Abstract 1617: Tumor evolution during therapy in ovarian cancer

Abstract The evolution of tumors from diagnosis to relapse in ovarian high-grade serous carcinoma (HGSC) patients is poorly understood. Consequently, it is unknown whether diagnostic samples are representative enough to guide treatment directions at relapse, or whether acquired changes during therapy provide targets in patients with relapses. To answer these questions and characterize tumor evolution during treatment, we used data from >700 tissue and plasma samples from 200 HGSC patients belonging to the observational, longitudinal DECIDER trial (NCT04846933). Mutations from whole-genome sequencing data from tissue samples (2-12 per patient) were used to construct phylogenetic trees. The trees were corrected by the copy-number alterations and curated to integrate circulating tumor DNA (ctDNA) exome- and targeted-sequencing data from plasma samples. Evolutionary states presenting within and between sample heterogeneity were evaluated through clonal complexity and divergence. Additionally, genetic differences between persistent and non-persistent subclones were studied to identify features affecting treatment resistance. Our results indicate that the majority of subclones survive chemotherapy treatment and major subclonal replacement takes place in only a few patients. Within-sample heterogeneity was higher in plasma samples than in ascites, highlighting the importance of ctDNA samples to estimate persistent subclones. Additionally, our recently reported evolutionary states (Lahtinen et al. Cancer Cell 2023) were often altered by the treatment induced selection pressure. At late relapses, subclone compositions typical of maintaining evolutionary state tumors were less common, and a higher number of acquired subclones were detected, suggesting further evolution of the persisting clones. In summary, chemotherapy does not suppress heterogeneity in HGSC tumors. Interestingly, patients with the worst prognosis have a stable composition of multiple clones in their tumors, and tumors with low heterogeneity responded better to primary treatment. Relapse samples show lower within-sample heterogeneity and further evolution. Furthermore, we detected several evolutionary trajectories from stable, persistent cancer subclone populations to highly dynamic subclone structures. This renders diagnostic samples suitable to guide relapse treatment decisions in a subset of patients with HGSC but not for all. Our characterization of the dynamics of tumor clonal heterogeneity during treatment allows to define better therapeutic interventions for HGSC patients with relapsed disease. Citation Format: Sampsa Kalervo Hautaniemi, Jaana Oikkonen, Alexandra Lahtinen, Mai T.N. Nguyen, Giovanni Marchi, Kari Lavikka, Anna Rajavuori, Sakari Hietanen, Anni Virtanen, Johanna Hynninen. Tumor evolution during therapy in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1617.