Abstract 2135: Multi-omics characterization of chemo-refractory HGSC patients
Authors: Muranen Taru A. , Rajavuori Anna , Afenteva Daria , Huhtinen Kaisa , Isoviita Veli-Matti , Jamalzadeh Sanaz , Lahtinen Alexandra , Lavikka Kari , Li Yilin , Marchi Giovanni , Oikkonen Jaana , Zhang Kaiyang , Virtanen Anni , Hynninen Johanna , Hautaniemi Sampsa 
Published: April 2023

Neoadjuvant chemotherapy (NACT) is the preferred treatment strategy for high-grade serous (ovarian) cancer (HGSC) patients, if optimal cytoreduction is estimated unachievable at the time of the diagnosis. In such cases, intrinsic sensitivity to standard-of-care (platinum and taxane combination therapy) is a major determinant of the disease progression.

The DECIDER project is an international effort to overcome the mechanisms of chemo-resistance by integration of clinical, imaging and multi-omics data layers from a prospective cohort of &gt;300 HGSC patients. In the DECIDER cohort, NACT was chosen as the treatment for 46% of the patients, of whom 31 had intrinsically chemo-refractory disease, defined as progressive or stable disease (SD/PD) at the end of the primary therapy and progression-free interval (PFI) shorter than 45 days. A reference group comprised 60 patients with partial or complete response (PR/CR) after primary therapy and PFI longer than six months. The rest of the NACT-treated patients had at least partial relapse but PFI between one to six months.

Herein, we tested the enrichment of clinicopathological and molecular features in the refractory and reference groups. Furthermore, we studied all NACT-treated patients, using a three-state survival model with primary progression and death as events of interest, and characterized survival associations with Cox regression. RNA sequencing data were used to identify cellular states and pathway activities, with the goal of revealing molecular level differences that drive early resistance to chemotherapy. Whole genome sequencing data were integrated to the gene expression-based results, to identify causal genetic aberrations. Additionally, the molecular features were tested against clinicopathological features and known HGSC driver mutations.

Our results suggest that the resistance to primary therapy predicts decreased survival, so that the mean time to death was 13.6 months for patients with SD/PD and about 5 months longer for patients with at least partial response. As expected, a higher pathological chemotherapy response score (CRS) predicted increased time to progression and a longer time from primary progression to death. However, there was only marginal difference in the distribution of the CRS between the chemo-refractory and responsive groups. In a multivariable model, mutation signature-based homologous recombination (HR) deficiency was associated with a longer time to primary progression, whereas the time from progression to death was associated only with loss-of-function mutations in HR genes. Interestingly, tumor mutation burden, whole genome duplication, or the level of tumor cell proliferation were not associated with chemo-resistance or patient survival. Immune cell infiltration in solid tissue samples was very low, except for one responsive patient, and was not associated with chemo-response.

Citation Format: Taru A. Muranen, Anna Rajavuori, Daria Afenteva, Kaisa Huhtinen, Veli-Matti Isoviita, Sanaz Jamalzadeh, Alexandra Lahtinen, Kari Lavikka, Yilin Li, Giovanni Marchi, Jaana Oikkonen, Kaiyang Zhang, Anni Virtanen, Johanna Hynninen, Sampsa Hautaniemi. Multi-omics characterization of chemo-refractory HGSC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2135.