Carboplatin in the neoadjuvant treatment of triple-negative breast cancer—ready for prime time?
Authors: T. Foukakis
Journal: Annals of Oncology (2018)

Neoadjuvant chemotherapy (NACT) in early breast cancer is noninferior to adjuvant chemotherapy, increases the rates of breast conserving surgery and provides the opportunity for biomarker research, testing of new therapeutic agents and adapting the neoadjuvant regimen or adding postoperative chemotherapy when response to primary therapy is deemed to be suboptimal [1.Asselain B. Barlow W. Bartlett J. et al.Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials.Lancet Oncol. 2018; 19: 27-39Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar, 2.Masuda N. Lee S.J. Ohtani S. et al.Adjuvant capecitabine for breast cancer after preoperative chemotherapy.N Engl J Med. 2017; 376: 2147-2159Crossref PubMed Scopus (859) Google Scholar]. Especially in triple-negative breast cancer (TNBC), NACT results in pathological complete response (pCR) in more than 30% of patients, which is strongly associated with a better prognosis with a hazard ratio of 0.16 (95% CI 0.11–0.25) [3.Cortazar P. Zhang L. Untch M. et al.Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.Lancet. 2014; 384: 164-172Abstract Full Text Full Text PDF PubMed Scopus (2613) Google Scholar]. Thus, optimizing NACT and increasing pCR rates has been considered a promising approach for improving prognosis in TNBC. The addition of carboplatin to standard NACT with anthracyclines and taxanes improves pCR rates with the cost of higher short-term hematological toxicity, as seen in three randomized clinical trials [4.Loibl S. O'Shaughnessy J. Untch M. et al.Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.Lancet Oncol. 2018; 19: 497-509Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar, 5.Sikov W.M. Berry D.A. Perou C.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. 2015; 33: 13-21Crossref PubMed Scopus (651) Google Scholar, 6.von Minckwitz G. Schneeweiss A. Loibl S. 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. 2014; 15: 747-756Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar] and a recent meta-analysis [7.Poggio F. Bruzzone M. Ceppi M. et al.Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis.Ann Oncol. 2018; 29: 1497-1508Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar]. Based on the available data, carboplatin is generally not recommended as a standard of care in an unselected TNBC population [8.Curigliano G. Burstein H.J. Winer E.P. et al.De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017.Ann Oncol. 2017; 28: 1700-1712Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar]. Efforts to select a clinically or biologically defined subgroup of patients who benefit from the addition of carboplatin have to date not been conclusive. In this issue of the journal, Loibl et al. present an updated analysis of the GeparSixto trial, in which 315 patients with TNBC were treated preoperatively with weekly paclitaxel plus nonpegylated liposomal doxorubicin plus bevacizumab with or without carboplatin, reporting overall survival results as well as the evaluation of homologous recombination deficiency (HRD) as prognostic and predictive marker [9.Loibl S. Weber K.E. Timms K.M. et al.Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response—final results from GeparSixto.Ann Oncol. 2018; 29Abstract Full Text Full Text PDF Scopus (146) Google Scholar]. This is the first report of extended follow-up and survival results of the trials investigating the addition of carboplatin in this setting. A 6% absolute benefit by the addition of carboplatin was observed, however, this difference was not statistically significant. Although the analysis was a predefined secondary end point, the study was by design not adequately powered to detect survival differences. Additionally, as acknowledged by the authors, the observed difference both in disease-free survival and overall survival may reflect the fact that carboplatin was added to a nonstandard regimen not containing an alkylating agent. Updated results of the CALBG 40603 [5.Sikov W.M. Berry D.A. Perou C.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. 2015; 33: 13-21Crossref PubMed Scopus (651) Google Scholar] and the BrighTNess [4.Loibl S. O'Shaughnessy J. Untch M. et al.Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.Lancet Oncol. 2018; 19: 497-509Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar] trials will shed light on whether cyclophosphamide can be a less toxic substitute for carboplatin and a pooled analysis of long-term outcomes in the three trials may have adequate power to show if carboplatin is associated with survival benefit. The trials carried out to date will however not be able to define the place of carboplatin in the emerging standards of care that include adjuvant chemotherapy in patients with residual disease after NACT [2.Masuda N. Lee S.J. Ohtani S. et al.Adjuvant capecitabine for breast cancer after preoperative chemotherapy.N Engl J Med. 2017; 376: 2147-2159Crossref PubMed Scopus (859) Google Scholar] or the addition of nonchemotherapy agents currently under evaluation, such as checkpoint inhibitors added to pre- or postoperative chemotherapy. Most efforts to identify predictive markers for carboplatin have been driven by the hypothesis that tumors with deficient homologous recombination, such as those with BRCA1 or BRCA2 mutations, may be better targeted by carboplatin due to their inability to effectively repair double-strand DNA breaks induced by platinum salts. In the metastatic setting, the TNT trial comparing carboplatin versus docetaxel as first-line treatment of TNBC demonstrated that in patients with germline BRCA1/2 (gBRCA) mutations, the objective response rates with carboplatin were double those of docetaxel [10.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 (507) Google Scholar]. However, BRCA1 methylation or low gene expression and an HRD assay by Myriad genetics assessed in archival primary tumors did not have a predictive value [10.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 (507) Google Scholar]. In contrast, a previous report from the GeparSixto trial showed that gBRCA mutations were prognostic for pCR, but it was merely patients without gBRCA mutations that benefited from the addition of carboplatin [11.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 (233) Google Scholar]. Similar findings are seen in the BrighTNess trial, supporting a role of carboplatin in wild-type gBRCA1/2. The Myriad HRD assay investigated by Loibl et al. has the advantage of being potentially applicable to clinical practice and provides a phenotypical measurement of homologous recombination defects, capturing not only those caused by gBRCA mutations, but also by somatic mutations, methylation or transcriptional down-regulation of BRCA1/2. HRD testing of pretreatment tumor samples in BrighTNess [12.Telli M.L. Metzger O. Timms K. et al.Evaluation of homologous recombination deficiency (HRD) status with pathological response to carboplatin +/- veliparib in BrighTNess, a randomized phase 3 study in early stage TNBC.J Clin Oncol. 2018; 36 (519): 519Crossref Google Scholar] and in GeparSixto reported in this issue of Annals of Oncology indicate that the assay is prognostic, or perhaps predictive for chemosensitivity in general rather than for carboplatin in particular. Alternatively, the lack of interaction between the HRD assay and treatment seen in both trials could also be attributable to lack of power, supporting a simultaneous analysis of the studies also for the correlative end points. Additional markers of DNA repair capacity such as somatic excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), and ribonucleotide reductase M1 (RRM1) have been implicated as predictors to platinum salts in lung cancer [13.Besse B. Olaussen K.A. Soria JC. ERCC1 and RRM1: ready for prime time?.J Clin Oncol. 2013; 31: 1050-1060Crossref PubMed Scopus (63) Google Scholar]. These proteins have not been thoroughly studied in breast cancer treated with carboplatin and could potentially be explored in GeparSixto. A previous publication in the GeparSixto trial has investigated tumor-infiltrating lymphocytes in pretreatment tumor samples as predictors of therapy response [14.Denkert C. von Minckwitz G. Brase J.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. 2015; 33: 983-991Crossref PubMed Scopus (725) Google Scholar]. This analysis showed that lymphocyte-predominant TNBC had significantly higher pCR rates, especially in patients treated with carboplatin (74% versus 43% without carboplatin), however, the interaction test was negative. Interestingly, lymphocyte-predominant and HRD cases did not overlap, but their predictive value when combined was not tested. The neoadjuvant setting and design of the GeparSixto, BrighTNess and CALGB 40603 trials with a comparator group without carboplatin allows for additional predictive biomarkers to be investigated, provided that tumor tissue is available for analysis. Differential response to carboplatin could be explored within Lehmann's subtypes of TNBC [15.Lehmann B.D. Bauer J.A. Chen X. et al.Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.J Clin Invest. 2011; 121: 2750-2767Crossref PubMed Scopus (3471) Google Scholar], as indicated by a recent analysis of a nonrandomized trial [16.Echavarria I. Lopez-Tarruella S. Picornell A. et al.Pathological response in a triple-negative breast cancer cohort treated with neoadjuvant carboplatin and docetaxel according to Lehmann's refined classification.Clin Cancer Res. 2018; 24: 1845-1852Crossref PubMed Scopus (63) Google Scholar], or correlated with specific genomic profiles that may confer de novo resistance [17.Kim C. Gao R. Sei E. et al.Chemoresistance evolution in triple-negative breast cancer delineated by single-cell sequencing.Cell. 2018; 173: 879-893.e813Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar]. Immune response markers as suggested by Denkert et al. [14.Denkert C. von Minckwitz G. Brase J.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. 2015; 33: 983-991Crossref PubMed Scopus (725) Google Scholar] deserve further evaluation both in pretreatment samples and after short exposure to therapy [18.Matikas A. Lovrot J. Ramberg A. et al.Dynamic evaluation of the immune infiltrate and immune function genes as predictive markers for neoadjuvant chemotherapy in hormone receptor positive, HER2 negative breast cancer.Oncoimmunology. 2018; 7: e1466017Crossref PubMed Scopus (16) Google Scholar], in the completed chemotherapy trials but also in the ongoing studies of NACT in combination with checkpoint inhibitors. TF is a recipient of the Senior Clinical Investigator Award from the Swedish Cancer Society (grant number CAN 2017/1043). No other funding was provided for this editorial.