Abstract 325: A functional homologous recombination assay predicts primary chemotherapy response and long-term survival in ovarian cancer patients

Abstract

Abstract Background: High-grade serous ovarian cancer (HGSOC) is the most common and aggressive type of ovarian cancer (OC) and the fifth most common malignancy occurring in women, meaning that 1 in 70 will develop OC during her lifetime. The current first-line treatment for HGSOC patients consists of cytoreductive surgery and platinum/taxanes-based chemotherapy. Homologous recombination deficiency (HRD) correlates with platinum sensitivity in OC patients, which clinically is the most useful predictor of sensitivity to PARPi. To date, there are no reliable diagnostic tools to anticipate response to platinum-based chemotherapy, thus we aimed to develop an ex vivo functional HRD detection test that could predict both platinum-sensitivity and patient eligibility to targeted drug treatments. Methods: We obtained a functional HR score by quantifying homologous recombination (HR) repair after ionizing radiation-induced DNA damage in primary ovarian cancer samples (n=24). Samples spontaneously clustered in 3 categories: HR-deficient, HR-low and HR-proficient. We analysed the HR score association with platinum sensitivity and treatment response, platinum-free interval (PFI) and overall survival (OS), and compared it with other clinical parameters (treatment strategy, FIGO stage, age). In parallel, we performed DNA sequencing of HR genes to assess if functional HRD can be predicted by currently offered genetic screening. Results: Low HR scores predicted primary platinum sensitivity with high statistical significance (p=0.001) and associated with longer PFI (HR-deficient vs HR-proficient: 531 vs 113 days). The HR score was the only factor that significantly correlated with improved OS (HR score <35 vs ≥35, hazard ratio=0.12, 95% CI=0.02 to 0.79, p=0.026). At the genomic level, we identified a few mutations of unclear significance in HR genes but, overall, DNA sequencing failed to predict functional HRD. Conclusions: We developed an ex vivo assay that detects tumor functional HRD and an HR score able to predict platinum sensitivity, which holds the clinically relevant potential to become the routine companion diagnostic in the management of ovarian cancer patients. Citation Format: Manuela Tumiati, Sakari Hietanen, Johanna Hynninen, Elina Pietilä, Anniina Färkkilä, Katja Kaipio, Amjad Alkodsi, Minna Tuominen, Sampsa Hautaniemi, Olli Carpén, Liisa Kauppi. A functional homologous recombination assay predicts primary chemotherapy response and long-term survival in ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 325.