Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Triple-negative breast cancer: disease entity or title of convenience?

Abstract

This Review outlines the understanding and management of triple-negative breast cancer (TNBC). TNBC shares morphological and genetic abnormalities with basal-like breast cancer (BLBC), a subgroup of breast cancer defined by gene-expression profiling. However, TNBC and BLBC tumors are heterogeneous and overlap is incomplete. Breast cancers found in BRCA1 mutation carriers are also frequently triple negative and basal like. TNBC and BLBC occur most frequently in young women, especially African Americans, and tend to exhibit aggressive, metastatic behavior. These tumors respond to conventional chemotherapy but relapse more frequently than hormone receptor-positive, luminal subtypes and have a worse prognosis. New systemic therapies are urgently needed as most patients with TNBC and/or BLBC relapse with distant metastases, and hormonal therapies and HER2-targeted agents are ineffective in this group of tumors. Poly (ADP-ribose) polymerase inhibitors, angiogenesis inhibitors, EGFR-targeted agents, and src kinase and mTOR inhibitors are among the therapeutic agents being actively investigated in clinical trials in patients with TNBC and/or BRCA1-associated tumors. Increased understanding of the genetic abnormalities involved in the pathogenesis of TNBC, BLBC and BRCA1-associated tumors is opening up new therapeutic possibilities for these hard-to-treat breast cancers.

Key Points

  • Triple-negative breast cancer (TNBC), a subgroup that lacks expression of hormone receptors and HER2, overlaps with basal-like breast cancer (BLBC), a subgroup that expresses cytokeratins and other non-luminal (basal) genes

  • Breast cancers occurring in patients with germline BRCA1 mutations are often triple negative and basal like, and BRCA1 defects or deficiency may be involved in sporadic TNBC and BLBC

  • Although heterogeneous, TNBCs and BLBCs typically occur in younger women, and are associated with a range of adverse biological features including high grade, high mitotic count and p53 positivity

  • Although responsive to chemotherapy, TNBCs and BLBCs tend to relapse and metastasize early and have a worse prognosis than other tumor subtypes

  • There are no specific therapies for patients with TNBC or BLBC; new treatments under investigation include novel cytotoxics, poly (ADP-ribose) polymerase inhibitors, angiogenesis inhibitors, EGFR-targeted agents, and src kinase inhibitors

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Shared features of triple-negative, basal-like and BRCA1-associated breast cancers.

References

  1. 1

    Reis-Filho, J. S. & Tutt, A. N. J. Triple negative tumours: a critical review. Histopathology 52, 108–118 (2008).

    CAS  Google Scholar 

  2. 2

    Viale, G. et al. Invasive ductal carcinoma of the breast with the “triple-negative” phenotype: prognostic implications of EGFR immunoreactivity. Breast Cancer Res. Treat. 116, 317–328 (2009).

    CAS  PubMed  Google Scholar 

  3. 3

    Bauer, K. R., Brown, M., Cress, R. D., Parise, C. A. & Caggiano, V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a lpopulation-based study from the California Cancer Registry. Cancer 109, 1721–1728 (2007).

    PubMed  Google Scholar 

  4. 4

    Morris, G. J. et al. Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: a single-institution compilation compared with the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Cancer 110, 876–884 (2007).

    PubMed  Google Scholar 

  5. 5

    Kyndi, M. et al. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group. J. Clin. Oncol. 26, 1419–1426 (2008).

    CAS  PubMed  Google Scholar 

  6. 6

    Dent, R. et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin. Cancer Res. 13, 4429–4434 (2007).

    PubMed  Google Scholar 

  7. 7

    Rakha, E. A. et al. Prognostic markers in triple-negative breast cancer. Cancer 109, 25–32 (2007).

    CAS  PubMed  Google Scholar 

  8. 8

    Tan, D. S. P. et al. Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Res. Treat. 111, 27–44 (2008).

    CAS  PubMed  Google Scholar 

  9. 9

    Cheang, M. C. et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin. Cancer Res. 14, 1368–1376 (2008).

    CAS  PubMed  Google Scholar 

  10. 10

    Kreike, B. et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res. 9, R65 (2007).

    PubMed  PubMed Central  Google Scholar 

  11. 11

    Weigelt, B. et al. Refinement of breast cancer classification by molecular characterization of histological special types. J. Pathol. 216, 141–150 (2008).

    CAS  PubMed  Google Scholar 

  12. 12

    Carey, L. A. et al. Potential predictive markers of benefit from cetuximab in metastatic breast cancer: an analysis of two randomized phase 2 trials [abstract]. Cancer Res. 69 (Suppl.), a2014 (2009).

    Google Scholar 

  13. 13

    Carey, L. A. et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295, 2492–2502 (2006).

    CAS  PubMed  Google Scholar 

  14. 14

    Sasa, M., Bando, Y., Takahashi, M., Hirose, T. & Nagao, T. Screening for basal marker expression is necessary for decision of therapeutic strategy for triple-negative breast cancer. J. Surg. Oncol. 97, 30–34 (2008).

    PubMed  Google Scholar 

  15. 15

    Dabbs, D. J., Chivukula, M., Carter, G. & Bhargava, R. Basal phenotype of ductal carcinoma in situ: recognition and immunohistologic profile. Mod. Pathol. 19, 1506–1511 (2006).

    CAS  PubMed  Google Scholar 

  16. 16

    Van de Rijn, M. et al. Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome. Am. J. Pathol. 161, 1991–1996 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Shin, B. K. et al. Breast carcinomas expressing basal markers have poor clinical outcome regardless of estrogen receptor status. Oncol. Rep. 19, 617–625 (2008).

    PubMed  Google Scholar 

  18. 18

    Tsutsui, S., Ohno, S., Murakami, S., Hachitanda, Y. & Oda, S. Prognostic value of epidermal growth factor receptor (EGFR) and its relationship to the estrogen receptor status in 1029 patients with breast cancer. Breast Cancer Res. Treat. 71, 67–75 (2002).

    PubMed  Google Scholar 

  19. 19

    Boström, P. et al. Analysis of cyclins A, B1, D1 and E in breast cancer in relation to tumour grade and other prognostic factors. BMC Res. Notes 17, 140 (2009).

    Google Scholar 

  20. 20

    Voduc, D., Nielsen, T. O., Cheang, M. C. & Foulkes, W. D. The combination of high cyclin E and Skp2 expression in breast cancer is associated with a poor prognosis and the basal phenotype. Hum. Pathol. 39, 1431–1437 (2008).

    CAS  PubMed  Google Scholar 

  21. 21

    Westfall, M. D. & Pietenpol, J. A. p63: Molecular complexity in development and cancer. Carcinogenesis 25, 857–864 (2004).

    CAS  PubMed  Google Scholar 

  22. 22

    Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Sørlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).

    Google Scholar 

  24. 24

    Sorlie, T. et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl Acad. Sci. USA 100, 8418–8423 (2003).

    CAS  PubMed  Google Scholar 

  25. 25

    Herschkowitz, J. I. et al. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. 8, R76 (2007).

    PubMed  PubMed Central  Google Scholar 

  26. 26

    Charafe-Jauffret, E. et al. Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 25, 2273–2284 (2006).

    CAS  PubMed  Google Scholar 

  27. 27

    Parker, J. S. et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J. Clin. Oncol. 27, 1160–1167 (2009).

    PubMed  PubMed Central  Google Scholar 

  28. 28

    Nielsen, T. O. et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin. Cancer Res. 10, 5367–5374 (2004).

    CAS  PubMed  Google Scholar 

  29. 29

    Gusterson, B. A., Ross, D. T., Heath, V. J. & Stein, T. Basal cytokeratins and their relationship to the cellular origin and functional classification of breast cancer. Breast Cancer Res. 7, 143–148 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Lakhani, S. R. & O'Hare, M. J. The mammary myoepithelial cell--Cinderella or ugly sister? Breast Cancer Res. 3, 1–4 (2001).

    CAS  PubMed  Google Scholar 

  31. 31

    Palacios, J. et al. Anomalous expression of P-cadherin in breast carcinoma. Correlation with E-cadherin expression and pathological features. Am. J. Pathol. 146, 605–612 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Sotiriou, C. et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc. Natl Acad. Sci. USA 100, 10393–10398 (2003).

    CAS  PubMed  Google Scholar 

  33. 33

    Moyano, J. V. et al. AlphaB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer. J. Clin. Invest. 116, 261–270 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Shien, T. et al. Frequent overexpression of epidermal growth factor receptor (EGFR) in mammary high grade ductal carcinomas with myoepithelial differentiation. J. Clin. Pathol. 58, 1299–1304 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Abd El-Rehim, D. M. et al. Expression of luminal and basal cytokeratins in human breast carcinoma. J. Pathol. 203, 661–671 (2004).

    PubMed  Google Scholar 

  36. 36

    Bertolo, C. et al. Differences and molecular immunohistochemical parameters in the subtypes of infiltrating ductal breast cancer. Am. J. Clin. Pathol. 130, 414–424 (2008).

    CAS  PubMed  Google Scholar 

  37. 37

    Rodriguez-Pinilla, S. M. et al. Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin. Cancer Res. 12, 1533–1539 (2006).

    CAS  PubMed  Google Scholar 

  38. 38

    Jones, C. et al. Molecular cytogenetic identification of subgroups of grade III invasive ductal breast carcinomas with different clinical outcomes. Clin. Cancer Res. 10, 5988–5997 (2004).

    CAS  PubMed  Google Scholar 

  39. 39

    Liu, H., Fan, Q., Zhang, Z., Yu, H. & Meng, F. Basal-HER2 phenotype shows poorer survival than basal-like phenotype in hormone receptor-negative invasive breast cancers. Hum. Pathol. 39, 167–174 (2008).

    CAS  PubMed  Google Scholar 

  40. 40

    Livasy, C. A. et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod. Pathol. 19, 264–271 (2006).

    CAS  PubMed  Google Scholar 

  41. 41

    Waddell, N. et al. Subtypes of familial breast tumours revealed by expression and copy number profiling. Breast Cancer Res. Treat. doi:10.1007/s10549-009-0653-1.

    PubMed  Google Scholar 

  42. 42

    Richardson, A. L. et al. X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9, 121–132 (2006).

    CAS  Google Scholar 

  43. 43

    Turner, N., Tutt, A. & Ashworth, A. Hallmarks of 'BRCAness' in sporadic cancers. Nat. Rev. Cancer 4, 814–819 (2004).

    CAS  PubMed  Google Scholar 

  44. 44

    Korsching, E. et al. The origin of vimentin expression in invasive breast cancer: epithelial-mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential? J. Pathol. 206, 451–457 (2005).

    CAS  PubMed  Google Scholar 

  45. 45

    Korsching, E. 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. 82, 1525–1533 (2002).

    CAS  PubMed  Google Scholar 

  46. 46

    Herschkowitz, J. I., He, X., Fan, C. & Perou, C. M. The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res. 10, R75 (2008).

    PubMed  PubMed Central  Google Scholar 

  47. 47

    Sarrió, D. et al. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 68, 989–997 (2008).

    PubMed  Google Scholar 

  48. 48

    Vincent-Salomon, A. & Thiery, J. P. Host microenvironment in breast cancer development: epithelial-mesenchymal transition in breast cancer development. Breast Cancer Res. 5, 101–106 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Petersen, O. W. et al. The plasticity of human breast carcinoma cells is more than epithelial to mesenchymal conversion. Breast Cancer Res. 3, 213–217 (2001).

    CAS  PubMed  Google Scholar 

  50. 50

    Jones, C. et al. Expression profiling of purified normal human luminal and myoepithelial breast cells: identification of novel prognostic markers for breast cancer. Cancer Res. 64, 3037–3045 (2004).

    CAS  PubMed  Google Scholar 

  51. 51

    Gordon, L. A. et al. Breast cell invasive potential relates to the myoepithelial phenotype. Int. J. Cancer 106, 8–16 (2003).

    CAS  PubMed  Google Scholar 

  52. 52

    Creighton, C. J. et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl Acad. Sci. USA 106, 13820–13825 (2009).

    CAS  PubMed  Google Scholar 

  53. 53

    Hennessy, B. T. et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 69, 4116–4124 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Deugnier, M. A. et al. EGF controls the in vivo developmental potential of a mammary epithelial cell line possessing progenitor properties. J. Cell Biol. 159, 453–463 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Kim, M. J. et al. Clinicopathologic significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and Her2/neu-overexpressing phenotypes. Hum. Pathol. 37, 1217–1226 (2006).

    CAS  PubMed  Google Scholar 

  56. 56

    Reis-Filho, J. S. et al. Novel and classic myoepithelial/stem cell markers in metaplastic carcinomas of the breast. Appl. Immunohistochem. Mol. Morphol. 11, 1–8 (2003).

    CAS  PubMed  Google Scholar 

  57. 57

    Jacquemier, J. et al. Typical medullary breast carcinomas have a basal/myoepithelial phenotype. J. Pathol. 207, 260–268 (2005).

    CAS  PubMed  Google Scholar 

  58. 58

    Van Laere, S. J. et al. Identification of cell-of-origin breast tumor subtypes in inflammatory breast cancer by gene expression profiling. Breast Cancer Res. Treat. 95, 243–255 (2006).

    PubMed  Google Scholar 

  59. 59

    Bertucci, F. et al. Gene expression profiling identifies molecular subtypes of inflammatory breast cancer. Cancer Res. 65, 2170–2178 (2005).

    CAS  PubMed  Google Scholar 

  60. 60

    Adélaïde, J. et al. Integrated profiling of basal and luminal breast cancers. Cancer Res. 67, 11565–11575 (2007).

    PubMed  Google Scholar 

  61. 61

    Chin, K. et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10, 529–541 (2006).

    CAS  PubMed  Google Scholar 

  62. 62

    Melchor, L. et al. Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes. Oncogene 27, 3165–3175 (2008).

    CAS  PubMed  Google Scholar 

  63. 63

    Chin, S. F. et al. High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer. Genome Biol. 8, R215 (2007).

    PubMed  PubMed Central  Google Scholar 

  64. 64

    Rakha, E. A. & Ellis, I. O. Triple-negative/basal-like breast cancer: review. Pathology 41, 40–47 (2009).

    PubMed  Google Scholar 

  65. 65

    Rakha, E. A. et al. Are triple negative tumours and basal-like breast cancer synonymous? Breast Cancer Res. 9, 404 (2007).

    PubMed  PubMed Central  Google Scholar 

  66. 66

    Rouzier, R. et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin. Cancer Res. 11, 5678–5685 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Banerjee, S. et al. Basal-like breast carcinomas: clinical outcome and response to chemotherapy. J. Clin. Pathol. 59, 729–735 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Rakha, E. A. et al. Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin. Cancer Res. 15, 2302–2310 (2009).

    CAS  PubMed  Google Scholar 

  69. 69

    Van't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    CAS  Google Scholar 

  70. 70

    Foulkes, W. D. et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J. Natl Cancer Inst. 95, 1482–1485 (2003).

    CAS  PubMed  Google Scholar 

  71. 71

    Lakhani, S. R. et al. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin. Cancer Res. 11, 5175–5180 (2005).

    CAS  PubMed  Google Scholar 

  72. 72

    Lidereau, R. et al. Major improvement in the efficacy of BRCA1 mutation screening using morphoclinical features of breast cancer. Cancer Res. 60, 1206–1210 (2000).

    CAS  PubMed  Google Scholar 

  73. 73

    Stefansson, O. A. et al. Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes. Breast Cancer Res. 11, R47 (2009).

    PubMed  PubMed Central  Google Scholar 

  74. 74

    Ashworth, A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J. Clin. Oncol. 26, 3785–3790 (2008).

    CAS  PubMed  Google Scholar 

  75. 75

    Carey, L. A. Targeted chemotherapy? Platinum in BRCA1-dysfunctional breast cancer. J. Clin. Oncol. 28, 361–363 (2010).

    CAS  PubMed  Google Scholar 

  76. 76

    Alli, E., Sharma, V. B., Sunderesakumar, P. & Ford, J. M. Defective repair of oxidative DNA damage in triple-negative breast cancer confers sensitivity to inhibition of poly(ADP-ribose) polymerase. Cancer Res. 69, 3589–3596 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Rakha, E. A. et al. Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum. Pathol. 39, 857–865 (2008).

    CAS  PubMed  Google Scholar 

  78. 78

    Turner, N. C. et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26, 2126–2132 (2007).

    CAS  PubMed  Google Scholar 

  79. 79

    Matros, E. et al. BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles. Breast Cancer Res. Treat. 91, 179–186 (2005).

    CAS  PubMed  Google Scholar 

  80. 80

    Perreard, L. et al. Classification and risk stratification of invasive breast carcinomas using a real-time quantitative RT-PCR assay. Breast Cancer Res. 8, R23 (2006).

    PubMed  PubMed Central  Google Scholar 

  81. 81

    Tang, P., Wang, J. & Bourne, P. Molecular classifications of breast carcinoma with similar terminology and different definitions: are they the same? Hum. Pathol. 39, 506–513 (2008).

    CAS  PubMed  Google Scholar 

  82. 82

    Harris, L. N. et al. Molecular subtypes of breast cancer in relation to paclitaxel response and outcomes in women with metastatic disease: results from CALGB 9342. Breast Cancer Res. 8, R66 (2006).

    PubMed  PubMed Central  Google Scholar 

  83. 83

    Stead, L. A. et al. Triple-negative breast cancers are increased in black women regardless of age or body mass index. Breast Cancer Res. 11, R18 (2009).

    PubMed  PubMed Central  Google Scholar 

  84. 84

    Huo, D. et al. Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer. J. Clin. Oncol. 27, 4515–4521 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Yin, W. J. et al. Clinicopathological features of the triple-negative tumors in Chinese breast cancer patients. Breast Cancer Res. Treat. 115, 325–333 (2009).

    PubMed  Google Scholar 

  86. 86

    Lin, C. et al. Triple negative breast carcinoma is a prognostic factor in Taiwanese women. BMC Cancer 9, 192 (2009).

    PubMed  PubMed Central  Google Scholar 

  87. 87

    Kurebayashi, J. et al. The prevalence of intrinsic subtypes and prognosis in breast cancer patients of different races. Breast 16 (Suppl. 2), S72–S77 (2007).

    PubMed  Google Scholar 

  88. 88

    Lund, M. J. et al. Molecular differences between the triple negative tumors of African-American women and white women [abstract]. San Antonio Breast Cancer Symp. a2087 (2008).

  89. 89

    Millikan, R. C. et al. Epidemiology of basal-like breast cancer. Breast Cancer Res. Treat. 109, 123–139 (2008).

    PubMed  Google Scholar 

  90. 90

    Liu, B. et al. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle 8, 2031–2040 (2009).

    CAS  PubMed  Google Scholar 

  91. 91

    Jiralerspong, S. et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J. Clin. Oncol. 27, 3297–3302 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Goodwin, P. J., Ligibel, J. A. & Stambolic, V. Metformin in breast cancer: time for action. J. Clin. Oncol. 27, 3271–3273 (2009).

    CAS  PubMed  Google Scholar 

  93. 93

    Dolle, J. M. et al. Risk factors for triple-negative breast cancer in women under the age of 45 years. Cancer Epidemiol. Biomarkers Prev. 18, 1157–1166 (2009).

    PubMed  PubMed Central  Google Scholar 

  94. 94

    Foulkes, W. D. et al. Disruption of the expected positive correlation between breast tumor size and lymph node status in BRCA1-related breast carcinoma. Cancer 98, 1569–1577 (2003).

    PubMed  Google Scholar 

  95. 95

    Uematsu, T., Kasami, M. & Yuen, S. Triple-negative breast cancer: correlation between MR imaging and pathologic findings. Radiology 250, 638–647 (2009).

    PubMed  Google Scholar 

  96. 96

    Lin, N. U. 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 113, 2638–2645 (2008).

    PubMed  PubMed Central  Google Scholar 

  97. 97

    Minn, A. J. et al. Lung metastasis genes couple breast tumor size and metastatic spread. Proc. Natl Acad. Sci. USA 104, 6740–6745 (2007).

    CAS  PubMed  Google Scholar 

  98. 98

    Jumppanen, M. et al. Basal-like phenotype is not associated with patient survival in estrogen-receptor-negative breast cancers. Breast Cancer Res. 9, R16 (2007).

    PubMed  PubMed Central  Google Scholar 

  99. 99

    Nguyen, P. L. et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J. Clin. Oncol. 26, 2373–2378 (2008).

    PubMed  Google Scholar 

  100. 100

    Voduc, K. D. et al. Breast cancer subtypes and the risk of local and regional relapse. J. Clin. Oncol. 28, 1684–1691 (2010).

    PubMed  Google Scholar 

  101. 101

    Berry, D. A. et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295, 1658–1667 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Carey, L. A. et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin. Cancer Res. 13, 2329–2334 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Tanner, M. et al. Topoisomerase II alpha gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401. J. Clin. Oncol. 24, 2428–2436 (2006).

    CAS  PubMed  Google Scholar 

  104. 104

    Troester, M. A. et al. Cell-type-specific responses to chemotherapeutics in breast cancer. Cancer Res. 64, 4218–4226 (2004).

    CAS  PubMed  Google Scholar 

  105. 105

    Falo, C. et al. HER-2/neu status and response to CMF: retrospective study in a series of operable breast cancer treated with primary CMF chemotherapy. J. Cancer Res. Clin. Oncol. 133, 423–429 (2007).

    CAS  PubMed  Google Scholar 

  106. 106

    Cheang, M. et al. Anthracyclines in basal breast cancer: the NCIC-CTG trial MA5 comparing adjuvant CMF to CEF [abstract]. J. Clin. Oncol. 27 (15 Suppl.), a519 (2009).

    Google Scholar 

  107. 107

    Kennedy, R. D., Quinn, J. E., Mullan, P. B., Johnston, P. G. & Harkin, D. P. The role of BRCA1 in the cellular response to chemotherapy. J. Natl Cancer Inst. 96, 1659–1668 (2004).

    CAS  PubMed  Google Scholar 

  108. 108

    Byrski, T. et al. Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res. Treat. 115, 359–363 (2009).

    CAS  PubMed  Google Scholar 

  109. 109

    Sirohi, B. et al. Platinum-based chemotherapy in triple-negative breast cancer. Ann. Oncol. 19, 1847–1852 (2008).

    CAS  PubMed  Google Scholar 

  110. 110

    Uhm, J. E. et al. Treatment outcomes and clinicopathologic characteristics of triple-negative breast cancer patients who received platinum-containing chemotherapy. Int. J. Cancer 124, 1457–1462 (2009).

    CAS  PubMed  Google Scholar 

  111. 111

    Silver, D. P. et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J. Clin. Oncol. 28, 1145–1153 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Delaloge, S. et al. Preliminary safety and activity results of trabectedin in a phase II trial dedicated to triple-negative (ER, PR, HER2), HER2+++, or BRCA 1/2 germ-line-mutated metastatic breast cancer (MBC) patients (pts) [abstract]. J. Clin. Oncol. 27 (15 Suppl.), a1010 (2009).

    Google Scholar 

  113. 113

    Denduluri, N. & Swain, S. M. Ixabepilone for the treatment of solid tumors: a review of clinical data. Expert Opin. Investig. Drugs 17, 423–435 (2008).

    CAS  PubMed  Google Scholar 

  114. 114

    Rugo, H. S. et al. Ixabepilone plus capecitabine vs capecitabine in patients with triple negative tumors: a pooled analysis of patients from two large phase III clinical studies [abstract]. San Antonio Breast Cancer Symp. a3057 (2008).

  115. 115

    Rouleau, M., Patel, A., Hendzel, M. J., Kaufmann, S. H. & Poirier, G. G. PARP inhibition: PARP1 and beyond. Nat. Rev. Cancer 10, 293–301 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

    CAS  PubMed  Google Scholar 

  117. 117

    Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Plummer, R. et al. Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin. Cancer Res. 14, 7917–7923 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Plummer, R. et al. First and final report of a phase II study of the poly (ADP-ribose) polymerase (PARP) inhibitor, AG014699, in combination with temozolomide (TMZ) in patients with metastatic malignant melanoma (MM) [abstract]. J. Clin. Oncol. 24 (18 Suppl.), a8013 (2006).

    Google Scholar 

  120. 120

    Kopetz, S. et al. First in human phase I study of BSI-201, a small molecule inhibitor of poly ADP-ribose polymerase (PARP) in subjects with advanced solid tumors [abstract]. J. Clin. Oncol. 26 (Suppl.), a3577 (2008).

    Google Scholar 

  121. 121

    Mahany, J. J. et al. A phase IB study evaluating BSI-201 in combination with chemotherapy in subjects with advanced solid tumors [abstract]. J. Clin. Oncol. 26 (Suppl.), a3579 (2008).

    Google Scholar 

  122. 122

    O'Shaughnessy, 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 metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial [abstract]. J. Clin. Oncol. 26 (Suppl.), a3 (2009).

    Google Scholar 

  123. 123

    Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

    CAS  PubMed Central  Google Scholar 

  124. 124

    Tutt, A. 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 376, 235–244 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Gelmon, K. A. et al. 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 [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a3002 (2010).

    Google Scholar 

  126. 126

    Isakoff, S. J. et al. A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a1019 (2010).

    Google Scholar 

  127. 127

    Miller, K. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 357, 2666–2676 (2007).

    CAS  Google Scholar 

  128. 128

    Miles, D. W. 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. 28, 3239–3247 (2010).

    CAS  PubMed  Google Scholar 

  129. 129

    Ryan, P. D. et al. Neoadjuvant cisplatin and bevacizumab in triple negative breast cancer (TNBC): safety and efficacy [abstract]. J. Clin. Oncol. 27 (15 Suppl.), a551 (2009).

    Google Scholar 

  130. 130

    Burstein, H. J. et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J. Clin. Oncol. 26, 1810–1816 (2008).

    CAS  PubMed  Google Scholar 

  131. 131

    Bhargava, R. et al. EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations. Mod. Pathol. 18, 1027–1033 (2005).

    CAS  PubMed  Google Scholar 

  132. 132

    Reis-Filho, J. S. et al. EGFR amplification and lack of activating mutations in metaplastic breast carcinomas. J. Pathol. 209, 445–453 (2006).

    CAS  PubMed  Google Scholar 

  133. 133

    Nechushtan, H., Steinberg, H. & Peretz, T. Prelimenary results of a phase I/II of a combination of cetuximab and taxane for triple negative breast cancer patients [abstract]. J. Clin. Oncol. 27 (15 Suppl.), e12018 (2009).

    Google Scholar 

  134. 134

    Carey, L. A. et al. TBCRC 001: EGFR inhibition with cetuximab added to carboplatin in metastatic triple-negative (basal-like) breast cancer. J. Clin. Oncol. 26 (Suppl.), a1009 (2008).

    Google Scholar 

  135. 135

    O'Shaughnessy, J. et al. Preliminary results of a randomized phase II study of weekly irinotecan/carboplatin with or without cetuximab in patients with metastatic breast cancer [abstract 308]. Breast Cancer Res. Treat. 106 (Suppl. 1), S32 (2007).

    Google Scholar 

  136. 136

    Verbeek, B. S. et al. c-Src protein expression is increased in human breast cancer. An immunohistochemical and biochemical analysis. J. Pathol. 180, 383–388 (1996).

    CAS  PubMed  Google Scholar 

  137. 137

    Hiscox, S. et al. Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells. Breast Cancer Res. Treat. 97, 263–274 (2006).

    CAS  PubMed  Google Scholar 

  138. 138

    Finn, R. S. et al. Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Res. Treat. 105, 319–326 (2007).

    CAS  PubMed  Google Scholar 

  139. 139

    Finn, R. S. et al. Phase II trial of dasatinib in triple-negative breast cancer: results of study CA180059 [abstract]. San Antonio Breast Cancer Symp. a3118 (2008).

  140. 140

    Savage, K. et al. Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis. Clin. Cancer Res. 13, 90–101 (2007).

    CAS  PubMed  Google Scholar 

  141. 141

    Savage, K. et al. Distribution and significance of caveolin 2 expression in normal breast and invasive breast cancer: an immunofluorescence and immunohistochemical analysis. Breast Cancer Res. Treat. 110, 245–256 (2008).

    CAS  PubMed  Google Scholar 

  142. 142

    Farmer, P. et al. Identification of molecular apocrine breast tumours by microarray analysis. Oncogene 24, 4660–4671 (2005).

    CAS  Google Scholar 

  143. 143

    Agoff, S. N., Swanson, P. E., Linden, H., Hawes, S. E. & Lawton, T. J. Androgen receptor expression in estrogen receptor-negative breast cancer. Immunohistochemical, clinical, and prognostic associations. Am. J. Clin. Pathol. 120, 725–731 (2003).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank C. Barton (consultant of Fondazione Michelangelo, the non-profit organization that organized the seminar on TNBC) for assistance in preparing the manuscript.

Author information

Affiliations

Authors

Contributions

All authors researched the data for the article and provided a substantial contribution to discussions of the content. L. Carey wrote the article and all authors contributed to the review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Luca Gianni.

Ethics declarations

Competing interests

E. Winer has received grants or research support from Genentech. D. Cameron acts as a consultant for and has received research support from Pfizer and Roche and is a consultant for Sanofi-Aventis. L. Gianni acts as a consultant for Biogen Idec, Eisai, Genentech, GlaxoSmithKline, Millennium Pharmaceuticals, Novartis, Roche and Sanofi-Aventis. L. Carey and G. Viale declare no competing interests.

Supplementary information

Supplementary Table 1

Ongoing randomized trials of treatment in TNBC, BLBC and/or BRCA1 breast cancer (DOC 84 kb)

Supplementary Table 2

Ongoing trials of PARP inhibitors in TNBC, BLBC and/or BRCA1 breast cancer (DOC 93 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Carey, L., Winer, E., Viale, G. et al. Triple-negative breast cancer: disease entity or title of convenience?. Nat Rev Clin Oncol 7, 683–692 (2010). https://doi.org/10.1038/nrclinonc.2010.154

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing