• Filgrastim or Pegfilgrastim support (drug/dose/schedule not specified)

14-day cycle for 4 cycles

References

1. Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; Breast Cancer Investigators of the Hellenic Oncology Research Group (HORG), Athens, Greece. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article contains verified protocol PubMed

Docetaxel monotherapy

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D: Docetaxel
T: Taxotere (Docetaxel)
dT: doceTaxel

Regimen #1, 100 mg/m² q3wk x 4

Study	Evidence	Comparator	Efficacy
Sparano et al. 2008 (ECOG E1199)	Phase III	Paclitaxel, q3wk dosing	Seems to have superior DFS
		Paclitaxel, weekly dosing Docetaxel, weekly dosing	Not reported
Eiermann et al. 2011 (BCIRG-005)	Phase III	See link	See link
Slamon et al. 2011 (BCIRG 006)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients in BCIRG 006 were HER2-positive.

Preceding treatment

• AC x 4

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

21-day cycle for 4 cycles

Regimen #2, 75 mg/m² q3wk

Study	Evidence	Comparator	Efficacy
Mavroudis et al. 2017	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Epirubicin x 4

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

21-day cycle for 4 cycles

Regimen #3, 100 mg/m² q3wk x 3

Study	Evidence	Comparator	Efficacy
Joensuu et al. 2006 (FinHer)	Phase III	TH (Taxotere) VH	Seems not superior
		Vinorelbine	Superior DDFS
Roché et al. 2006 (FNCLCC PACS 01)	Phase III	See link	See link
Ejlertsen et al. 2017 (DBCG 07-READ)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients in FinHer without HER2/neu amplification were only randomized to this or the vinorelbine arm. Patients in DBCG 07-READ were TOP2A normal as determined by FISH.

Preceding treatment

• FinHer: Breast surgery with axillary lymph node dissection or sentinel lymph node biopsy, within 12 weeks
• FNCLCC PACS 01: FEC x 3
• DBCG 07-READ: EC x 3

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• FinHer: FEC

Regimen #4, 35 mg/m² weekly

Study	Evidence	Comparator	Efficacy
Sparano et al. 2008 (ECOG E1199)	Phase III	Paclitaxel, q3wk dosing	Seems not superior
		Paclitaxel, weekly dosing Docetaxel, q3wk dosing	Not reported

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• AC x 4

Chemotherapy

• Docetaxel (Taxotere) 35 mg/m² IV over 60 minutes once per week

12-week course

References

1. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article contains verified protocol PubMed
   1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. link to original article PubMed
2. Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. link to original article PubMed
3. Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. link to original article link to PMC article PubMed
   1. Update: Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-Term Follow-Up of the E1199 Phase III Trial Evaluating the Role of Taxane and Schedule in Operable Breast Cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. link to original article link to PMC article PubMed
4. Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article PubMed
5. Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martin M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press M, Sauter G, Lindsay MA, Riva A, Buyse M, Drevot P, Taupin H, Mackey JR. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011 Oct 10;29(29):3877-84. Epub 2011 Sep 12. link to original article contains verified protocol PubMed
   1. Update: Mackey JR, Pieńkowski T, Crown J, Sadeghi S, Martin M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press MF, Sauter G, Lindsay M, Houé V, Buyse M, Drevot P, Hitier S, Bensfia S, Eiermann W; Translational Research In Oncology (TRIO)/ Breast Cancer International Research Group (BCIRG)-005 investigators. Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. Ann Oncol. 2016 Jun;27(6):1041-7. Epub 2016 Mar 2. link to original article PubMed
6. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. link to original article link to PMC article PubMed
7. Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: Final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article PubMed
8. Mavroudis D, Saloustros E, Boukovinas I, Papakotoulas P, Kakolyris S, Ziras N, Christophylakis C, Kentepozidis N, Fountzilas G, Rigas G, Varthalitis I, Kalbakis K, Agelaki S, Hatzidaki D, Georgoulias V. Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group. Br J Cancer. 2017 Jul 11;117(2):164-170. Epub 2017 Jun 22. link to original articlecontains verified protocol PubMed
9. Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. link to original article contains verified protocol PubMed

EC

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EC: Epirubicin and Cyclophosphamide

Regimen #1, 90/600 x 4

Study	Evidence
Earl et al. 2017 (tAnGo)	Non-randomized portion of RCT

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Paclitaxel versus TG

Regimen #2, 90/600 x 3

Study	Evidence	Comparator	Efficacy
Ejlertsen et al. 2017 (DBCG 07-READ)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients were TOP2A normal as determined by FISH.

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Docetaxel

Regimen #3, with range

Study	Evidence
von Minckwitz et al. 2017 (APHINITY)	Non-randomized portion of RCT

Patients in APHINITY had HER2-positive breast cancer. Note that ranges for EC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• TH (Taxol) versus THP (Taxol) or TH (Taxotere) versus THP (Taxotere)

Regimen #4, 100/830

Study	Evidence	Comparator	Efficacy
Piccart et al. 2001	Phase III	CMF	Seems not superior
		Moderate-dose EC	Seems to have superior OS

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 830 mg/m² IV once on day 1

21-day cycle for 8 cycles

Regimen #5, 60/500

Study	Evidence	Comparator	Efficacy
Piccart et al. 2001	Phase III	CMF	Not reported
		High-dose EC	Seems to have inferior OS

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 8 cycles

References

1. Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. link to original article PubMed
2. Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella (GIM) investigators. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article PubMed
3. Earl HM, Hiller L, Howard HC, Dunn JA, Young J, Bowden SJ, McDermaid M, Waterhouse AK, Wilson G, Agrawal R, O'Reilly S, Bowman A, Ritchie DM, Goodman A, Hickish T, McAdam K, Cameron D, Dodwell D, Rea DW, Caldas C, Provenzano E, Abraham JE, Canney P, Crown JP, Kennedy MJ, Coleman R, Leonard RC, Carmichael JA, Wardley AM, Poole CJ; tAnGo trial collaborators. Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):755-769. Epub 2017 May 4. link to original article contains protocol PubMed
4. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed
5. Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. link to original article contains verified protocol PubMed

Epirubicin monotherapy

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Regimen #1, 100 mg/m²

Study	Evidence	Comparator	Efficacy
Poole et al. 2006 (NEAT/BR9601)	Phase III	See link	See link
Cameron et al. 2017 (TACT2)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Complete surgical excision

Chemotherapy

• Epirubicin (Ellence) 100 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• NEAT and BR9601: CMF
• TACT2: capecitabine versus CMF

Regimen #2, 90 mg/m²

Study	Evidence	Comparator	Efficacy
Mavroudis et al. 2017	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 90 mg/m² IV over 5 to 15 minutes once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Docetaxel

References

1. Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article contains verified protocol PubMed
2. Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article PubMed
3. Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. link to original article link to PMC article contains verified protocol PubMed
4. Mavroudis D, Saloustros E, Boukovinas I, Papakotoulas P, Kakolyris S, Ziras N, Christophylakis C, Kentepozidis N, Fountzilas G, Rigas G, Varthalitis I, Kalbakis K, Agelaki S, Hatzidaki D, Georgoulias V. Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group. Br J Cancer. 2017 Jul 11;117(2):164-170. Epub 2017 Jun 22. link to original articlecontains verified protocol PubMed

FAC

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FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide
CAF: Cyclophosphamide, Adriamycin (Doxorubicin), Fluorouracil

Regimen #1, 500/50/500

Study	Evidence	Comparator	Efficacy
Martin et al. 2005 (BCIRG 001)	Phase III	TAC	Inferior OS
Martín et al. 2010 (GEICAM 9805)	Phase III	TAC	Inferior DFS
Martín et al. 2013 (GEICAM/2003-02)	Phase III	FAC-wP	Seems to have inferior DFS

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV over 15 minutes once on day 1, given second
• Doxorubicin (Adriamycin) 50 mg/m² IV over 15 minutes once on day 1, given first
• Cyclophosphamide (Cytoxan) 500 mg/m² IV over 1 to 5 minutes once on day 1, given third

Supportive medications

• If patients had febrile neutropenia or infection: Ciprofloxacin (Cipro) 500 mg PO BID on days 5 to 14 of every cycle
• G-CSF not originally routinely administered unless patients had febrile neutropenia:
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 4 to 11
  • OR Lenograstim (Granocyte) 150 mcg/m² SC once per day on days 4 to 11

21-day cycle for 6 cycles

Regimen #2

Study	Evidence	Comparator	Efficacy
Hutchins et al. 2005 (INT-0102)	Phase III	CMF	Seems to have superior OS

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14
• Doxorubicin (Adriamycin) 30 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8

28-day cycle for 6 cycles

Treatment in

Regimen #3

Study	Evidence	Comparator	Efficacy
Buzdar et al. 1984	Phase III	FAC + BCG	Seems not superior

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV once per day on days 1 & 8
• Doxorubicin (Adriamycin) 40 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 400 mg/m² IV once on day 1

21-day cycles until cumulative doxorubicin dose of 300 mg/m² reached.

After reaching cumulative maximum doxorubicin, patients would go on to receive maintenance CMF. This is now obsolete.

Regimen #4, with range

Study	Evidence
von Minckwitz et al. 2017 (APHINITY)	Non-randomized portion of RCT

Patients in APHINITY had HER2-positive breast cancer. Note that ranges for FAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• TH (Taxol) versus THP (Taxol) or TH (Taxotere) versus THP (Taxotere)

References

1. Buzdar AU, Blumenschein GR, Smith TL, Powell KC, Hortobagyi GN, Yap HY, Schell FC, Barnes BC, Ames FC, Martin RG, Hersh EM. Adjuvant chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide, with or without Bacillus Calmette-Guerin and with or without irradiation in operable breast cancer. A prospective randomized trial. Cancer. 1984 Feb 1;53(3):384-9. link to original article contains verified protocol PubMed
   1. Update: Buzdar AU, Kau SW, Smith TL, Hortobagyi GN. Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol. 1989 Apr;12(2):123-8. PubMed
2. Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group 001 Investigators. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. link to original article contains protocol PubMed
   1. Update: Mackey JR, Martin M, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano MR, Vinholes J, Pinter T, Rodríguez-Lescure A, Colwell B, Whitlock P, Provencher L, Laing K, Walde D, Price C, Hugh JC, Childs BH, Bassi K, Lindsay MA, Wilson V, Rupin M, Houé V, Vogel C; TRIO/BCIRG 001 investigators. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. Lancet Oncol. 2013 Jan;14(1):72-80. Epub 2012 Dec 12. link to original article PubMed
3. Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article PubMed
4. Martín M, Seguí MA, Antón A, Ruiz A, Ramos M, Adrover E, Aranda I, Rodríguez-Lescure A, Grosse R, Calvo L, Barnadas A, Isla D, Martinez del Prado P, Ruiz Borrego M, Zaluski J, Arcusa A, Muñoz M, López Vega JM, Mel JR, Munarriz B, Llorca C, Jara C, Alba E, Florián J, Li J, López García-Asenjo JA, Sáez A, Rios MJ, Almenar S, Peiró G, Lluch A; GEICAM 9805 Investigators. Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med. 2010 Dec 2;363(23):2200-10. link to original article PubMed
5. Martín M, Ruiz A, Ruiz Borrego M, Barnadas A, González S, Calvo L, Margelí Vila M, Antón A, Rodríguez-Lescure A, Seguí-Palmer MA, Muñoz-Mateu M, Dorca Ribugent J, López-Vega JM, Jara C, Espinosa E, Mendiola Fernández C, Andrés R, Ribelles N, Plazaola A, Sánchez-Rovira P, Salvador Bofill J, Crespo C, Carabantes FJ, Servitja S, Chacón JI, Rodríguez CA, Hernando B, Álvarez I, Carrasco E, Lluch A. Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. J Clin Oncol. 2013 Jul 10;31(20):2593-9. Epub 2013 Jun 3. link to original article PubMed
6. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed

FEC

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FEC: Fluorouracil, Epirubicin, Cyclophosphamide
CEF: Cyclophosphamide, Epirubicin, Fluorouracil

Regimen #1, 500/100/500 x 3

Study	Evidence	Comparator	Efficacy
Roché et al. 2006 (FNCLCC PACS 01)	Phase III	See link	See link
Baselga et al. 2012 (NeoALTTO)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients in NeoALTTO all had HER2-positive disease.

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• FNCLCC PACS 01: Docetaxel
• NeoALTTO: Lapatinib or Lapatinib & Trastuzumab or Trastuzumab, according to initial randomization

Regimen #2, 500/100/500 x 6

Study	Evidence	Comparator	Efficacy
Roché et al. 2006 (FNCLCC PACS 01)	Phase III	FEC-D	Seems to have inferior OS

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 6 cycles

Regimen #3, 600/60/600 x 3

Study	Evidence
Joensuu et al. 2006 (FinHer)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• HER2-negative: Docetaxel x 3 versus vinorelbine x 3
• HER2-positive: Docetaxel x 3 versus TH x 3 versus vinorelbine x 3 versus VH x 3

Chemotherapy

• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 60 mg/m² IV once on day 1
• Fluorouracil (5-FU) 600 mg/m² IV once on day 1

21-day cycle for 3 cycles

Regimen #4, 600/60/600 x 6

Study	Evidence	Comparator	Efficacy
del Mastro et al. 2016 (GONO-MIG5)	Phase III	EP x 4	Seems not superior

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 60 mg/m² IV once on day 1
• Fluorouracil (5-FU) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles

Regimen #5, 600/90/600 x 4

Study	Evidence	Comparator	Efficacy
Martín et al. 2008 (GEICAM 9906)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Treatment followed by 3 weeks of no treatment, then paclitaxel.

Regimen #6, 600/90/600 x 6

Study	Evidence	Comparator	Efficacy
Martín et al. 2008 (GEICAM 9906)	Phase III	FEC x 4, then P	Inferior DFS

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles

Regimen #7, oral cyclophosphamide

Study	Evidence	Comparator	Efficacy
Levine et al. 1998 (NCIC CTG MA5)	Phase III	CMF	Superior RFS
Coombes et al. 2005 (ICCG HDT trial)	Phase III	FEC x 3, then HDT	Seems not superior

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 75 mg/m² PO once per day on days 1 to 14
• Epirubicin (Ellence) 60 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8

28-day cycle for 6 cycles

References

1. Coombes RC, Bliss JM, Wils J, Morvan F, Espié M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A, McArdle C, Pérez-López FR, Vassilopoulos P, Ferreira EP, Chilvers CE, Coombes G, Woods EM, Marty M. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. The International Collaborative Cancer Group. J Clin Oncol. 1996 Jan;14(1):35-45. link to original article PubMed
2. Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CK, Tu D. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1998 Aug;16(8):2651-8. link to original article PubMed
   1. Update: Levine MN, Pritchard KI, Bramwell VH, Shepherd LE, Tu D, Paul N; National Cancer Institute of Canada Clinical Trials Group. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol. 2005 Aug 1;23(22):5166-70. link to original article PubMed
3. French Adjuvant Study Group. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2001 Feb 1;19(3):602-11. link to original article PubMed
   1. Update: Bonneterre J, Roché H, Kerbrat P, Brémond A, Fumoleau P, Namer M, Goudier MJ, Schraub S, Fargeot P, Chapelle-Marcillac I. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2005 Apr 20;23(12):2686-93. link to original article PubMed
4. Fumoleau P, Kerbrat P, Romestaing P, Fargeot P, Brémond A, Namer M, Schraub S, Goudier MJ, Mihura J, Monnier A, Clavère P, Serin D, Seffert P, Pourny C, Facchini T, Jacquin JP, Sztermer JF, Datchary J, Ramos R, Luporsi E. Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial. J Clin Oncol. 2003 Jan 15;21(2):298-305. link to original article PubMed
5. Coombes RC, Howell A, Emson M, Peckitt C, Gallagher C, Bengala C, Tres A, Welch R, Lawton P, Rubens R, Woods E, Haviland J, Vigushin D, Kanfer E, Bliss JM. High dose chemotherapy and autologous stem cell transplantation as adjuvant therapy for primary breast cancer patients with four or more lymph nodes involved: long-term results of an international randomised trial. Ann Oncol. 2005 May;16(5):726-34. Epub 2005 Apr 7. link to original article PubMed
6. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article contains verified protocol PubMed
   1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. link to original article PubMed
7. Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. link to original article PubMed
8. Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Cold S, Edlund P, Ewertz M, Jensen BB, Kamby C, Nordenskjold B, Bergh J. Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer. Eur J Cancer. 2007 Mar;43(5):877-84. Epub 2007 Feb 16. link to original article PubMed
9. Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM 9906 Study Investigators. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. link to original article contains verified protocol PubMed
10. Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article PubMed
11. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains verified protocol PubMed
    1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
12. Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella (GIM) investigators. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article PubMed
13. Del Mastro L, Levaggi A, Michelotti A, Cavazzini G, Adami F, Scotto T, Piras M, Danese S, Garrone O, Durando A, Accortanzo V, Bighin C, Miglietta L, Pastorino S, Pronzato P, Castiglione F, Landucci E, Conte P, Bruzzi P. 5-Fluorouracil, epirubicin and cyclophosphamide versus epirubicin and paclitaxel in node-positive early breast cancer: a phase-III randomized GONO-MIG5 trial. Breast Cancer Res Treat. 2016 Jan;155(1):117-26. link to original article contains verified protocol PubMed
14. Coombes RC, Kilburn LS, Tubiana-Mathieu N, Olmos T, Van Bochove A, Perez-Lopez FR, Palmieri C, Stebbing J, Bliss JM. Epirubicin dose and sequential hormonal therapy-Mature results of the HMFEC randomised phase III trial in premenopausal patients with node positive early breast cancer. Eur J Cancer. 2016 Jun;60:146-53. Epub 2016 Apr 26. link to original article PubMed
15. Kerbrat P, Desmoulins I, Roca L, Levy C, Lortholary A, Marre A, Delva R, Rios M, Viens P, Brain É, Serin D, Edel M, Debled M, Campone M, Mourret-Reynier MA, Bachelot T, Foucher-Goudier MJ, Asselain B, Lemonnier J, Martin AL, Roché H. Optimal duration of adjuvant chemotherapy for high-risk node-negative (N-) breast cancer patients: 6-year results of the prospective randomised multicentre phase III UNICANCER-PACS 05 trial (UCBG-0106). Eur J Cancer. 2017 Jul;79:166-175. Epub 2017 May 11. link to original article PubMed
16. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed

Paclitaxel monotherapy

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T: Taxol (Paclitaxel)
P: Paclitaxel
pT: pacliTaxel

Regimen #1, 80 mg/m² weekly

Study	Evidence	Comparator	Efficacy	Toxicity
Romond et al. 2005 (NSABP B-31)	Phase III	TH	Inferior OS	Might have inferior DASI score
Romond et al. 2005 (NCCTG N9831)	Phase III	See link	See link
Sparano et al. 2008 (ECOG E1199)	Phase III	Paclitaxel q3wk	Superior OS
		Docetaxel q3wk Docetaxel weekly	Not reported
Shulman et al. 2012 (CALGB 40101)	Phase III	ddAC x 4	Seems not superior
		ddAC x 6	Seems not superior
		Weekly paclitaxel x 18	Seems not superior

Patients in NSABP B-31 and NCCTG N9831 were HER2-positive. This paclitaxel dosing schedule was an option after 2003 in NSABP B-31, and was used for all patients in NCCTG N9831. In CALGB 40101, this is the dosing before a mid-protocol amendment in 2003.

Preceding treatment

• AC x 4

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV over 60 minutes once per week

12-week course

Regimen #2, 100 mg/m² weekly

Study	Evidence	Comparator	Efficacy
Martín et al. 2008 (GEICAM 9906)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• FEC x 4

Chemotherapy

• Paclitaxel (Taxol) 100 mg/m² IV once per week

8 week course

Regimen #3, 175 mg/m² q3wk

Study	Evidence	Comparator	Efficacy
Henderson et al. 2003 (INT 0148/CALGB 9344)	Phase III	Observation	Superior OS
Citron et al. 2003 (CALGB 9741)	Non-randomized portion of RCT
Romond et al. 2005 (NSABP B-31)	Phase III	TH	Inferior OS
Sparano et al. 2008 (ECOG E1199)	Phase III	Paclitaxel weekly	Inferior OS
		Docetaxel q3wk	Seems to have inferior DFS
		Docetaxel weekly	Seems not superior
Earl et al. 2017 (tAnGo)	Phase III	TG	Seems not superior

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients in NSABP B-31 were HER2-positive.

Preceding treatment

• INT 0148/CALGB 9344: AC x 4 versus high-dose AC x 4 versus very-high-dose AC x 4
• CALGB 9741, NSABP B-31, and ECOG E1199: AC x 4
• tAnGo: EC x 4

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

21-day cycle for 4 cycles

Regimen #4, 225 mg/m² q3wk

Study	Evidence	Comparator	Efficacy
Mamounas et al. 2005 (NSABP B-28)	Phase III	Observation	Superior PFS

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• AC x 4

Chemotherapy

• Paclitaxel (Taxol) 225 mg/m² IV over 3 hours once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• NCCTG N9831: H

References

1. Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. link to original article contains verified protocol PubMed
2. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains verified protocol PubMed
3. Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. link to original article PubMed
4. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. link to original article PubMed
   1. Update: Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. Epub 2011 Oct 31. link to original article link to PMC article PubMed
   2. Update: Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. link to original article link to PMC article PubMed
   3. Update and HRQoL analysis: Ganz PA, Romond EH, Cecchini RS, Rastogi P, Geyer CE Jr, Swain SM, Jeong JH, Fehrenbacher L, Gross HM, Brufsky AM, Flynn PJ, Wahl TA, Seay TE, Wade JL 3rd, Biggs DD, Atkins JN, Polikoff J, Zapas JL, Mamounas EP, Wolmark N. Long-term follow-up of cardiac function and quality of life for patients in NSABP protocol B-31/NRG Oncology: a randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel and trastuzumab in patients with node-positive breast cancer with tumors overexpressing human epidermal growth factor receptor 2. J Clin Oncol. 2017 Dec 10;35(35):3942-3948. Epub 2017 Oct 26. link to original article link to PMC article PubMed
5. Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. link to original article link to PMC article PubMed
   1. Update: Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. link to original article link to PMC article PubMed
6. Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM 9906 Study Investigators. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. link to original article contains verified protocol PubMed
7. Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains verified protocol link to study protocol PDF link to PMC article PubMed
   1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to PMC article PubMed
8. Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella (GIM) investigators. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article PubMed
9. Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: Final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article PubMed
10. Earl HM, Hiller L, Howard HC, Dunn JA, Young J, Bowden SJ, McDermaid M, Waterhouse AK, Wilson G, Agrawal R, O'Reilly S, Bowman A, Ritchie DM, Goodman A, Hickish T, McAdam K, Cameron D, Dodwell D, Rea DW, Caldas C, Provenzano E, Abraham JE, Canney P, Crown JP, Kennedy MJ, Coleman R, Leonard RC, Carmichael JA, Wardley AM, Poole CJ; tAnGo trial collaborators. Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):755-769. Epub 2017 May 4. link to original article contains protocol PubMed

TAC (Taxotere)

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TAC: Taxotere (Docetaxel), Adriamycin (Doxorubicin), Cyclophosphamide

Regimen

Study	Evidence	Comparator	Efficacy
Martin et al. 2005 (BCIRG 001)	Phase III	FAC	Superior OS
Martín et al. 2010 (GEICAM 9805)	Phase III	FAC	Superior DFS
Eiermann et al. 2011 (BCIRG-005)	Phase III	AC, then T	Seems not superior
Swain et al. 2013 (NSABP B-38)	Phase III	ddAC, then ddP	Seems not superior
		ddAC, then ddPG	Seems not superior
Blum et al. 2017 (USOR 06-090; NSABP-46-I/USOR 07132; NSABP B-49)	Phase III	TC	Seems to have superior IDFS

Note: Blum et al. 2017 is a pooled analysis of three RCTs, some of which had arms other than TAC and TC. Refer to the paper for further details.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1, administered third, one hour after cyclophosphamide
• Doxorubicin (Adriamycin) 50 mg/m² IV over 15 minutes once on day 1, administered first
• Cyclophosphamide (Cytoxan) 500 mg/m² IV over 1 to 5 minutes once on day 1, administered second

Supportive medications

• Dexamethasone (Decadron) 8 mg PO every 12 hours x 6 total doses, starting the day before treatment
• Ciprofloxacin (Cipro) 500 mg PO BID on days 5 to 14 of every cycle (prophylaxis)
• G-CSF not originally routinely administered unless patients had febrile neutropenia, but some guidelines recommend one of the following:
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 4 to 11
  • Lenograstim (Granocyte) 150 mcg/m² SC once per day on days 4 to 11

21-day cycle for 6 cycles

References

1. Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group 001 Investigators. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. link to original article contains protocol PubMed
   1. Update: Mackey JR, Martin M, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano MR, Vinholes J, Pinter T, Rodríguez-Lescure A, Colwell B, Whitlock P, Provencher L, Laing K, Walde D, Price C, Hugh JC, Childs BH, Bassi K, Lindsay MA, Wilson V, Rupin M, Houé V, Vogel C; TRIO/BCIRG 001 investigators. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. Lancet Oncol. 2013 Jan;14(1):72-80. Epub 2012 Dec 12. link to original article PubMed
2. Martín M, Seguí MA, Antón A, Ruiz A, Ramos M, Adrover E, Aranda I, Rodríguez-Lescure A, Grosse R, Calvo L, Barnadas A, Isla D, Martinez del Prado P, Ruiz Borrego M, Zaluski J, Arcusa A, Muñoz M, López Vega JM, Mel JR, Munarriz B, Llorca C, Jara C, Alba E, Florián J, Li J, López García-Asenjo JA, Sáez A, Rios MJ, Almenar S, Peiró G, Lluch A; GEICAM 9805 Investigators. Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med. 2010 Dec 2;363(23):2200-10. link to original article PubMed
3. Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martin M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press M, Sauter G, Lindsay MA, Riva A, Buyse M, Drevot P, Taupin H, Mackey JR. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011 Oct 10;29(29):3877-84. Epub 2011 Sep 12. link to original article contains verified protocol PubMed
   1. Update: Mackey JR, Pieńkowski T, Crown J, Sadeghi S, Martin M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press MF, Sauter G, Lindsay M, Houé V, Buyse M, Drevot P, Hitier S, Bensfia S, Eiermann W; Translational Research In Oncology (TRIO)/ Breast Cancer International Research Group (BCIRG)-005 investigators. Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. Ann Oncol. 2016 Jun;27(6):1041-7. Epub 2016 Mar 2. link to original article PubMed
4. Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. link to original article link to PMC article contains verified protocol PubMed
5. Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains verified protocol PubMed

TC (Taxotere)

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TC: Taxotere (Docetaxel), Cyclophosphamide

Regimen #1, 4 cycles

Study	Evidence	Comparator	Efficacy
Jones et al. 2006 (US Oncology Trial 9735)	Phase III	AC	Seems to have superior OS
Blum et al. 2017 (USOR 06-090; NSABP-46-I/USOR 07132; NSABP B-49)	Phase III	TAC	Seems to have inferior IDFS

Note: Blum et al. 2017 is a pooled analysis of three RCTs, some of which had arms other than TAC and TC. Refer to the paper for further details.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive medications

• All cycles given with Filgrastim (Neupogen) support

21-day cycle for 4 cycles

Regimen #2, 6 cycles

Study	Evidence	Comparator	Efficacy
Mavroudis et al. 2016 (HORG CT/07.17)	Phase III	ddFEC, then D	Inconclusive whether non-inferior

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles

References

1. Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Anthony SP, Mennel RG, Boehm KA, Meyer WG, Asmar L. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006 Dec 1;24(34):5381-7. Erratum in: J Clin Oncol. 2007 May 1;25(13):1819. link to original article PubMed
   1. Update: Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. Epub 2009 Feb 9. link to original article PubMed
2. Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; Breast Cancer Investigators of the Hellenic Oncology Research Group (HORG), Athens, Greece. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article contains verified protocol PubMed
3. Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains verified protocol PubMed

Vinorelbine monotherapy

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V: Vinorelbine

Regimen

Study	Evidence	Comparator	Efficacy
Joensuu et al. 2006 (FinHer)	Phase III	Docetaxel	Inferior DDFS
		TH (Taxotere) VH	Seems not superior

Patients without HER2/neu amplification were only randomized to this arm verus the docetaxel arm.

Preceding treatment

• Surgery

Chemotherapy

• Vinorelbine (Navelbine) as follows:
  • Cycles 1 & 2: 25 mg/m² IV over 5 to 10 minutes once per day on days 1, 8, 15
  • Cycle 3: 25 mg/m² IV over 5 to 10 minutes once per day on days 1 & 8

21-day cycle for 3 cycles

Subsequent treatment

• FEC

References

1. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article contains verified protocol PubMed
   1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. link to original article PubMed

Adjuvant endocrine therapy

Anastrozole monotherapy

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Regimen #1, 5-year course

Study	Evidence	Comparator	Efficacy
Howell et al. 2005 (ATAC)	Phase III	Anastrozole & Tamoxifen	Not reported
		Tamoxifen	Seems to have superior DFS
Goss et al. 2013 (NCIC CTG MA.27)	Phase III	Exemestane	Seems not superior

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day

5-year course of therapy

Regimen #2, 3-year course

Study	Evidence	Comparator	Efficacy	Toxicity
Kaufmann et al. 2007 (ARNO 95)	Phase III	See link	See link
Tjan-Heijnen et al. 2017 (DATA)	Phase III	6 y of anastrozole	Might have inferior DFS	Less toxic

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• ARNO 95: Tamoxifen x 2 y
• DATA: Tamoxifen x 2-3 y

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day

3-year course

Regimen #3, 6-year course

Study	Evidence	Comparator	Efficacy	Toxicity
Tjan-Heijnen et al. 2017 (DATA)	Phase III	3 y of anastrozole	Might have superior DFS	More toxic

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Tamoxifen x 2-3 y

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day

6-year course

References

1. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005 Jan 1-7;365(9453):60-2. link to original article PubMed
   1. Update: Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group, Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008 Jan;9(1):45-53. link to original article PubMed
   2. Update: Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF; ATAC/LATTE investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010 Dec;11(12):1135-41. link to original article PubMed
2. Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, von Minckwitz G. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol. 2007 Jul 1;25(19):2664-70. Epub 2007 Jun 11. link to original article PubMed
3. Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Johnson DB, Tozer R, D'Souza DP, Chalchal H, Spadafora S, Stearns V, Perez EA, Liedke PE, Lang I, Elliott C, Gelmon KA, Chapman JA, Shepherd LE. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 2013 Apr 10;31(11):1398-404. Epub 2013 Jan 28. link to original article contains verified protocol link to PMC article PubMed
4. Tjan-Heijnen VCG, van Hellemond IEG, Peer PGM, Swinkels ACP, Smorenburg CH, van der Sangen MJC, Kroep JR, De Graaf H, Honkoop AH, Erdkamp FLG, van den Berkmortel FWPJ, de Boer M, de Roos WK, Linn SC, Imholz ALT, Seynaeve CM; Dutch Breast Cancer Research Group (BOOG) for the DATA Investigators. Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1502-1511. Epub 2017 Oct 12. Erratum in: Lancet Oncol. 2017 Nov;18(11):e642. link to original article contains verified protocol PubMed

Exemestane monotherapy

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OFS: Ovarian Function Suppression

Regimen #1, with OFS

Study	Evidence	Comparator	Efficacy
Pagani et al. 2014 (TEXT/SOFT)	Phase III	Tamoxifen	Superior DFS
		Tamoxifen & OFS	Superior DFS

These regimens are intended for premenopausal patients. Pagani et al. 2014 report on two trials, but only SOFT had the tamoxifen only arm.

Endocrine therapy

• Exemestane (Aromasin) 25 mg PO once per day
• Ovarian Suppression as follows:
  • TEXT: Triptorelin (Trelstar LA) 3.75 mg IM every 28 days
    • "Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin."
  • SOFT: Choice of mechanism left to investigators

5 years of therapy

Regimen #2, no OFS

Study	Evidence	Comparator	Efficacy
Mamounas et al. 2008 (NSABP B-33)	Phase III	Placebo	Superior RFS
Goss et al. 2013 (NCIC CTG MA.27)	Phase III	Anastrozole	Seems not superior

Preceding treatment

• NSABP B-33: Tamoxifen x 5y

Endocrine therapy

• Exemestane (Aromasin) 25 mg PO once per day

5-year course of therapy

Regimen #3, 2 to 3-year course

Study	Evidence	Comparator	Efficacy
Coombes et al. 2004 (Intergroup Exemestane Study)	Phase III	See link	See link
van de Velde et al. 2011 (TEAM)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. The Intergroup Exemestane Study gave a range of 2 to 3 years of therapy. TEAM gave a range of 2 to 2.5 years of therapy.

Preceding treatment

• Tamoxifen x 2-3y

Endocrine therapy

• Exemestane (Aromasin) 25 mg PO once per day

2 to 3 years to complete a 5-year course

References

1. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11;350(11):1081-92. link to original article PubMed
   1. Update: Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70. link to original article PubMed
2. Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol. 2008 Apr 20;26(12):1965-71. Epub 2008 Mar 10. link to original article PubMed
3. van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011 Jan 22;377(9762):321-31. link to original article contains verified protocol PubMed
   1. Update: Derks MGM, Blok EJ, Seynaeve C, Nortier JWR, Kranenbarg EM, Liefers GJ, Putter H, Kroep JR, Rea D, Hasenburg A, Markopoulos C, Paridaens R, Smeets JBE, Dirix LY, van de Velde CJH. Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1211-1220. Epub 2017 Jul 18. link to original article PubMed
4. Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Johnson DB, Tozer R, D'Souza DP, Chalchal H, Spadafora S, Stearns V, Perez EA, Liedke PE, Lang I, Elliott C, Gelmon KA, Chapman JA, Shepherd LE. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 2013 Apr 10;31(11):1398-404. Epub 2013 Jan 28. link to original article contains verified protocol link to PMC article PubMed
5. Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Perez EA, Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G, Coates AS, Gelber RD, Goldhirsch A, Francis PA; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Jul 10;371(2):107-18. Epub 2014 Jun 1. link to original article contains verified protocol link to PMC article PubMed

Letrozole monotherapy

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Regimen #1, 5 years of therapy

Study	Evidence	Comparator	Efficacy
Goss et al. 2003 (NCIC CTG MA.17)	Phase III	Placebo	Superior DFS
Breast International Group (BIG) 1-98 Collaborative Group 2006	Phase III	Letrozole, then Tamoxifen	Seems not superior (*)
		Tamoxifen	Superior OS (*)
		Tamoxifen, then Letrozole	Seems not superior (*)
Goss et al. 2016 (NCIC CTG MA.17R)	Phase III	Letrozole x 10y	Inferior DFS

Efficacy reported for BIG 1-98 based on the 2011 update.

Preceding treatment

• NCIC CTG MA.17: Most patients received 5 years of tamoxifen therapy prior to starting letrozole
• NCIC CTG MA.17R: Letrozole for 5 years

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

5-year course of therapy

Regimen #2, 10 years of therapy

Study	Evidence	Comparator	Efficacy
Goss et al. 2016 (NCIC CTG MA.17R)	Phase III	Letrozole x 5y	Superior DFS

Continuation of treatment was started within 2 years of the completion of the first 5 years of treatment.

Preceding treatment

• Letrozole for 5 years

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

5 additional years for a total 10-year course of therapy

Regimen #3, 2 years of therapy

Study	Evidence	Comparator	Efficacy
Breast International Group (BIG) 1-98 Collaborative Group 2006	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

2-year course

Treatment followed by tamoxifen.

Regimen #4, 3 years of therapy

Study	Evidence	Comparator	Efficacy
Breast International Group (BIG) 1-98 Collaborative Group 2006	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Tamoxifen x 2y

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

3-year course

References

1. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802. Epub 2003 Oct 9. link to original article PubMed
   1. Update: Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005 Sep 7;97(17):1262-71. link to original article PubMed
   2. Update: Muss HB, Tu D, Ingle JN, Martino S, Robert NJ, Pater JL, Whelan TJ, Palmer MJ, Piccart MJ, Shepherd LE, Pritchard KI, He Z, Goss PE. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: NCIC CTG intergroup trial MA.17. J Clin Oncol. 2008 Apr 20;26(12):1956-64. Epub 2008 Mar 10. link to original article PubMed
   3. Subgroup analysis: Goss PE, Ingle JN, Pater JL, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Tu D. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol. 2008 Apr 20;26(12):1948-55. Epub 2008 Mar 10. link to original article PubMed
   4. Update: Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012 Mar 1;30(7):718-21. Epub 2011 Oct 31. link to original article link to PMC article PubMed
2. Breast International Group (BIG) 1-98 Collaborative Group, Thürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. Wardly, Andrew [corrected to Wardley, Andrew ]. link to original article PubMed
   1. Update: Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007 Feb 10;25(5):486-92. Epub 2007 Jan 2. link to original article PubMed
   2. Subgroup analysis: Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thürlimann B, Coates AS, Viale G; BIG 1-98 Collaborative and International Breast Cancer Study Groups. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008 Jan;9(1):23-8. Epub 2007 Dec 20. link to original article PubMed
   3. Subgroup analysis: Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol. 2008 Apr 20;26(12):1972-9. Epub 2008 Mar 10. link to original article PubMed
   4. Update: Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG 1-98 Collaborative Group; International Breast Cancer Study Group (IBCSG). Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. link to original article link to PMC article PubMed
3. Zdenkowski N, Forbes JF, Boyle FM, Kannourakis G, Gill PG, Bayliss E, Saunders C, Della-Fiorentina S, Kling N, Campbell I, Mann GB, Coates AS, Gebski V, Davies L, Thornton R, Reaby L, Cuzick J, Green M; Australia and New Zealand Breast Cancer Trials Group. Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised, controlled trial. Ann Oncol. 2016 May;27(5):806-12. Epub 2016 Feb 9. link to original article PubMed
4. Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, Gelmon K, Whelan T, Strasser-Weippl K, Rubin S, Sturtz K, Wolff AC, Winer E, Hudis C, Stopeck A, Beck JT, Kaur JS, Whelan K, Tu D, Parulekar WR. Extending aromatase-inhibitor adjuvant therapy to 10 Years. N Engl J Med. 2016 Jul 21;375(3):209-19. Epub 2016 Jun 5. link to original article link to PMC article contains verified protocol PubMed
5. Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg E, Duijm-de Carpentier M, Putter H, van den Bosch J, Maartense E, van Leeuwen-Stok AE, Liefers GJ, Nortier JWR, Rutgers EJT, van de Velde CJH; IDEAL Study Group. Optimal duration of extended adjuvant endocrine therapy for early breast cancer; results of the IDEAL trial (BOOG 2006-05). J Natl Cancer Inst. 2018 Jan 1;110(1). Epub 2017 Aug 23. link to original article PubMed

Leuprolide monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Schmid et al. 2007 (TABLE)	Phase III	CMF	Superior OS

Endocrine therapy

• Leuprolide (Lupron) 3-month depot 11.25 mg SC

Every 3 months x 2 years

References

1. Schmid P, Untch M, Kossé V, Bondar G, Vassiljev L, Tarutinov V, Lehmann U, Maubach L, Meurer J, Wallwiener D, Possinger K. Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol. 2007 Jun 20;25(18):2509-15. link to original article contains verified protocol PubMed

Observation

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Regimen

Study	Evidence	Comparator	Efficacy
Rydén et al. 2005 (SBII:2pre)	Phase III	Tamoxifen	Inferior RFS
Hutchins et al. 2005 (INT-0102)	Phase III	Tamoxifen	Seems not superior

No further treatment. Used as a comparator arm.

Preceding treatment

• INT-0102: CAF x 6 versus CMF x 6

References

1. Rydén L, Jönsson PE, Chebil G, Dufmats M, Fernö M, Jirström K, Källström AC, Landberg G, Stål O, Thorstenson S, Nordenskjöld B; South Swedish Breast Cancer Group; South-East Swedish Breast Cancer Group. Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: a randomised, controlled trial with long-term follow-up. Eur J Cancer. 2005 Jan;41(2):256-64. link to original article PubMed
   1. Update: Ekholm M, Bendahl PO, Fernö M, Nordenskjöld B, Stål O, Rydén L. Two Years of Adjuvant Tamoxifen Provides a Survival Benefit Compared With No Systemic Treatment in Premenopausal Patients With Primary Breast Cancer: Long-Term Follow-Up (> 25 years) of the Phase III SBII:2pre Trial. J Clin Oncol. 2016 Jul 1;34(19):2232-8. Epub 2016 May 9. link to original article PubMed
2. Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article PubMed
3. Zdenkowski N, Forbes JF, Boyle FM, Kannourakis G, Gill PG, Bayliss E, Saunders C, Della-Fiorentina S, Kling N, Campbell I, Mann GB, Coates AS, Gebski V, Davies L, Thornton R, Reaby L, Cuzick J, Green M; Australia and New Zealand Breast Cancer Trials Group. Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised, controlled trial. Ann Oncol. 2016 May;27(5):806-12. Epub 2016 Feb 9. link to original article PubMed

Placebo

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Regimen

Study	Evidence	Comparator	Efficacy
Fisher et al. 2001 (NSABP B-23)	Phase III	Tamoxifen	Seems not superior
Goss et al. 2003 (NCIC CTG MA.17)	Phase III	Letrozole	Inferior DFS
Mamounas et al. 2008 (NSABP B-33)	Phase III	Exemestane	Inferior RFS

No active treatment. Used as a comparator arm.

Preceding treatment

• NSABP B-23: CMF x 6 versus AC x 4
• NCIC CTG MA.17: Tamoxifen x 5y
• NSABP B-33: Tamoxifen x 5y

References

1. Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article PubMed
2. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802. Epub 2003 Oct 9. link to original article PubMed
   1. Update: Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005 Sep 7;97(17):1262-71. link to original article PubMed
   2. Update: Muss HB, Tu D, Ingle JN, Martino S, Robert NJ, Pater JL, Whelan TJ, Palmer MJ, Piccart MJ, Shepherd LE, Pritchard KI, He Z, Goss PE. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: NCIC CTG intergroup trial MA.17. J Clin Oncol. 2008 Apr 20;26(12):1956-64. Epub 2008 Mar 10. link to original article PubMed
   3. Subgroup analysis: Goss PE, Ingle JN, Pater JL, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Tu D. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol. 2008 Apr 20;26(12):1948-55. Epub 2008 Mar 10. link to original article PubMed
   4. Update: Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012 Mar 1;30(7):718-21. Epub 2011 Oct 31. link to original article link to PMC article PubMed
3. Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol. 2008 Apr 20;26(12):1965-71. Epub 2008 Mar 10. link to original article PubMed

Tamoxifen monotherapy

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OFS: Ovarian Function Suppression

Regimen #1, 1 year

Study	Evidence	Comparator	Efficacy
Eljertsen et al. 2013 (DBCG 82C)	Phase III	CMFT	Inferior DFS
		Tamoxifen & RT	Not reported

Endocrine therapy

• Tamoxifen (Nolvadex) 30 mg PO once per day

1 year of therapy

Regimen #2, 2 years

Study	Evidence	Comparator	Efficacy
Coombes et al. 2004 (Intergroup Exemestane Study)	Phase III	See link	See link
Breast International Group (BIG) 1-98 Collaborative Group 2006	Phase III	See link	See link
Kaufmann et al. 2007 (ARNO 95)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. The Intergroup Exemestane Study gave a range of 2 to 3 years of therapy.

Endocrine therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day

2-year course

Subsequent treatment

• Intergroup Exemestane Study: Exemestane
• BIG 1-98: Letrozole
• ARNO 95: Anastrozole

Regimen #3, 3 years

Study	Evidence	Comparator	Efficacy
Breast International Group (BIG) 1-98 Collaborative Group 2006	Phase III	See link	See link
van de Velde et al. 2011 (TEAM)	Phase III	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. TEAM gave a range of 2.5 to 3 years of therapy.

Preceding treatment

• BIG 1-98: Letrozole x 2y

Endocrine therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day

3-year course

Subsequent treatment

• TEAM: Exemestane

Regimen #4, 5 years, no OFS

Study	Evidence	Comparator	Efficacy
Fisher et al. 2001 (NSABP B-23)	Phase III	Placebo	Seems not superior
Assikis et al. 2003	Phase III	FAC, then MV	Seems not superior
Coombes et al. 2004 (Intergroup Exemestane Study)	Phase III	Tamoxifen x 2-3y, then Exemestane x 2-3y	Might have inferior OS (*)
Hutchins et al. 2005 (INT-0102)	Phase III	Observation	Seems not superior
Breast International Group (BIG) 1-98 Collaborative Group 2006	Phase III	Letrozole	Inferior OS (*)
		Letrozole x 2y, then Tamoxifen x 3y	Not reported
		Tamoxifen x 2y, then Letrozole x 3y	Not reported
Kaufmann et al. 2007 (ARNO 95)	Phase III	Tamoxifen x 2y, then Anastrozole x 3y	Seems to have inferior OS
Mamounas et al. 2008 (NSABP B-33)	Non-randomized portion of RCT
van de Velde et al. 2011 (TEAM)	Phase III	Tamoxifen x 2.5-3y, then Exemestane x 2-2.5y	Seems not superior
Davies et al. 2013 (ATLAS)	Phase III	Tamoxifen x 10 years	Inferior OS
Pagani et al. 2014 (SOFT)	Phase III	Exemestane & OFS	Inferior DFS
		Tamoxifen & OFS	Might have inferior DFS (*)
Chapman et al. 2015 (NCIC CTG MA.14 & NSABP B-29)	Phase III	Tamoxifen & Octreotide LAR	Seems not superior

Note: Pagani et al. 2014 reports on two trials, but only SOFT had the tamoxifen only arm; efficacy for this arm is as reported in Francis et al. 2015. Efficacy for BIG 1-98 is based on the 2011 update.

Preceding treatment

• NSABP B-23: CMF x 6 versus AC x 4
• INT-0102: CAF x 6 versus CMF x 6

Endocrine therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day

5 years of therapy

Subsequent treatment

• NSABP B-33: Exemestane versus Placebo

Regimen #5, 5 years with OFS

Study	Evidence	Comparator	Efficacy
Pagani et al. 2014 (TEXT/SOFT)	Phase III	Exemestane & OFS	Inferior DFS
		Tamoxifen	Might have superior DFS (*)

These regimens are intended for premenopausal patients. Pagani et al. 2014 reports on two trials, but only SOFT had the tamoxifen only arm; efficacy for this arm is as reported in Francis et al. 2015.

Endocrine therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day
• Ovarian Suppression as follows:
  • TEXT: Triptorelin (Trelstar LA) 3.75 mg IM every 28 days
    • "Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin."
  • SOFT: Choice of mechanism left to investigators

5 years of therapy

Regimen #6, 10 years

Study	Evidence	Comparator	Efficacy
Davies et al. 2013 (ATLAS)	Phase III	Tamoxifen x 5 years	Superior OS

Endocrine therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day

10 years of therapy

References

1. Review: Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN. Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol. 1995 Feb;13(2):513-29. link to original article PubMed
2. Preliminary results from the cancer research campaign trial evaluating tamoxifen duration in women aged fifty years or older with breast cancer. Current Trials working Party of the Cancer Research Campaign Breast Cancer Trials Group. J Natl Cancer Inst. 1996 Dec 18;88(24):1834-9. Erratum in: J Natl Cancer Inst 1997 Apr 16;89(8):590. PubMed
   1. Update: Hackshaw A, Roughton M, Forsyth S, Monson K, Reczko K, Sainsbury R, Baum M. Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer. J Clin Oncol. 2011 May 1;29(13):1657-63. Epub 2011 Mar 21. link to original article PubMed
3. Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article PubMed
4. Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, Valero V, Walters R, Singletary E, Ames F, Hortobagyi G. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer. 2003 Jun 1;97(11):2716-23. link to original article contains protocol PubMed
5. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11;350(11):1081-92. link to original article PubMed
   1. Update: Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70. link to original article PubMed
6. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005 Jan 1-7;365(9453):60-2. link to original article PubMed
   1. Update: Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group, Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008 Jan;9(1):45-53. link to original article PubMed
   2. Update: Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF; ATAC/LATTE investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010 Dec;11(12):1135-41. link to original article PubMed
7. Rydén L, Jönsson PE, Chebil G, Dufmats M, Fernö M, Jirström K, Källström AC, Landberg G, Stål O, Thorstenson S, Nordenskjöld B; South Swedish Breast Cancer Group; South-East Swedish Breast Cancer Group. Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: a randomised, controlled trial with long-term follow-up. Eur J Cancer. 2005 Jan;41(2):256-64. link to original article PubMed
   1. Update: Ekholm M, Bendahl PO, Fernö M, Nordenskjöld B, Stål O, Rydén L. Two years of adjuvant tamoxifen provides a survival benefit compared with no systemic treatment in premenopausal patients with primary breast cancer: Long-term follow-up (> 25 years) of the phase III SBII:2pre trial. J Clin Oncol. 2016 Jul 1;34(19):2232-8. Epub 2016 May 9. link to original article PubMed
8. Review: Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 May 14-20;365(9472):1687-717. link to original article PubMed
9. Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article PubMed
10. Breast International Group (BIG) 1-98 Collaborative Group, Thürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. Wardly, Andrew [corrected to Wardley, Andrew ]. link to original article PubMed
    1. Update: Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007 Feb 10;25(5):486-92. Epub 2007 Jan 2. link to original article PubMed
    2. Subgroup analysis: Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thürlimann B, Coates AS, Viale G; BIG 1-98 Collaborative and International Breast Cancer Study Groups. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008 Jan;9(1):23-8. Epub 2007 Dec 20. link to original article PubMed
    3. Subgroup analysis: Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol. 2008 Apr 20;26(12):1972-9. Epub 2008 Mar 10. link to original article PubMed
    4. Update: Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG 1-98 Collaborative Group.; International Breast Cancer Study Group (IBCSG). Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. link to original article link to PMC article PubMed
11. Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, von Minckwitz G. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol. 2007 Jul 1;25(19):2664-70. Epub 2007 Jun 11. link to original article PubMed
12. Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol. 2008 Apr 20;26(12):1965-71. Epub 2008 Mar 10. link to original article PubMed
13. van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011 Jan 22;377(9762):321-31. link to original article contains verified protocol PubMed
    1. Update: Derks MGM, Blok EJ, Seynaeve C, Nortier JWR, Kranenbarg EM, Liefers GJ, Putter H, Kroep JR, Rea D, Hasenburg A, Markopoulos C, Paridaens R, Smeets JBE, Dirix LY, van de Velde CJH. Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1211-1220. Epub 2017 Jul 18. link to original article PubMed
14. Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Medeiros Alencar VH, Badran A, Bonfill X, Bradbury J, Clarke M, Collins R, Davis SR, Delmestri A, Forbes JF, Haddad P, Hou MF, Inbar M, Khaled H, Kielanowska J, Kwan WH, Mathew BS, Mittra I, Müller B, Nicolucci A, Peralta O, Pernas F, Petruzelka L, Pienkowski T, Radhika R, Rajan B, Rubach MT, Tort S, Urrútia G, Valentini M, Wang Y, Peto R; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013 Mar 9;381(9869):805-16. Erratum in: Lancet. 2013 Mar 9;381(9869):804. link to original article contains verified protocol link to PMC article PubMed
15. Ejlertsen B, Jensen MB, Elversang J, Rasmussen BB, Andersson M, Andersen J, Nielsen DL, Cold S, Mouridsen HT. One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer. Eur J Cancer. 2013 Sep;49(14):2986-94. Epub 2013 Jun 8. link to original article contains verified protocol PubMed
16. Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Perez EA, Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G, Coates AS, Gelber RD, Goldhirsch A, Francis PA; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Jul 10;371(2):107-18. Epub 2014 Jun 1. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Francis PA, Regan MM, Fleming GF, Láng I, Ciruelos E, Bellet M, Bonnefoi HR, Climent MA, Da Prada GA, Burstein HJ, Martino S, Davidson NE, Geyer CE Jr, Walley BA, Coleman R, Kerbrat P, Buchholz S, Ingle JN, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Colleoni M, Viale G, Coates AS, Goldhirsch A, Gelber RD; SOFT Investigators; International Breast Cancer Study Group. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015 Jan 29;372(5):436-46. Epub 2014 Dec 11. link to original article link to PMC article PubMed
17. Chapman JA, Costantino JP, Dong B, Margolese RG, Pritchard KI, Shepherd LE, Gelmon KA, Wolmark N, Pollak MN. Octreotide LAR and tamoxifen versus tamoxifen in phase III randomize early breast cancer trials: NCIC CTG MA.14 and NSABP B-29. Breast Cancer Res Treat. 2015 Sep;153(2):353-60. Epub 2015 Aug 15. link to original article link to PMC article PubMed

Metastatic disease, endocrine therapy

Abemaciclib & Anastrozole

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Regimen

Study	Evidence	Comparator	Efficacy
Goetz et al. 2017 (MONARCH 3)	Phase III	Anastrozole	Superior PFS

Chemotherapy

• Abemaciclib (Verzenio) 150 mg PO BID
• Anastrozole (Arimidex) 1 mg PO once per day

28-day cycles

References

1. Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017 Nov 10;35(32):3638-3646. Epub 2017 Oct 2. link to original article contains verified protocol PubMed

Abemaciclib & Fulvestrant

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Regimen

Study	Evidence	Comparator	Efficacy
Sledge et al. 2017 (MONARCH 2)	Phase III	Fulvestrant	Superior PFS

Chemotherapy

• Abemaciclib (Verzenio) 150 mg PO BID
• Fulvestrant (Faslodex) as follows:
  • Cycle 1: 500 mg IM once per day on days 1 & 15
  • Cycle 2 onwards: 500 mg IM once on day 1

28-day cycles

References

1. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017 Sep 1;35(25):2875-2884. Epub 2017 Jun 3. link to original article contains verified protocol PubMed

Abemaciclib & Letrozole

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Regimen

Study	Evidence	Comparator	Efficacy
Goetz et al. 2017 (MONARCH 3)	Phase III	Letrozole	Superior PFS

Chemotherapy

• Abemaciclib (Verzenio) 150 mg PO BID
• Letrozole (Femara) 2.5 mg PO once per day

28-day cycles

References

1. Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017 Nov 10;35(32):3638-3646. Epub 2017 Oct 2. link to original article contains verified protocol PubMed

Anastrozole monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Howell et al. 2002	Phase III	Fulvestrant	Seems to have non-inferior TTP
Bergh et al. 2012 (FACT)	Phase III	Anastrozole & Fulvestrant	Seems not superior
Mehta et al. 2012 (SWOG S0226)	Phase III	Anastrozole & Fulvestrant	Seems to have inferior OS
Robertson et al. 2016 (FALCON)	Phase III	Fulvestrant	Seems to have inferior PFS
Goetz et al. 2017 (MONARCH 3)	Phase III	Abemaciclib & Anastrozole	Inferior PFS
Tripathy et al. 2017 (MONALEESA-7)	Phase III	Anastrozole & Ribociclib	Inferior PFS

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day

Supportive medications

• For premenopausal patients:
  • MONALEESA-7: Goserelin (Zoladex) 3.8 mg SC once every 28 days

References

1. Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A, Morris C. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002 Aug 15;20(16):3396-403. link to original article PubMed
2. Bergh J, Jönsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattström D, Lindemann JP, Wiklund F, Henriksson R. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012 Jun 1;30(16):1919-25. Epub 2012 Feb 27. link to original article contains verified protocol PubMed
3. Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, Hortobagyi GN. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435-44. link to original article contains verified protocol link to PMC article PubMed
4. Robertson JF, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A, Shparyk Y, Cardona-Huerta S, Cheung KL, Philco-Salas MJ, Ruiz-Borrego M, Shao Z, Noguchi S, Rowbottom J, Stuart M, Grinsted LM, Fazal M, Ellis MJ. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005. Epub 2016 Nov 28. link to original article contains protocol PubMed
5. Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017 Nov 10;35(32):3638-3646. Epub 2017 Oct 2. link to original article contains verified protocol PubMed
6. Abstract: Tripathy D, Sohn J, Im S-A, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz S, Chow L, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu Y-S. First-line ribociclib vs placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from the randomized phase III MONALEESA-7 trial. 2017 Dec SABCS Abstract 828 link to abstract contains protocol

Anastrozole & Fulvestrant

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Regimen

Study	Evidence	Comparator	Efficacy
Bergh et al. 2012 (FACT)	Phase III	Anastrozole	Seems not superior
Mehta et al. 2012 (SWOG S0226)	Phase III	Anastrozole	Seems to have superior OS

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day
• Fulvestrant (Faslodex) 500 mg IM once on day 1, then 250 mg IM once per day on days 14 & 28, then 250 mg IM once every four weeks
  • Patients in SWOG S0226 who progressed while on therapy were allowed to receive a higher dose, 500 mg IM once every four weeks

28-day cycles

References

1. Bergh J, Jönsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattström D, Lindemann JP, Wiklund F, Henriksson R. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012 Jun 1;30(16):1919-25. Epub 2012 Feb 27. link to original article contains verified protocol PubMed
2. Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, Hortobagyi GN. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435-44. link to original article contains verified protocol link to PMC article PubMed

Anastrozole & Ribociclib

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Regimen

Study	Evidence	Comparator	Efficacy
Tripathy et al. 2017 (MONALEESA-7)	Phase III	Anastrozole	Superior PFS

Therapy

• Anastrozole (Arimidex) 1 mg PO once per day
• Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21

Supportive medications

• Goserelin (Zoladex) 3.8 mg SC once every 28 days

28-day cycles

References

1. Abstract: Tripathy D, Sohn J, Im S-A, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz S, Chow L, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu Y-S. First-line ribociclib vs placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from the randomized phase III MONALEESA-7 trial. 2017 Dec SABCS Abstract 828 link to abstract contains protocol

Exemestane monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Chia et al. 2008 (EFECT)	Phase III	Fulvestrant	Seems not superior
Baselga et al. 2011 (BOLERO-2)	Phase III	Everolimus & Exemestane	Inferior PFS

Endocrine therapy

• Exemestane (Aromasin) 25 mg PO once per day

References

1. Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson JF, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008 Apr 1;26(10):1664-70. Epub 2008 Mar 3. link to original article PubMed
2. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520-9. Epub 2011 Dec 7. link to original article contains verified protocol PubMed
   1. Update: Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013 Oct;30(10):870-84. Erratum in: Adv Ther. 2014 Sep;31(9):1008-9. link to PMC article PubMed

See references for Exemestane (Aromasin)

Exemestane & Everolimus

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Regimen

Study	Evidence	Comparator	Efficacy
Baselga et al. 2011 (BOLERO-2)	Phase III	Exemestane	Superior PFS

Therapy

• Everolimus (Afinitor) 10 mg PO once per day
• Exemestane (Aromasin) 25 mg PO once per day

Given until progression of disease or unacceptable toxicity

References

1. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520-9. Epub 2011 Dec 7. link to original article contains verified protocol PubMed
   1. Update: Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013 Oct;30(10):870-84. Erratum in: Adv Ther. 2014 Sep;31(9):1008-9. link to PMC article PubMed

Fulvestrant monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Howell et al. 2002	Phase III	Anastrozole	Seems to have non-inferior TTP
Howell et al. 2004	Phase III	Tamoxifen	Might have inferior TTP
Chia et al. 2008 (EFECT)	Phase III	Exemestane	Seems not superior
Di Leo et al. 2010 (CONFIRM)	Phase III	Fulvestrant 250 mg	Superior PFS
Turner et al. 2015 (PALOMA-3)	Phase III (C)	Fulvestrant & Palbociclib	Inferior PFS
Robertson et al. 2016 (FALCON)	Phase III	Anastrozole	Seems to have superior PFS
Baselga et al. 2017 (BELLE-2)	Phase III (C)	Buparlisib & Fulvestrant	Inferior PFS
Sledge et al. 2017 (MONARCH 2)	Phase III (C)	Abemaciclib & Fulvestrant	Inferior PFS
Di Leo et al. 2017 (BELLE-3)	Phase III (C)	Buparlisib & Fulvestrant	Inferior PFS

Note: while this regimen was inferior in BELLE-2 and BELLE-3, the authors note that "no further studies [of this combination] are being pursued because of the toxicity associated with [the experimental arm]."

Endocrine therapy

• Fulvestrant (Faslodex) as follows:
  • Cycle 1: 500 mg IM once per day on days 1 & 15
  • Cycle 2 onwards: 500 mg IM once on day 1

28-day cycles

References

1. Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A, Morris C. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002 Aug 15;20(16):3396-403. link to original article PubMed
2. Howell A, Robertson JF, Abram P, Lichinitser MR, Elledge R, Bajetta E, Watanabe T, Morris C, Webster A, Dimery I, Osborne CK. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol. 2004 May 1;22(9):1605-13. link to original article PubMed
3. Perey L, Paridaens R, Hawle H, Zaman K, Nolé F, Wildiers H, Fiche M, Dietrich D, Clément P, Köberle D, Goldhirsch A, Thürlimann B. Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00). Ann Oncol. 2007 Jan;18(1):64-9. Epub 2006 Oct 9. link to original article PubMed
4. Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson JF, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008 Apr 1;26(10):1664-70. Epub 2008 Mar 3. link to original article PubMed
5. Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Garnett S, Lindemann JP, Sapunar F, Martin M. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010 Oct 20;28(30):4594-600. Epub 2010 Sep 20. Erratum in: J Clin Oncol. 2011 Jun 1;29(16):2293. link to original articlePubMed
6. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. Epub 2015 Jun 1. link to original article contains verified protocol PubMed
   1. Update: Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425-39. Epub 2016 Mar 3. link to original articlePubMed
7. Robertson JF, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A, Shparyk Y, Cardona-Huerta S, Cheung KL, Philco-Salas MJ, Ruiz-Borrego M, Shao Z, Noguchi S, Rowbottom J, Stuart M, Grinsted LM, Fazal M, Ellis MJ. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005. Epub 2016 Nov 28. link to original article contains protocol PubMed
8. Baselga J, Im SA, Iwata H, Cortés J, De Laurentiis M, Jiang Z, Arteaga CL, Jonat W, Clemons M, Ito Y, Awada A, Chia S, Jagiełło-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Takahashi M, Vuylsteke P, Hachemi S, Dharan B, Di Tomaso E, Urban P, Massacesi C, Campone M. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Jul;18(7):904-916. Epub 2017 May 30. link to original articlelink to PMC article contains protocol PubMed
9. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017 Sep 1;35(25):2875-2884. Epub 2017 Jun 3. link to original article contains verified protocol PubMed
10. Di Leo A, Johnston S, Lee KS, Ciruelos E, Lønning PE, Janni W, O'Regan R, Mouret-Reynier MA, Kalev D, Egle D, Csőszi T, Bordonaro R, Decker T, Tjan-Heijnen VCG, Blau S, Schirone A, Weber D, El-Hashimy M, Dharan B, Sellami D, Bachelot T. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Jan;19(1):87-100. Epub 2017 Dec 7. link to original article contains protocol PubMed

Fulvestrant & Palbociclib

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Regimen

Study	Evidence	Comparator	Efficacy
Turner et al. 2015 (PALOMA-3)	Phase III	Fulvestrant	Superior PFS

Therapy

• Fulvestrant (Faslodex) 500 mg IM once every 2 weeks for 3 doses, then once every 4 weeks
• Palbociclib (Ibrance) 125 mg PO once per day on days 1 to 21

28-day cycles

References

1. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. Epub 2015 Jun 1. link to original article contains verified protocol PubMed
   1. Update: Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425-39. Epub 2016 Mar 3. link to original article PubMed

Letrozole monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Finn et al. 2015 (PALOMA-1/TRIO-18)	Randomized Phase II	Letrozole & Palbociclib	Inferior PFS
Dickler et al. 2016 (CALGB 40503)	Phase III	Letrozole & Bevacizumab	Seems to have inferior PFS
Hortobagyi et al. 2016 (MONALEESA-2)	Phase III	Letrozole & Ribociclib	Inferior PFS
Finn et al. 2016 (PALOMA-2)	Randomized Phase II	Letrozole & Palbociclib	Inferior PFS
Goetz et al. 2017 (MONARCH 3)	Phase III	Abemaciclib & Letrozole	Inferior PFS
Tripathy et al. 2017 (MONALEESA-7)	Phase III	Letrozole & Ribociclib	Inferior PFS

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

Supportive medications

• For premenopausal patients:
  • MONALEESA-7: Goserelin (Zoladex) 3.8 mg SC once every 28 days

References

See references for Letrozole (Femara)

1. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. link to original article contains verified protocol PubMed
2. Dickler MN, Barry WT, Cirrincione CT, Ellis MJ, Moynahan ME, Innocenti F, Hurria A, Rugo HS, Lake DE, Hahn O, Schneider BP, Tripathy D, Carey LA, Winer EP, Hudis CA. Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer: CALGB 40503 (Alliance). J Clin Oncol. 2016 Aug 1;34(22):2602-9. Epub 2016 May 2. link to original article contains protocol link to PMC article PubMed
3. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Blackwell KL, André F, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Petrakova K, Hart LL, Villanueva C, Chan A, Jakobsen E, Nusch A, Burdaeva O, Grischke EM, Alba E, Wist E, Marschner N, Favret AM, Yardley D, Bachelot T, Tseng LM, Blau S, Xuan F, Souami F, Miller M, Germa C, Hirawat S, O'Shaughnessy J. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016 Nov 3;375(18):1738-1748. Epub 2016 Oct 7.link to original article contains verified protocol PubMed
4. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Diéras V, Slamon DJ. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. link to original article contains verified protocol PubMed
5. Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017 Nov 10;35(32):3638-3646. Epub 2017 Oct 2. link to original article contains verified protocol PubMed
6. Abstract: Tripathy D, Sohn J, Im S-A, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz S, Chow L, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu Y-S. First-line ribociclib vs placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from the randomized phase III MONALEESA-7 trial. 2017 Dec SABCS Abstract 828 link to abstract contains protocol

Letrozole & Palbociclib

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Regimen

Study	Evidence	Comparator	Efficacy
Finn et al. 2015 (PALOMA-1/TRIO-18)	Randomized Phase II	Letrozole	Superior PFS
Finn et al. 2016 (PALOMA-2)	Phase III	Letrozole	Superior PFS

Therapy

• Letrozole (Femara) 2.5 mg PO once per day
• Palbociclib (Ibrance) 125 mg PO once per day on days 1 to 21

28-day cycles

References

1. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. link to original article contains verified protocol PubMed
2. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Diéras V, Slamon DJ. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. link to original article contains verified protocol PubMed

Letrozole & Ribociclib

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Regimen

Study	Evidence	Comparator	Efficacy
Hortobagyi et al. 2016 (MONALEESA-2)	Phase III	Letrozole	Superior PFS
Tripathy et al. 2017 (MONALEESA-7)	Phase III	Letrozole	Superior PFS

Therapy

• Letrozole (Femara) 2.5 mg PO once per day
• Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21

Supportive medications

• For premenopausal patients:
  • MONALEESA-7: Goserelin (Zoladex) 3.8 mg SC once every 28 days

28-day cycles

References

1. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Blackwell KL, André F, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Petrakova K, Hart LL, Villanueva C, Chan A, Jakobsen E, Nusch A, Burdaeva O, Grischke EM, Alba E, Wist E, Marschner N, Favret AM, Yardley D, Bachelot T, Tseng LM, Blau S, Xuan F, Souami F, Miller M, Germa C, Hirawat S, O'Shaughnessy J. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016 Nov 3;375(18):1738-1748. Epub 2016 Oct 7. link to original article contains verified protocol PubMed
2. Abstract: Tripathy D, Sohn J, Im S-A, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz S, Chow L, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu Y-S. First-line ribociclib vs placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from the randomized phase III MONALEESA-7 trial. 2017 Dec SABCS Abstract 828 link to abstract contains protocol

Ribociclib & Tamoxifen

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Regimen

Study	Evidence	Comparator	Efficacy
Tripathy et al. 2017 (MONALEESA-7)	Phase III	Tamoxifen	Superior PFS

Therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day
• Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21

Supportive medications

• Goserelin (Zoladex) 3.8 mg SC once on day 1

28-day cycles

References

1. Abstract: Tripathy D, Sohn J, Im S-A, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz S, Chow L, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu Y-S. First-line ribociclib vs placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from the randomized phase III MONALEESA-7 trial. 2017 Dec SABCS Abstract 828 link to abstract contains protocol

Tamoxifen monotherapy

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Regimen #1, standard dosing (20 mg per day)

Study	Evidence	Comparator	Efficacy
Hayes et al. 1995	Phase III	Toremifene 60 mg per day	Seems not superior
		Toremifene 200 mg per day	Seems not superior
Howell et al. 2004	Phase III	Fulvestrant	Might have superior TTP
Bachelot et al. 2012	Randomized Phase II	Tamoxifen & Everolimus	Inferior OS
Tripathy et al. 2017 (MONALEESA-7)	Phase III	Ribociclib & Tamoxifen	Inferior PFS

Endocrine therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day

Supportive medications

• For premenopausal patients:
  • MONALEESA-7: Goserelin (Zoladex) 3.8 mg SC once every 28 days

Regimen #2, high-dose (40 mg per day)

Study	Evidence	Comparator	Efficacy
Gershanovich et al. 1997	Phase III	Toremifene 60 mg per day	Seems not superior
		Toremifene 240 mg per day	Seems not superior
Pyrhönen et al. 1997	Phase III	Toremifene 60 mg per day	Seems to have superior TTP

Endocrine therapy

• Tamoxifen (Nolvadex) 40 mg PO once per day

References

1. Hayes DF, Van Zyl JA, Hacking A, Goedhals L, Bezwoda WR, Mailliard JA, Jones SE, Vogel CL, Berris RF, Shemano I et al. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2556-66. link to original article PubMed
2. Gershanovich M, Garin A, Baltina D, Kurvet A, Kangas L, Ellmén J. A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Eastern European Study Group. Breast Cancer Res Treat. 1997 Sep;45(3):251-62. link to original article PubMed
3. Pyrhönen S, Valavaara R, Modig H, Pawlicki M, Pienkowski T, Gundersen S, Bauer J, Westman G, Lundgren S, Blanco G, Mella O, Nilsson I, Hietanen T, Hindy I, Vuorinen J, Hajba A. Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study. Br J Cancer. 1997;76(2):270-7. link to PMC article PubMed
4. Howell A, Robertson JF, Abram P, Lichinitser MR, Elledge R, Bajetta E, Watanabe T, Morris C, Webster A, Dimery I, Osborne CK. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol. 2004 May 1;22(9):1605-13. link to original article PubMed
5. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaëth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study. J Clin Oncol. 2012 Aug 1;30(22):2718-24. Epub 2012 May 7. link to original article contains verified protocol PubMed
6. Abstract: Tripathy D, Sohn J, Im S-A, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz S, Chow L, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu Y-S. First-line ribociclib vs placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from the randomized phase III MONALEESA-7 trial. 2017 Dec SABCS Abstract 828 link to abstract contains protocol

See references for Tamoxifen (Nolvadex)

Tamoxifen & Everolimus

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Regimen

Study	Evidence	Comparator	Efficacy
Bachelot et al. 2012	Randomized Phase II	Tamoxifen	Superior OS

Therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day
• Everolimus (Afinitor) 10 mg PO once per day

Given until progression of disease or unacceptable toxicity

References

1. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaëth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study. J Clin Oncol. 2012 Aug 1;30(22):2718-24. Epub 2012 May 7. link to original article contains verified protocol PubMed

Toremifene monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Hayes et al. 1995	Phase III	Tamoxifen	Seems not superior
		Toremifene 200 mg per day	Seems not superior
Gershanovich et al. 1997	Phase III	Tamoxifen 40 mg per day	Seems not superior
		Toremifene 240 mg per day	Seems not superior
Pyrhönen et al. 1997	Phase III	Tamoxifen 40 mg per day	Seems to have inferior TTP

Endocrine therapy

• Toremifene (Fareston) 60 mg PO once per day

Given until progression

References

1. Hayes DF, Van Zyl JA, Hacking A, Goedhals L, Bezwoda WR, Mailliard JA, Jones SE, Vogel CL, Berris RF, Shemano I et al. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2556-66. link to original article PubMed
2. Gershanovich M, Garin A, Baltina D, Kurvet A, Kangas L, Ellmén J. A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Eastern European Study Group. Breast Cancer Res Treat. 1997 Sep;45(3):251-62. link to original article PubMed
3. Pyrhönen S, Valavaara R, Modig H, Pawlicki M, Pienkowski T, Gundersen S, Bauer J, Westman G, Lundgren S, Blanco G, Mella O, Nilsson I, Hietanen T, Hindy I, Vuorinen J, Hajba A. Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study. Br J Cancer. 1997;76(2):270-7. link to PMC article PubMed
4. Toremifene (Fareston) package insert

Metastatic disease, single agent therapy

Abemaciclib monotherapy

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Regimen

Study	Evidence	ORR
Dickler et al. 2017 (MONARCH 1)	Phase II	20% (95% CI 13-27.5)

Chemotherapy

• Abemaciclib (Verzenio) 200 mg PO BID

Continued until progression

References

1. Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, Wildiers H, Hudis CA, O'Shaughnessy J, Zamora E, Yardley DA, Frenzel M, Koustenis A, Baselga J. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 Inhibitor, as a single agent, in patients with refractory HR(+)/HER2(-) metastatic breast cancer. Clin Cancer Res. 2017 Sep 1;23(17):5218-5224. Epub 2017 May 22. link to original article link to PMC article contains protocol PubMed

Capecitabine monotherapy

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Regimen #1, 650 mg/m² BID, continuous

Study	Evidence	Comparator	Efficacy
Stockler et al. 2011	Phase III	CMF	Seems to have superior OS
		Intermittent Capecitabine	Seems not superior

Chemotherapy

• Capecitabine (Xeloda) 650 mg/m² PO BID

21-day cycles

Regimen #2, 1000 mg/m² BID

Study	Evidence	Comparator	Efficacy
Bajetta et al. 2005	Phase II
Robert et al. 2011 (RIBBON-1)	Phase III	Capecitabine & Bevacizumab	Inferior PFS
Stockler et al. 2011	Phase III	CMF	Seems to have superior OS
		Continuous Capecitabine	Seems not superior

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO BID on days 1 to 14

21-day cycles

Regimen #3, 1250 mg/m² BID

Study	Evidence	Comparator	Efficacy
Bajetta et al. 2005	Phase II
Geyer et al. 2006	Phase III	Capecitabine & Lapatinib	Inferior TTP
Thomas et al. 2007	Phase III	Capecitabine & Ixabepilone	Inferior PFS
von Minckwitz et al. 2009 (GBG 26/BIG 3-05)	Phase III	Capecitabine & Trastuzumab	Seems to have inferior TTP
Sparano et al. 2010	Phase III	Capecitabine & Ixabepilone	Inferior PFS
Crown et al. 2013	Phase III	Capecitabine & Sunitinib	Seems not superior
Harbeck et al. 2016 (PELICAN)	Phase III	Pegylated liposomal doxorubicin	Inconclusive whether non-inferior
Yamamoto et al. 2016 (JO21095)	Non-randomized portion of RCT
Zhang et al. 2017 (BG01-1323L)	Phase III	Capecitabine & Utidelone	Inferior PFS
Robson et al. 2017 (OlympiAD)	Phase III	Olaparib	Inferior PFS

Patients in GBG 26/BIG 3-05 had HER2-positive disease. Patients in OlympiAD had confirmed deleterious or suspected deleterious germline BRCA mutation.

Preceding treatment

• JO21095: Docetaxel, with PD

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO BID on days 1 to 14

21-day cycles

References

1. Bajetta E, Procopio G, Celio L, Gattinoni L, Della Torre S, Mariani L, Catena L, Ricotta R, Longarini R, Zilembo N, Buzzoni R. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol. 2005 Apr 1;23(10):2155-61. Epub 2005 Feb 14. link to original article contains verified protocol PubMed
2. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. link to original article contains verified protocol PubMed
   1. Update: Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B, Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Rubin S, Stein S, Geyer CE. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008 Dec;112(3):533-43. link to original article PubMed
   2. Update: Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010;15(9):924-34. link to original article link to PMC article PubMed
3. Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. link to original article contains verified protocol PubMed
4. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol. 2009 Apr 20;27(12):1999-2006. Epub 2009 Mar 16. link to original article contains verified protocol PubMed
   1. Update: von Minckwitz G, Schwedler K, Schmidt M, Barinoff J, Mundhenke C, Cufer T, Maartense E, de Jongh FE, Baumann KH, Bischoff J, Harbeck N, Lück HJ, Maass N, Zielinski C, Andersson M, Stein RC, Nekljudova V, Loibl S; GBG 26/BIG 03-05 study group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011 Oct;47(15):2273-81. Epub 2011 Jul 7. link to original article contains verified protocol PubMed
5. Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63.link to original article contains verified protocol link to PMC article PubMed
6. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed
7. Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4498-504. Epub 2011 Oct 24. link to original article contains verified protocol PubMed
8. Crown JP, Diéras V, Staroslawska E, Yardley DA, Bachelot T, Davidson N, Wildiers H, Fasching PA, Capitain O, Ramos M, Greil R, Cognetti F, Fountzilas G, Blasinska-Morawiec M, Liedtke C, Kreienberg R, Miller WH Jr, Tassell V, Huang X, Paolini J, Kern KA, Romieu G. Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol. 2013 Aug 10;31(23):2870-8. Epub 2013 Jul 15. link to original article contains verified protocol PubMed
9. Harbeck N, Saupe S, Jäger E, Schmidt M, Kreienberg R, Müller L, Otremba BJ, Waldenmaier D, Dorn J, Warm M, Scholz M, Untch M, de Wit M, Barinoff J, Lück HJ, Harter P, Augustin D, Harnett P, Beckmann MW, Al-Batran SE; PELICAN Investigators. A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat. 2017 Jan;161(1):63-72. Epub 2016 Oct 31. link to original article link to PMC article contains verified protocol PubMed
10. Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article contains verified protocol PubMed
11. Zhang P, Sun T, Zhang Q, Yuan Z, Jiang Z, Wang XJ, Cui S, Teng Y, Hu XC, Yang J, Pan H, Tong Z, Li H, Yao Q, Wang Y, Yin Y, Sun P, Zheng H, Cheng J, Lu J, Zhang B, Geng C, Liu J, Peng R, Yan M, Zhang S, Huang J, Tang L, Qiu R, Xu B; BG01-1323L study group. Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracyclines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial. Lancet Oncol. 2017 Mar;18(3):371-383. Epub 2017 Feb 11. link to original article contains protocol PubMed
12. Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017 Aug 10;377(6):523-533. Epub 2017 Jun 4. link to original article contains verified protocol PubMed

Docetaxel monotherapy

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D: Docetaxel
T: Taxotere (Docetaxel)

Regimen #1, 40 mg/m² 6 weeks out of 8

Study	Evidence
Burstein et al. 2000	Phase II

Chemotherapy

• Docetaxel (Taxotere) 40 mg/m² IV once per week for weeks 1 to 6, then off for weeks 7 & 8

8-week cycles

Regimen #2, 60 mg/m² q3wk

Study	Evidence	Comparator	Efficacy	Toxicity
Harvey et al. 2006	Phase III	Lower-dose q3wk docetaxel	Might have inferior TTP
		Standard-dose q3wk docetaxel	Might have inferior TTP
Takashima et al. 2015 (SELECT BC)	Phase III	S-1	Seems to have non-inferior OS	Inferior EQ-5D score

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

21-day cycles

Regimen #3, 60 mg/m² q4wk

Study	Evidence	Comparator	Efficacy	Toxicity
Takashima et al. 2015 (SELECT BC)	Phase III	S-1	Seems to have non-inferior OS	Inferior EQ-5D score

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

28-day cycles

Regimen #4, 70 mg/m²

Study	Evidence	Comparator	Efficacy
Yamamoto et al. 2016 (JO21095)	Phase III	Capecitabine & Docetaxel	Seems to have inferior OS

Chemotherapy

• Docetaxel (Taxotere) 70 mg/m² IV once on day 1

21-day cycles

'At progression, this arm was pre-assigned to transition to capecitabine.

Regimen #5, 75 mg/m² q3wk

Study	Evidence	Comparator	Efficacy	Toxicity
Harvey et al. 2006	Phase III	Low-dose q3wk docetaxel	Might have superior TTP
		Standard-dose q3wk docetaxel	Might have inferior TTP
Robert et al. 2011 (RIBBON-1)	Phase III	Docetaxel & Bevacizumab	Inferior PFS
Takashima et al. 2015 (SELECT BC)	Phase III	S-1	Seems to have non-inferior OS	Inferior EQ-5D score

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycles

Regimen #6, 75 mg/m² q4wk

Study	Evidence	Comparator	Efficacy	Toxicity
Takashima et al. 2015 (SELECT BC)	Phase III	S-1	Seems to have non-inferior OS	Inferior EQ-5D score

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

28-day cycles

Regimen #7, 100 mg/m²

Study	Evidence	Comparator	Efficacy
Chan et al. 1999 (303 Study Group)	Phase III	Doxorubicin	Superior ORR
O'Shaughnessy et al. 2002	Phase III	Capecitabine & Docetaxel	Seems to have inferior OS
Marty et al. 2005 (M77001)	Phase III	Docetaxel & Trastuzumab	Seems to have inferior OS
Harvey et al. 2006	Phase III	Low-dose q3wk docetaxel	Might have superior TTP
		Lower-dose q3wk docetaxel	Might have superior TTP
Gradishar et al. 2009	Phase III	Higher-dose weekly nanoparticle albumin-bound paclitaxel	Inferior PFS
		Lower-dose weekly nanoparticle albumin-bound paclitaxel	Seems not superior
		q3wk nanoparticle albumin-bound paclitaxel	Seems not superior
Robert et al. 2011 (RIBBON-1)	Phase III	Docetaxel & Bevacizumab	Inferior PFS

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

21-day cycles

Note: the 303 Study Group stopped treatment after 7 cycles.

References

1. Review: Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. PubMed
2. Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. link to original article PubMed
3. Alexandre J, Bleuzen P, Bonneterre J, Sutherland W, Misset JL, Guastalla J, Viens P, Faivre S, Chahine A, Spielman M, Bensmaïne A, Marty M, Mahjoubi M, Cvitkovic E. Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients. J Clin Oncol. 2000 Feb;18(3):562-73. link to original article PubMed
4. Burstein HJ, Manola J, Younger J, Parker LM, Bunnell CA, Scheib R, Matulonis UA, Garber JE, Clarke KD, Shulman LN, Winer EP. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol. 2000 Mar;18(6):1212-9. link to original article PubMed content property of HemOnc.org
5. O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article contains verified protocol PubMed
6. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1;23(19):4265-74. Epub 2005 May 23. link to original article contains verified protocol PubMed
7. Harvey V, Mouridsen H, Semiglazov V, Jakobsen E, Voznyi E, Robinson BA, Groult V, Murawsky M, Cold S. Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol. 2006 Nov 1;24(31):4963-70. Epub 2006 Oct 10. link to original article PubMed
8. Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. Epub 2009 May 26. Erratum in: J Clin Oncol. 2011 Jul 1;29(19):2739. link to original article contains verified protocol PubMed
9. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed
10. Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. link to original article link to PMC article PubMed
11. Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article contains verified protocol PubMed

Doxorubicin monotherapy

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Regimen #1

Study	Evidence	Comparator	Efficacy
O'Brien et al. 2004 (CAELYX Breast Cancer Study Group)	Phase III	Pegylated liposomal doxorubicin	Seems to have non-inferior PFS

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

21-day cycles

Regimen #2

Study	Evidence	Comparator	Efficacy
Chan et al. 1999 (303 Study Group)	Phase III	Docetaxel	Inferior ORR

Chemotherapy

• Doxorubicin (Adriamycin) 75 mg/m² IV once on day 1

21-day cycle for up to 7 cycles

Regimen #3

Study	Evidence	Comparator	Efficacy
Gundersen et al. 1986	Phase III	VAC	Seems not superior

Chemotherapy

• Doxorubicin (Adriamycin) 20 mg/m² IV once per week

Duration not specified

References

1. Gundersen S, Kvinnsland S, Klepp O, Kvaløy S, Lund E, Høst H. Weekly adriamycin versus VAC in advanced breast cancer. A randomized trial. Eur J Cancer Clin Oncol. 1986 Dec;22(12):1431-4. link to SD article PubMed
2. Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. link to original article PubMed
3. O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. link to original article PubMed

Doxorubicin liposomal monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
O'Brien et al. 2004 (CAELYX Breast Cancer Study Group)	Phase III	Doxorubicin	Seems to have non-inferior PFS
Harbeck et al. 2016 (PELICAN)	Phase III	Capecitabine	Inconclusive whether non-inferior

Chemotherapy

• Pegylated liposomal doxorubicin (Doxil) 50 mg/m² IV over up to 60 minutes once on day 1
  • If infusion reactions occurred, infusion could be given over up to 90 minutes

28-day cycles

References

1. O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. link to original article contains verified protocol PubMed
2. Harbeck N, Saupe S, Jäger E, Schmidt M, Kreienberg R, Müller L, Otremba BJ, Waldenmaier D, Dorn J, Warm M, Scholz M, Untch M, de Wit M, Barinoff J, Lück HJ, Harter P, Augustin D, Harnett P, Beckmann MW, Al-Batran SE; PELICAN Investigators. A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat. 2017 Jan;161(1):63-72. Epub 2016 Oct 31. link to original article link to PMC article contains verified protocol PubMed

Epirubicin monotherapy

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Regimen #1, 40 mg/m²

Study	Evidence	Comparator	Efficacy
Bastholt et al. 1996	Phase III	Epirubicin 60 mg/m2	Seems not superior
		Epirubicin 90 mg/m2	Inferior TTP
		Epirubicin 135 mg/m2	Seems not superior

Chemotherapy

• Epirubicin (Ellence) 40 mg/m² IV once on day 1

21-day cycles

Regimen #2, 60 mg/m²

Study	Evidence	Comparator	Efficacy
Bastholt et al. 1996	Phase III	Epirubicin 40 mg/m2	Seems not superior
		Epirubicin 90 mg/m2	Seems not superior
		Epirubicin 135 mg/m2	Seems not superior

Chemotherapy

• Epirubicin (Ellence) 60 mg/m² IV once on day 1

21-day cycles

Regimen #3, 90 mg/m²

Study	Evidence	Comparator	Efficacy
Bastholt et al. 1996	Phase III	Epirubicin 40 mg/m2	Superior TTP
		Epirubicin 60 mg/m2	Seems not superior
		Epirubicin 135 mg/m2	Seems not superior

Chemotherapy

• Epirubicin (Ellence) 90 mg/m² IV once on day 1

21-day cycles

Regimen #4, 135 mg/m²

Study	Evidence	Comparator	Efficacy
Bastholt et al. 1996	Phase III	Epirubicin 40 mg/m2	Seems not superior
		Epirubicin 60 mg/m2	Seems not superior
		Epirubicin 90 mg/m2	Seems not superior

Chemotherapy

• Epirubicin (Ellence) 135 mg/m² IV once on day 1

21-day cycles

References

1. Bastholt L, Dalmark M, Gjedde SB, Pfeiffer P, Pedersen D, Sandberg E, Kjaer M, Mouridsen HT, Rose C, Nielsen OS, Jakobsen P, Bentzen SM. Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 1996 Apr;14(4):1146-55. link to original article contains verified protocol PubMed

Eribulin monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Cortes et al. 2011 (EMBRACE)	Phase III	Investigator's choice	Seems to have superior OS
Robson et al. 2017 (OlympiAD)	Phase III	Olaparib	Inferior PFS

Patients in OlympiAD had confirmed deleterious or suspected deleterious germline BRCA mutation.

Chemotherapy

• Eribulin (Halaven) 1.4 mg/m² IV over 2 to 5 minutes once per day on days 1 & 8

21-day cycles

References

1. Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. Epub 2011 Mar 2. link to original article contains protocol PubMed
2. Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017 Aug 10;377(6):523-533. Epub 2017 Jun 4. link to original article contains verified protocol PubMed

Gemcitabine monotherapy

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Regimen

Study	Evidence
Carmichael et al. 1995	Phase II
Spielmann et al. 2001	Phase II

Chemotherapy

• Gemcitabine (Gemzar) 800 to 1200 mg/m² IV once per day on days 1, 8, 15

28-day cycles

References

1. Carmichael J, Possinger K, Phillip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. link to original article PubMed
2. Spielmann M, Llombart-Cussac A, Kalla S, Espié M, Namer M, Ferrero JM, Diéras V, Fumoleau P, Cuvier C, Perrocheau G, Ponzio A, Kayitalire L, Pouillart P. Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology. 2001;60(4):303-7. link to original article PubMed

Paclitaxel monotherapy

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Regimen #1, 175 mg/m² q3wk dosing

Study	Evidence	Comparator	Efficacy	Toxicity
Seidman et al. 1995	Phase II
Slamon et al. 2001	Phase III	TH	Seems to have inferior OS
Gradishar et al. 2005	Phase III	Nanoparticle albumin-bound paclitaxel	Inferior TTP
Seidman et al. 2008 (CALGB 9840)	Phase III	Weekly paclitaxel	Inferior OS
Albain et al. 2008	Phase III	Gemcitabine & Paclitaxel	Seems to have inferior OS
Takashima et al. 2015 (SELECT BC)	Phase III	S-1	Seems to have non-inferior OS	Inferior EQ-5D score

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

21-day cycles

Regimen #2, 175 mg/m² q4wk dosing

Study	Evidence	Comparator	Efficacy	Toxicity
Takashima et al. 2015 (SELECT BC)	Phase III	S-1	Seems to have non-inferior OS	Inferior EQ-5D score

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

28-day cycles

Regimen #3, 80 mg/m² weekly dosing

Study	Evidence	Comparator	Efficacy
Perez et al. 2001	Phase II
Seidman et al. 2008 (CALGB 9840)	Phase III	Every three-week paclitaxel	Superior OS

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per week

28-day cycles

Regimen #4, 3 weeks on, 1 week off

Study	Evidence	Comparator	Efficacy	Toxicity
Miller et al. 2007	Phase III	Paclitaxel & Bevacizumab	Inferior PFS
Takashima et al. 2015 (SELECT BC)	Phase III	S-1	Seems to have non-inferior OS	Inferior EQ-5D score
Miles et al. 2016 (MERiDiAN)	Phase III	Paclitaxel & Bevacizumab	Inferior PFS

Note: both Miller et al. 2007 and MERiDiAN specified 90 mg/m²; SELECT BC gave a range of 80 to 100 mg/m².

Chemotherapy

• Paclitaxel (Taxol) 80 to 100 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen #5, 250 mg/m² q3wk dosing

Study	Evidence
Seidman et al. 1995	Phase II

Note: this is the dose used in untreated patients in Seidman et al. 1995. It is not a common dosing.

Chemotherapy

• Paclitaxel (Taxol) 250 mg/m² IV over 3 hours once on day 1

21-day cycles

References

1. Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J et al. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2575-81. link to original article PubMed
2. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed
3. Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001 Nov 15;19(22):4216-23. link to original article PubMed
4. Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article contains verified protocol PubMed
5. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. link to original article PubMed
6. Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed
7. Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. link to original article PubMed
8. Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. link to original article contains verified protocol PubMed
   1. HRQoL analysis: Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. link to original article link to PMC article PubMed
9. Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, Im SA, Canon JL, Shparyk Y, Yardley DA, Masuda N, Ro J, Denduluri N, Hubeaux S, Quah C, Bais C, O'Shaughnessy J. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer. 2017 Jan;70:146-155. Epub 2016 Nov 4. link to original article contains protocol PubMed
10. Martín M, Chan A, Dirix L, O'Shaughnessy J, Hegg R, Manikhas A, Shtivelband M, Krivorotko P, Batista López N, Campone M, Ruiz Borrego M, Khan QJ, Beck JT, Ramos Vázquez M, Urban P, Goteti S, Di Tomaso E, Massacesi C, Delaloge S. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4). Ann Oncol. 2017 Feb 1;28(2):313-320. link to original article PubMed

Paclitaxel, nanoparticle albumin-bound monotherapy

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Example orders

• Example orders for Paclitaxel, nanoparticle albumin-bound (Abraxane) in breast cancer

Regimen #1, 100 mg/m², 3 weeks out of 4

Study	Evidence	Comparator	Efficacy
Gradishar et al. 2009	Randomized Phase II	Docetaxel	Seems not superior
		Weekly nab-paclitaxel (150 mg/m2)	Not reported
		q3wk nab-paclitaxel	Not reported

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen #2, 150 mg/m² weekly, 3 weeks out of 4

Study	Evidence	Comparator	Efficacy
Gradishar et al. 2009	Randomized Phase II	Docetaxel	Superior PFS
		Weekly nab-paclitaxel (100 mg/m2)	Not reported
		q3wk nab-paclitaxel	Not reported

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 150 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen #3, 260 mg/m² q3wk

Study	Evidence	Comparator	Efficacy
Gradishar et al. 2005	Phase III	Paclitaxel	Superior TTP
Robert et al. 2011 (RIBBON-1)	Phase III	nab-Paclitaxel & Bevacizumab	Inferior PFS

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m² IV over 30 minutes once on day 1

Supportive medications

• Gradishar et al. 2005: No corticosteroid or antihistamine premedication

21-day cycles

Regimen #4, 300 mg/m² q3wk

Study	Evidence	Comparator	Efficacy
Gradishar et al. 2009	Randomized Phase II	Docetaxel	Seems not superior
		Weekly nab-paclitaxel (100 mg/m2)	Not reported
		Weekly nab-paclitaxel (150 mg/m2)	Not reported

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 300 mg/m² IV over 30 minutes once on day 1

21-day cycles

References

1. Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article contains verified protocol PubMed
2. Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. Epub 2009 May 26. Erratum in: J Clin Oncol. 2011 Jul 1;29(19):2739. link to original article contains verified protocol PubMed
3. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed

Pemetrexed monotherapy

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Regimen #1

Study	Evidence
Robert et al. 2011	Phase II

Chemotherapy

• Pemetrexed (Alimta) 600 mg/m² IV once on day 1

Supportive medications

• Dexamethasone (Decadron) 4 mg PO BID the day before, day of, and day after chemotherapy
• Folic acid 350 to 1000 mcg PO once per day, to start at least 5 days prior to start of pemetrexed therapy, to continue throughout therapy with pemetrexed, and until 3 weeks after the last dose of pemetrexed
• Cyanocobalamin (Vitamin B12) 1000 mcg IM every 8 to 10 weeks, the first dose given at least 1 week prior to start of pemetrexed therapy, to continue throughout therapy with pemetrexed, and until 3 weeks after the last dose of pemetrexed

14-day cycles

Regimen #2

Study	Evidence
Gomez et al. 2006	Phase II

Patients in the study were "chemotherapy-naïve, with advanced (T4 and N0-N2, M0, M1) breast cancer."

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

Supportive medications

• Dexamethasone (Decadron) 4 mg PO BID the day before, day of, and day after chemotherapy
• Folic acid 350 to 1000 mcg PO once per day, to start 5 to 7 days prior to start of pemetrexed therapy, to continue throughout therapy with pemetrexed
• Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, the first dose given before the study's pretreatment biopsy, to continue throughout therapy with pemetrexed

21-day cycle for up to 3 cycles

References

1. Gomez HL, Santillana SL, Vallejos CS, Velarde R, Sanchez J, Wang X, Bauer NL, Hockett RD, Chen VJ, Niyikiza C, Hanauske AR. A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression. Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):832-8. link to original article contains verified protocol PubMed
2. Robert NJ, Conkling PR, O'Rourke MA, Kuefler PR, McIntyre KJ, Zhan F, Asmar L, Wang Y, Shonukan OO, O'Shaughnessy JA. Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer. Breast Cancer Res Treat. 2011 Feb;126(1):101-8. Epub 2010 Dec 25. link to original article contains verified protocol PubMed

S-1 monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Takashima et al. 2015 (SELECT BC)	Phase III	Docetaxel Paclitaxel	Seems to have non-inferior OS	Superior EQ-5D score

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) as follows:
  • BSA less than 1.25 m²: 40 mg PO BID on days 1 to 28
  • BSA at least 1.25 m² and less than 1.5 m²: 50 mg PO BID on days 1 to 28
  • BSA 1.5 m² or more: 60 mg PO BID on days 1 to 28

42-day cycles

References

1. Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. link to original article contains verified protocol PubMed
   1. HRQoL analysis: Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. link to original article link to PMC article PubMed

Vinorelbine monotherapy

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Regimen #1

Study	Evidence	Comparator	Efficacy
Robson et al. 2017 (OlympiAD)	Phase III	Olaparib	Inferior PFS

Patients had confirmed deleterious or suspected deleterious germline BRCA mutation.

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycles

Regimen #2, weekly dosing

Study	Evidence
Gasparini et al. 1994	Phase II
Zelek et al. 2001	Phase II

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per week

References

1. Gasparini G, Caffo O, Barni S, Frontini L, Testolin A, Guglielmi RB, Ambrosini G. Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol. 1994 Oct;12(10):2094-101. link to original article PubMed
2. Zelek L, Barthier S, Riofrio M, Fizazi K, Rixe O, Delord JP, Le Cesne A, Spielmann M. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer. 2001 Nov 1;92(9):2267-72. PubMed
3. Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017 Aug 10;377(6):523-533. Epub 2017 Jun 4. link to original article contains verified protocol PubMed

Metastatic disease, combination chemotherapy

AC

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AC: Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen #1, with range

Study	Evidence	Comparator	Efficacy
Robert et al. 2011 (RIBBON-1)	Phase III	AC & Bevacizumab	Inferior PFS

Chemotherapy

• Doxorubicin (Adriamycin) 50 to 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for up to 8 cycles

Regimen #2, 60/600

Study	Evidence	Comparator	Efficacy
Fisher et al. 1990 (NSABP B-15)	Phase III	AC, then CMF	Seems not superior
		CMF	Seems not superior
Slamon et al. 2001	Phase III	ACH	Seems to have inferior OS
Nabholtz et al. 2003	Phase III	AT (Taxotere)	Seems to have inferior TTP

Note: patients in Slamon et al. 2001 had not previously received adjuvant (postoperative) therapy with an anthracycline.

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycles

References

1. Jones SE, Durie BG, Salmon SE. Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer. Cancer. 1975 Jul;36(1):90-7. link to original article PubMed
2. Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol. 1990 Sep;8(9):1483-96. link to original article PubMed
3. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed
4. Nabholtz JM, Falkson C, Campos D, Szanto J, Martin M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. link to original article PubMed
5. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed

AC & Bevacizumab

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AC & Bevacizumab: Adriamycin (Doxorubicin), Cyclophosphamide, Bevacizumab

Regimen #1, with range

Study	Evidence	Comparator	Efficacy
Robert et al. 2011 (RIBBON-1)	Phase III	AC	Superior PFS

Chemotherapy

• Doxorubicin (Adriamycin) 50 to 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for up to 8 cycles

Subsequent treatment

• Bevacizumab maintenance, if no PD

References

1. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed

AT (Taxol)

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AT: Adriamycin (Doxorubicin) & Taxol (Paclitaxel)

Regimen

Study	Evidence
Gianni et al. 1995	Non-randomized

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Paclitaxel (Taxol) 125 to 200 mg/m² IV once on day 1

21-day cycles

References

1. Gianni L, Munzone E, Capri G, Fulfaro F, Tarenzi E, Villani F, Spreafico C, Laffranchi A, Caraceni A, Martini C et al. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol. 1995 Nov;13(11):2688-99. link to original article PubMed

AT (Taxotere)

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AT: Adriamycin (Doxorubicin), Taxotere (Docetaxel)

Regimen

Study	Evidence	Comparator	Efficacy
Nabholtz et al. 2003	Phase III	AC	Seems to have superior TTP

Chemotherapy

• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycles

References

1. Nabholtz JM, Falkson C, Campos D, Szanto J, Martin M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. link to original article PubMed

Capecitabine & Bevacizumab

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Regimen

Study	Evidence	Comparator	Efficacy
Robert et al. 2011 (RIBBON-1)	Phase III	Capecitabine	Superior PFS
Lang et al. 2013 (TURANDOT)	Phase III	Paclitaxel & Bevacizumab	Non-inferior OS (*)
Welt et al. 2016 (CARIN)	Phase III	Capecitabine, Vinorelbine, Bevacizumab	Might have inferior PFS

Note: efficacy for TURANDOT is based on the 2016 update.

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO BID on days 1 to 14
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed
2. Lang I, Brodowicz T, Ryvo L, Kahan Z, Greil R, Beslija S, Stemmer SM, Kaufman B, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Messinger D, Zielinski C; Central European Cooperative Oncology Group. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol. 2013 Feb;14(2):125-33. Epub 2013 Jan 10. link to original article PubMed
   1. Update: Zielinski C, Láng I, Inbar M, Kahán Z, Greil R, Beslija S, Stemmer SM, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Petruzelka L, Eniu A, Nisenbaum B, Dank M, Anghel R, Messinger D, Brodowicz T; TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1230-9. Epub 2016 Aug 5. link to original article contains protocol PubMed
3. Welt A, Marschner N, Lerchenmueller C, Decker T, Steffens CC, Koehler A, Depenbusch R, Busies S, Hegewisch-Becker S. Capecitabine and bevacizumab with or without vinorelbine in first-line treatment of HER2/neu-negative metastatic or locally advanced breast cancer: final efficacy and safety data of the randomised, open-label superiority phase 3 CARIN trial. Breast Cancer Res Treat. 2016 Feb;156(1):97-107. link to PMC article PubMed

Capecitabine & Docetaxel

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TX: Taxotere (Docetaxel) and Xeloda (Capecitabine)
XT: Xeloda (Capecitabine) and Taxotere (Docetaxel)

Regimen #1, 825/60

Study	Evidence	Comparator	Efficacy
Yamamoto et al. 2016 (JO21095)	Phase III	Docetaxel	Seems to have superior PFS

Chemotherapy

• Capecitabine (Xeloda) 825 mg/m² PO BID days 1 to 14
• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

21-day cycles

Regimen #2, 1250/75

Study	Evidence	Comparator	Efficacy
O'Shaughnessy et al. 2002	Phase III	Docetaxel	Seems to have superior OS

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO BID days 1 to 14
• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

21-day cycles

References

1. O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article contains verified protocol PubMed
2. Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article contains verified protocol PubMed

Capecitabine & Ixabepilone

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Regimen

Study	Evidence	Comparator	Efficacy
Thomas et al. 2007	Phase III	Capecitabine	Superior PFS
Sparano et al. 2010	Phase III	Capecitabine	Superior PFS

Chemotherapy

• Capecitabine (Xeloda) 2000 mg/m² PO once per day on days 1 to 14
• Ixabepilone (Ixempra) 40 mg/m² IV once on day 1

21-day cycles

References

1. Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. link to original article contains verified protocol PubMed
2. Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. link to original article contains protocol link to PMC article PubMed

Capecitabine & Paclitaxel

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TX: Taxol (Paclitaxel), Xeloda (Capecitabine)

Regimen

Study	Evidence
Blum et al. 2006	Phase II

Chemotherapy

• Capecitabine (Xeloda) 825 mg/m² (rounded to nearest 500 mg) PO BID on days 1 to 14
• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. Blum JL, Dees EC, Chacko A, Doane L, Ethirajan S, Hopkins J, McMahon R, Merten S, Negron A, Neubauer M, Ilegbodu D, Boehm KA, Asmar L, O'Shaughnessy JA. Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2006 Sep 20;24(27):4384-90. Epub 2006 Aug 22. link to original article contains verified protocol PubMed

Capecitabine & Paclitaxel, nanoparticle albumin-bound

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Regimen

Study	Evidence
Schwartzberg et al. 2011	Phase II

Chemotherapy

• Capecitabine (Xeloda) 825 mg/m² (rounded to nearest 500 mg) PO BID on days 1 to 15
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. Schwartzberg LS, Arena FP, Mintzer DM, Epperson AL, Walker MS. Phase II multicenter trial of albumin-bound paclitaxel and capecitabine in first-line treatment of patients with metastatic breast cancer. Clin Breast Cancer. 2012 Apr;12(2):87-93. Epub 2011 Dec 6. link to original article contains protocol PubMed

Carboplatin & Gemcitabine

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Regimen

Study	Evidence
Nagourney et al. 2008	Pilot, <20 pts

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV over 60 minutes once per day on days 1 & 8
• Gemcitabine (Gemzar) 800 mg/m² IV over 60 minutes once per day on days 1 & 8

21-day cycles, given until complete remission, progression of disease, or unacceptable toxicity

References

1. Nagourney RA, Flam M, Link J, Hager S, Blitzer J, Lyons W, Sommers BL, Evans S. Carboplatin plus gemcitabine repeating doublet therapy in recurrent breast cancer. Clin Breast Cancer. 2008 Oct;8(5):432-5. link to original article contains protocol PubMed

Cisplatin & Vinorelbine

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Regimen

Study	Evidence
Ray-Coquard et al. 1998	Phase II
Vassilomanolakis et al. 2000	Phase II

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 60 minutes once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV over 5 to 10 minutes once per day on days 1 & 8

Supportive medications

• Normal saline 200 mL bolus after Vinorelbine (Navelbine) to prevent phlebitis
• Normal saline 2000 mL with KCl (unspecified amount of KCl) IV over 4 hours (infusion rate: 500 mL/H) once prior to Cisplatin (Platinol)
• Furosemide (Lasix) 40 mg IV once 20 minutes prior to Cisplatin (Platinol)
• Normal saline 1000 mL and D5W 1000 mL IV over 4 hours (overall infusion rate: 500 mL/H; paper did not say whether fluids were given sequentially or concurrently) once after Cisplatin (Platinol)
• 5-HT3 antagonists used

21-day cycle for up to 6 cycles or progression of disease

References

1. Ray-Coquard I, Biron P, Bachelot T, Guastalla JP, Catimel G, Merrouche Y, Droz JP, Chauvin F, Blay JY. Vinorelbine and cisplatin (CIVIC regimen) for the treatment of metastatic breast carcinoma after failure of anthracycline- and/or paclitaxel-containing regimens. Cancer. 1998 Jan 1;82(1):134-40. PubMed
2. Vassilomanolakis M, Koumakis G, Barbounis V, Demiri M, Pateras H, Efremidis AP. Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines. Ann Oncol. 2000 Sep;11(9):1155-60. link to original article contains verified protocol Pubmed

CMF

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CMF: Cyclophosphamide, Methotrexate, Fluorouracil

Regimen

Study	Evidence	Comparator	Efficacy
Bull et al. 1978	Phase III	CAF	Might have inferior ORR
Fisher et al. 1990 (NSABP B-15)	Phase III	AC	Seems not superior
		AC, then CMF	Seems not superior
Stadtmauer et al. 2000 (Philadelphia Bone Marrow Transplant Group)	Phase III	CMF x 4-6, then HDT	Seems not superior
Ackland et al. 2001 (HEPI 013)	Phase III	CEF	Inferior TTP
Stockler et al. 2011	Phase III	Continuous Capecitabine Intermittent Capecitabine	Seems to have inferior OS

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/m² IV oncer per day on days 1 & 8

28-day cycles

References

1. Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. link to original article PubMed
2. Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol. 1990 Sep;8(9):1483-96. link to original article PubMed
3. Stadtmauer EA, O'Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, Brodsky I, Martino S, Lazarus HM, Erban JK, Sickles C, Glick JH. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med. 2000 Apr 13;342(15):1069-76. link to original article PubMed
4. Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol. 2001 Feb 15;19(4):943-53. link to original article PubMed
5. Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4498-504. Epub 2011 Oct 24. link to original article PubMed

Docetaxel & Bevacizumab

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Regimen #1, docetaxel 75 mg/m²

Study	Evidence	Comparator	Efficacy
Robert et al. 2011 (RIBBON-1)	Phase III	Docetaxel	Superior PFS

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

Regimen #2, docetaxel 100 mg/m²

Study	Evidence	Comparator	Efficacy
Robert et al. 2011 (RIBBON-1)	Phase III	Docetaxel	Superior PFS

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed

EC

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EC: Epirubicin & Cyclophosphamide

Regimen #1, 75/600

Study	Evidence	Comparator	Efficacy
Slamon et al. 2001	Phase III	ECH	Seems to have inferior OS
Langley et al. 2005 (UKNCRI AB01)	Phase III	EP	Seems not superior

Chemotherapy

• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

Regimen #2, with range

Study	Evidence	Comparator	Efficacy
Robert et al. 2011 (RIBBON-1)	Phase III	EC & Bevacizumab	Inferior PFS

Chemotherapy

• Epirubicin (Ellence) 90 to 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for up to 8 cycles

References

1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed
2. Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005 Nov 20;23(33):8322-30. link to original article PubMed
3. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed

EC & Bevacizumab

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EC & Bevacizumab: Epirubicin, Cyclophosphamide, Bevacizumab

Regimen

Study	Evidence	Comparator	Efficacy
Robert et al. 2011 (RIBBON-1)	Phase III	EC	Superior PFS

Chemotherapy

• Epirubicin (Ellence) 90 to 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for up to 8 cycles

Subsequent treatment

• Bevacizumab maintenance, if no PD

References

1. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed

EP

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EP: Epirubicin, Paclitaxel

Regimen

Study	Evidence	Comparator	Efficacy
Langley et al. 2005 (UKNCRI AB01)	Phase III	EC	Seems not superior

Chemotherapy

• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

References

1. Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005 Nov 20;23(33):8322-30. link to original article PubMed

FAC

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FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide
CAF: Cyclophosphamide, Adriamycin (Doxorubicin), Fluorouracil

Regimen #1, 21-day cycles, 5-FU 1 out of 3 weeks

Study	Evidence	Comparator	Efficacy
Robert et al. 2011 (RIBBON-1)	Phase III	FAC & Bevacizumab	Inferior PFS

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for up to 8 cycles

Regimen #2, 21-day cycles, 5-FU 2 out of 3 weeks

Study	Evidence	Comparator	Efficacy
Hortobagyi et al. 1979	Phase III	FAC-BCG	Inferior OS in responders
Assikis et al. 2003	Phase III	See link	See link

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8 or days 1 & 4
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycles

Subsequent treatment

• MV

Regimen #3, 28-day cycles

Study	Evidence	Comparator	Efficacy
Bull et al. 1978	Phase III	CMF	Might have superior ORR

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8
• Doxorubicin (Adriamycin) 30 mg/m² IV once per day on days 1 & 8
• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14

28-day cycles

References

1. Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. link to original article PubMed
2. Hortobagyi GN, Gutterman JU, Blumenschein GR, Tashima CK, Burgess MA, Einhorn L, Buzdar AU, Richman SP, Hersh EM. Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG. Cancer. 1979 Nov;44(5):1955-62. link to original article PubMed
3. Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, Valero V, Walters R, Singletary E, Ames F, Hortobagyi G. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer. 2003 Jun 1;97(11):2716-23. link to original article contains protocol PubMed
4. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed

FAC & Bevacizumab

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FAC & Bevacizumab: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide, Bevacizumab

Regimen

Study	Evidence	Comparator	Efficacy
Robert et al. 2011 (RIBBON-1)	Phase III	FAC	Superior PFS

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for up to 8 cycles

Subsequent treatment

• Bevacizumab maintenance, if no PD

References

1. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed

FEC

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FEC: Fluorouracil, Epirubicin, Cyclophosphamide
CEF: Cyclophosphamide, Epirubicin, Fluorouracil

Regimen #1, 500/50/400, 2 out of 4 weeks

Study	Evidence	Comparator	Efficacy
Ackland et al. 2001 (HEPI 013)	Phase III	CMF	Superior TTP

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8
• Epirubicin (Ellence) 50 mg/m² IV once per day on days 1 & 8
• Cyclophosphamide (Cytoxan) 400 mg/m² IV once per day on days 1 & 8

28-day cycle for 6 to 8 cycles

Regimen #2, 500/50/500 ("FEC 50")

Study	Evidence	Comparator	Efficacy
Brufman et al. 1997 (HEPI 010)	Phase III	FEC 100	Inferior ORR

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once once on day 1

21-day cycle for 6 to 8 cycles

Regimen #3, 500/100/500 ("FEC 100")

Study	Evidence	Comparator	Efficacy
Brufman et al. 1997 (HEPI 010)	Phase III	FEC 50	Superior ORR

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once once on day 1

21-day cycle for 6 to 8 cycles

Regimen #4, 600/60/600 ("CEF21")

Study	Evidence	Comparator	Efficacy
Del Mastro et al. 2001	Phase III	HD-CEF14	Seems not superior

Chemotherapy

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once once on day 1

21-day cycle for 8 to 12 cycles

Regimen #5, with range

Study	Evidence	Comparator	Efficacy
Robert et al. 2011 (RIBBON-1)	Phase III	FEC & Bevacizumab	Inferior PFS

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 to 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once once on day 1

21-day cycle for up to 8 cycles

References

1. Brufman G, Colajori E, Ghilezan N, Lassus M, Martoni A, Perevodchikova N, Tosello C, Viaro D, Zielinski C. Doubling epirubicin dose intensity (100 mg/m² versus 50 mg/m²) in the FEC regimen significantly increases response rates. An international randomised phase III study in metastatic breast cancer. The Epirubicin High Dose (HEPI 010) Study Group. Ann Oncol. 1997 Feb;8(2):155-62. link to original article contains verified protocol PubMed
2. Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol. 2001 Feb 15;19(4):943-53. link to original article PubMed
3. Del Mastro L, Venturini M, Lionetto R, Carnino F, Guarneri D, Gallo L, Contu A, Pronzato P, Vesentini L, Bergaglio M, Comis S, Rosso R. Accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with standard CEF in metastatic breast cancer patients: results of a multicenter, randomized phase III study of the Italian Gruppo Oncologico Nord-Ouest-Mammella Inter Gruppo Group. J Clin Oncol. 2001 Apr 15;19(8):2213-21. link to original article contains verified protocol PubMed
4. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed

FEC & Bevacizumab

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FEC & Bevacizumab: Fluorouracil, Epirubicin, Cyclophosphamide, Bevacizumab

Regimen

Study	Evidence	Comparator	Efficacy
Robert et al. 2011 (RIBBON-1)	Phase III	FEC	Superior PFS

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 to 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for up to 8 cycles

Subsequent treatment

• Bevacizumab maintenance, if no PD

References

1. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed

GT (Taxol)

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GT: Gemcitabine, Taxol (Paclitaxel)

Regimen

Study	Evidence	Comparator	Efficacy
Albain et al. 2008	Phase III	Paclitaxel	Seems to have superior OS

Chemotherapy

• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8; on day 1, administer after paclitaxel
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycles

References

1. Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. link to original article PubMed

Paclitaxel & Bevacizumab

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Regimen

Study	Evidence	Comparator	Efficacy
Miller et al. 2007	Phase III	Paclitaxel	Superior PFS
Lang et al. 2013 (TURANDOT)	Phase III	Capecitabine & Bevacizumab	Non-inferior OS (*)
Miles et al. 2016 (MERiDiAN)	Phase III	Paclitaxel	Superior PFS

Note: efficacy for TURANDOT is based on the 2016 update.

Chemotherapy

• Paclitaxel (Taxol) 90 mg/m² IV over 60 minutes once per day on days 1, 8, 15
• Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15

28-day cycles

References

1. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. link to original article PubMed
2. Lang I, Brodowicz T, Ryvo L, Kahan Z, Greil R, Beslija S, Stemmer SM, Kaufman B, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Messinger D, Zielinski C; Central European Cooperative Oncology Group. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol. 2013 Feb;14(2):125-33. Epub 2013 Jan 10. link to original article PubMed
   1. Update: Zielinski C, Láng I, Inbar M, Kahán Z, Greil R, Beslija S, Stemmer SM, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Petruzelka L, Eniu A, Nisenbaum B, Dank M, Anghel R, Messinger D, Brodowicz T; TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1230-9. Epub 2016 Aug 5. link to original article contains protocol PubMed
3. Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, Im SA, Canon JL, Shparyk Y, Yardley DA, Masuda N, Ro J, Denduluri N, Hubeaux S, Quah C, Bais C, O'Shaughnessy J. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer. 2017 Jan;70:146-155. Epub 2016 Nov 4. link to original article contains protocol PubMed

Paclitaxel, nanoparticle albumin-bound & Bevacizumab

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Example orders

• Example orders for Paclitaxel, nanoparticle albumin-bound & Bevacizumab in breast cancer

Regimen

Study	Evidence	Comparator	Efficacy
Robert et al. 2011 (RIBBON-1)	Phase III	nab-Paclitaxel	Superior PFS

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m² IV once on day 1
• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed

Vinorelbine & Bevacizumab

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Example orders

• Example orders for Vinorelbine and Bevacizumab in breast cancer

Regimen

Study	Evidence
Burstein et al. 2008	Phase II

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per week
• Bevacizumab (Avastin) 10 mg/kg IV once every other week

Given until progression of disease or unacceptable toxicity

References

1. Burstein HJ, Chen YH, Parker LM, Savoie J, Younger J, Kuter I, Ryan PD, Garber JE, Chen H, Campos SM, Shulman LN, Harris LN, Gelman R, Winer EP. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res. 2008 Dec 1;14(23):7871-7. link to original article contains verified protocol PubMed

Metastatic disease, maintenance after first-line therapy

Bevacizumab monotherapy

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FEC & Bevacizumab: Fluorouracil, Epirubicin, Cyclophosphamide, Bevacizumab

Regimen

Study	Evidence
Robert et al. 2011 (RIBBON-1)	Non-randomized portion of RCT

Preceding treatment

• AC x 8 or EC x 8 or FAC x 8 or FEC x 8

Chemotherapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed

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