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05-06-2014 | Triple-negative breast cancer | Article

Molecular Heterogeneity of Triple-Negative Breast Cancer

Journal: Current Breast Cancer Reports

Authors: Vandana G. Abramson, Ingrid A. Mayer

Publisher: Springer US

Abstract

Triple-negative breast cancers (TNBCs) are a group of aggressive breast cancers with a greater incidence of relapse, stage-for-stage, than ER/PR-positive and HER2-positive breast cancers, despite optimum loco-regional and systemic therapy. To date, no single targeted therapy has been approved for treatment of TNBC, and cytotoxic chemotherapy remains the standard systemic treatment. Recently, gene expression analysis identified six distinct TNBC subtypes, each with unique biology. In this review we discuss current and forthcoming therapeutic strategies and novel approaches to targeted treatment of these TNBC subtypes.
Literature
1.
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–2.PubMedCrossRef
2.
Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10(16):5367–74.PubMedCrossRef
3.
Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14(5):1368–76.CrossRef
4.
Fulford LG, Easton DF, Reis-Filho JS, Sofronis A, Gillett CE, Lakhani SR, et al. Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast. Histopathology. 2006;49(1):22–34.PubMedCrossRef
5.
Fulford LG, Reis-Filho JS, Ryder K, Jones C, Gillett CE, Hanby A, et al. Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival. Breast Cancer Res BCR. 2007;9(1):R4.CrossRef
6.
Arnes JB, Brunet JS, Stefansson I, Begin LR, Wong N, Chappuis PO, et al. Placental cadherin and the basal epithelial phenotype of BRCA1-related breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11(11):4003–11.CrossRef
7.
Subhawong AP, Subhawong T, Nassar H, Kouprina N, Begum S, Vang R, et al. Most basal-like breast carcinomas demonstrate the same Rb-/p16+ immunophenotype as the HPV-related poorly differentiated squamous cell carcinomas which they resemble morphologically. Am J Surg Pathol. 2009;33(2):163–75.PubMedCentralPubMedCrossRef
8.
Reis-Filho JS, Savage K, Lambros MB, James M, Steele D, Jones RL, et al. Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis. Modern Pathol Off J United States Can Acad Pathol Inc. 2006;19(7):999–1009.CrossRef
9.
Rakha EA, Ellis IO, Reis-Filho JS. Immunohistochemical heterogeneity of breast carcinomas negative for estrogen receptors, progesterone receptors and Her2/neu (basal-like breast carcinomas). Modern Pathol Off J United States Can Academy Pathol Inc. 2008;21(8):1060–1. author reply 1–2.CrossRef
10.
Bertucci F, Finetti P, Cervera N, Esterni B, Hermitte F, Viens P, et al. How basal are triple-negative breast cancers? Int J Cancer. 2008;123(1):236–40.PubMedCrossRef
11.
Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(8):1160–7.CrossRef
12.
de Ronde JJ, Hannemann J, Halfwerk H, Mulder L, Straver ME, Vrancken Peeters MJ, et al. Concordance of clinical and molecular breast cancer subtyping in the context of preoperative chemotherapy response. Breast Cancer Res Treat. 2010;119(1):119–26.PubMedCrossRef
13.
Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. Epub 2012/09/25.
14.
Andre F, Job B, Dessen P, Tordai A, Michiels S, Liedtke C, et al. Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res. 2009;15(2):441–51.PubMedCrossRef
15.
Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell. 2009;16(2):115–25.PubMedCentralPubMedCrossRef
16.
Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65(7):2554–9.PubMedCrossRef
17.
Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486(7403):395–9.PubMed
18.•
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750–67. This article describes the identification of six TNBC subtypes with unique gene expression: two basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. Gene expression analysis enabled identification of TNBC cell line models representative of these subtypes, against which different targeted therapy was tested. This provided proof of concept that analysis of distinct gene-expression profiles can be used as the basis of therapy selection, which may be useful for assigning TNBC patients to more appropriate targeted therapy. PubMedCentralPubMedCrossRef
19.
Masuda H, Baggerl KA, Wang Y, Zhang Y, Gonzalez-Angulo AM, Meric-Bernstam F, et al. Differential pathologic complete response rates after neoadjuvant chemotherapy among molecular subtypes of triple-negative breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(15 suppl):Abstract 1005. Presented at - 2013 ASCO Annual Meeting.
20.
Matros E, Wang ZC, Lodeiro G, Miron A, Iglehart JD, Richardson AL. BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles. Breast Cancer Res Treat. 2005;91(2):179–86.PubMedCrossRef
21.
Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer. 2004;4(10):814–9.PubMedCrossRef
22.
Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, et al. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28(7):1145–53.PubMedCentralPubMedCrossRef
23.
Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, et al. Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Res Treat. 2008;108(2):289–96.PubMedCrossRef
24.
Von Minckwitz G, Schneeweiss A, Salat C. A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). J Clin Oncol 2013;31(suppl):abst 1004.
25.
Sikov W, Berry D, Perou C, Singh B, Cirrincione C, Tolaney S, et al. Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel (P) followed by dose-dense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance). San Antonio Breast Cancer Symposium 2013. 2013; Oral Session 5:01.
26.
Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014. Epub 2014/02/18.
27.
Turner N, Tutt A, Ashworth A. Targeting the DNA repair defect of BRCA tumours. Curr Opin Pharmacol. 2005;5(4):388–93.PubMedCrossRef
28.
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21.PubMedCrossRef
29.
O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364(3):205–14.PubMedCrossRef
30.
O’Shaughnessy J SL, 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). J Clin Oncol. 2011;29:abstract #1007.
31.
Telli M, Jensen K, Kurian A. PrECOG 0105: Final efficacy results from a phase II study of gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer. J Clin Oncol 2013;31(suppl):abstr 1003.
32.
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, 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(9737):235–44.PubMedCrossRef
33.
Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852–61.PubMedCrossRef
34.
Rugo HS, Olopade O, DeMichele A, van’t Veer L, Buxton M, Hylton N, et al. Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL. San Antonio Breast Cancer Symposium. 2013; Session 5:Abstract 02.
35.
Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012. Epub 2012/04/13
36.
Ibrahim YH, Garcia-Garcia C, Serra V, He L, Torres-Lockhart K, Prat A, et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2012;2(11):1036–47.PubMedCrossRef