Introduction/Background*High-grade serous ovarian cancer (HGSOC) is typified by extensive genomic instability and intra-tumoural heterogeneity (ITH). The majority of patients relapse and eventually acquire resistance to platinum-based chemotherapy. Diverse mechanisms leading to platinum resistance and a lack of predictive biomarkers means that matching the best treatment options to patients is difficult. This study aims to characterise the extent of spatial and temporal ITH in advanced stage HGSOC at presentation and relapse.
Methodology Patients (n=49) having maximal effort upfront-debulking surgery for advanced HGSOC underwent a tumour mapping of their tumour dissemination patterns. Tumour biopsies were collected (range 4-15, median 9), 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. Ki67 proliferation index was assessed from tumour sections collected prior to DNA extraction.
Result(s)*Extensive genomic variations in patterns of evolution for different patients’ tumours was observed, including the relationship between matched primary tumours and relapsed disease. Widespread variations in CCNE1, MYC and PTEN CN were observed across multiple disseminated tumours in the same patients, and higher CCNE1 correlated with poor patient outcome (p=0.038). Extensive heterogeneity in Ki67 proliferation index was observed across the cohort, 77% of patients had tumour scores covering low, moderate and/or high Ki67 scoring categories.
Conclusion*Broad ITH was observed at the genomic level across this cohort. Extensive CN variations in genes such as CCNE1, across multiple disseminated samples within patients, and widespread variations in proliferative index between multi-site tumours, indicates that a single tumour biopsy does not accurately depict disseminated HGSOC biology, and therefore should not be used for as a basis for prediction of patient prognosis or outcomes.
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