774P - CCNE1 amplification defines a good prognostic subgroup among BRCAwt/HRDneg advanced high-grade ovarian cancer (HGOC)

Background

Around 50% of HGOC is characterized as negative for homologous recombination deficiency (HRDneg) based on lack of BRCA mutation and low genomic instability score (GIS). ∼15% of HGOC patients harbor CCNE1 amplification (CCNE1amp) which has been presumed to be associated with chemoresistance, HRDneg and poor prognosis. We aimed to determine the genomic profiles and outcome of CCNE1amp HGOC in comparison to non-CCNE1amp HRDneg HGOC.

Methods

We conducted a retrospective analysis of patients (pts) with advanced HGOC (excluding clear-cell and mucinous histology) with available genomic data from Institut Gustave Roussy, France and National University Cancer Institute, Singapore. CCNE1amp BRCA1/2 and RAD51C/D mutations were detected by next-generation sequencing on tumor samples. GIS was evaluated by Myriad MyChoice or Foundation Medicine LOH. Progression free survival (PFS) (date of diagnosis to first progression) and pathological response to neoadjuvant chemotherapy by chemotherapy response score (CRS) were collected.

Results

We identified 55 CCNE1amp and 104 HRDneg non-CCNE1amp tumors. Pts with CCNE1amp tumor were significantly older (64 versus 61.5 years, p<0.01). Overall, 81% were high-grade serous, 8% carcinosarcomas, and 62% benefited from complete cytoreductive surgery. As expected, no BRCA1/2 or RAD51C/D mutations were detected in the CCNE1amp cohort. 19% of CCNE1amp tumors were classified HRD positive and 81% HRDneg. Among CCNE1amp, 31% of patients experienced a good pathological response (CRS3) versus 18% in the HRDneg cohort (p=0.26). Median PFS was 21.1 months in the CCNE1amp cohort versus 14.2 months in the HRDneg cohort (p=0.008) and median overall survival was 55.3 months versus 42.9 months (p=0.044). In multivariate analysis including completeness of surgery, CCNE1amp was statistically associated with better PFS, HR=1.6 (95%CI 1.06-2.5).

Conclusions

We report clinical and molecular features associated with CCNE1 amplification in advanced HGOC. As expected CCNE1 amplifications are mutually exclusive from BRCA mutations, however 20% were HRD according to GIS. We observed unexpected high rates of CRS3, and significantly improved outcomes compared to non-CCNE1amp HRDneg tumors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

F. Blanc-Durand: Financial Interests, Personal, Speaker, Consultant, Advisor: Eisai; Financial Interests, Personal, Other: GSK; Financial Interests, Institutional, Research Grant: AZ; Financial Interests, Personal, Steering Committee Member: Cureety. N.Y.L. Ngoi: Financial Interests, Institutional, Invited Speaker: MSD, AstraZeneca, ASGO, JSGO; Financial Interests, Institutional, Advisory Board: Merck/Pfizer, AstraZeneca. P. Pautier: Financial Interests, Personal, Advisory Board, 2015, 2022: PharmaMar; Financial Interests, Institutional, Advisory Board, 2020: Roche, Clovis; Financial Interests, Institutional, Advisory Board, 2021: AstraZeneca; Financial Interests, Personal, Advisory Board, 2019-2020: AstraZeneca; Financial Interests, Institutional, Advisory Board: GSK; Financial Interests, Personal, Advisory Board, 2018-2019: Roche; Financial Interests, Institutional, Advisory Board, 2022: MSD; Financial Interests, Personal and Institutional, Research Grant: PharmaMar; Financial Interests, Research Grant: ONXEO. K. Ouali: Financial Interests, Institutional, Other, As part of the Drug Development Department (DITEP), KO is principal/sub-Investigator of Clinical Trials for AbbVie, Adaptimmune, Adlai Nortye USA Inc., Aduro Biotech, Agios Pharmaceuticals, Amgen, AstraZeneca Ab, AstraZeneca, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, BeiGene, BicycleTx Ltd., Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals, Inc., Cato Research, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, EverImmune, Exelixis, Faron Pharmaceuticals Ltd., Foghorn Therapeutics Inc., Forma Tharapeutics, Gamamabs, Genentech, Genmab, GSK, H3 Biomedicine, F. Hoffmann-La Roche AG, IGM Biosciences, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D LLC, K-Group Beta, Kinnate Biopharma, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France,: Various drug companies. A. Leary: Financial Interests, Personal, Advisory Board: Zentalis; Financial Interests, Personal, Invited Speaker, Educational: GSK, Medscape; Financial Interests, Personal, Writing Engagement, Educational: Onko+; Financial Interests, Institutional, Other, Steering committee: MSD; Financial Interests, Institutional, Advisory Board: GSK, AZ, Clovis, Ability Pharma, MSD, Merck Serono, Apmonia, Blueprint; Financial Interests, Institutional, Invited Speaker, Educational: Kephren publishing; Financial Interests, Institutional, Other, Consultancy: Orion; Financial Interests, Institutional, Invited Speaker: AZ, Clovis; Financial Interests, Personal, Other, Consultancy: GLG; Financial Interests, Institutional, Research Grant, PI translational research: ARCAGY-GINECO, Sanofi, AZ; Financial Interests, Institutional, Funding, CI clinical trial: AZ; Financial Interests, Institutional, Research Grant, Int CI clinical trial: OSE Immuno; Financial Interests, Institutional, Funding, PI clinical trial: Agenus, BMS, Iovance, GSK; Financial Interests, Institutional, Funding, PI 5 clinical trials: Roche; Financial Interests, Institutional, Funding, PI 2 clinical trials: AZ; Financial Interests, Institutional, Funding, PI 3 clinical trials and steering committee: MSD; Non-Financial Interests, Institutional, Other, Academic research project: Owkin, LXRepair; Non-Financial Interests, Personal, Proprietary Information, IDMC member: Clovis; Non-Financial Interests, Personal, Proprietary Information, IDMC chair: Pfizer; Non-Financial Interests, Member: GCIG. D.S. Tan: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Merck Serono, Roche, Eisai, GSK, Takeda; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, MSD, Eisai, Roche, Genmab, GSK, Boehringer Ingelheim; Financial Interests, Personal, Stocks/Shares: Asian Microbiome Library (AMiLi); Financial Interests, Institutional, Research Grant: Roche, Bayer, Karyopharm Therapeutics, AstraZeneca; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Bergen Bio; Financial Interests, Institutional, Local PI: Zeria Pharmaceutical Co Ltd., Bayer, Byondis B.V.; Non-Financial Interests, Leadership Role, Ex society president: Gynecologic Cancer Group Singapore; Non-Financial Interests, Member of Board of Directors: Gynaecologic Cancer Intergroup (GCIG); Non-Financial Interests, Leadership Role, Ex- Chair: Asia-Pacific Gynecologic Oncology Trials Group (APGOT); Non-Financial Interests, Institutional, Product Samples, Research Study: MSD, Eisai, AstraZeneca. All other authors have declared no conflicts of interest.