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A mutational signature that can be reliably detected from panel-sequencing data is associated with response to olaparib
In breast cancer patients, PARP inhibitors such as olaparib are approved for BRCA1/2 carriers, but there is growing evidence of benefit in additional patients, so there is a clinical need for a more comprehensive biomarker of response. New data recently published in Clinical Cancer Reserch show that patients with homologous recombination deficiency (HRD) beyond BRCA1/2 mutations can be identified by a method to detect mutational signature 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data.
The SigMA method to select who could benefit from PARP inhibitors, previously developed by the authors, was applied to patients with ovarian or breast cancer from two independent datasets; results show that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome-sequencing data from the same patient samples demonstrated highly concordant results and superior performance in comparison with the genomic instability score. HRD can thus be detected reliably from panel-sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCA1/2 mutations who might benefit from PARP inhibitors. «This work brings mutational signatures closer to the clinic by not only confirming our ability to reliably detect Sig3 from clinical sequencing but also relating these to meaningful clinical outcomes such as progression-free survival and objective response rate», authors say. «Our method is unique that it detects Sig3 from routine clinical sequencing targeting a few hundred genes, whereas previous methods for Sig3 detection required whole-exome or whole-genome sequencing that are not routine care. Sig3 could be used to design clinical trials to identify patients who will benefit from PARP inhibitors with high probability, without additional sequencing costs».