Abstract A10: Phenotypic and genomic characterization of intratumoral heterogeneity in high-grade serous ovarian cancer
Cunnea P., Curry E., Nixon K., Wulandari R., Thol K., Kwok CH., Ploski J., McNeish I., Christie E., Bowtell D., Fotopoulou C.
Abstract High-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer, accounting for more than 70% of all epithelial ovarian cancers. It is characterized by high degrees of genomic instability and heterogeneity, with the majority of patients eventually acquiring resistance to platinum chemotherapy. The diversity in platinum-resistance mechanisms and limited effective predictive biomarkers mean delivering the best treatment options for patient tumor remains challenging. The purpose of this study is to understand the extent of intratumoral heterogeneity (ITH) in advanced-stage HGSOC and how this changes over time at relapse, to describe the molecular mechanisms behind peritoneal dissemination, and to delineate the link between ITH at the molecular and phenotypic levels. Patients undergoing radical upfront debulking for advanced HGS ovarian cancer underwent tumor mapping of their tumor dissemination patterns (n=50). Biopsies were collected from disseminated tumors (range 4-15, median=9), snap frozen, and placed in short-term cultures. Tumor cultures were treated with cisplatin, apoptosis/viability assayed and IC50 for cisplatin determined. DNA was extracted from frozen tumors (5 tumors per patient plus germline) and Illumina Human OmniExpress genotyping performed. Allele-specific copy number (CN) was quantified using ASCAT. Genomic heterogeneity was quantified as the estimated number of CN aberration events distinct between each pair of deposits. Clonal diversity within a patient’s deposits was calculated using the difference between within-patient and between-patient heterogeneity. When relapsed, patients had paired biopsies collected for genomic and phenotypic analysis. Broad heterogeneity was observed in response to platinum treatment in vitro across cases at the phenotypic level (n=50), with higher variances in apoptosis induction observed in patients with platinum-resistant disease. Genomic analysis of copy number data revealed widespread variations in patterns of evolution for different patients’ tumors, including the relationship between primary deposits and relapsed disease. Variations in CCNE1 CN were observed across multiple tumors in the same patients, and overall higher CCNE1 CN associated with poorer patient outcome (p=0.041). Extensive heterogeneity is observed at the phenotypic and genomic levels in HGSOC patients, which correlates with the subsequent development of platinum-resistant disease. CCNE1 copy number variations across multiple intra-abdominal samples within patients indicate that single-site biopsies do not truly represent overall disseminated HGSOC biology and may have implications for overinterpretation of studies relating to outcome and platinum resistance. Citation Format: Paula Cunnea, Ed Curry, Katherine Nixon, Ratri Wulandari, Kerstin Thol, Chun Hei Kwok, Jennifer Ploski, Iain McNeish, Elizabeth Christie, David Bowtell, Christina Fotopoulou. Phenotypic and genomic characterization of intratumoral heterogeneity in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A10.