Introduction/Background High-grade serous ovarian cancer (HGSOC) is typified by high degrees of genomic instability and heterogeneity, with the majority of patients eventually acquiring resistance to platinum chemotherapy. Matching the best treatment options to patients remains challenging due to diverse platinum resistance mechanisms and limited effective predictive biomarkers. This study aims to understand the extent of intra-tumoural heterogeneity (ITH) in advanced stage HGSOC, and how this changes over time at relapse, and define the link between ITH at molecular and phenotypic levels.
Methodology High tumour-load HGSOC patients (n=53) undergoing radical upfront-debulking underwent a tumour mapping of their tumour dissemination patterns. Tumour biopsies were collected (range 4–15, median=9), placed in short-term cultures, treated with cisplatin and apoptosis/viability assayed. DNA was extracted (5 tumours per patient) and Illumina Human OmniExpress genotyping performed. Allele-specific copy number (CN) was quantified using ASCAT. The sum of differences in gene-level CN estimates was used to define genomic dissimilarity of deposits. When relapsed, patients had paired biopsies.
Results Tumour deposits varied extensively to each other at the copy-number level, possibly reflecting divergence from different tumour sub-clones. Different degrees of heterogeneity were observed in different patients, which appeared to correlate with progression-free survival and variance in apoptosis induction across tumours in the patient series. Patients who developed platinum-resistant disease tended to be more polyclonal. Higher CCNE1 CN associated with in-vitro chemoresistance (p=0.019, r=-0.170), and poorer patient outcome (p=0.041). However, extensive variations in CCNE1 CN were observed across multiple tumours in the same patients.
Conclusion Vast heterogeneity is observed at the phenotypic and genomic level in HGSOC patients with direct correlation with later development of platinum-resistant disease. Extensive variations in CCNE1 CN across multiple intra-abdominal samples within the same patient, suggests that single site biopsies cannot accurately represent overall disseminated HGSOC biology and has implications for overinterpretation of studies relating to outcome and platinum-resistance.
Disclosure Professor Christina Fotopoulou COI: advisory boards and honoraria from Roche, Tesaro, Sequana, Olympus, Astra Zeneca.
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