788P - Molecular profiling of p53 mutant endometrial cancer reveals distinct subgroups with opportunities for personalized therapeutic approaches

Background

Endometrial cancer (EC) can be classified into four molecular subgroups: POLE mutant, MSI/dMMR, non-specific profiles and P53 mutant (P53mut). P53mut EC comprise ∼20% of cases and have the worst prognosis. There is an urgent medical need to better understand P53mut EC in order to propose effective new therapeutic strategies.

Methods

We conducted a retrospective analysis of P53abn EC patients from PORTEC3 (NCT00411138) with available DNA for a large-scale panel sequencing (Discovery Cohort). Results were confirmed on an independent cohort of EC patients (Gustave Roussy, France and National University Cancer Institute, Singapore) identified by their molecular profile using FoundationOneCDX or FoundationOne Liquid CDX panel (Validation Cohort). Molecular findings were correlated with clinicopathologic features from medical record review.

Results

39 P53abn cases were included in the discovery cohort. Molecular profiling was able to distinguish 4 mutually exclusive subgroups: CCNE1 amplified (15%), ERBB2 amplified (21%), PTEN alteration (21%) and a non-specific group. In the Validation Cohort, 71 P53mut EC patients were included. 40 patients were molecularly characterized on tumor tissue and 31 on circulating tumor DNA. Median age was 66 years, 38% presented with primary metastatic diseases, 40% were serous, 30% endometrioid and 20% carcinosarcoma. We detected the same four molecular subgroups defined by CCNE1amp (13%), ERBB2amp (16%), and PTEN mutation or loss (34%). These subgroups were also almost exclusive to one another. Only two patients (3%) harbored co-alterations. In terms of outcomes, we did not observe any overall survival difference between these subgroups.

Conclusions

Among P53mut EC, we detected 3 nearly mutually-exclusive molecular subgroups: CCNE1 amplified, ERBB2 amplified and PTEN loss, accounting together for 60% of cases. Whether these subgroups might benefit from personalized therapeutic strategies is currently being explored.

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, Invited Speaker: Eisai; Financial Interests, Personal, Member of Board of Directors: Cureety; Financial Interests, Institutional, Research Grant: AZ; Other, Travel: GSK. S. de Boer: Financial Interests, Institutional, Coordinating PI: Varian. N. Singh: Financial Interests, Personal, Advisory Board, December 2019: Invited member of one-day advisory board/expert panel for discussion of introducing tumour BRCA testing within the National health Service in the UK: AstraZeneca-MSD; Financial Interests, Personal, Advisory Board, Early 2021 : Invited member of advisory board/expert panel advising on mismatch repair testing in endometrial cancer within the National health Service in the UK: GSK; Non-Financial Interests, Institutional, Other, Offer of support of upcoming research project through supplying discounted reagents for POLE testing in endometrial cancer biopsies. The project has obtained funding but has not gone through the IRAS ethical and NHS Health Research Authority approval process so far: Thermo Fisher Scientific (UK). H. Mackay: Financial Interests, Personal, Advisory Board: Eisai, GAK; Financial Interests, Personal, Other, Associate Editor: British Journal of Cancer. L. Mileshkin: Financial Interests, Institutional, Coordinating PI, Institutional funding from BeiGene for an investigator-initiated trial: BeiGene; Non-Financial Interests, Other, Co-chair of the Steering Committee for the CUPISCO trial in CUP (non-remunerated): Roche; Non-Financial Interests, Member, Member of multiple other cancer organisations as above: ASCO, MOGA, COSA, IGCS, GCIG. C.L. Scott: Financial Interests, Personal, Advisory Board, Scientific Advisory Board, member, Sept 2021-current: OncologyOne; Financial Interests, Institutional, Royalties, Royalties via my institution Walter and Eliza Hall Institution of Medical Research: Venetoclax; Financial Interests, Institutional, Research Grant, Research grant, PI, To my laboratory, including provision of drugs for research: AstraZeneca; Financial Interests, Institutional, Funding, Research grant, PI, To my laboratory, including provision of drug: Eisai, Sierra Oncology; Financial Interests, Institutional, Other, In kind research support including provision of drug, to my laboratory: Clovis Oncology; Financial Interests, Institutional, Other, In kind research support, provision of drug, to my laboratory: BeiGene; Financial Interests, Institutional, Coordinating PI, Funding of the SOLACE2 trial, Study Chair and PI, Steering committee, Chair: AstraZeneca; Financial Interests, Institutional, Coordinating PI, Provision of study drug, Eribulin, for the EPOCH trial, Study Chair: Eisai; Financial Interests, Institutional, Coordinating PI, Provision of study drug, Pembrolizumab, for the EPOCH trial, Study Chair: MSD; Financial Interests, Institutional, Steering Committee Member, EMBRACE clinical trial, AZ supplied olaparib, My role, member of the steering committee; performing translation (funds from govt grant): AstraZeneca; Financial Interests, Institutional, Funding, Research grant, To my laboratory, including provision of drug for research: Boehringer Ingelheim; Non-Financial Interests, Advisory Role, Advisory Boards, member: AstraZeneca; Non-Financial Interests, Advisory Role, Advisory Board, Member: Eisai; Non-Financial Interests, Advisory Role, Advisory Board, member: Sierra Oncology, Roche, Takeda, MSD, GSK; Non-Financial Interests, Advisory Role, Advisory Board, Chair: EpsilaBio; Non-Financial Interests, Institutional, Proprietary Information, Research collaboration, provision of drugs and discussion of commercial in confidence information: AstraZeneca, Eisai; Non-Financial Interests, Institutional, Product Samples, Research collaboration, provision of drugs: AstraZeneca, Eisai; Non-Financial Interests, Institutional, Proprietary Information, Research collaboration, provision of drugs: Boehringer Ingelheim; Non-Financial Interests, Other, Board, Chair: International Rare Cancer Initiative; Other, PI, funded by the Australian Government as part of the Australian Genomic Cancer Medicine Centre (AGCMC) (OMICO): Australian Rare Cancer Portal. N.Y.L. Ngoi: Financial Interests, Institutional, Invited Speaker: MSD, AstraZeneca, ASGO, JSGO; Financial Interests, Institutional, Advisory Board: Merck/Pfizer, AstraZeneca. 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. 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. All other authors have declared no conflicts of interest.