The GeparSixto randomized clinical trial¹ assessed the efficacy of adding neoadjuvant carboplatin to a regimen of paclitaxel, non–pegylated doxorubicin hydrochloride, and targeted therapy for triple-negative breast cancer (TNBC) and ERBB2/HER2 (OMIM 164870)–positive breast cancer. Targeted therapy included lapatinib and trastuzumab for ERBB2/HER2-positive breast cancer and bevacizumab for TNBC. Of the patients with TNBC, 90 of 158 (57%) achieved a pathological complete response (pCR) with carboplatin therapy compared with 67 of 157 patients (42.7%) without carboplatin therapy (P = .015; ypT0/is ypN0 definition).¹ Of the patients with ERBB2/HER2-positive tumors, 72 of 137 (52.6%) achieved a pCR with carboplatin compared with 67 of 136 patients (49.3%) without carboplatin (P = .58; ypT0/is ypN0 definition).¹ Thus, the addition of neoadjuvant carboplatin to the anthracycline and taxane–containing regimen substantially increased pCR rates in patients with TNBC but not in patients with ERBB2/HER2-positive breast cancer. The GeparSixto trial used a nonstandard neoadjuvant chemotherapy regimen that included low-dose doxorubicin and no cyclophosphamide. In the Cancer and Leukemia Group B (CALGB 40603 Alliance) trial, standard neoadjuvant chemotherapy (paclitaxel, dose-dense doxorubicin, and cyclophosphamide) of patients with TNBC revealed elevated pCR rates when carboplatin was added,² but an event-free survival benefit was not observed.³

In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients were randomized to paclitaxel plus non-pegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study endpoints disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in FFPE tumor samples of 193/315 (61.3%) participants with TNBC. HR deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). A significantly better DFS (hazard ratio 0.56, 95%CI 0.34-0.93; P=0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) (odds ratio (OR) 2.60, 95%CI 1.26-5.37, P=0.008). Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P=0.001), but only marginally in HR non-deficient tumors (from 20.0% to 29.6%, P=0.540; test for interaction P=0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P=0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR non-deficient (hazard ratio 0.44, 0.17–1.17, P=0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P=0.059). The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.

Purpose: We elucidated the value of tumor-infiltrating lymphocytes (TIL) as an independent predictor for pathologic complete response (pCR) rate and as a prognostic marker for disease-free survival (DFS) in patients with HER2-positive breast cancer in the neoadjuvant setting. Experimental Design: We evaluated stromal TILs in 498 HER2-positive breast cancer samples of the neoadjuvant GeparQuattro (G4) and GeparQuinto (G5) trials. Levels of TILs were determined as a continuous parameter per 10% increase and as lymphocyte-predominant breast cancer (LPBC; ≥ 60% TILs), and correlated with pCR rate and DFS. Results: In the complete cohort, HER2-positive LPBC cases had a significantly increased pCR rates compared with non-LPBC types. They were significant predictors for pCR in univariate (10% TILs: OR 1.12, P = 0.002; LPBC: OR 2.02, P = 0.002) and multivariate analyses (10% TILs: OR 1.1, P = 0.014; LPBC: OR 1.87, P = 0.009). This effect was also detectable in the trastuzumab-treated (10% TILs: OR 1.12, P = 0.018; LPBC: OR 2.08, P = 0.013) but not in the lapatinib-treated subgroup. We identified a low-risk (pCR/LPBC) and a high-risk group (no pCR/no LPBC) regarding DFS. In triple-positive breast cancer, TILs are of more prognostic relevance than pCR. Conclusions: We could demonstrate the predictive and prognostic impact of TILs in HER2-positive breast cancer in the neoadjuvant setting. In combination with pCR rate, TILs may help to stratify prognostic subgroups, thereby guiding future therapy decisions. Clin Cancer Res; 22(23); 5747–54. ©2016 AACR.