Introduction/Background High-grade serous ovarian cancer (HGSOC) is characterised by high degrees of genomic instability and heterogeneity, with most patients eventually acquiring resistance to platinum-based chemotherapy. Matching the best treatment options to patients remains problematic 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, at presentation and relapse, and to define the link between ITH at the genomic and phenotypic levels.
Methodology Patients (n=49) undergoing radical upfront-debulking for advanced HGSOC at Hammersmith Hospital, UK, 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 (25μM overnight) and apoptosis/viability assayed. When relapsed, patients also had paired biopsies collected for genomic and phenotypic analysis. DNA was extracted from tumours (5 per patient, n=49 patients plus relapse samples) 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 tumour deposits. Clonal diversity within a patient’s deposits was calculated using the difference between within-patient and between-patient heterogeneity.
Results Broad heterogeneity was detected in response to platinum treatment across cases at the phenotypic level in vitro (n=49), with higher variances in apoptosis induction observed in patients with platinum resistant disease. Genomic analysis revealed widespread variations in patterns of evolution for different patients’ tumours, including the relationship between primary tumours and relapsed disease. Extensive variations in CCNE1, MYC and PTEN CN were observed across multiple tumours in the same patients, and overall higher CCNE1 CN associated with poorer patient outcome (p=0.038).
Conclusion Vast intra-tumoural heterogeneity is observed at the phenotypic and genomic level in HGSOC patients. Extensive copy number variations in genes such as CCNE1, MYC and PTEN across multiple disseminated samples within patients, indicates that sampling of a single tumour site does not accurately represent overall disseminated HGSOC biology and has implications for overinterpretation of studies relating to outcome and platinum-resistance.
Disclosures CF: advisory boards and honoraria from Roche, Tesaro, Sequana, Olympus, Astra Zeneca. Other authors have no disclosures to declare.
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