Ann Oncol. 2021 Sep 11:S0923-7534(21)04478-1. doi: 10.1016/j.annonc.2021.09.003. Online ahead of print.
ABSTRACT
BACKGROUND: Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT).
PATIENTS AND METHODS: This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were performed between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (myChoiceHRD). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was pre-defined as a RAD51 score ≤10% (RAD51-low).
RESULTS: Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% (95%CI 79-93%). In patients with RAD51-high tumors, pCR was similar between treatment arms (PMCb 31% vs PM 39%, odds ratio (OR) 0.71, 0.23-2.24, p=0.56). Patients with RAD51-low tumors benefited from PMCb (pCR 66% vs 33%, OR 3.96, 1.56-10.05, p=0.004; interaction test p=0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in RAD51-high (hazard ratio (HR) 0.40, log-rank p=0.11) and RAD51-low (0.45, p=0.11) groups.
CONCLUSIONS: The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.
PMID:34520831 | DOI:10.1016/j.annonc.2021.09.003
