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Purpose: Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. Experimental Design: We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. Results: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. Conclusions: Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. See related commentary by Yang et al., p. 2730

BackgroundPlatinum-based neoadjuvant chemotherapy (NACT) followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase III trials,evaluation of response to NACT using Response Evaluation Criteria in Solid Tumours (RECIST)and CA125 was not reported. We describeRECIST and Gynecologic Cancer InterGroup (GCIG)CA125 responses in patients receiving platinum-based NACT followed by DPS in the phase III trial, ICON8.MethodsICON8 was an international, multicentre, randomised, phase III trial in which women ≥18 years old with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy >12 weeks and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO;1988) stage IC-IIA high-grade serous, clear cell or any poorly differentiated/grade 3 histological subtype or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube or primary peritoneum were randomised (1:1:1) to receive either intravenous (IV) carboplatin (AUC5/6)and IV paclitaxel (175mg/m2by body surface area [BSA])on day 1 of every 21-day cycle(control arm)or IV carboplatin (AUC5/6)on day 1 and IV paclitaxel (80mg/m2by BSA)on days 1, 8 and 15 of every 21-day cycle(dose-fractionated paclitaxelarm) or IV carboplatin (AUC2)and IV paclitaxel (80mg/m2by BSA)on days 1, 8 and 15 of every 21-day cycle(dose-fractionated carboplatin and paclitaxelarm). Randomisation occurred using a minimisation method and patients where stratified according to GCIG group, disease stage and timing and outcome of cytoreductive surgery. Neither patients nor clinicians were masked to their allocated group. The scheduling of surgery and use of NACTwere determined by local multidisciplinary case review. In this post-hoc 5exploratory analysis of ICON8, progression-free survival (PFS) was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This is different to the intention-to-treat primary PFS efficacy analysis of ICON8, which definedPFS as the time from randomisation to the date of clinical or radiological progression or death, whichever occurred first. This post-hoc exploratory analysis includes only women recruited to ICON8thatwere planned for NACT followed by DPS and had RECIST v1.1 and/or GCIG CA125 evaluable disease. ICON8isclosed for enrolment and follow-up, and registered with ClinicalTrials.gov, number: NCT01654146. Findings: BetweenJune 6,2011 and November 28,2014,1,566 women were enrolled in ICON8.Seven hundred and seventy-nine women were planned forNACT followed by DPS(NACT-DPS). In the NACT-DPS population,94% had FIGO stage IIIC/IV disease. Five hundred and sixty-four women had RECIST evaluable disease at trial entry and the complete or partial response rate (CR/PR) was 62%(348/564). Seven hundred and twenty-seven women were evaluable by GCIG CA125 criteria at the time of diagnosis and 84%(610/727) had a CA125 response. The median PFS was 14.4 months (95% CI [confidence interval] 9.2-28.0months; 297 events) for RECIST CR/PR and 13.3 months (95% CI 8.1-20.1months; 171 events) for RECIST stable disease(SD). The median PFS for those women with a GCIG CA125 response was 13.8 months (95% CI 8.8-23.4months; 544 events) and 9.7 months (95% CI 5.8-14.5months; 111 events) for those without. Complete cytoreduction(R0) was achieved in 56% (187/335) of women with RECISTCR/PRand42% (73/172) with RECIST SD. Complete cytoreduction (R0) was achieved in50% (290/576) and 30% (30/101) of women 6with and without a GCIG CA125 response, respectively. The median follow-up was 29.5 months (interquartile range:15.6-54.3months) for the NACT-DPS population.InterpretationThe RECIST-defined radiological response was lower than frequently quoted to patients in the clinic. RECIST v1.1 and GCIGCA125 responses to NACT for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients likely to benefit from DPS, but instead used in conjunction with the patient’s clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST v1.1 or GCIG CA125 response.