Abstract 1257: Response to primary therapy predicts tumor evolution dynamics at relapse in ovarian cancer

Abstract Chemotherapy resistance is a major contributor of cancer-related deaths. Resistance can either be acquired during treatments or pre-exist at the time of the diagnosis. Previous studies on high-grade serous carcinoma (HGSC) have shown contradictory findings on the role of genetic causes explaining emergence of chemotherapy resistance at relapses, for example selection of resistant clones during chemotherapy. HGSC is often diagnosed at an advanced stage, showing multiple genetically heterogeneous clones present before therapeutic intervention. While most patients respond well to primary therapy, cancer relapses within few years, leading to treatment resistance. To understand genetic impact on emergence of resistance, we used matched pretreatment and treated samples from 214 unselected HGSC patients collected at DECIDER trial (NCT04846933). We constructed phylogenetic trees based on whole-genome sequencing of 804 tumor samples and whole-exome sequencing of 63 circulating tumor DNA (ctDNA) samples from plasma. Cancer evolution analysis identified patients with and without selection during treatments: patients with remained heterogeneity with stalled evolution, and others dominated by subclones originating from single resistant clone. Patients with better primary therapy outcome were linked to re-expansion of a single major clone at relapse, while multiple ancestral clones founded relapse populations in poorer outcome patients. The single-clone expansion pattern also emerged in later relapses, after multiple lines of therapy. Majority of the relapsed cancers evolved further from the ancestral clones already present at pretreatment. The relapse emerging subclonal mutations affected pathways such as carbohydrate metabolism and cAMP signaling. In contrast, sensitive clones eliminated by treatment carried mutations affecting extracellular matrix and NTRK3 signaling. Interestingly, some cancers did not acquire new mutations at relapse, despite becoming chemoresistant, suggesting that non-genetic mechanisms, such as phenotypic plasticity or microenvironmental factors, might underlie their resistance. In summary, we discovered heterogeneous cancer evolution trajectories during treatment which were linked to mutations in key pathways and prior therapy responses. While chemotherapy often selects persistent cancer subclones that seed later relapses, some patients acquire resistance through non-genetic mechanisms, highlighting the complexity of cancer evolution and resistance dynamics. Understanding these dynamics is crucial to define better therapeutic interventions in these poor prognosis patients with advanced HGSC. Citation Format: Jaana Oikkonen, Giulia Micoli, Susanna Holmström, Kari Lavikka, Mai T. Nguyen, Yilin Li, Giovanni Marchi, Anna Rajavuori, Heidi Koskela, Johanna Hynninen, Sampsa Hautaniemi. Response to primary therapy predicts tumor evolution dynamics at relapse in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1257.