It is an urgent effort to identify patients with homologous recombination deficiency (HRD) who do not have BRCA1/2 mutations, since these patients may benefit from PARP medicines. Researchers had previously established a method to consistently diagnose HRD from the restricted sequencing data produced from gene-focused panel sequencing. This method was able to detect mutational signature 3 (Sig3), which they had dubbed SigMA, which is linked with HRD using clinical panel sequencing data.
They applied this method to patients from 2 independent datasets: 1: patients with high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120; NCT01623349), and 2: patients with TNBC who received neoadjuvant olaparib in the phase II PETREMAC trial (NCT02624973). Sig3 as discovered by SigMA is found to have a positive association with better progression-free survival and objective responses, according to their findings.
In addition, a comparison of the Sig3 detection in the panel and the exome-sequencing data from the same patient samples indicated highly concordant results and superior performance in comparison with the genomic instability score. Their studies showed that HRD may be reliably diagnosed using panel-sequencing data that is collected as part of routine clinical care, and that this approach might identify patients who potentially benefit from PARP medicines beyond those with germline BRCA1/2mut. It would be prudent to do a prospective clinical utility assessment.