BRCA mutations and Homologous Recombination Deficiency (HRD) testing in ovarian cancer

Ovarian cancer (OC) is the fifth most common cause of cancer-related mortality worldwide and represents the leading cause of death for gynecological malignancies. Nevertheless, over the last years, the advances in the comprehension of tumor biology have favored the development of novel efficacious therapeutic agents, such as the poly (ADP-ribose) polymerase inhibitor (PARPi). The inability to efficiently repair DNA double-strand breaks using the homologous recombination repair pathway is defined as homologous recombination deficiency (HRD) and is detected in about 50% of high-grade serous ovarian cancer (HGSOC). The HRD status, due to germline or somatic BRCA1 DNA Repair Associated (BRCA1) and BRCA2 DNA Repair Associated (BRCA2) mutations in around 22% of cases, has been associated with increased sensitivity to PARP inhibition and to platinum-based chemotherapy, thus reshaping treatment algorithm. However, HRD is a complex genomic signature and several potential pitfalls and challenges can be encountered in HRD diagnostics. Notably, different methods of analysis have been developed to introduce HRD testing in the clinical setting such as: 1) Evaluation of Germline or somatic mutations of genes in the Homologous Recombination Repair (HRR) pathway; 2) Evaluation of Genomic scars and genomic instability profiles; 3) HRR functional status assessment by nuclear RAD51 expression. Moreover, HRD status dynamically evolves under treatment pressure. Indeed, HR genes revertant mutations (BRCA1-2, RAD51C/D) and or epigenetic alteration, such as BRCA1 methylation decrease or loss, may eventually occur, thus restoring HR and eventually resulting in PARPi and platinum chemotherapy resistance.

Therefore, great research efforts are focusing on the development and validation of novel effective assays to effectively detect HR status in OC. In addition, new compounds targeting HR and DDR actors beyond BRCA1 and BRCA2, are emerging to overcome or eventually prevent PARPi resistance. In this Research Topic, we mainly aim to discuss the current major evidence of the evolving role of HRD detection in OC patient selection. Additionally, we want to explore the HR-related mechanisms associated with PARPi resistance and the most promising strategies emerging to target them.

We welcome the submission of Original Research, Review, Mini Review, and Perspective Articles that cover, but are not limited to:
- Current HRD assays differences, pitfalls, and limitations
- Predictive/prognostic value of genomic and epigenomic BRCA alterations
- HR restoration and PARPi resistance
- BRCAness profile: PARPi sensitivity and resistance.
- Current and novel potential therapeutic strategies targeting DDR actors
- Turning HR proficient in HR deficient OC

Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.

Topic Editor Dr. Umberto Malapelle has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientific, Eli Lilly, Diaceutics, GSK, Merck and AstraZeneca, Janssen, Diatech, Novartis and Hedera unrelated to the current work. The Editor Dr. De Angelis has received personal fees (as consultant and/or speaker bureau) from Roche, MSD, Eli Lilly, GSK, AstraZeneca, Novartis, Pfizer, GILEAD and Daiichi Sankyo, and has received research grants (to Institution) from Novartis, GILEAD, and Daiichi Sankyo. The other Topic Editors declare no competing interests with regard to the Research Topic subject.