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Epidemiology, risk factors and the clinical approach to ER/PR negative, HER2-negative (Triple-negative) breast cancer

Carey K Anders, MD
Lisa A Carey, MD
Section Editor
Daniel F Hayes, MD
Deputy Editor
Sadhna R Vora, MD


Triple-negative breast cancer is a term that has historically been applied to cancers that are low in expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Triple-negative breast cancer tends to behave more aggressively than other types of breast cancer. Unlike other breast cancer subtypes (ie, ER-positive, HER2-positive subtypes), there are no approved targeted treatments available, other than the administration of chemotherapy. For purposes of this review, we will consider "triple-negative" to mean cancers that have ≤1 percent expression of ER and PR as determined by immunohistochemistry (IHC), and that are either 0-1+ by IHC, or 2+ and fluorescence in situ hybridization (FISH)-negative (not amplified), according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines [1-3]. Although the basic principles of diagnosis and management of triple-negative breast cancer are similar to those of breast cancer in general, many aspects, including risk factors, molecular and pathologic characteristics, natural history, and chemotherapy sensitivity, are unique to triple-negative breast cancer and will be reviewed here.

A more extensive discussion on surgical management, neoadjuvant chemotherapy, adjuvant chemotherapy of nonmetastatic breast cancer, and the treatment of metastatic breast cancer is covered separately.

(See "Overview of the treatment of newly diagnosed, non-metastatic breast cancer".)

(See "Systemic treatment for metastatic breast cancer: General principles".)


Triple-negative breast cancer accounts for approximately 20 percent of breast cancers diagnosed worldwide, which amounts to almost 200,000 cases each year [4]. Triple-negative breast cancer is more commonly diagnosed in women younger than 40 years compared with hormone-positive breast cancer. In one study, there was a twofold higher attributable risk of triple-negative breast cancer in women under 40 years compared with women over 50 years (odds ratio [OR] 2.13, 95% CI 1.34-3.39) [5]. In addition, triple-negative breast cancer appears to be more common among black women compared with white women (OR 2.41, 95% CI 1.81-3.21) [5].

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Literature review current through: Sep 2017. | This topic last updated: Jun 06, 2017.
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  1. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med 2010; 134:e48.
  2. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010; 28:2784.
  3. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013; 31:3997.
  4. Swain S. Triple-Negative Breast Cancer: Metastatic Risk and Role of Platinum Agents 2008 ASCO Clinical Science Symposium, 2008. June 3, 2008.
  5. Trivers KF, Lund MJ, Porter PL, et al. The epidemiology of triple-negative breast cancer, including race. Cancer Causes Control 2009; 20:1071.
  6. Gonzalez-Angulo AM, Timms KM, Liu S, et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 2011; 17:1082.
  7. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk assessment: Breast and Ovarian. Version 4.2013. http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf (Accessed on November 26, 2013).
  8. Millikan RC, Newman B, Tse CK, et al. Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 2008; 109:123.
  9. Parise CA, Bauer KR, Brown MM, Caggiano V. Breast cancer subtypes as defined by the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) among women with invasive breast cancer in California, 1999-2004. Breast J 2009; 15:593.
  10. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006; 295:2492.
  11. Phipps AI, Chlebowski RT, Prentice R, et al. Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer. J Natl Cancer Inst 2011; 103:470.
  12. Palmer JR, Viscidi E, Troester MA, et al. Parity, lactation, and breast cancer subtypes in African American women: results from the AMBER Consortium. J Natl Cancer Inst 2014; 106.
  13. Anderson KN, Schwab RB, Martinez ME. Reproductive risk factors and breast cancer subtypes: a review of the literature. Breast Cancer Res Treat 2014; 144:1.
  14. Pierobon M, Frankenfeld CL. Obesity as a risk factor for triple-negative breast cancers: a systematic review and meta-analysis. Breast Cancer Res Treat 2013; 137:307.
  15. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007; 13:4429.
  16. Collett K, Stefansson IM, Eide J, et al. A basal epithelial phenotype is more frequent in interval breast cancers compared with screen detected tumors. Cancer Epidemiol Biomarkers Prev 2005; 14:1108.
  17. Livasy CA, Karaca G, Nanda R, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 2006; 19:264.
  18. Burstein MD, Tsimelzon A, Poage GM, et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res 2015; 21:1688.
  19. Bertucci F, Finetti P, Cervera N, et al. How basal are triple-negative breast cancers? Int J Cancer 2008; 123:236.
  20. Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012; 486:395.
  21. Carey LA, Rugo HS, Marcom IW, et al. TBCRC 001: EGFR inhibition with cetuximab added to carboplatin in metastatic triple-negative (basal-like) breast cancer (abstract 1009). J Clin Oncol 2008; 26:1009.
  22. Korsching E, Packeisen J, Agelopoulos K, et al. Cytogenetic alterations and cytokeratin expression patterns in breast cancer: integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis. Lab Invest 2002; 82:1525.
  23. Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 2004; 10:5367.
  24. 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.
  25. Teschendorff AE, Miremadi A, Pinder SE, et al. An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol 2007; 8:R157.
  26. Prat A, Parker JS, Karginova O, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 2010; 12:R68.
  27. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001; 98:10869.
  28. Troester MA, Herschkowitz JI, Oh DS, et al. Gene expression patterns associated with p53 status in breast cancer. BMC Cancer 2006; 6:276.
  29. Cheang MC, Martin M, Nielsen TO, et al. Quantitative hormone receptors, triple-negative breast cancer (TNBC), and molecular subtypes: A collaborative effort of the BIG-NCI NABCG. J Clin Oncol 30, 2012 (suppl; abstr 1008).
  30. Iwamoto T, Booser D, Valero V, et al. Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ER-positive by immunohistochemistry. J Clin Oncol 2012; 30:729.
  31. 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 2008; 26:1275.
  32. 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.
  33. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 2006; 295:1658.
  34. Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 2007; 357:1496.
  35. Hugh J, Hanson J, Cheang MC, et al. Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 2009; 27:1168.
  36. Martín M, Rodríguez-Lescure A, Ruiz A, et al. Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer. Breast Cancer Res Treat 2010; 123:149.
  37. Theriault RL, Litton JK, Mittendorf EA, et al. Age and survival estimates in patients who have node-negative T1ab breast cancer by breast cancer subtype. Clin Breast Cancer 2011; 11:325.
  38. Vaz-Luis I, Keating NL, Lin NU, et al. Duration and toxicity of adjuvant trastuzumab in older patients with early-stage breast cancer: a population-based study. J Clin Oncol 2014; 32:927.
  39. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003; 100:8418.
  40. Lin NU, Vanderplas A, Hughes ME, et al. Clinicopathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the National Comprehensive Cancer Network. Cancer 2012; 118:5463.
  41. Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer 2004; 4:814.
  42. Smid M, Wang Y, Zhang Y, et al. Subtypes of breast cancer show preferential site of relapse. Cancer Res 2008; 68:3108.
  43. Lin NU, Claus E, Sohl J, et al. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer 2008; 113:2638.
  44. Hicks DG, Short SM, Prescott NL, et al. Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR. Am J Surg Pathol 2006; 30:1097.
  45. Niwińska A, Murawska M, Pogoda K. Breast cancer subtypes and response to systemic treatment after whole-brain radiotherapy in patients with brain metastases. Cancer 2010; 116:4238.
  46. Anders CK, Deal AM, Miller CR, et al. The prognostic contribution of clinical breast cancer subtype, age, and race among patients with breast cancer brain metastases. Cancer 2011; 117:1602.
  47. Hull DF 3rd, Clark GM, Osborne CK, et al. Multiple estrogen receptor assays in human breast cancer. Cancer Res 1983; 43:413.
  48. Amir E, Clemons M, Freedman OC, et al. Tissue confirmation of disease recurrence in patients with breast cancer: Pooled analysis of two large prospective studies (abstract #1007). J Clin Oncol 2010; 28:15s.
  49. Simmons C, Miller N, Geddie W, et al. Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases? Ann Oncol 2009; 20:1499.
  50. Amir E, Clemons M. Should a biopsy be recommended to confirm metastatic disease in women with breast cancer? Lancet Oncol 2009; 10:933.
  51. Khasraw M, Brogi E, Seidman AD. The need to examine metastatic tissue at the time of progression of breast cancer: is re-biopsy a necessity or a luxury? Curr Oncol Rep 2011; 13:17.
  52. Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017; 377:523.
  53. Byrski T, Gronwald J, Huzarski T, et al. Neoadjuvant chemotherapy with Cisplatin in BRCA1 mutation carriers – results of treatment. Hereditary Cancer in Clinical Practice 2012, 10(Suppl 3):A3.
  54. Tutt A, et al. The TNT Trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple-negative or BRCA1/2 breast cancer. Abstract S3-01, AACR-SABCS, San Antonio, TX.
  55. Baselga J, Gomez P, Awada A, et al. The addition of cetuximab to cisplatin increases overall response rate and progression-free survival ini metastatic triple negative breast cancer: results of a randomized phase II study (abstract 2740). Data presented at the 2010 meeting of the European Society of Medical Oncology, Milan, Italy, October 8-12, 2010. http://annonc.oxfordjournals.org/content/21/suppl_8 (Accessed on September 07, 2011).
  56. O'Shaughnessy J, Weckstein D, Vukelja S, et al. Preliminary results of a randomized phase II study of weekly irinotecan/carboplatin with or without cetuximab in patients with metastatic breast cancer. San Antonio Breast Cancer Symposium, 2007. Abstract 308.
  57. Isakoff SJ, Goss PE, Mayer EL, et al. TBCRC009: A multicenter phase II study of cisplatin or carboplatin for metastatic triple-negative breast cancer and evaluation of p63/p73 as a biomarker of response (abstract). J Clin Oncol 2011; 29:86s. Abstract available online at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=76639 (Accessed on July 08, 2011).
  58. O'Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC) (abstract 1007). J Clin Oncol 2011; 29:81s. Abstract available online at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=78038 (Accessed on July 08, 2011).
  59. Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol 2012; 30:2615.
  60. 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.
  61. Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2010; 28:3239.
  62. Brufsky A, Valero V, Tiangco, B, et al. Impact of bevacizumab (BEV) on efficacy of second-line chemotherapy (CT) for triple-negative breast cancer (TNBC): Analysis of RIBBON-2 (abstract 1010). J Clin Oncol 2011; 29:82s. Abstract available online at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=78329 (Accessed on July 08, 2011).
  63. Miles DW, Diéras V, Cortés J, et al. First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol 2013; 24:2773.
  64. Cameron D, Brown J, Dent R, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 2013; 14:933.
  65. Tentori L, Graziani G. Chemopotentiation by PARP inhibitors in cancer therapy. Pharmacol Res 2005; 52:25.
  66. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434:913.
  67. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434:917.
  68. O'Shaughnessy J, Osborne C, Pippen J, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with triple-negative breast cancer (TNBC): Results of a randomized phase II trial. J Clin Oncol 2009. 27: p. Abstract 3.
  69. Tutt A, Robson M, Garber JE, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. J Clin Oncol 2009; 27(18s): p. Abstract CRA501.
  70. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361:123.
  71. 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.
  72. Gelmon KA, Hirte HW, Robidoux A, et al. Macpherson, and A.M. Oza, Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer. J Clin Oncol 2010; 28(15s): p. abstr 3002.
  73. O'Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 2011; 364:205.
  74. Dent RA, Lindeman GJ, Clemons M, et al. Safety and efficacy of the oral PARP inhibitor olaparib (AZD2281) in combination with paclitaxel for the first- or second-line treatment of patients with metastatic triple-negative breast cancer: Results from the safety cohort of a phase I/II multicenter trial. J Clin Oncol 2010; 28(15s).
  75. Isakoff SJ, Overmoyer B, Tung NM, et al. A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. J Clin Oncol 2010; 28(15s): p. abstr 1019.
  76. Cochrane DR, Bernales S, Jacobsen BM, et al. Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res 2014; 16:R7.
  77. Collins LC, Cole KS, Marotti JD, et al. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses' Health Study. Mod Pathol 2011; 24:924.
  78. 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.
  79. 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 33, 2015 (suppl; abstr 1003)
  80. Iglesia MD, Vincent BG, Parker JS, et al. Prognostic B-cell signatures using mRNA-seq in patients with subtype-specific breast and ovarian cancer. Clin Cancer Res 2014; 20:3818.
  81. Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol 2011; 29:1949.
  82. 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.
  83. Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). American Association for Cancer Research 106th Annual Meeting 2015; Philadelphia, PA.