HRR testing including BRCA1/2 can guide therapy in Ovarian Cancer

Specific types of DNA damage, such as mismatches during replication, single- or double-strand DNA breaks, can result in the activation of specific signalling and repair cascades such as homologous recombination repair (HRR) in normal cells to repair the damage. However, deficiencies in these repair pathways result in the accumulation of DNA damage, genomic instability, and an increased risk of developing cancers, particularly breast and ovarian cancers. Hence, it is important to test for mutations in the repair genes including the well-known BRCA1, BRCA2, plus others such as RAD51C, RAD51D, PALB2, and ATM, to improve the selection of targeted therapies like PARP inhibitors namely Olaparib, Niraparib, Rucaparib, and Talazoparib.

To determine the potential for PARP inhibitors in Indian ovarian cancers, we have been sequencing our 1100+ ovarian cancer resection cases using a 43-gene HRR NGS panel. We have identified several cases with BRCA mutations, as well as other HRR pathogenic/likely-pathogenic mutations in ARID1A, ATR, ATM, CDK12, CHEK2, RAD51B, FANCC, and FANCE genes. In the DNA damage response signaling pathway shown below, these genes are marked with an asterisk to indicate mutations identified in our ovarian cancer samples. These oncogenic alterations may predict response to PARP inhibitors and guide the choice of therapy to improve ovarian cancer patient lives.