Abstract PR-001: Stable subclones and acquired genomic events present after treatment of HGSC
Authors: Oikkonen Jaana , Lahtinen Alexandra , Nguyen Mai T.N. , Marchi Giovanni , Lavikka Kari , Rajavuori Anna , Huhtinen Kaisa , Hietanen Sakari , Virtanen Anni , Hynninen Johanna 
Published: March 2024

Abstract
Ovarian high-grade serous carcinoma (HGSC) is commonly diagnosed at an advanced stage, showing multiple genetically heterogeneous clones existing prior to therapeutic intervention. Most of the patients respond well to primary therapy, but cancer relapses within few years and develops treatment resistance. Genomics changes in tumors during therapy are poorly known. Thus, we characterized subclonal changes and their contribution to treatment resistance and outcome in over 150 patients with HGSC. We used over 700 longitudinal tissue and plasma samples from the prospective, longitudinal, multiregion DECIDER study. Patients were treated either with primary debulking surgery and platinum-taxane chemotherapy, or by neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) and adjuvant chemotherapy. Tumor samples from pre-chemotherapy, at IDS and at relapses underwent whole-genome sequencing (WGS), and plasma samples were sequenced with either whole-exome sequencing or targeted cancer-gene panels. Phylogenetic trees were constructed from WGS samples (2-12 per patient) and curated to use information gathered 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 survived treatment. Major subclonal replacement was detected only in few patients, whereas remaining heterogeneity with acquired focal copy-numbers and mutations was commonly detected. Within-sample heterogeneity was higher at plasma samples than ascites, which underlined the importance of ctDNA sampling to estimate persistent subclones. Additionally, evolutionary states were often altered by the changing selection pressure caused by treatments. Direction of these responses varied after NACT: some patients moved towards our earlier identified maintaining state (Lahtinen et al. Cancer Cell 2023) with similar subclonal compositions between sampled sites whereas others moved towards adaptive state with high number of sample-specific subclones. At late relapses, subclone compositions typical in maintaining state tumors were less common and higher number of acquired subclones were detected, suggesting further evolution of the persisting clones. Taken together, chemotherapy treatment does not suppress heterogeneity in HGSC tumors. Bottleneck events causing survival of only a few subclones were rare. Treatments altered evolutionary states of the cancers, and most tumors revealed acquired mutations at relapses. Overall, we detected various evolutionary trajectories from stable, persistent cancer subclone populations to highly dynamic subclone structures. Understanding these dynamics of tumor clonal heterogeneity during treatment is crucial to define better therapeutic interventions in these poor prognosis patients with advanced HGSC.
Citation Format: Jaana Oikkonen, Alexandra Lahtinen, Mai T.N. Nguyen, Giovanni Marchi, Kari Lavikka, Anna Rajavuori, Kaisa Huhtinen, Sakari Hietanen, Anni Virtanen, Johanna Hynninen. Stable subclones and acquired genomic events present after treatment of HGSC [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr PR-001.