Association of RAD51 with homologous recombination deficiency (HRD) in triple-negative breast cancer (TNBC): Analysis of the GeparSixto trial
Currently available genetic tests analyzing homologous recombination deficiency (HRD) have limited predictive value
During the ESMO Breast Cancer 2021 Congress, in virtual format, a retrospective and blinded analysis of the GeparSixto randomized clinical trial comparing the performance of a functional test for HRD analysis from a RAD51 nuclear foci score versus genetic/genomic HRD testing was presented; the performance of this functional test to select patients with triple-negative breast cancer sensitive to platinum-based neoadjuvant chemotherapy was also evaluated.
In this trial, patients with triple-negative breast cancer received neoadjuvant paclitaxel + non-pegylated liposomal doxorubicin + bevacizumab (PM) or paclitaxel + doxorubicin + carboplatin (PMCb). Functional HRD biomarkers (RAD51, BRCA1 and yH2AX nuclear foci) were quantified in tumor samples fixed in formalin-fixed and paraffin-embedded tumor samples.
The concordance analyses were performed between the RAD51 score and the BRCA status of the tumor (tBRCA) or the genomic HRD score (myChoice® CDx). Associations with clinical outcomes were studied by logistic (pathological complete response, PCR) and Cox (disease-free survival, DFS). Functional HRD was predefined as a RAD51 score ≤ 10%, i.e., RAD51-low.
Findings:
RAD51, BRCA1, and yH2AX were successfully scored on 133 out of 200 tissue samples (67%). Functional HRD by RAD51-low was evidenced in 81 of 133 tumors (62%).
The RAD51 test identified 93% of tBRCA-mutated tumors and 45% of the 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, the PCR rate was similar between the treatment arms (PMCb 31% vs PM 39%; p = 0.561). Women with RAD51-low tumors benefited from PMCb (66% versus 33%; OR 3.96; p = 0.023). The addition of carboplatin showed a trend of improvement in disease-free survival DFS in both RAD51-high (HR: 0.40; p = 0.125) and RAD51-low (HR 0.45; p = 0.124) groups, although it was statistically non-significant.
The researchers conclude that the RAD51 test is highly concordant with the tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding carboplatin to neoadjuvant chemotherapy in triple-negative breast cancer TNBC. With these data, further technological development and validation of scientific data may lead to the incorporation of RAD51-testing in clinical decision-making.
References:
- Llop-Guevara A, et al. Association of RAD51 with Homologous Recombination Deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial. Abstract 20. ESMO Breast Cancer Virtual Congress 2021. Annals of Oncology (2021) 32 (suppl_2): S21-S36. 10.1016/annonc/annonc503.
