Triple negative breast cancer (TNBC) is associated with a poor prognosis compared to other types of breast cancer. The classification of 'triple negative' is not one homogenous tumor type, but rather is made up of multiple molecularly and biologically diverse tumor subtypes. At present, no approved targeted therapy exists and the standard remains cytotoxic chemotherapy. The identification of TNBC subtypes has provided a basis for identifying possible targeted therapeutic options. In addition, the recognition that some TNBCs share characteristics similar to tumors arising in patients with germline BRCA mutations has led to consideration of DNA damaging agents as a potential treatment option. Multiple investigational approaches are also underway, including immune checkpoint inhibition, poly (ADP-ribose) polymerase inhibition, and androgen receptor blockage. The limited options available for systemic treatment of TNBC will hopefully expand as more is learned about the complex biology and molecular targets of this group of breast cancers. This review will discuss the biology of TNBC, current treatment options, and promising experimental strategies.
Triple negative, breast cancer, therapeutics
Tarah Ballinger, Jill Kremer and Kathy Miller have nothing to disclose in relation to this article. No funding was received in the publication of this article.
Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.
September 09, 2016 Accepted:
October 15, 2016
Kathy Miller, Indiana Cancer Pavilion, Suite 473, 535 Barnhill Dr, Indianapolis, IN 46202-5289, US. E: firstname.lastname@example.org
Triple negative breast cancer (TNBC) is defined by a lack of expression of estrogen receptor (ER) and progesterone receptor (PR), and a lack of overexpression or amplification of human epidermal growth factor 2 (HER2) on tumor cells. TNBC accounts for approximately 15–20% of all breast cancers diagnosed in the United States.1 It is more common in African American women, younger women, and those with a germline BRCA1 mutation. Due to lack of ER, PR, and HER2 and the significant heterogeneity among TNBC, no approved targeted therapies exist and standard treatment remains cytotoxic chemotherapy. While response rates to chemotherapy in early stage disease are high, patients remain at high risk for relapse and prognosis remains inferior to other types of breast cancer.
Subtyping and molecular characteristics
In a seminal paper by Perou et al., gene expression profiling was used to categorize breast cancers into five molecular subtypes. The basal-like type is characterized by lack of ER, PR, and HER2 expression, expression of cytokeratins and EGFR, and a clinically more aggressive phenotype.2 This subtype overlaps with TNBC but the terms are not synonymous; in fact, about one fourth of TNBCs are not basal-like by gene expression, and some non-TNBCs are basal-like by molecular profiling (see Figure 1).3,4 As more is discovered about the biology of TNBC, it has become clear that this category of breast cancer is not one homogeneous tumor type, but rather is made up of a group of molecularly diverse tumor subtypes. These subtypes have varying gene expression profiles, clinical characteristics, and responses to treatment. In an effort to translate the heterogeneity of TNBC into rational clinical design, Lehmann and colleagues further characterized TNBC into six distinct subtypes based on molecular profiles, each with unique drivers and clinical phenotypes. These subtypes include basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor(LAR).5 Each exhibited different sensitivities to therapeutic agents, both in cell line models and in some retrospective clinical trials. For example, the BL1 subtype responds preferentially to platinum agents and responds significantly better to neoadjuvant chemotherapy than the BL2 subtype. The mesenchymal and luminal subtypes have greater sensitivity to phosphatidylinositol 3- kinase (PI3K) pathway inhibitors, while the LAR subtype is more sensitive to androgen receptor antagonists, with a relative insensitivity to standard chemotherapy.5–9
This heterogeneity and the lack of targetable oncogenic mutations have made the development of novel strategies for TNBC difficult. Common genomic alterations in TNBC result in dysregulated cell cycle progression and resistance to apoptosis, including the loss of TP53, RB1, BRCA1, and PTEN, as well as gain of function alterations in the cyclins/cyclin-dependent kinases (CCNE1, CCND1, CDK4, CDK6) and the PI3K pathway, including PIK3CA mutations.10–12 The most common of these alterations
is a mutation or loss of TP53, which is present in 68% of TNBCs and 80% of basal-like breast cancers in The Cancer Genome Atlas (TCGA), but is yet to have a targeted therapeutic agent.10
1. Anders CK, Carey LA, Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer, Clin Breast Cancer, 2009;9(Suppl 2):S73–81.
2. Perou CM, Sorlie T, Eisen MB, et al., Molecular portraits of human breast tumours, Nature, 2000;406:747–52.
3. Bertucci F, Finetti P, Cervera N, et al., How basal are triple-negative breast cancers?, Int J Cancer, 2008;123:236–40.
4. Prat A, Adamo B, Cheang MC, et al., Molecular characterization of basal-like and non-basal-like triple-negative breast cancer, Oncologist, 2013;18:123–33.
5. Lehmann BD, Bauer JA, Chen X, et al., Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies, J Clin Invest, 2011;121:2750–67.
6. Abramson VG, Lehmann BD, Ballinger TJ, et al., Subtyping of triple-negative breast cancer: implications for therapy, Cancer, 2015;121:8–16.
7. Masuda H, Baggerly KA, Wang Y, et al., Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes, Clin Cancer Res, 2013;19:5533–40.
8. Gucalp A, Tolaney S, Isakoff SJ, et al., Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer, Clin Cancer Res, 2013;19:5505–12.
9. Lehmann BD, Jovanovic B, Chen X, et al., Refinement of Triple- Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection, PLoS One, 2016;11:e0157368.
10. Cancer Genome Atlas N, Comprehensive molecular portraits of human breast tumours, Nature, 2012;490:61–70.
11. Shah SP, Roth A, Goya R, et al., The clonal and mutational evolution spectrum of primary triple-negative breast cancers, Nature, 2012;486:395–9.
12. Sharma P, Biology and Management of Patients With Triple- Negative Breast Cancer, Oncologist, 2016
13. Bianchini G, Balko JM, Mayer IA, et al., Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease, Nat Rev Clin Oncol, 2016; [epub ahead of print].
14. von Minckwitz G, Untch M, Blohmer JU, et al., Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes, J Clin Oncol, 2012;30:1796–804.
15. Cortazar P, Zhang L, Untch M, et al., Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis, Lancet, 2014;384:164–72.
16. Sikov WM BD, Perou CM, et al., Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance). Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR, Cancer Res, 2016;76(4 Suppl):Abstract nr S2–05.
17. Carey LA, Dees EC, Sawyer L, et al., The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes, Clin Cancer Res, 2007;13:2329–34.
18. Liedtke C, Mazouni C, Hess KR, et al., Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer, J Clin Oncol, 26:1275–81.
19. Gennari A, Sormani MP, Pronzato P, et al., HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials, J Natl Cancer Inst, 2008;100:14–20.
20. Jones SE, Savin MA, Holmes FA, et al.,Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer, J Clin Oncol, 2006;24:5381–7.
21. Blum JL, Flynn PJ, Yothers G, et al., Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophosphamide (TC) v anthracycline/ taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2-negative breast cancer. Program and abstracts of the 2016 American Society of Clinical Oncology Annual Meeting; June 3-7, 2016; Chicago, Illinois. Abstract 1000.
22. Cameron D, Brown J, Dent R, et al., Adjuvant bevacizumabcontaining therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial, Lancet Oncol, 2013;14:933–42.
23. O'Shaughnessy J, Koeppen H, Xiao Y, et al., Patients with Slowly Proliferative Early Breast Cancer Have Low Five-Year Recurrence Rates in a Phase III Adjuvant Trial of Capecitabine, Clin Cancer Res, 2015;21:4305–11.
24. Swain SM, Tang G, Geyer CE, Jr., et al., 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;31:3197–204.
25. Toi M, Lee S-J, Lee ES, et al., A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04). Program and abstracts of the San Antonio Breast Cancer Symposium; December 8–12, 2015; San Antonio, Texas. Abstract S1–07.
26. Le Du F, Eckhardt BL, Lim B, et al., Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype?, Oncotarget, 2015;6:12890–908.
27. Byrski T, Huzarski T, Dent R, et al., Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients, Breast Cancer Res Treat, 2009;115:359–63.
28. Silver DP, Richardson AL, Eklund AC, et al., Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer, J Clin Oncol, 2010;28:1145–53.
29. von Minckwitz G, Schneeweiss A, Loibl S, 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;15:747–56.
30. von Minckwitz G, Loibl S, Schneeweiss A, et al., Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2- positive early breast cancer (GeparSixto). 2015 San Antonio Breast Cancer Symposium. Abstract S2-04. Presented December 9, 2015.
31. Dent R, Trudeau M, Pritchard KI, et al., Triple-negative breast cancer: clinical features and patterns of recurrence, Clin Cancer Res, 2007;13:4429–34.
32. Dear RF, McGeechan K, Jenkins MC, et al., Combination versus sequential single agent chemotherapy for metastatic breast cancer, Cochrane Database Syst Rev, 2013;CD008792.
33. Jones SE, Erban J, Overmoyer B, et al., Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer, J Clin Oncol, 2005;23:5542–51.
34. Rugo HS, Barry WT, Moreno-Aspitia A, et al., Randomized Phase III Trial of Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance), J Clin Oncol, 2015;33:2361–9.
35. Miller K, Wang M, Gralow J, et al., Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer, N Engl J Med, 2007;357:2666–76.
36. Cortes J, O'Shaughnessy J, Loesch D, 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;377:914–23.
37. Oostendorp LJ, Stalmeier PF, Donders AR, et al., Efficacy and safety of palliative chemotherapy for patients with advanced breast cancer pretreated with anthracyclines and taxanes: a systematic review, Lancet Oncol, 2011;12:1053–61.
38. O'Shaughnessy J, Capecitabine and docetaxel in advanced breast cancer: analyses of a phase III comparative trial, Oncology (Williston Park), 2002;16:17–22.
39. Kaufman PA, Awada A, Twelves C, et al., Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane, J Clin Oncol, 2015;33:594–601.
40. Twelves C, Awada A, Cortes J, et al., Subgroup Analyses from a Phase 3, Open-Label, Randomized Study of Eribulin Mesylate Versus Capecitabine in Pretreated Patients with Advanced or Metastatic Breast Cancer, Breast Cancer (Auckl), 2016;10:77–84.
41. Blackstein M, Vogel CL, Ambinder R, et al., Gemcitabine as firstline therapy in patients with metastatic breast cancer: a phase II trial, Oncology, 2002;62:2–8.
42. Rha SY, Moon YH, Jeung HC, et al., Gemcitabine monotherapy as salvage chemotherapy in heavily pretreated metastatic breast cancer, Breast Cancer Res Treat, 2005;90:215–21.
43. Fumoleau P, Delgado FM, Delozier T, et al., Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy, J Clin Oncol, 1993;11:1245–52.
44. Martin M, Ruiz A, Munoz M, et al., Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial, Lancet Oncol, 2007;8:219–25.
45. Feher O, Vodvarka P, Jassem J, et al., First-line gemcitabine versus epirubicin in postmenopausal women aged 60 or older with metastatic breast cancer: a multicenter, randomized, phase III study, Ann Oncol, 2005;16:899–908.
46. Tutt A, et al: The TNT trial. 2014 San Antonio Breast Cancer Symposium. Abstract S3-01. Presented December 11, 2014.
47. Loi S, Sirtaine N, Piette F, et al., Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98, J Clin Oncol, 2013;31:860–7.
48. Anders CK, Abramson V, Tan T, et al., The Evolution of Triple- Negative Breast Cancer: From Biology to Novel Therapeutics, Am Soc Clin Oncol Educ Book, 2016;35:34–42.
49. Ali HR, Glont SE, Blows FM, et al., PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes, Ann Oncol, 2015;26:1488–93.
50. Nanda R, Chow LQ, Dees EC, et al., Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study, J Clin Oncol, 2016;34:2460–7.
51. Leisha A, Emens FSB, Cassier P, Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC) American Association of Cancer Research Philadelphia, PA, April 2015. Abstract 2859
52. Dirix LY, Takacs I, Nikolinakos P, et al., Avelumab (MSB0010718C), an anti–PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. 2015 San Antonio Breast Cancer Symposium. Abstract S1-04. Presented December 9, 2015.
53. Adams S, Diamond J, Hamilton E, et al., Phase Ib trial of atezolizumab in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). Presented at: American Society of Clinical Oncology annual meeting. Chicago, Illinois. June 2016. Abstract 1009.
54. Bendell J, Saleh M, Rose AA, et al., Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with locally advanced or metastatic breast cancer, J Clin Oncol, 2014;32:3619–25.
55. Yardley DA, Weaver R, Melisko ME, et al., EMERGE: A Randomized Phase II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB-Expressing Breast Cancer, J Clin Oncol, 2015;33:1609–19.
56. An ADC for Triple-Negative Breast Cancer, Cancer Discov, 2016 Jan;6(1):OF8.
57. Rugo HS, Olopade OI, DeMichele A, et al., Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer, N Engl J Med, 2016;375:23–34.
58. Tutt A, Robson M, Garber JE, et al., Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial, Lancet, 2010;376:235–44.
59. Gelmon KA, Tischkowitz M, Mackay H, et al., Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study, Lancet Oncol, 2011;12:852–61.
60. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al., Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation, J Clin Oncol, 2015;33:244–50.
61. Balmana J, Tung NM, Isakoff SJ, et al., Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors, Ann Oncol, 2014;25:1656–63.
62. Pahuja S, Beumer JH, Appleman LJ, et al., Outcome of BRCA 1/2-mutated (BRCA+) and triple-negative, BRCA wild type (BRCAwt) breast cancer patients in a phase I study of single-agent veliparib (V), J Clin Oncol, 2014;32:135.
63. Somlo G, Frankel PH, Luu TH, et al., Efficacy of the combination of ABT-888 (veliparib) and carboplatin in patients with BRCAassociated breast cancer, J Clin Oncol, 2013;31:1024.
64. Wesolowski R, Zhao M, Geyer SM, et al., Phase I trial of the PARP inhibitor veliparib (V) in combination with carboplatin (C) in metastatic breast cancer (MBC), J Clin Oncol, 2014;32:1075.
65. De Bono JS, Mina LA, Gonzalez M, et al., First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors, J Clin Oncol, 2013;31:2580.
66. Sandhu SK, Schelman WR, Wilding G, et al., The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 doseescalation trial, Lancet Oncol, 2013;14:882–92.
67. Wang C, Pan B, Zhu H, et al., Prognostic value of androgen receptor in triple negative breast cancer: A meta-analysis, Oncotarget, 2016
68. Traina TA, Miller K, Yardley DA, et al., Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC), J Clin Oncol, 2015;33:(suppl; abstr 1003).