Skip to main content

Systemic Treatment of HER2-Negative Metastatic Breast Cancer

  • Chapter
  • First Online:
Breast Cancer
  • 2150 Accesses

Abstract

Chemotherapy regimens, either single-agent or combination, should be considered for patients with triple-negative metastatic or recurrent breast cancer or patients with hormone receptor-positive tumors and who are at high risk for a visceral crisis. No convincing data support the superiority of combination chemotherapy over single-agent chemotherapy. Although combination regimens may increase objective response rates, they also result in increased toxicity without any overall survival advantage. Patients who carry a BRCA mutation and have triple-negative or endocrine therapy-resistant metastatic breast cancer should be considered for platinum-based chemotherapy if they have received an anthracycline and a taxane in an adjuvant or metastatic setting. Poly (ADP)-ribose polymerase (PARP) inhibitors may be an option for patients with BRCA mutations. An understanding of the biology of breast cancer has led to important advances in the development of targeted therapies; however, metastatic breast cancer remains an incurable disease for most patients. As we continue to learn to use genomic medicine and harness the immune system to guide drug development, it is important to start combining drugs by using biologically informed translational science to optimize the patient outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. American Cancer Society. Cancer facts & figures 2014. Atlanta: American Cancer Society; 2014.

    Google Scholar 

  2. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.

    Article  CAS  PubMed  Google Scholar 

  3. Niikura N, Odisio BC, Tokuda Y, Symmans FW, Hortobagyi GN, Ueno NT. Latest biopsy approach for suspected metastases in patients with breast cancer. Nat Rev Clin Oncol. 2013;10(12):711–9.

    Article  CAS  PubMed  Google Scholar 

  4. Figueroa-Magalhaes MC, Jelovac D, Connolly RM, Wolff AC. Treatment of HER2-positive breast cancer. Breast. 2014;23(2):128–36.

    Article  PubMed  Google Scholar 

  5. Dalmau E, Armengol-Alonso A, Munoz M, Segui-Palmer MA. Current status of hormone therapy in patients with hormone receptor positive (HR+) advanced breast cancer. Breast. 2014;23(6):710–20.

    Article  PubMed  Google Scholar 

  6. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363(20):1938–48.

    Article  CAS  PubMed  Google Scholar 

  7. Hughes LL, Gray RJ, Solin LJ, Robert NJ, Martino S, Tripathy D, et al. Efficacy of radiotherapy for ovarian ablation: results of a breast intergroup study. Cancer. 2004;101(5):969–72.

    Article  PubMed  Google Scholar 

  8. Sverrisdottir A, Johansson H, Johansson U, Bergh J, Rotstein S, Rutqvist L, et al. Interaction between goserelin and tamoxifen in a prospective randomised clinical trial of adjuvant endocrine therapy in premenopausal breast cancer. Breast Cancer Res Treat. 2011;128(3):755–63.

    Article  CAS  PubMed  Google Scholar 

  9. Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, et al. 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;28(30):4594–600.

    Article  PubMed  Google Scholar 

  10. Ingle JN, Krook JE, Green SJ, Kubista TP, Everson LK, Ahmann DL, et al. Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer. J Clin Oncol. 1986;4(2):178–85.

    Article  CAS  PubMed  Google Scholar 

  11. Robertson JFR, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomized, double-blind, phase 3 trial. Lancet. 2016;388(10063):2997–3005.

    Article  CAS  Google Scholar 

  12. Goss PE, Winer EP, Tannock IF, Schwartz LH. Randomized phase III trial comparing the new potent and selective third-generation aromatase inhibitor vorozole with megestrol acetate in postmenopausal advanced breast cancer patients. North American Vorozole Study Group. J Clin Oncol. 1999;17(1):52–63.

    Article  CAS  PubMed  Google Scholar 

  13. Bonneterre J, Buzdar A, Nabholtz JM, Robertson JF, Thurlimann B, von Euler M, et al. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer. 2001;92(9):2247–58.

    Article  CAS  PubMed  Google Scholar 

  14. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001;19(10):2596–606.

    Article  CAS  PubMed  Google Scholar 

  15. Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, et al. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008;26(30):4883–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, et al. Exemestane improves survival in metastatic breast cancer: results of a phase III randomized study. Clin Breast Cancer. 2000;1(Suppl 1):S15–8.

    Article  PubMed  Google Scholar 

  17. Campos SM, Guastalla JP, Subar M, Abreu P, Winer EP, Cameron DA. A comparative study of exemestane versus anastrozole in patients with postmenopausal breast cancer with visceral metastases. Clin Breast Cancer. 2009;9(1):39–44.

    Article  CAS  PubMed  Google Scholar 

  18. Brufman G, Isacson R, Haim N, Gez E, Sulkes A. Megestrol acetate in advanced breast carcinoma after failure to tamoxifen and/or aminoglutethimide. Oncology. 1994;51(3):258–61.

    Article  CAS  PubMed  Google Scholar 

  19. Paplomata E, O'Regan R. The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol. 2014;6(4):154–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–9.

    Article  CAS  PubMed  Google Scholar 

  21. Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, et al. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol. 2013;31(2):195–202.

    Article  CAS  PubMed  Google Scholar 

  22. Maass N, Harbeck N, Mundhenke C, Lerchenmuller C, Barinoff J, Luck HJ, et al. Everolimus as treatment for breast cancer patients with bone metastases only: results of the phase II RADAR study. J Cancer Res Clin Oncol. 2013;139(12):2047–56.

    Article  CAS  PubMed  Google Scholar 

  23. Fleming GF, Ma CX, Huo D, Sattar H, Tretiakova M, Lin L, et al. Phase II trial of temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat. 2012;136(2):355–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ma CX, Luo J, Naughton M, Ademuyiwa F, Suresh R, Griffith M, et al. A phase I trial of BKM120 (Buparlisib) in combination with fulvestrant in postmenopausal women with estrogen receptor-positive metastatic breast cancer. Clin Cancer Res. 2016;22(7):1583–91.

    Article  CAS  PubMed  Google Scholar 

  25. Mayer IA, Abramson VG, Isakoff SJ, Forero A, Balko JM, Kuba MG, et al. Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2014;32(12):1202–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Baselga J, Im SA, Iwata H, editors. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): first results from the randomized, phase III BELLE-2 trial. In: San Antonio breast cancer symposium, San Antonio, TX; 2015.

    Google Scholar 

  27. Di Leo A, Seok Lee K, Ciruelos E, editors. BELLE-3: a phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2-, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment. In: San Antonio breast cancer symposium, San Antonio, TX; 2016.

    Google Scholar 

  28. Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol. 2013;14(10):989–98.

    Article  CAS  PubMed  Google Scholar 

  29. Bergh J, Jonsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattstrom D, et al. 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;30(16):1919–25.

    Article  CAS  PubMed  Google Scholar 

  30. Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367(5):435–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. 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;16(1):25–35.

    Article  CAS  PubMed  Google Scholar 

  32. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016;375(20):1925–36.

    Article  CAS  PubMed  Google Scholar 

  33. Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209–19.

    Article  CAS  PubMed  Google Scholar 

  34. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. 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;17(4):425–39.

    Article  CAS  PubMed  Google Scholar 

  35. Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28(20):3271–7.

    Article  PubMed  Google Scholar 

  36. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687–717.

    Article  Google Scholar 

  37. Chan S, Friedrichs K, Noel D, Pinter T, Van Belle S, Vorobiof D, et al. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999;17(8):2341–54.

    Article  CAS  PubMed  Google Scholar 

  38. Bastholt L, Dalmark M, Gjedde SB, Pfeiffer P, Pedersen D, Sandberg E, et al. 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;14(4):1146–55.

    Article  CAS  PubMed  Google Scholar 

  39. O’Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, et al. 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;15(3):440–9.

    Article  PubMed  Google Scholar 

  40. Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005;23(24):5542–51.

    Article  CAS  PubMed  Google Scholar 

  41. Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, et al. 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;26(10):1642–9.

    Article  CAS  PubMed  Google Scholar 

  42. 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;19(22):4216–23.

    Article  CAS  PubMed  Google Scholar 

  43. Burstein HJ, Manola J, Younger J, Parker LM, Bunnell CA, Scheib R, et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol. 2000;18(6):1212–9.

    Article  CAS  PubMed  Google Scholar 

  44. Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23(31):7794–803.

    Article  CAS  PubMed  Google Scholar 

  45. Zelek L, Barthier S, Riofrio M, Fizazi K, Rixe O, Delord JP, et al. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer. 2001;92(9):2267–72.

    Article  CAS  PubMed  Google Scholar 

  46. Roche H, Yelle L, Cognetti F, Mauriac L, Bunnell C, Sparano J, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy. J Clin Oncol. 2007;25(23):3415–20.

    Article  CAS  PubMed  Google Scholar 

  47. Rivera E, Gomez H. Chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone. Breast Cancer Res. 2010;12(Suppl 2):S2.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Denduluri N, Low JA, Lee JJ, Berman AW, Walshe JM, Vatas U, et al. Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously untreated with taxanes. J Clin Oncol. 2007;25(23):3421–7.

    Article  CAS  PubMed  Google Scholar 

  49. Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007;25(23):3407–14.

    Article  CAS  PubMed  Google Scholar 

  50. Thomas E, Tabernero J, Fornier M, Conte P, Fumoleau P, Lluch A, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol. 2007;25(23):3399–406.

    Article  CAS  PubMed  Google Scholar 

  51. Cortes J, Vahdat L, Blum JL, Twelves C, Campone M, Roche H, et al. Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2010;28(25):3922–8.

    Article  CAS  PubMed  Google Scholar 

  52. Vahdat LT, Pruitt B, Fabian CJ, Rivera RR, Smith DA, Tan-Chiu E, et al. Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2009;27(18):2954–61.

    Article  CAS  PubMed  Google Scholar 

  53. Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914–23.

    Article  CAS  PubMed  Google Scholar 

  54. Blum JL, Dieras V, Lo Russo PM, Horton J, Rutman O, Buzdar A, et al. Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer. 2001;92(7):1759–68.

    Article  CAS  PubMed  Google Scholar 

  55. Bajetta E, Procopio G, Celio L, Gattinoni L, Della Torre S, Mariani L, et al. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol. 2005;23(10):2155–61.

    Article  CAS  PubMed  Google Scholar 

  56. Blackstein M, Vogel CL, Ambinder R, Cowan J, Iglesias J, Melemed A. Gemcitabine as first-line therapy in patients with metastatic breast cancer: a phase II trial. Oncology. 2002;62(1):2–8.

    Article  CAS  PubMed  Google Scholar 

  57. Rha SY, Moon YH, Jeung HC, Kim YT, Sohn JH, Yang WI, et al. Gemcitabine monotherapy as salvage chemotherapy in heavily pretreated metastatic breast cancer. Breast Cancer Res Treat. 2005;90(3):215–21.

    Article  CAS  PubMed  Google Scholar 

  58. von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15(7):747–56.

    Article  Google Scholar 

  59. Villarreal-Garza C, Khalaf D, Bouganim N, Clemons M, Pena-Curiel O, Baez-Revueltas B, et al. Platinum-based chemotherapy in triple-negative advanced breast cancer. Breast Cancer Res Treat. 2014;146(3):567–72.

    Article  CAS  PubMed  Google Scholar 

  60. Tutt A, Tovey H, Cheang MCU, Kernaghan S, Kilburn L, Gazinska P, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med. 2018;24(5):628–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Penault-Llorca F, Viale G. Pathological and molecular diagnosis of triple-negative breast cancer: a clinical perspective. Ann Oncol. 2012;23(Suppl 6):vi19–22.

    Article  PubMed  Google Scholar 

  62. Lehmann BD, Jovanovic B, Chen X, Estrada MV, Johnson KN, Shyr Y, et al. Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS One. 2016;11(6):e0157368.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534(7605):47–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364(3):205–14.

    Article  PubMed  Google Scholar 

  66. O’Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, et al. 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;32(34):3840–7.

    Article  PubMed  Google Scholar 

  67. Patel AG, De Lorenzo SB, Flatten KS, Poirier GG, Kaufmann SH. Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro. Clin Cancer Res. 2012;18(6):1655–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Audeh MW. Novel treatment strategies in triple-negative breast cancer: specific role of poly(adenosine diphosphate-ribose) polymerase inhibition. Pharmacogenomics Pers Med. 2014;7:307–16.

    Article  Google Scholar 

  69. Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–33.

    Article  CAS  PubMed  Google Scholar 

  70. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmana J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244–50.

    Article  CAS  PubMed  Google Scholar 

  71. Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey JA, Consortium TBCR, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res. 2013;19(19):5505–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O’Shaughnessy J, et al. Enzalutamide for the treatment of androgen receptor—expressing triple-negative breast cancer. J Clin Oncol. 2018;36(9):884–90.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Dent R, Schmid P, Cortes J, editors. ENDEAR: a randomized international phase 3 study comparing the efficacy and safety of enzalutamide in combination with paclitaxel chemotherapy or as monotherapy vs placebo with paclitaxel in patients with advanced diagnostic-positive triple-negative breast cancer. In: San Antonio breast cancer symposium, San Antonio, TX; 2016.

    Google Scholar 

  74. Goldenberg DM, Cardillo TM, Govindan SV, Rossi EA, Sharkey RM. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). Oncotarget. 2015;6(26):22496–512.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Starodub AN, Ocean AJ, Shah MA, Guarino MJ, Picozzi VJ Jr, Vahdat LT, et al. First-in-human trial of a novel anti-Trop-2 antibody-SN-38 conjugate, sacituzumab govitecan, for the treatment of diverse metastatic solid tumors. Clin Cancer Res. 2015;21(17):3870–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bardia A, Diamond J, Mayer IA, editors. Safety and efficacy of anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in heavily pretreated patients with TNBC. In: San Antonia breast cancer symposium, San Antonio, TX; 2016.

    Google Scholar 

  77. Rose AA, Grosset AA, Dong Z, Russo C, Macdonald PA, Bertos NR, et al. Glycoprotein nonmetastatic B is an independent prognostic indicator of recurrence and a novel therapeutic target in breast cancer. Clin Cancer Res. 2010;16(7):2147–56.

    Article  CAS  PubMed  Google Scholar 

  78. O’Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002;20(12):2812–23.

    Article  PubMed  Google Scholar 

  79. Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, et al. Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008;26(24):3950–7.

    Article  PubMed  Google Scholar 

  80. Mauri D, Kamposioras K, Tsali L, Bristianou M, Valachis A, Karathanasi I, Georgiou C, Polyzos NP. Overall survival benefi t for weekly vs. three-weekly, taxanes regimens in advanced breast cancer: a meta-analysis. Cancer Treat Rev. 2010;36:69.

    Article  CAS  PubMed  Google Scholar 

  81. Sirohi B, Arnedos M, Popat S, Ashley S, Nerurkar A, Walsh G, et al. Platinum-based chemotherapy in triple-negative breast cancer. Ann Oncol. 2008;19(11):1847–52.

    Article  CAS  PubMed  Google Scholar 

  82. Chew HK, Doroshow JH, Frankel P, Margolin KA, Somlo G, Lenz HJ, et al. Phase II studies of gemcitabine and cisplatin in heavily and minimally pretreated metastatic breast cancer. J Clin Oncol. 2009;27(13):2163–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Staudacher L, Cottu PH, Dieras V, Vincent-Salomon A, Guilhaume MN, Escalup L, et al. Platinum-based chemotherapy in metastatic triple-negative breast cancer: the Institut Curie experience. Ann Oncol. 2011;22(4):848–56.

    Article  CAS  PubMed  Google Scholar 

  84. Kumler I, Christiansen OG, Nielsen DL. A systematic review of bevacizumab efficacy in breast cancer. Cancer Treat Rev. 2014;40(8):960–73.

    Article  CAS  PubMed  Google Scholar 

  85. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666–76.

    Article  CAS  PubMed  Google Scholar 

  86. Robert NJ, Dieras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al. 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;29(10):1252–60.

    Article  CAS  PubMed  Google Scholar 

  87. Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O’Neill V, et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011;29(32):4286–93.

    Article  CAS  PubMed  Google Scholar 

  88. Brufsky A, Valero V, Tiangco B, Dakhil S, Brize A, Rugo HS, et al. Second-line bevacizumab-containing therapy in patients with triple-negative breast cancer: subgroup analysis of the RIBBON-2 trial. Breast Cancer Res Treat. 2012;133(3):1067–75.

    Article  CAS  PubMed  Google Scholar 

  89. Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, et al. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(12):1351–60.

    Article  CAS  PubMed  Google Scholar 

  90. Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, et al. Final results of the TANIA randomized phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016;27(11):2046–52.

    Article  CAS  PubMed  Google Scholar 

  91. Puglisi F, Cortes J, Vrdoljak E, Gligorov J, Marschner N, Zielinski C, et al. Subgroup efficacy analyses of the randomized phase III TANIA trial evaluating continued or reintroduced bevacizumab (BEV) after 1st-line BEV for HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). SABCS; 2014, PD2-4.

    Google Scholar 

  92. Cortes J, Vrdoljak E, Puglisi F, Marschner N, Gligorov J, Zielinski C, et al. Plasma (p) biomarker results from the TANIA trial evaluating continued or reintroduced bevacizumab (BEV) after 1st-line BEV for HER2-negative metastatic breast cancer (mBC). SABCS; 2014, PD2-4.

    Google Scholar 

  93. Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010;70(5):2085–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Soria JC, DeBraud F, Bahleda R, Adamo B, Andre F, Dienstmann R, et al. Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors. Ann Oncol. 2014;25(11):2244–51.

    Article  PubMed  Google Scholar 

  95. de la Cruz-Merino L, Palazón-Carrión N, Henao-Carrasco F, Nogales-Fernández E, Álamo-de la Gala M, Vallejo-Benítez A, et al. New horizons in breast cancer: the promise of immunotherapy. Clin Transl Oncol. 2018. https://doi.org/10.1007/s12094-018-1907-3.

  96. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Muenst S, Soysal SD, Gao F, Obermann EC, Oertli D, Gillanders WE. The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2013;139(3):667–76.

    Article  CAS  PubMed  Google Scholar 

  100. Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34(21):2460–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Adams S, Schmid P, Hope S, editors. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A. In: 2017 ASCO annual meeting, Chicago, IL; 2017.

    Google Scholar 

  102. Emens LA, Braiteh FS, Cassier P, editors. Inhibition of PDL1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). In: San Antonio breast symposium, San Antonio, TX; 2015.

    Google Scholar 

  103. Kuss JT, Muss HB, Hoen H, Case LD. Tamoxifen as initial endocrine therapy for metastatic breast cancer: long term follow-up of two Piedmont Oncology Association (POA) trials. Breast Cancer Res Treat. 1997;42(3):265–74.

    Article  CAS  PubMed  Google Scholar 

  104. Boccardo F, Rubagotti A, Perrotta A, Amoroso D, Balestrero M, De Matteis A, et al. Ovarian ablation versus goserelin with or without tamoxifen in pre-perimenopausal patients with advanced breast cancer: results of a multicentric Italian study. Ann Oncol. 1994;5(4):337–42.

    Article  CAS  PubMed  Google Scholar 

  105. Klijn JG, Beex LV, Mauriac L, van Zijl JA, Veyret C, Wildiers J, et al. Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst. 2000;92(11):903–11.

    Article  CAS  PubMed  Google Scholar 

  106. Howell A, Robertson JF, Abram P, Lichinitser MR, Elledge R, Bajetta E, et al. 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;22(9):1605–13.

    Article  CAS  PubMed  Google Scholar 

  107. Thurlimann B, Hess D, Koberle D, Senn I, Ballabeni P, Pagani O, et al. Anastrozole (‘Arimidex’) versus tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer: results of the double-blind cross-over SAKK trial 21/95—a sub-study of the TARGET (Tamoxifen or ‘Arimidex’ Randomized Group Efficacy and Tolerability) trial. Breast Cancer Res Treat. 2004;85(3):247–54.

    Article  PubMed  Google Scholar 

  108. Muss HB, Case LD, Atkins JN, Bearden JD, Cooper MR, Cruz JM, et al. Tamoxifen versus high-dose oral medroxyprogesterone acetate as initial endocrine therapy for patients with metastatic breast cancer: a Piedmont Oncology Association study. J Clin Oncol. 1994;12(8):1630–8.

    Article  CAS  PubMed  Google Scholar 

  109. Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, et al. 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;28(20):3256–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Bayraktar, S., Aydiner, A. (2019). Systemic Treatment of HER2-Negative Metastatic Breast Cancer. In: Aydiner, A., Igci, A., Soran, A. (eds) Breast Cancer . Springer, Cham. https://doi.org/10.1007/978-3-319-96947-3_22

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-96947-3_22

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-96946-6

  • Online ISBN: 978-3-319-96947-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics