Adjuvant Capecitabine-Containing Chemotherapy Benefit and Homologous Recombination Deficiency Status Among Early-Stage TNBC Patients in the FinXX trial

Abstract Background: Recent data demonstrate that patients with early-stage triple negative breast cancer (TNBC) benefit from escalating adjuvant treatment with capecitabine. However, since a substantial proportion of patients does not benefit, predictive biomarkers to select those individuals upfront are needed. Over half of all TNBCs have a BRCA1-like DNA copy number signature similar to the profile found in germline BRCA1-mutated breast cancers and indicative for homologous recombination deficiency. We evaluate this signature as a predictive biomarker for capecitabine benefit in archived specimens of the randomized controlled FinXX trial. Additionally, we compared the concordance of our DNA-based BRCA1-like classifier with the RNA-based NanoString BRCAness signature. Methods: Early-stage TNBC patients were randomized between adjuvant capecitabine-containing chemotherapy (TX+CEX: capecitabine plus docetaxel, followed by cyclophosphamide, epirubicin and capecitabine) and conventional adjuvant chemotherapy (T+CEF: docetaxel, followed by cyclophosphamide, epirubicin, and fluorouracil). Breast tumor BRCA1-like status was determined on low coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridization algorithm. We used interaction analysis in proportional hazards models to evaluate whether benefit of adjuvant capecitabine-containing versus conventional chemotherapy differs between BRCA1-like and non-BRCA1-like tumors in early-stage TNBC patients.Results: For 129 (63.9%) of the 202 TNBC patients the BRCA1-like status could be determined. Thirty-five recurrences and 32 deaths occurred during a median follow-up of 10.7 years. The capecitabine effect on recurrence-free survival did not significantly differ between the 68 patients (52.7%) with a BRCA1-like tumor (HR 0.66, 95% CI 0.24-1.81) and others (HR 0.23, 95% CI 0.08-0.70, P interaction = 0.17), also after adjustment for clinico-pathological variables. Conclusions: In the FinXX trial, the BRCA1-like status was not associated with a differential benefit from capecitabine-containing adjuvant chemotherapy compared to conventional chemotherapy in the TNBC subgroup. Based on this study, it is unlikely that the BRCA1-like classifier can be used to distinguish patients who do and do not benefit from capecitabine-enriched standard adjuvant chemotherapy.