New Strategies for Triple-Negative Breast Cancer—Deciphering the Heterogeneity

Triple-negative breast cancer (TNBC) is a heterogeneous disease; gene expression analyses recently identified six distinct TNBC subtypes, each displaying a unique biology. Exploring novel approaches to treatment of these subtypes is critical because less than 30% of women with metastatic breast cancer survive five years and virtually all women with metastatic TNBC will ultimately die of their disease despite systemic therapy. To date, not a single targeted therapy has been approved for the treatment of TNBC and cytotoxic chemotherapy remains the standard treatment. We discuss the current and upcoming therapeutic strategies being explored in an attempt to “target” TNBC. Clin Cancer Res; 20(4); 782–90. ©2014 AACR.

[1]  K. Hess,et al.  Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  Kwok-Kin Wong,et al.  Targeting the PI3K signaling pathway in cancer. , 2010, Current opinion in genetics & development.

[3]  Jeff Myers,et al.  Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. , 2009, Clinical breast cancer.

[4]  O. Fernandez-Capetillo,et al.  Nuclear phosphoinositide 3-kinase β controls double-strand break DNA repair , 2010, Proceedings of the National Academy of Sciences.

[5]  Mark Yoffe,et al.  Iniparib plus chemotherapy in metastatic triple-negative breast cancer. , 2011, The New England journal of medicine.

[6]  Zhi Hu,et al.  An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. , 2008, Cancer research.

[7]  Yonghong Xiao,et al.  Association of BRCA1 with Rad51 in Mitotic and Meiotic Cells , 1997, Cell.

[8]  A. Bardia,et al.  Abstract PD1-6: A randomized phase II neoadjuvant study of cisplatin, paclitaxel with or without everolimus (an mTOR inhibitor) in patients with stage II/III triple-negative breast cancer (TNBC) , 2013 .

[9]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Y. Shyr,et al.  Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis , 2011, Proceedings of the National Academy of Sciences.

[11]  P. Fasching,et al.  Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  Wei Zhou,et al.  In vivo Antitumor Activity of MEK and Phosphatidylinositol 3-Kinase Inhibitors in Basal-Like Breast Cancer Models , 2009, Clinical Cancer Research.

[13]  C. Perou,et al.  Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. , 2006, JAMA.

[14]  J. Kładny,et al.  Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients , 2009, Breast Cancer Research and Treatment.

[15]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[16]  S. Narod,et al.  Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence , 2007, Clinical Cancer Research.

[17]  G. Mills,et al.  Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance , 2012, Nature Medicine.

[18]  J. Pietenpol,et al.  p63 and epithelial biology. , 2006, Experimental cell research.

[19]  A. Richardson,et al.  BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles , 2005, Breast Cancer Research and Treatment.

[20]  J. Pietenpol,et al.  Identification and use of biomarkers in treatment strategies for triple‐negative breast cancer subtypes , 2014, The Journal of pathology.

[21]  D. Sgroi,et al.  The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. , 2007, The Journal of clinical investigation.

[22]  Z. Szallasi,et al.  Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  X. Chen,et al.  Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. , 2011, The Journal of clinical investigation.

[24]  Lei He,et al.  PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. , 2012, Cancer discovery.

[25]  K Miller,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). , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  Irmtraud M. Meyer,et al.  The clonal and mutational evolution spectrum of primary triple-negative breast cancers , 2012, Nature.

[27]  A. Tutt,et al.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial , 2010, The Lancet.

[28]  Xi Chen,et al.  TNBCtype: A Subtyping Tool for Triple-Negative Breast Cancer , 2012, Cancer informatics.

[29]  M. Rezai,et al.  A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). , 2013 .

[30]  A. Børresen-Dale,et al.  TP53 and breast cancer , 2003, Human mutation.

[31]  P. Conte,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 , 2009 .

[32]  P. Baas,et al.  Choice of tumour markers in patients with neuroendocrine tumours is dependent on the histological grade. A marker study of Chromogranin A, Neuron specific enolase, Progastrin-releasing peptide and cytokeratin fragments. , 2012, European journal of cancer.

[33]  Daniel Birnbaum,et al.  How basal are triple‐negative breast cancers? , 2008, International journal of cancer.

[34]  Mark Robson,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 , 2010, The Lancet.

[35]  Robin L. Jones,et al.  The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer , 2009, Breast Cancer Research and Treatment.

[36]  C. Perou,et al.  Epidemiology of basal-like breast cancer , 2008, Breast Cancer Research and Treatment.

[37]  R. Weichselbaum,et al.  The Breast Cancer Susceptibility Gene BRCA1 Is Required for Subnuclear Assembly of Rad51 and Survival following Treatment with the DNA Cross-linking Agent Cisplatin* , 2000, The Journal of Biological Chemistry.

[38]  P. Pandolfi,et al.  Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. , 2012, Cancer discovery.

[39]  R. Gelber,et al.  Pathologic complete remission rate after cisplatin-based primary chemotherapy in breast cancer: correlation with p63 expression , 2008, Cancer Chemotherapy and Pharmacology.

[40]  A. D’Andrea,et al.  S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. , 2002, Blood.

[41]  W. Gerald,et al.  Androgen Receptor Levels and Association with PIK3CA Mutations and Prognosis in Breast Cancer , 2009, Clinical Cancer Research.

[42]  D. Berry,et al.  Abstract S5-01: 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) , 2013 .

[43]  K. A. Gelmon.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial , 2011 .

[44]  H. Mackay,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. , 2011, The Lancet. Oncology.

[45]  Yoshio Miki,et al.  Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage , 2004, Cancer science.

[46]  A. Ashworth,et al.  Hallmarks of 'BRCAness' in sporadic cancers , 2004, Nature Reviews Cancer.

[47]  J. Manola,et al.  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. , 2013 .

[48]  S. Ding,et al.  Abnormality of the DNA double-strand-break checkpoint/repair genes, ATM, BRCA1 and TP53, in breast cancer is related to tumour grade , 2004, British Journal of Cancer.

[49]  A. Ashworth,et al.  Targeting the DNA repair defect of BRCA tumours. , 2005, Current opinion in pharmacology.