Breast cancer, triple negative

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Hermina Fernandes, MD, FACP
University of North Dakota
Bismarck, ND

Note: this page has regimens which are specific to breast cancer that is triple negative. Please see the breast cancer page for other chemotherapy regimens.

23 regimens on this page
24 variants on this page

Contents


Guidelines

ASCO

Neoadjuvant chemotherapy

AC

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AC: Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen

Study Evidence
Rugo 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.

Preceding treatment

  • T x 12 wk versus Paclitaxel & VC x 12 wk

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. I-SPY 2: Rugo HS, Olopade OI, DeMichele A, Yau C, van 't Veer LJ, Buxton MB, Hogarth M, Hylton NM, Paoloni M, Perlmutter J, Symmans WF, Yee D, Chien AJ, Wallace AM, Kaplan HG, Boughey JC, Haddad TC, Albain KS, Liu MC, Isaacs C, Khan QJ, Lang JE, Viscusi RK, Pusztai L, Moulder SL, Chui SY, Kemmer KA, Elias AD, Edmiston KK, Euhus DM, Haley BB, Nanda R, Northfelt DW, Tripathy D, Wood WC, Ewing C, Schwab R, Lyandres J, Davis SE, Hirst GL, Sanil A, Berry DA, Esserman LJ; I-SPY 2 Investigators. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016 Jul 7;375(1):23-34. link to original article contains verified protocol link to PMC article PubMed

Carboplatin & Docetaxel

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CbD: Carboplatin & Docetaxel

Regimen

Study Evidence Efficacy
Sharma et al. 2016 Phase II 56-59% pCR rate

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

References

  1. Sharma P, López-Tarruella S, García-Saenz JA, Ward C, Connor CS, Gómez HL, Prat A, Moreno F, Jerez-Gilarranz Y, Barnadas A, Picornell AC, Del Monte-Millán M, Gonzalez-Rivera M, Massarrah T, Pelaez-Lorenzo B, Palomero MI, González Del Val R, Cortes J, Fuentes Rivera H, Bretel Morales D, Márquez-Rodas I, Perou CM, Wagner JL, Mammen JM, McGinness MK, Klemp JR, Amin AL, Fabian CJ, Heldstab J, Godwin AK, Jensen RA, Kimler BF, Khan QJ, Martin M. Efficacy of neoadjuvant carboplatin plus docetaxel in triple-negative breast cancer: Combined analysis of two cohorts. Clin Cancer Res. 2017 Feb 1;23(3):649-657. Epub 2016 Jun 14. link to original article contains protocol link to PMC article PubMed

Carboplatin & Paclitaxel

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Regimen

Study Evidence Comparator Comparative Efficacy
Sikov et al. 2014 (CALGB 40603) Phase III (E) Paclitaxel Superior pCR rate
Loibl et al. 2018 (BrighTNess) Phase III (E) 1. Carboplatin, Paclitaxel, Veliparib Seems not superior
2. Paclitaxel Not reported in abstract

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

21-day cycle for 4 cycles

Subsequent treatment

References

  1. CALGB 40603: Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015 Jan 1;33(1):13-21. Epub 2014 Aug 4. link to original article link to PMC article contains verified protocol PubMed
  2. BrighTNess: Loibl S, O'Shaughnessy J, Untch M, Sikov WM, Rugo HS, McKee MD, Huober J, Golshan M, von Minckwitz G, Maag D, Sullivan D, Wolmark N, McIntyre K, Ponce Lorenzo JJ, Metzger Filho O, Rastogi P, Symmans WF, Liu X, Geyer CE Jr. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):497-509. Epub 2018 Feb 28. link to original article contain protocol PubMed

Carboplatin & nab-Paclitaxel

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Regimen

Study Evidence Comparator Comparative Efficacy
Gluz et al. 2018 (WSG-ADAPT-TN) Phase III (E) Gemcitabine & nab-Paclitaxel Superior pCR rate

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. WSG-ADAPT-TN: Gluz O, Nitz U, Liedtke C, Christgen M, Grischke EM, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Bangemann N, Lindner C, Kuemmel S, Clemens M, Potenberg J, Staib P, Kohls A, von Schumann R, Kates R, Kates R, Schumacher J, Wuerstlein R, Kreipe HH, Harbeck N. Comparison of neoadjuvant nab-paclitaxel+carboplatin vs nab-paclitaxel+gemcitabine in triple-negative breast cancer: randomized WSG-ADAPT-TN trial results. J Natl Cancer Inst. 2018 Jun 1;110(6):628-637. link to original article contains verified protocol PubMed

Cisplatin monotherapy

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Regimen

Study Evidence Efficacy
Silver et al. 2010 Phase II 50% good pathologic response

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, Juul N, Leong CO, Calogrias D, Buraimoh A, Fatima A, Gelman RS, Ryan PD, Tung NM, De Nicolo A, Ganesan S, Miron A, Colin C, Sgroi DC, Ellisen LW, Winer EP, Garber JE. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1145-53. Epub 2010 Jan 25. link to original article contains verified protocol link to PMC article PubMed

ddAC

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ddAC: dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen

Study Evidence
Sikov et al. 2014 (CALGB 40603) Non-randomized portion of RCT
Rugo 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.

Preceding treatment

  • CALGB 40603: Carboplatin & Bevacizumab x 4 versus Carboplatin & Paclitaxel x 4 versus Carboplatin, Paclitaxel, Bevacizumab versus T x 12 wk
  • I-SPY2: T x 12 wk versus Paclitaxel & VC x 12 wk

Chemotherapy

Supportive medications

14-day cycle for 4 cycles

Subsequent treatment

References

  1. CALGB 40603: Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015 Jan 1;33(1):13-21. Epub 2014 Aug 4. link to original article link to PMC article contains verified protocol PubMed
  2. I-SPY 2: Rugo HS, Olopade OI, DeMichele A, Yau C, van 't Veer LJ, Buxton MB, Hogarth M, Hylton NM, Paoloni M, Perlmutter J, Symmans WF, Yee D, Chien AJ, Wallace AM, Kaplan HG, Boughey JC, Haddad TC, Albain KS, Liu MC, Isaacs C, Khan QJ, Lang JE, Viscusi RK, Pusztai L, Moulder SL, Chui SY, Kemmer KA, Elias AD, Edmiston KK, Euhus DM, Haley BB, Nanda R, Northfelt DW, Tripathy D, Wood WC, Ewing C, Schwab R, Lyandres J, Davis SE, Hirst GL, Sanil A, Berry DA, Esserman LJ; I-SPY 2 Investigators. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016 Jul 7;375(1):23-34. link to original article contains verified protocol link to PMC article PubMed

Docetaxel & Bevacizumab

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Regimen

Study Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2012 (GeparQuinto) Phase III (E) 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

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

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

EC & Bevacizumab

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EC & Bevacizumab: Epirubicin, Cyclophosphamide, Bevacizumab

Regimen

Study Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2012 (GeparQuinto) Phase III (E) 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

21-day cycle for 4 cycles

Subsequent treatment

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

Paclitaxel monotherapy

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T: Taxol (Paclitaxel)
wP: weekly Paclitaxel

Regimen

Study Evidence Comparator Comparative Efficacy
Sikov et al. 2014 (CALGB 40603) Phase III (C) Carboplatin & Paclitaxel
Carboplatin, Paclitaxel, Bevacizumab
Paclitaxel & Bevacizumab
Inferior pCR rate
Rugo et al. 2016 (I-SPY 2) Adaptively Randomized Phase II (C) Paclitaxel & VC Seems to have inferior pCR rate
Loibl et al. 2018 (BrighTNess) Phase III (C) 1. Carboplatin & Paclitaxel Not reported in abstract
2. Carboplatin, Paclitaxel, Veliparib 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

28-day cycle for 3 cycles

Subsequent treatment

References

  1. CALGB 40603: Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015 Jan 1;33(1):13-21. Epub 2014 Aug 4. link to original article link to PMC article contains verified protocol PubMed
  2. I-SPY 2: Rugo HS, Olopade OI, DeMichele A, Yau C, van 't Veer LJ, Buxton MB, Hogarth M, Hylton NM, Paoloni M, Perlmutter J, Symmans WF, Yee D, Chien AJ, Wallace AM, Kaplan HG, Boughey JC, Haddad TC, Albain KS, Liu MC, Isaacs C, Khan QJ, Lang JE, Viscusi RK, Pusztai L, Moulder SL, Chui SY, Kemmer KA, Elias AD, Edmiston KK, Euhus DM, Haley BB, Nanda R, Northfelt DW, Tripathy D, Wood WC, Ewing C, Schwab R, Lyandres J, Davis SE, Hirst GL, Sanil A, Berry DA, Esserman LJ; I-SPY 2 Investigators. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016 Jul 7;375(1):23-34. link to original article contains verified protocol link to PMC article PubMed
  3. BrighTNess: Loibl S, O'Shaughnessy J, Untch M, Sikov WM, Rugo HS, McKee MD, Huober J, Golshan M, von Minckwitz G, Maag D, Sullivan D, Wolmark N, McIntyre K, Ponce Lorenzo JJ, Metzger Filho O, Rastogi P, Symmans WF, Liu X, Geyer CE Jr. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):497-509. Epub 2018 Feb 28. link to original article contain protocol PubMed

Neoadjuvant response criteria

Clinical response rate (cRR)

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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

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  • 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)

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  • The RCB is calculated as follows: RCB = 1.4 (finv*dprim)0.17 + [4(1 - 0.75LN)dmet]0.17
    • where dprim is derived from the bidimensional diameters of the primary tumor bed in the resected specimen, finv is the proportion of the primary tumor bed that contains invasive carcinoma, LN is the number of axillary lymph nodes containing metastatic carcinoma, and dmet 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)

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  • 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

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  • 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

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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

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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) & Cyclophosphamide

Regimen

Study Evidence Comparator Comparative Efficacy
Fisher et al. 1990 (NSABP B-15) Phase III (E-RT) 1. AC, then CMF Seems not superior
2. CMF Seems not superior
Yardley et al. 2017 (TITAN - breast) Non-randomized portion of RCT

Note: NSABP B-15 was conducted prior to routine testing of HER2, so it technically included "double-negative" patients. TITAN is labeled "TITAN - breast" so as not to confuse it with the trial by the same name in NSCLC.

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

  • TITAN: Ixabepilone versus Paclitaxel

References

  1. NSABP B-15: Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG, Shibata H, Paterson AHG, Sutherland CM, Robert NJ, Ager PJ, Levy L, Wolter J, Wozniak T, Fisher ER, Deutsch M. 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 contains verified protocol PubMed
    1. Pooled update: Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, Wolmark N. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27. link to original article PubMed
  2. TITAN: Yardley DA, Arrowsmith ER, Daniel BR, Eakle J, Brufsky A, Drosick DR, Kudrik F, Bosserman LD, Keaton MR, Goble SA, Bubis JA, Priego VM, Pendergrass K, Manalo Y, Bury M, Gravenor DS, Rodriguez GI, Inhorn RC, Young RR, Harwin WN, Silver C, Hainsworth JD, Burris HA 3rd. TITAN: phase III study of doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early-stage triple-negative breast cancer. Breast Cancer Res Treat. 2017 Aug;164(3):649-658. Epub 2017 May 15. link to original article contains verified protocol PubMed

Bevacizumab-containing therapy

Study Evidence Comparator Comparative Efficacy
Cameron et al. 2013 (BEATRICE) Phase III (E) Standard adjuvant therapy Seems not superior

This is the negative experimental arm of an important negative trial, so is included here for reference purposes, only.

Preceding treatment

Chemotherapy

References

  1. BEATRICE: Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, Steger GG, Suter TM, Toi M, Parmar M, Laeufle R, Im YH, Romieu G, Harvey V, Lipatov O, Pienkowski T, Cottu P, Chan A, Im SA, Hall PS, Bubuteishvili-Pacaud L, Henschel V, Deurloo RJ, Pallaud C, Bell R. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol. 2013 Sep;14(10):933-42. Epub 2013 Aug 7. link to original article PubMed
    1. Update: Bell R, Brown J, Parmar M, Toi M, Suter T, Steger GG, Pivot X, Mackey J, Jackisch C, Dent R, Hall P, Xu N, Morales L, Provencher L, Hegg R, Vanlemmens L, Kirsch A, Schneeweiss A, Masuda N, Overkamp F, Cameron D. Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer. Ann Oncol. 2017 Apr 1;28(4):754-760. link to original article PubMed

Capecitabine monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Masuda et al. 2017 (CREATE-X) Phase III (E) Standard therapy Superior OS

Note: All patients in CREATE-X had residual disease at time of surgical resection. Although this trial was not specifically for TNBC, a large number (N=286) of enrolled patients had TNBC, and the survival benefit appeared limited to this group in the subgroup analysis.

Preceding treatment

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

Chemotherapy

21-day cycle for 6 to 8 cycles

References

  1. CREATE-X: 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

CMF

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CMF: Cyclophosphamide, Methotrexate, Fluorouracil

Variant #1, 1000/50/2000

Study Evidence Comparator Comparative Efficacy
Ploner et al. 2003 Phase III (C) AV-CMF Seems not superior

Note: this trial was conducted prior to routine testing of HER2, so it technically included "double-negative" patients.

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

Variant #2, 1400/80/1200

Study Evidence Comparator Comparative Efficacy
Fisher et al. 1990 (NSABP B-15) Phase III (C) 1. AC Seems not superior
2. AC, then CMF Seems not superior

Note: this trial was conducted prior to routine testing of HER2, so it technically included "double-negative" patients.

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

References

  1. NSABP B-15: Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG, Shibata H, Paterson AHG, Sutherland CM, Robert NJ, Ager PJ, Levy L, Wolter J, Wozniak T, Fisher ER, Deutsch M. 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 contains verified protocol PubMed
  2. Ploner F, Jakesz R, Hausmaninger H, Kolb R, Stierer M, Fridrik M, Steindorfer P, Gnant M, Haider K, Mlineritsch B, Tschurtschenthaler G, Steger G, Seifert M, Kubista E, Samonigg H; Austrian Breast and Colorectal Cancer Study Group. Randomised trial: One cycle of anthracycline-containing adjuvant chemotherapy compared with six cycles of CMF treatment in node-positive, hormone receptor-negative breast cancer patients. Onkologie. 2003 Apr;26(2):115-9. link to original article contains verified protocol PubMed

FAC

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

Regimen

Study Evidence Comparator Comparative Efficacy
Fetting et al. 1998 (INT-0108) Phase III (C) 16-week CAF Seems not superior

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

References

  1. INT-0108: Fetting JH, Gray R, Fairclough DL, Smith TJ, Margolin KA, Citron ML, Grove-Conrad M, Cella D, Pandya K, Robert N, Henderson IC, Osborne CK, Abeloff MD. Sixteen-week multidrug regimen versus cyclophosphamide, doxorubicin, and fluorouracil as adjuvant therapy for node-positive, receptor-negative breast cancer: an Intergroup study. J Clin Oncol. 1998 Jul;16(7):2382-91. link to original article PubMed

Observation

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Regimen

Study Evidence Comparator Comparative Efficacy
Jakesz et al. 1998 Phase III (C) AV-CMF Seems not superior
Nasr et al. 2015 Phase III (C) CM Seems to have inferior OS
Colleoni et al. 2016 (IBCSG 22-00) Phase III (C) CM Seems not superior

Note: Jakesz et al. 1998 was conducted prior to routine testing of HER2, so it technically included "double-negative" patients. No further treatment after surgery.

Preceding treatment

  • Jakesz et al. 1998: Surgery
  • IBCSG 22-00: Surgery, then adjuvant chemotherapy

References

  1. Jakesz R, Samonigg H, Gnant M, Kubista E, Steindorfer P, Hausmaninger H, Sevelda P, Tschurtschenthaler B, Fridrik M, Stierer M, Kolb R, Steger G; Austrian Breast Cancer Study Group. Very low-dose adjuvant chemotherapy in steroid receptor negative stage I breast cancer patients. Eur J Cancer. 1998 Jan; 34 (1): 66-70. link to original article PubMed
  2. Nasr KE, Osman MA, Elkady MS, Ellithy MA. Metronomic methotrexate and cyclophosphamide after carboplatin included adjuvant chemotherapy in triple negative breast cancer: a phase III study. Ann Transl Med. 2015 Nov;3(19):284. link to original article link to PMC article PubMed
  3. IBCSG 22-00: Colleoni M, Gray KP, Gelber S, Láng I, Thürlimann B, Gianni L, Abdi EA, Gomez HL, Linderholm BK, Puglisi F, Tondini C, Kralidis E, Eniu A, Cagossi K, Rauch D, Chirgwin J, Gelber RD, Regan MM, Coates AS, Price KN, Viale G, Goldhirsch A. Low-dose oral cyclophosphamide and methotrexate maintenance for hormone receptor-negative early breast cancer: International Breast Cancer Study Group trial 22-00. J Clin Oncol. 2016 Oct 1;34(28):3400-8. Epub 2016 Jun 20. link to original article link to PMC article PubMed

Metastatic disease, first-line therapy

Carboplatin & Gemcitabine

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GC: Gemcitabine & Carboplatin

Regimen

Study Evidence Comparator Comparative Efficacy
O'Shaughnessy et al. 2011 (TCD11485) Randomized Phase II (C) GC & Iniparib Inferior OS
O'Shaughnessy et al. 2014 (EFC11486) Phase III (C) GC & Iniparib Might have inferior PFS

Chemotherapy

21-day cycles

References

  1. TCD11485: O'Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, Koo IC, Sherman BM, Bradley C. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011 Jan 20;364(3):205-14. Epub 2011 Jan 5. link to original article contains protocol PubMed
  2. EFC11486: O'Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, Robert N, Hellerstedt B, Saleh M, Richards P, Specht JM, Yardley DA, Carlson RW, Finn RS, Charpentier E, Garcia-Ribas I, Winer EP. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2014 Dec 1;32(34):3840-7. Epub 2014 Oct 27. link to original article contains protocol PubMed

Cisplatin & Docetaxel

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TP: Taxotere (Docetaxel) & Platinol (Cisplatin)

Regimen

Study Evidence Comparator Comparative Efficacy
Fan et al. 2012 Phase III (E) TX Seems to have superior OS

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. Fan Y, Xu BH, Yuan P, Ma F, Wang JY, Ding XY, Zhang P, Li Q, Cai RG. Docetaxel-cisplatin might be superior to docetaxel-capecitabine in the first-line treatment of metastatic triple-negative breast cancer. Ann Oncol. 2013 May;24(5):1219-25. Epub 2012 Dec 5. link to original article contains protocol PubMed

Cisplatin & Gemcitabine

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Regimen

Study Evidence Comparator Comparative Efficacy
Hu et al. 2015 (CBCSG006) Phase III (E) Gemcitabine & Paclitaxel Superior PFS

Chemotherapy

21-day cycle for up to 8 cycles

References

  1. CBCSG006: Hu XC, Zhang J, Xu BH, Cai L, Ragaz J, Wang ZH, Wang BY, Teng YE, Tong ZS, Pan YY, Yin YM, Wu CP, Jiang ZF, Wang XJ, Lou GY, Liu DG, Feng JF, Luo JF, Sun K, Gu YJ, Wu J, Shao ZM. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):436-46. Epub 2015 Mar 18. link to original article contains protocol PubMed

Docetaxel monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Tutt et al. 2018 (TNT) Phase III (C) Carboplatin Seems not superior

Chemotherapy

21-day cycle for 6 cycles

References

  1. TNT: Tutt A, Tovey H, Cheang MCU, Kernaghan S, Kilburn L, Gazinska P, Owen J, Abraham J, Barrett S, Barrett-Lee P, Brown R, Chan S, Dowsett M, Flanagan JM, Fox L, Grigoriadis A, Gutin A, Harper-Wynne C, Hatton MQ, Hoadley KA, Parikh J, Parker P, Perou CM, Roylance R, Shah V, Shaw A, Smith IE, Timms KM, Wardley AM, Wilson G, Gillett C, Lanchbury JS, Ashworth A, Rahman N, Harries M, Ellis P, Pinder SE, Bliss JM. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med. 2018 May;24(5):628-637. Epub 2018 Apr 30. link to original article link to PMC article PubMed

FAC

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FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide

Regimen

Study Evidence Comparator Comparative Efficacy
Pandya et al. 2007 (ECOG E3185) Phase III (C) CAF/TsAVbH Seems not superior

Chemotherapy

28-day cycle for up to 6 cycles

References

  1. ECOG E3185: Pandya KJ, Hu P, Osborne CK, Falkson G, Tormey DC; Eastern Cooperative Oncology Group. Phase III study of standard combination versus rotating regimen of induction chemotherapy in patients with hormone insensitive metastatic breast cancer: an Eastern Cooperative Oncology Group Intergroup Study (E3185). Am J Clin Oncol. 2007 Apr;30(2):113-25. link to original article contains verified protocol PubMed

Paclitaxel monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Kim et al. 2017 (LOTUS) Randomized Phase II (C) Ipatasertib & Paclitaxel Seems to have inferior PFS

Chemotherapy

28-day cycles

References

  1. LOTUS: Kim SB, Dent R, Im SA, Espié M, Blau S, Tan AR, Isakoff SJ, Oliveira M, Saura C, Wongchenko MJ, Kapp AV, Chan WY, Singel SM, Maslyar DJ, Baselga J; LOTUS investigators. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017 Oct;18(10):1360-1372. Epub 2017 Aug 8. link to original article PubMed

nab-Paclitaxel monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Schmid et al. 2018 (IMpassion130) Phase III (C) nab-Paclitaxel & Atezolizumab Might have inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

28-day cycles

References

  1. IMpassion130: Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Diéras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018 Nov 29;379(22):2108-2121. Epub 2018 Oct 20. link to original article contains verified protocol PubMed

nab-Paclitaxel & Atezolizumab

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Regimen

Study Evidence Comparator Comparative Efficacy
Schmid et al. 2018 (IMpassion130) Phase III (E-RT) nab-Paclitaxel Might have superior OS

Chemotherapy

28-day cycles

References

  1. IMpassion130: Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Diéras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018 Nov 29;379(22):2108-2121. Epub 2018 Oct 20. link to original article contains verified protocol PubMed

Metastatic disease, subsequent lines of therapy

Capecitabine & Ixabepilone

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Regimen

Study Evidence Comparator Comparative Efficacy
Thomas et al. 2007 (CA163-046) Phase III (E) Capecitabine Superior PFS
Sparano et al. 2010 (CA163-048) Phase III (E) Capecitabine Superior PFS

Note: 25% of the patients in CA163-046 had TNBC.

Chemotherapy

21-day cycles

References

  1. CA163-046: 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
    1. Update: Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010 Jul;122(2):409-18. Epub 2010 May 8. link to original article PubMed
    2. Pooled subgroup analysis: Rugo HS, Roche H, Thomas E, Chung HC, Lerzo GL, Vasyutin I, Patel A, Vahdat L. Efficacy and safety of ixabepilone and capecitabine in patients with advanced triple-negative breast cancer: a pooled analysis from two large phase III, randomized clinical trials. Clin Breast Cancer. 2018 Dec;18(6):489-497. Epub 2018 Aug 4. link to SD article PubMed
  2. CA163-048: 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
    1. Pooled subgroup analysis: Rugo HS, Roche H, Thomas E, Chung HC, Lerzo GL, Vasyutin I, Patel A, Vahdat L. Efficacy and safety of ixabepilone and capecitabine in patients with advanced triple-negative breast cancer: a pooled analysis from two large phase III, randomized clinical trials. Clin Breast Cancer. 2018 Dec;18(6):489-497. Epub 2018 Aug 4. link to SD article PubMed

Carboplatin & Gemcitabine

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GC: Gemcitabine & Carboplatin

Regimen

Study Evidence Comparator Comparative Efficacy
O'Shaughnessy et al. 2014 (EFC11486) Phase III (C) GC & Iniparib Might have inferior PFS

Chemotherapy

21-day cycles

References

  1. EFC11486: O'Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, Robert N, Hellerstedt B, Saleh M, Richards P, Specht JM, Yardley DA, Carlson RW, Finn RS, Charpentier E, Garcia-Ribas I, Winer EP. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2014 Dec 1;32(34):3840-7. Epub 2014 Oct 27. link to original article contains protocol PubMed

Enzalutamide monotherapy

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Regimen

Study Evidence Efficacy
Traina et al. 2018 Phase II CBR @ 16 wks: 25% (95% CI 17-33)

Patients had AR-positive TNBC.

Hormonotherapy

Continued indefinitely

References

  1. Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O'Shaughnessy J, Gradishar W, Schmid P, Winer E, Kelly C, Nanda R, Gucalp A, Awada A, Garcia-Estevez L, Trudeau ME, Steinberg J, Uppal H, Tudor IC, Peterson A, Cortes J. Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol. 2018 Mar 20;36(9):884-890. Epub 2018 Jan 26. link to original article contains verified protocol PubMed

Investigational agents

Drugs with some degree of promising activity in clinical trials.