Selecting patients with triple negative breast cancer for platinum-based therapy: we still haven’t found what we’re looking for
Authors: M. Robson
Journal: Annals of Oncology (2018)

Triple negative breast cancer (TNBC; estrogen and progesterone receptor negative, HER2 nonamplified) remains one of the thorniest challenges in the field of breast oncology. Enthusiasm for the potential role of platinum-based chemotherapy in this setting arose the observations that breast cancers arising in women with germline mutations in BRCA1 are predominantly (but not exclusively) TNBC and that cells lacking functional BRCA1 (or BRCA2) protein are highly sensitive in vitro to agents such as cisplatin and carboplatin [1.Mavaddat N. Barrowdale D. Andrulis I.L. et al.Consortium of investigators of modifiers of BRCA1/2. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).Cancer Epidemiol Biomarkers Prev. 2012; 2012: 418-447Google Scholar, 2.Bhattacharyya A. Ear U.S. Koller B.H. 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.J Biol Chem. 2000; 275: 23899-23903Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar]. Subsequent work has shown that this sensitivity likely results from the inability of BRCA1/2-deficient cells to employ the homologous recombination (HR) DNA repair pathway to address the lesions induced by platinum-DNA adducts [3.Venkitaraman A.R. Tracing the network connecting BRCA and Fanconi anaemia proteins.Nat Rev Cancer. 2004; 4: 266-276Crossref PubMed Scopus (168) Google Scholar]. Given the phenotypic similarities between BRCA1-associated and sporadic TNBC, the hope has been that at least a subset of sporadic TNBC may also harbor homologous recombination deficiency (HRD), and therefore be similarly sensitive to platinum treatment [4.Lord C.J. Ashworth A. BRCAness revisited.Nat Rev Cancer. 2016; 16: 110-120Crossref PubMed Scopus (765) Google Scholar]. It has been challenging to define the clinical implications of the in vitro correlation between BRCA1/2 protein loss, HRD, and platinum sensitivity. A number of relatively small studies in both early- and late-stage settings suggested a high response rate to platinum for BRCA mutation-associated breast cancer compared with historical controls [5.Byrski T. Huzarski T. Dent R. et al.Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients.Breast Cancer Res Treat. 2014; 147: 401-405Crossref PubMed Scopus (206) Google Scholar, 6.Byrski T. Dent R. Blecharz P. et al.Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer.Breast Cancer Res. 2012; 14: R110.Crossref PubMed Scopus (162) Google Scholar, 7.Isakoff S.J. Mayer E.L. He L. et al.TBCRC009: a multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer.J Clin Oncol. 2015; 33: 1902-1909Crossref PubMed Scopus (308) Google Scholar], but these studies could not definitively address the question of whether platinum treatment was superior to conventional chemotherapy, or whether BRCA-deficient TNBC was generically chemo-sensitive, at least in the neoadjuvant setting. Two recent studies have clarified matters to a certain degree. The recently published TNT study randomized 376 women with metastatic TNBC (43 with germline mutations in BRCA1 or BRCA2) to single agent treatment with either carboplatin or docetaxel [8.Tutt A. Tovey H. Cheang M.C.U. et al.Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.Nat Med. 2018; 24: 628-637Crossref PubMed Scopus (498) Google Scholar]. Although there were no differences in overall response rate or progression-free survival (PFS) between the two arms, the women with germline mutations had a significantly better response to carboplatin and improved PFS, consistent with the preclinical observation of sensitivity. On the other hand, in the GeparSixto neoadjuvant trial, 315 patients with early-stage TNBC receiving presurgical treatment with an anthracycline-/taxane-based regimen were randomized to receive carboplatin or not [9.Hahnen E. Lederer B. Hauke J. et al.Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto Randomized Clinical Trial.JAMA Oncol. 2017; 3: 1378-1385Crossref PubMed Scopus (229) Google Scholar]. In an analysis of the subset of 291 women who underwent germline analysis, the pathologic complete response (pCR) rate was significantly higher for the 50 germline BRCA1/2 mutation carriers than for the women without mutations. However, the addition of carboplatin only significantly improved pCR rates compared with the nonplatinum containing regimen in women who did not carry germline mutations. Although this is a small study with limited power, it suggests that early-stage BRCA mutation-associated TNBC is more chemo-sensitive overall, without a clear incremental benefit to the addition of platinum in this setting. These two studies indicate that in the metastatic setting, platinum treatment preferentially benefits BRCA mutation carriers while, in the neoadjuvant setting, the benefit of platinum treatment accrues to a subset of women without mutations. This suggests that certain patients with sporadic TNBC have cancers that at diagnosis manifest a BRCA-like defect conferring sensitivity to platinum treatment, but that this population is relatively depleted in noncarrier women who experience recurrent disease. One hypothesis is that a subset of sporadic TNBC manifest a BRCA-like HRD phenotype (the so-called BRCAness), but that adjuvant treatment selects against this population such that the cells that constitute the recurrence no longer manifest this phenotype. The study in this issue of Zhang et al. [10.Zhang J. Lin Y. Sun X.J. et al.Biomarker assessment of the CBCSG006 trial: a randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer.Ann Oncol. 2018; 29: 1741-1747Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar] seeks to shed further light on this complicated question. In the parent study, women with metastatic TNBC were randomized to a gemcitabine-cisplatin regimen or to a gemcitabine-paclitaxel doublet. In the overall study population, women receiving the platinum doublet had a clinically marginal but statistically significant improvement in PFS (7.73 versus 6.07 months). A subset of patients from the overall study population (132/236; 55.9%) underwent germline analysis for panel of 28 genes, with 63 (47.7%) described as carrying mutations in at least one of the genes on the panel and therefore being classified as 'HRD', and 14 (10.6%) described as carrying BRCA1/2 mutations. There was a significant interaction between treatment, HRD status, and PFS, with higher response and PFS being seen in the 'HRD' group receiving platinum, but there was no significant interaction with BRCA status. The interpretation of these results is complicated by two factors. First, many of the genes included in the panel (e.g. CHEK2, CDH1, the Lynch Syndrome genes, and STK11) have no or an uncertain relationship to the HR repair pathway and mutations in these genes would not be expected to confer a platinum-sensitive phenotype. Second, most of the reported variants are missense variants that are considered of uncertain functional and clinical significance (VUS) in public databases such as ClinVar. For instance, only 5 of the 14 BRCA1/2 mutation carriers reported had protein-truncating mutations that would be generally accepted as pathogenic. This may explain the remarkably high rate of germline mutation described in the study. The inclusion of patients in the analysis who have VUS in accepted HR genes or even pathogenic mutations in genes that have an uncertain relationship to HR obscures the ability to discern the true relationship between germline HR mutations and platinum response. In sum, it now appears that mutations that are predicted to give risk to profound defects in HR (e.g. germline BRCA mutations) confer a generic sensitivity to DNA-damaging chemotherapy in the neoadjuvant setting and a specific sensitivity to platinum-based chemotherapy in the metastatic setting. It also appears that there are some patients with apparently sporadic TNBC who derive benefit from platinum therapy, both in the neoadjuvant setting as suggested by the GeparSixto study and in the metastatic setting as suggested by the parent study of Zhang et al. The so-called 'genomic scar' assays had utility in predicting response to platinum-based neoadjuvant therapy in at least one study [11.Telli M.L. Timms K.M. Reid J. et al.Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer.Clin Cancer Res. 2016; 22: 3764-3773Crossref PubMed Scopus (496) Google Scholar], although one such assay did not predict outcome in the TNT study. Recently, interest has grown in defining mutational signatures of HRD through extended genomic sequencing [12.Davies H. Glodzik D. Morganella S. et al.HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.Nat Med. 2017; 23: 517-525Crossref PubMed Scopus (514) Google Scholar, 13.Zhao E.Y. Shen Y. Pleasance E. et al.Homologous recombination deficiency and platinum-based therapy outcomes in advanced breast cancer.Clin Cancer Res. 2017; 23: 7521-7530Crossref PubMed Scopus (100) Google Scholar], although these are not yet available for routine clinical use. Regretfully, in TNBC, the search continues for an accessible biomarker other than germline BRCA mutations to reliably predict platinum response. None to declare.