The genomic landscape of recurrent ovarian high grade serous carcinoma: the BriTROC-1 study

The drivers of recurrence and resistance in ovarian high grade serous carcinoma (HGSC) remain unclear. We established BriTROC-1 to investigate the acquisition of resistance by collecting tumour biopsies from women with recurrent ovarian HGSC that had relapsed following at least one line of platinum-based chemotherapy. Patients underwent biopsy or secondary debulking surgery, with tumour samples fixed in methanol-based fixative. Normal and tumour DNA samples underwent tagged-amplicon panel sequencing. Tumour DNA underwent shallow whole genome sequencing (sWGS). Tissue microarrays (TMA), created from diagnosis samples, were stained for CD3, CD8, CD20 and FoxP3. 276 patients were recruited (209 platinum-sensitive, 67 platinum-resistant). Panel sequencing showed close concordance between diagnosis and relapse, with only 4 discordant cases, and no revertant mutations in BRCA1 or BRCA2 were identified in relapse samples. CN signatures were strongly correlated with immune cell infiltration. There was very strong concordance in copy number (CN) between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic CN alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Small increases in CN signature 3 and 7 exposure were observed between diagnosis and relapse across the whole cohort but were not present in matched sample pairs. Diagnosis samples from patients with primary platinum resistance had increased rates of CCNE1 and KRAS amplification and CN signature 6 exposure. The HGSC genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers. We have identified new genomic events at diagnosis, including KRAS amplification and CN signature 6 exposure, that are associated with primary platinum resistance. ### Competing Interest Statement G.M., F.M., A.M.P. and J.D.B. are founders and shareholders of Tailor Bio Ltd. ### Funding Statement This work was supported by Ovarian Cancer Action (grant number OCA_006 to IAMcN and JDB); the National Institute for Healthcare Research (NIHR) (grant number P77646 to IAMcN); the Wellcome Trust PhD programme in Mathematical Genomics and Medicine (grant number RG92770 to LMG); Cancer Research UK (grant numbers A15973, A15601, A18072, A17197, A19274 and A19694 to JDB, FM and IAMcN); the Beatson Cancer Charity and Hutchison Whampoa Limited. Infrastructure support was provided by Experimental Cancer Medicine Centres at participating sites. We also thank the Biorepository, Bioinformatics, Histopathology and Genomics Core Facilities of the Cancer Research UK Cambridge Institute and the Pathology Core at the Cancer Research UK Beatson Institute for technical support. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Cambridge Central Research Ethics Committee gave ethical approval for this work (Reference 12/EE/0349). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors