42MO - Interpreting somatic POLE mutations in endometrial cancer emerging from comprehensive genomic profiling

Background

Endometrial cancer (EC) patients harbouring recognized POLΕ gene mutations have exceptional survival outcomes. Considering the TCGA data and a pragmatic score provided by Leon-Castillo et al., 11 POLΕ mutations have been recognized as “hotspots”. While international guidelines encourage molecular testing and de-escalation of adjuvant treatment in early-stage EC, there's ongoing debate on whether POLE status should be prioritized over established prognostic factors in clinical decision-making. Moreover, the spread of comprehensive genome profiling programs (CGP) has underscored the need to interpret variants to date not considered hotspots. Here, we provide a genomic and clinical characterization of a large, prospective, EC population to better characterize POLΕ variants.

Methods

Patients diagnosed with epithelial EC who underwent surgery at Fondazione Policlinico Universitario A. Gemelli IRCCS were profiled with the Institutional CGP programme (ID: FPG500, NCT 06020625) using TruSight Oncology 500 high throughput. A mutational and signature analysis was then performed and integrated with clinical data.

Results

387 cases were included and categorized into four groups according to POLE status: A: hotspots mutations (n=40); B: mutation in the exonuclease domain (EDM) non-recognized as hotspots (n=7); C: mutations outside the EDM (n=14); D: non-pathogenic variants (n=326). Genomic features of the four groups are summarized in the table. Furthermore, we analyzed the most frequent co-altered genes with hotspot POLΕ mutations, identifying RASA1 and LRP1B. Adapting Leon-Castillo’s score in our cohort, we identified four patients who displayed different clinical and molecular characteristics compared to their supposed belonging Group. Table: 42MO

Medians (range) are reported for each value

Conclusions

Our results raise the question that additional features may be considered to better interpret the value of POLE status.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: GSK, Clovis Oncology, PharmaMar; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca, MSD; Financial Interests, Personal, Other, Consultancy: PharmaMar, AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen, Novartis; Financial Interests, Personal, Advisory Board, Invited member of advisory board and invited speaker: Seagen, Immunogen, Genmab; Financial Interests, Personal, Advisory Board, Invited member of advisory board: Oncoinvest, Corcept, Sutro; Financial Interests, Institutional, Funding, Grant for founding academic trials: MSD, Clovis Oncology, GSK, PharmaMar; Financial Interests, Institutional, Invited Speaker, ENGOT trial with institutional support for coordination: Clovis Oncology; Financial Interests, Institutional, Invited Speaker, ENGOT trial with institutional support for coordination: Genmab, MSD; Financial Interests, Institutional, Funding, Clinical trial/contracted research: AstraZeneca, Clovis Oncology, GSK, MSD, Seagen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, Immunogen, Incyte, Novartis, Roche; Non-Financial Interests, Personal, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Personal, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, Genmab; Non-Financial Interests, Personal, Principal Investigator, PI in several trials. No personal compensation received: MSD; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial. No personal compensation received: immunogen, Clovis Oncology, Roche, Incyte; Non-Financial Interests, Personal, Principal Investigator, PI of several trials, no personal compensation received: Novartis; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial, no personal compensation received: Seagen; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trials, no personal compensation received: PharmaMar; Non-Financial Interests, Personal, Member, Board of Directors: GCIG; Other, Personal, Other, Grants for traveling: AstraZeneca, Clovis Oncology, GSK. G. Scambia: Financial Interests, Personal, Invited Speaker, Speaker: Baxter Healthcare, GSK, Intuitive Surgical Inc., AstraZeneca & MSD, Olympus Europa, GSK, AstraZeneca & MSD, Olympus Europa; Financial Interests, Personal, Expert Testimony, Trainer: Covidien AG (Medtronic company); Financial Interests, Institutional, Invited Speaker, ‘IsoMSLN’ in Ovarian Cancer and Malignant Pleural Mesothelioma: Kiromic; Financial Interests, Institutional, Invited Speaker, Roll-over study for patients who have completed a previous cancer study with olaparib and who the investigator believes can benefit from continued treatment - ROSY-O: AstraZeneca; Financial Interests, Institutional, Invited Speaker, CATCH-R: Roll-over study to provide continuous access to clinical therapy with rucaparib.: Clovis Oncology; Financial Interests, Institutional, Invited Speaker, Phase 3, multicenter, placebo-controlled clinical study comparing chemo-immunotherapy (paclitaxel-carboplatin-oregovomab) versus chemotherapy (paclitaxel-carboplatin-placebo) in patients with advanced epithelial ovarian, tubal cancer of fallopian or peritoneal (FLORA-5): Oncoquest Pharmaceuticals Inc.; Financial Interests, Institutional, Invited Speaker, Phase 2b randomized, open-label, active comparator, parallel-group, multicenter study designed to evaluate the efficacy and safety of three different doses of the P2X3 receptor antagonist (BAY 1817080) versus placebo and Elagolix 150 mg in women with symptomatic endometriosis: Bayer AG; Financial Interests, Institutional, Invited Speaker, Usability of ITE transducers for sending electric fields for tumor treatment (TTFields): Novocure Ltd; Financial Interests, Institutional, Invited Speaker, Phase III, multicentre, open-label extension trial to evaluate long-term safety and efficacy in patients with advanced cancers currently undergoing treatment or in follow-up in a pembrolizumab trial.: Merck. C. Nero: Financial Interests, Personal, Other, Travel grant: Illumina, MSD. All other authors have declared no conflicts of interest.