Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease

Nature Reviews Clinical Oncology

Volumn 13, Issue 11, 2016, Pages 674-690

  Bianchini, Giampaolo ^a   Balko, Justin M ^b,c   Mayer, Ingrid A ^b   Sanders, Melinda E ^b   Gianni, Luca ^a  

^a SAN RAFFAELE HOSPITAL   (Italy)

^b VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^c VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANDROGEN RECEPTOR; ANTIANDROGEN; ANTINEOPLASTIC AGENT; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ESTROGEN RECEPTOR; HEAT SHOCK PROTEIN 90 INHIBITOR; HISTONE DEACETYLASE INHIBITOR; IMMUNE CHECKPOINT INHIBITOR; IMMUNOMODULATING AGENT; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE INHIBITOR; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PLATINUM COMPLEX; PROGESTERONE RECEPTOR; RAF PROTEIN; RAS PROTEIN; UNCLASSIFIED DRUG; BRAP PROTEIN, HUMAN; BRCA2 PROTEIN; BRCA2 PROTEIN, HUMAN; MITOGEN ACTIVATED PROTEIN KINASE; TUMOR MARKER; UBIQUITIN PROTEIN LIGASE;

ADVANCED CANCER; BREAST CARCINOGENESIS; CANCER CHEMOTHERAPY; CANCER CLASSIFICATION; CANCER DIAGNOSIS; CANCER IMMUNOTHERAPY; CANCER PATIENT; CANCER PROGNOSIS; CANCER RECURRENCE; CANCER STAGING; CLINICAL TRIAL (TOPIC); GERMLINE MUTATION; HISTOPATHOLOGY; HUMAN; IMMUNOHISTOCHEMISTRY; LOW RISK PATIENT; MOLECULAR GENETICS; MOLECULAR PATHOLOGY; MOLECULARLY TARGETED THERAPY; NONHUMAN; PREDICTIVE VALUE; PRIORITY JOURNAL; RECURRENCE RISK; REVIEW; TREATMENT RESPONSE; TRIPLE NEGATIVE BREAST CANCER; TUMOR ASSOCIATED LEUKOCYTE; TUMOR MICROENVIRONMENT; TUMOR SUPPRESSOR GENE; ANTAGONISTS AND INHIBITORS; CANCER STEM CELL; CLASSIFICATION; DRUG EFFECTS; FEMALE; GENETICS; IMMUNE SYSTEM; IMMUNOLOGY; IMMUNOTHERAPY; METABOLISM; MUTATION; PROCEDURES; PROGNOSIS; TRIPLE NEGATIVE BREAST NEOPLASMS;

ANDROGEN ANTAGONISTS; BIOMARKERS, TUMOR; BRCA2 PROTEIN; CLINICAL TRIALS AS TOPIC; FEMALE; HUMANS; IMMUNE SYSTEM; IMMUNOTHERAPY; MITOGEN-ACTIVATED PROTEIN KINASES; MOLECULAR TARGETED THERAPY; MUTATION; NEOPLASTIC STEM CELLS; PHOSPHATIDYLINOSITOL 3-KINASES; POLY(ADP-RIBOSE) POLYMERASE INHIBITORS; PROGNOSIS; TRIPLE NEGATIVE BREAST NEOPLASMS; UBIQUITIN-PROTEIN LIGASES;

EID: 84994112876     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2016.66     Document Type: Review

References (189)

1. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70 (2012
2. Banerji, S., et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405-409 (2012
3. Kandoth, C., et al. Mutational landscape and significance across 12 major cancer types. Nature 502, 333-339 (2013
4. Shah, S. P., et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486, 395-399 (2012
5. Curtis, C., et al. The genomic and transcriptomic architecture of 2, 000 breast tumours reveals novel subgroups. Nature 486, 346-352 (2012
6. National Comprehensive Cancer Network National Comprehensive Cancer Network Breast Cancer, https://www.nccn.org/store/login/login.aspx- ReturnURL=http://www.nccn.org/professionals/physician-gls/pdf/breast.pdf (2015
7. Malorni, L., et al. Clinical and biologic features of triple-negative breast cancers in a large cohort of patients with long-term follow up. Breast Cancer Res. Treat. 136, 795-804 (2012
8. Hammond, M. E., 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. 28, 2784-2795 (2010
9. Wolff, A. C., 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. 31, 3997-4013 (2013
10. McCullough, A. E., et al. Central pathology laboratory review of HER2 and ER in early breast cancer: an ALTTO trial [BIG 2 06/NCCTG N063D (Alliance)] ring study. Breast Cancer Res. Treat. 143, 485-492 (2014
11. Viale, G., et al. High concordance of protein (by IHC), gene (by FISH; HER2 only), and microarray readout (by TargetPrint) of ER, PgR, and HER2: results from the EORTC 10041/BIG 03-04 MINDACT trial. Ann. Oncol. 25, 816-823 (2014
12. Cheang, M. C., et al. Defining breast cancer intrinsic subtypes by quantitative receptor expression. Oncology 20, 474-482 (2015
13. Iwamoto, T., 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. 30, 729-734 (2012
14. Weigelt, B., & Reis-Filho, J. S. Histological and molecular types of breast cancer: is there a unifying taxonomy? Nat. Rev. Clin. Oncol. 6, 718-730 (2009
15. Bertucci, F., et al. Gene expression profiling shows medullary breast cancer is a subgroup of basal breast cancers. Cancer Res. 66, 4636-4644 (2006
16. Huober, J., et al. Prognosis of medullary breast cancer: analysis of 13 International Breast Cancer Study Group (IBCSG) trials. Ann. Oncol. 23, 2843-2851 (2012
17. Wetterskog, D., et al. Adenoid cystic carcinomas constitute a genomically distinct subgroup of triple-negative and basal-like breast cancers. J. Pathol. 226, 84-96 (2012
18. Perou, C., et al. Molecular portraits of human breast tumours. Nature 406, 747-752 (2000
19. Sorlie, T., et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869-10874 (2001
20. Parker, J. S., et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J. Clin. Oncol. 27, 1160-1167 (2009
21. Hoadley, K. A., et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158, 929-944 (2014
22. Foulkes, W. D., Smith, I. E., & Reis-Filho, J. S. Triple-negative breast cancer. N. Engl. J. Med. 363, 1938-1948 (2010
23. Prat, A., et al. Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncology 18, 123-133 (2013
24. Prat, A., et al. Predicting response and survival in chemotherapy-treated triple-negative breast cancer. Br. J. Cancer 111, 1532-1541 (2014
25. Sikov, W. M., et al. Abstract S4 05: impact of intrinsic subtype by PAM50 and other gene signatures on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) +/- carboplatin (Cb) or bevacizumab (Bev): CALGB 40603/150709 (Allianc. Cancer Res. 75, S4 05 (2015
26. Isakoff, S. J., et al. TBCRC009: a multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J. Clin. Oncol. 33, 1902-1909 (2015
27. Tutt, A., et al. Abstract S3 01: the TNT trial: a randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). Cancer Res. 75, S30 01 (2015
28. Carey, L., Winer, E., Viale, G., Cameron, D., & Gianni, L. Triple-negative breast cancer: disease entity or title of convenience- Nat. Rev. Clin. Oncol. 7, 683-692 (2010
29. Lehmann, B. D., et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest. 121, 2750-2767 (2011
30. Lehmann, B. D., & Pietenpol, J. A. Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J. Pathol. 232, 142-150 (2014
31. Masuda, H., et al. Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes. Clin. Cancer Res. 19, 5533-5540 (2013
32. Ciriello, G., et al. Emerging landscape of oncogenic signatures across human cancers. Nat. Genet. 45, 1127-1133 (2013
33. Lehmann, B. D., et al. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res. 16, 406 (2014
34. Bose, R., et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 3, 224-237 (2013
35. Jameson, J. L., & Longo, D. L. Precision medicine- personalized, problematic, and promising. N. Engl. J. Med. 372, 2229-2234 (2015
36. Redig, A. J., & J-nne, P. A. Basket trials and the evolution of clinical trial design in an era of genomic medicine. J. Clin. Oncol. http://dx.doi.org/10.1200/JCO.2014.59.8433 (2015
37. Stephens, P. J., et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400-404 (2012
38. Ding, L., et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999-1005 (2010
39. Navin, N., et al. Tumour evolution inferred by single-cell sequencing. Nature 472, 90-94 (2011
40. Wang, Y., et al. Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature 512, 155-160 (2014
41. Venkitaraman, A. R. Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu. Rev. Pathol. 4, 461-487 (2009
42. Atchley, D. P., et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J. Clin. Oncol. 26, 4282-4288 (2008
43. Turner, N., Tutt, A., & Ashworth, A. Hallmarks of-BRCAness- in sporadic cancers. Nat. Rev. Cancer 4, 814-819 (2004
44. Yun, M. H., & Hiom, K. CtIP BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle. Nature 459, 460-463 (2009
45. Yoshida, K., & Miki, Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci. 95, 866-871 (2004
46. Scully, R., et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88, 265-275 (1997
47. Taniguchi, T., et al S phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood 100 2414-2420 2002
48. Bhattacharyya, A., Ear, U. S., Koller, B. H., Weichselbaum, R. R., & Bishop, D. K. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J. Biol. Chem. 275, 23899-23903 (2000
49. Ding, S. L., et al. Abnormality of the DNA double-strand-break checkpoint/repair genes, ATM, BRCA1 and TP53, in breast cancer is related to tumour grade. Br. J. Cancer 90, 1995-2001 (2004
50. Antoniou, A., et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 72, 1117-1130 (2003
51. Foulkes, W. D., et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J. Natl Cancer Inst. 95, 1482-1485 (2003
52. Telli, M. L., et al. Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumor-based measure of genomic instability: PrECOG 0105. J. Clin. Oncol. 33, 1895-1901 (2015
53. Turner, N. C., et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26, 2126-2132 (2007
54. Watkins, J., et al. Genomic complexity profiling reveals that HORMAD1 overexpression contributes to homologous recombination deficiency in triple-negative breast cancers. Cancer Discov. 5, 488-505 (2015
55. Matros, E., et al. BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles. Breast Cancer Res. Treat. 91, 179-186 (2005
56. Turner, N. C., & Reis-Filho, J. S. Basal-like breast cancer and the BRCA1 phenotype. Oncogene 25, 5846-5853 (2006
57. Couch, F. J., et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J. Clin. Oncol. 33, 304-311 (2015
58. Schnurbein, G., et al. RAD51C deletion screening identifies a recurrent gross deletion in breast cancer and ovarian cancer families. Breast Cancer Res 15, R120 2013
59. Abkevich, V., et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br. J. Cancer 107, 1776-1782 (2012
60. Birkbak, N. J., et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov. 2, 366-375 (2012
61. Popova, T., et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res. 72, 5454-5462 (2012
62. Early Breast Cancer Trialists- Collaborative Group. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. Lancet 379, 432-444 (2012
63. Cortazar, P., et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384, 164-172 (2014
64. Carey, L. A., et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin. Cancer Res. 13, 2329-2334 (2007
65. Darb-Esfahani, S., et al Identification of biology-based breast cancer types with distinct predictive and prognostic features: role of steroid hormone and HER2 receptor expression in patients treated with neoadjuvant anthracycline/taxane-based chemotherapy. Breast Cancer Res 11, R69 (2009
66. Liedtke, C., et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J. Clin. Oncol. 26, 1275-1281 (2008
67. von Minckwitz, G., et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J. Clin. Oncol. 30, 1796-1804 (2012
68. Citron, M. L., et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J. Clin. Oncol. 21, 1431-1439 (2003
69. 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
70. Gluz, O., et al. Triple-negative high-risk breast cancer derives particular benefit from dose intensification of adjuvant chemotherapy: results of WSG AM 01 trial. Ann. Oncol. 19, 861-870 (2008
71. Henderson, I. C., et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J. Clin. Oncol. 21, 976-983 (2003
72. Mazouni, C., et al. Inclusion of taxanes, particularly weekly paclitaxel, in preoperative chemotherapy improves pathologic complete response rate in estrogen receptor-positive breast cancers. Ann. Oncol. 18, 874-880 (2007
73. Hayes, D. F., et al. HER2 and response to paclitaxel in node-positive breast cancer. N. Engl. J. Med. 357, 1496-1506 (2007
74. Bonotto, M., et al. Measures of outcome in metastatic breast cancer: insights from a real-world scenario. Oncologist 19, 608-615 (2014
75. Conlin, A. K., & Seidman, A. D. Taxanes in breast cancer: an update. Curr. Oncol. Rep. 9, 22-30 (2007
76. Cardoso, F., et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Ann. Oncol. 25, 1871-1888 (2014
77. Partridge, A. H., et al. Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2 negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 32, 3307-3329 (2014
78. Sparano, J. A., 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. 28, 3256-3263 (2010
79. 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
80. Jones, R. L., et al. The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer. Breast Cancer Res. Treat. 116, 53-68 (2009
81. Guarneri, V., et al. A prognostic model based on nodal status and Ki 67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy. Ann. Oncol. 20, 1193-1198 (2009
82. Byrski, T., et al. Pathologic complete response to neoadjuvant cisplatin in BRCA1 positive breast cancer patients. Breast Cancer Res. Treat. 147, 401-405 (2014
83. Silver, D. P., et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J. Clin. Oncol. 28, 1145-1153 (2010
84. Ryan, P. D. Neoadjuvant cisplatin and bevacizumab in triple negative breast cancer (TNBC): safety and efficacy [abstract] J. Clin. Oncol. 27 (Suppl.), 551 (2009
85. Sikov, W. M., et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J. Clin. Oncol. 33, 13-21 (2015
86. von Minckwitz, G., 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. 15, 747-756 (2014
87. Symmans, W. F., et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J. Clin. Oncol. 25, 4414-4422 (2007
88. Balko, J., et al. Profiling of triple-negative breast cancers after neoadjuvant chemotherapy identifies targetable molecular alterations in the treatment-refractory residual disease. Cancer Res 72, S3-S6 2012
89. Bauer, J. A., et al. RNA interference (RNAi) screening approach identifies agents that enhance paclitaxel activity in breast cancer cells. Breast Cancer Res 12, R41 2010
90. Balko, J. M., et al. Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nat. Med. 18, 1052-1059 (2012
91. Balko, J. M., et al. Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov. 4, 232-245 (2014
92. Audebert, M., Salles, B., & Calsou, P. Involvement of poly(ADP-ribose) polymerase 1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J. Biol. Chem. 279, 55117-55126 (2004
93. Shall, S., & De Murcia, G. Poly(ADP-ribose) polymerase 1: what have we learned from the deficient mouse model? Mutat. Res. 460, 1-15 (2000
94. Burkle, A. Poly(APD-ribosyl)ation, a DNA damage-driven protein modification and regulator of genomic instability. Cancer Lett. 163, 1-5 (2001
95. Farmer, H., et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917-921 (2005
96. Bryant, H. E., et al. Specific killing of BRCA2 deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913-917 (2005
97. Turner, N., Tutt, A., & Ashworth, A. Targeting the DNA repair defect of BRCA tumours. Curr. Opin. Pharmacol. 5, 388-393 (2005
98. Turner, N. C., et al. A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. EMBO J. 27, 1368-1377 2008
99. Calabrese, C. R., et al. Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase 1 inhibitor AG14361. J. Natl Cancer Inst. 96, 56-67 (2004
100. 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
101. Gelmon, K. A., 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. 12, 852-861 (2011
102. Sinha, G. Downfall of iniparib: a PARP inhibitor that doesn-t inhibit PARP after all. J. Natl Cancer Inst 106, djt447 2014
103. Rugo, H. S., et al. Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: first efficacy results from the I SPY 2 TRIAL [abstract]. Cancer Res. 73 (Suppl. 24), S5 02 (2013 S5 02
104. Dwadasi, S., et al. Cisplatin with or without rucaparib after preoperative chemotherapy in patients with triple-negative breast cancer (TNBC): Hoosier Oncology Group BRE09 146 [abstract]. J. Clin. Oncol. 32 (Suppl.), 1019 (2014
105. Gucalp, A., et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin. Cancer Res. 19, 5505-5512 (2013
106. Traina, T. A., et al. Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC) [abstract]. J. Clin. Oncol. 33 (Suppl.), 1003 (2015
107. Gonzalez-Angulo, A. M., et al. Androgen receptor levels and association with PIK3CA mutations and prognosis in breast cancer. Clin. Cancer Res. 15, 2472-2478 (2009
108. Stemke-Hale, K., et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 68, 6084-6091 (2008
109. Ibrahim, Y. H., et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2, 1036-1047 (2012
110. Peng, G., et al. Genome-wide transcriptome profiling of homologous recombination DNA repair. Nat. Commun. 5, 3361 (2014
111. Hoeflich, K. P., et al. In vivo antitumor activity of MEK and phosphatidylinositol 3 kinase inhibitors in basal-like breast cancer models. Clin. Cancer Res. 15, 4649-4664 (2009
112. Barretina, J., et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603-607 (2012
113. Giltnane, J. M., & Balko, J. M. Rationale for targeting the Ras/MAPK pathway in triple-negative breast cancer. Discov. Med. 17, 275-283 (2014
114. Cerami, E., et al. The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401-404 (2012
115. Craig, D. W., et al. Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities. Mol. Cancer Ther. 12, 104-116 (2013
116. Balko, J. M., et al. Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer. Cancer Res. 73, 6346-6358 (2013
117. Horiuchi, D., et al. MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. J. Exp. Med. 209, 679-696 (2012
118. Duncan, J. S., et al. Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell 149, 307-321 (2012
119. Infante, J. R., et al. A phase 1b study of trametinib, an oral mitogen-activated protein kinase kinase (MEK) inhibitor, in combination with gemcitabine in advanced solid tumours. Eur. J. Cancer 49, 2077-2085 (2013
120. Charafe-Jauffret, E., et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 69, 1302-1313 (2009
121. 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
122. Mani, S. A., et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704-715 (2008
123. Creighton, C. J., Chang, J. C., & Rosen, J. M. Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. J. Mammary Gland Biol. Neoplasia 15, 253-260 (2010
124. Charafe-Jauffret, E., et al. Aldehyde dehydrogenase 1 positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin. Cancer Res. 16, 45-55 (2010
125. Huang, E. H., et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 69, 3382-3389 (2009
126. Pontier, S. M., & Muller, W. J. Integrins in mammary-stem-cell biology and breast-cancer progression- a role in cancer stem cells- J. Cell Sci. 122, 207-214 (2009
127. Britton, K. M., et al. Breast cancer, side population cells and ABCG2 expression. Cancer Lett. 323, 97-105 (2012
128. 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
129. Neve, R M., et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10 515-527 2006
130. Marotta, L. L., et al. The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24- stem cell-like breast cancer cells in human tumors. J. Clin. Invest. 121, 2723-2735 (2011
131. DiMeo, T. A., et al. A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer. Cancer Res 69, 5364-5373 2009
132. Bhola, N. E., et al. TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer. J. Clin. Invest. 123, 1348-1358 (2013
133. Liu, S., et al. Hedgehog signaling and Bmi 1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 66, 6063-6071 (2006
134. Harrison, H., et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res. 70, 709-718 (2010
135. Carey, L. A., et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J. Clin. Oncol. 30, 2615-2623 (2012
136. Baselga, J., et al. Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J. Clin. Oncol. 31, 2586-2592 (2013
137. Hu, Y., Liu, J., & Huang, H. Recent agents targeting HIF 1a for cancer therapy. J. Cell. Biochem. 114, 498-509 (2013
138. Sameni, M., et al. Cabozantinib (XL184) inhibits growth and invasion of preclinical TNBC models. Clin. Cancer Res. 22, 923-934 (2016
139. Bianchi-Smiraglia, A., Paesante, S., & Bakin, A. V. Integrin-5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK- ERK signaling pathways. Oncogene 32, 3049-3058 (2013
140. Ehrlich, P.-eber den jetzigen Stand Der Karzinomforschung. Ned. Tijdschr. Geneeskd. 5, 273-290 (1909
141. Hodi, F. S., et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711-723 (2010
142. Topalian, S. L., et al. Safety, activity, and immune correlates of anti-PD 1 antibody in cancer. N. Engl. J. Med. 366, 2443-2454 (2012
143. Larkin, J., et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23-34 (2015
144. Rosenberg, S. A. Raising the bar: the curative potential of human cancer immunotherapy. Sci. Transl. Med. 4, 127ps8 (2012
145. Schadendorf, D., et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. http://dx.doi.org/10.1200/JCO.2014.56.2736 (2015)
146. Burnet, F. M. The concept of immunological surveillance. Prog. Exp. Tumor Res. 13, 1-27 (1970)
147. Schreiber, R. D., Old, L. J., & Smyth, M. J. Cancer immunoediting: integrating immunity-s roles in cancer suppression and promotion. Science 331, 1565-1570 (2011
148. Pusztai, L., Karn, T., Safonov, A., Abu-Khalaf, M. M., & Bianchini, G. New strategies in breast cancer: immunotherapy. Clin. Cancer Res. http://dx.doi.org/10.1158/1078 0432.CCR 15 1315 (2016
149. Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G., & Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48-61 (2015
150. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252-264 (2012
151. Topalian, S. L., Drake, C. G., & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450-461 (2015
152. Brown, S. D. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 24, 743-750 (2014
153. Loi, S., 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. 31, 860-867 (2013
154. Wimberly, H., et al. PD L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunol. Res. 3, 326-332 (2015
155. Ali, H. R., et al. PD L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Ann. Oncol. 26, 1488-1493 (2015
156. Mittendorf, E. A., et al. PD L1 expression in triple-negative breast cancer. Cancer Immunol. Res. 2, 361-370 (2014
157. Sabatier, R., et al. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget 6, 5449-5464 (2015
158. Spranger, S., etal. Up regulation of PD L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl. Med. 5, 200ra116 (2013
159. Crane, C. A., et al. PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene 28, 306-312 (2008
160. Aaltomaa, S., et al. Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur. J. Cancer 28, 859-864 (1992
161. Black, M. M., Speer, F. D., & Opler, S. R. Structural representations of tumor-host relationships in mammary carcinoma; biologic and prognostic significance. Am. J. Clin. Pathol. 26, 250-265 (1956
162. Schmidt, M., et al. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 68, 5405-5413 (2008
163. Bianchini, G., et al. Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J. Clin. Oncol. 28, 4316-4323 (2010
164. Desmedt, C., et al. Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin. Cancer Res. 14, 5158-5165 (2008
165. Callari, M., et al. Subtype specific metagene-based prediction of outcome after neoadjuvant and adjuvant treatment in breast cancer. Clin. Cancer Res. 22, 337-345 (2016
166. Gu Trantien, C., et al. CD4+ follicular helper T cell infiltration predicts breast cancer survival. J. Clin. Invest. 123, 2873-2892 (2013
167. Desmedt, C., et al. Multifactorial approach to predicting resistance to anthracyclines. J. Clin. Oncol. 29, 1578-1586 (2011
168. West, N. R. et al. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res. 13, R126 (2011).
169. Ignatiadis, M., et al. Gene modules and response to neoadjuvant chemotherapy in breast cancer subtypes: a pooled analysis. J. Clin. Oncol. 30, 1996-2004 (2012
170. Denkert, C., et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2 positive and triple-negative primary breast cancers. J. Clin. Oncol. 33, 983-991 (2015
171. Issa-Nummer, Y., et al. Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2 negative breast cancer- a substudy of the neoadjuvant GeparQuinto trial. PLoS ONE 8, e79775 2013
172. Zitvogel, L., Apetoh, L., Ghiringhelli, F., & Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59-73 (2008
173. Galluzzi, L., Senovilla, L., Zitvogel, L., & Kroemer, G. The secret ally: immunostimulation by anticancer drugs Nat. Rev. Drug Discov. 11 215-233 2012
174. Kang, T. H., et al. Chemotherapy acts as an adjuvant to convert the tumor microenvironment into a highly permissive state for vaccination-induced antitumor immunity. Cancer Res. 73, 2493-2504 (2013
175. Dieci, M. V., et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann. Oncol. 26, 1698-1704 (2015
176. Loi, S., et al. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD 1/PD L1 immune checkpoint inhibitors. Clin. Cancer Res. 22, 1499-1509 (2016
177. Dieci, M. V., et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann. Oncol. 25, 611-618 (2014
178. Teschendorff,A. E., Miremadi, A., Pinder, S. E., Ellis, I. O., & Caldas, C. An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol. 8, R157 (2
179. Rody, A., et al. T cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2 positive breast cancers. Breast Cancer Res 11, R15 (2009
180. Staaf, J., et al. Identification of subtypes in human epidermal growth factor receptor 2 positive breast cancer reveals a gene signature prognostic of outcome. J. Clin. Oncol. 28, 1813-1820 (2010
181. Sabatier, R., et al. A gene expression signature identifies two prognostic subgroups of basal breast cancer. Breast Cancer Res. Treat. 126, 407-420 (2011
182. Rody, A., et al. A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res 13, R97 (2011
183. Nagalla, S., et al. Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis. Genome Biol. 14, R34 (2013
184. Loi, S., et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann. Oncol. 25, 1544-1550 (2014
185. Adams, S., et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J. Clin. Oncol. 32, 2959-2966 (2014
186. Salgado, R., et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann. Oncol. 26, 259-271 (2015
187. Savas, P., et al. Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat. Rev. Clin. Oncol. 13, 228-241 (2016
188. Nanda, R., et al. A phase Ib study of pembrolizumab (MK 3475) in patients with advanced triple-negative breast cancer [abstract]. Cancer Res. 75, S1 09 2015
189. Emens, L., et al. Inhibition of PD L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC) [abstract]. Cancer Res. 75, 2859 (2015