RT Journal Article
SR Electronic
T1 2022-RA-1608-ESGO Clinical implications of genomic intratumoural heterogeneity in high grade serous ovarian cancer
JF International Journal of Gynecologic Cancer
JO Int J Gynecol Cancer
FD BMJ Publishing Group Ltd
SP A419
OP A420
DO 10.1136/ijgc-2022-ESGO.900
VO 32
IS Suppl 2
A1 Paula Cunnea
A1 Elizabeth L Christie
A1 Ed Curry
A1 Chun-Hei Kwok
A1 Ahwan Pandey
A1 Katherine Nixon
A1 Jennifer Ploski
A1 Jonathan Krell
A1 Iain McNeish
A1 David D Bowtell
A1 Christina Fotopoulou
YR 2022
UL http://ijgc.bmj.com/content/32/Suppl_2/A419.3.abstract
AB Introduction/Background High-grade serous ovarian cancer (HGSOC) is typified by extensive genomic instability and intra-tumoural heterogeneity (ITH). Most patients relapse and eventually acquire resistance to platinum- or PARP inhibitor-based therapy. Diverse mechanisms leading to therapy resistance and a lack of predictive biomarkers means that matching the best treatment options to patients is difficult. This study aims to describe the extent of spatial and temporal ITH in advanced stage HGSOC at presentation and relapse and its implications for patient management.Methodology Patients (n=49) undergoing maximal-effort upfront-debulking surgery for advanced HGSOC had a tumour mapping of their tumour dissemination. Tumour biopsies were collected (range 4–15) from patients, and also at time of relapse (n=10 patients). DNA was extracted from tumours (5 per patient, n=49 patients plus paired relapse samples) and Illumina Human OmniExpress genotyping performed. Allele-specific copy number (CN) was quantified using ASCAT. CN signature exposures were determined for all samples. Homologous recombination (HR) scores were estimated using a scarHRD algorithm, applying a cut-off >42 for HR-deficient.Results Extensive genomic variations in CN signature exposures for different patients’ tumours were observed, including between matched primary and relapse tumours. Increased CN signature exposure scores for Signatures 2 (p=0.00017), 4 (p=0.0029) and 6 (p=0.001) correlated with poor outcome in platinum-resistant/refractory patients, increased Signature 3 correlated with favourable outcome (p=0.00018) for platinum-sensitive and no-relapse patients. Variations in HR scores were observed across the cohort with one fifth of patients presenting with a mixed HR score profile across their tumour deposits, demonstrating both HR-deficient and HR-proficient tumours within patients.Conclusion Extensive CN variations in CN signature scores and mixed HR-deficiency/proficiency scores indicates that a single tumour biopsy does not accurately depict disseminated HGSOC biology, and therefore should not be used as the basis to derive biomarker profiles for prediction of patient treatment responses or outcomes.