735P - HRD signature (HRDsig) in endometrial cancer (EC)

Background

Homologous recombination deficiency (HRD) is caused by inactivation of HR repair (HRR) genes and renders tumors sensitive to PARP inhibitors (PARPi). HRDsig is a pan-tumor scar-based biomarker (Moore et al., 2023) and predicts PARPi benefit in ovarian and other cancers. We sought to evaluate HRDsig in EC as current clinical trials are investigating the efficacy of PARPi in EC.

Methods

Tissue biopsies were profiled using FoundationOne® or FoundationOne® CDx. Allelic status was predicted for BRCA1/2 alterations (BRCA alt) using a validated algorithm. HRDsig scores range 0-1 with ≥0.7 considered HRDsig+.

Results

HRDsig was detected in 691/10971 (6.3%) EC. Using ProMisE criteria, prevalence of HRDsig by molecular subgroup was: p53 abnormal (abn), 619/5446 (11.4%); no specific molecular profile (NSMP), 66/3289 (2.0%); mismatch repair deficient (MMRd), 6/2171 (0.3%); and POLE alt, 0/65 (0%). HRDsig by histology was: papillary serous, 247/2705 (9.1%); mixed histology, 17/305 (5.6%); clear cell, 22/446 (4.9%); and endometrioid, 120/3165 (3.8%). HRDsig was most common in endometrioid p53-abn EC, 100/686 (14.6%). Of 5446 p53abn EC, 281 (5.2%) had a BRCA alt, of which 185 (66%) were HRDsig+. Of BRCA alt predicted to be biallelic, 158/176 (90%) were HRDsig+. Additionally, 434 (8.0%) of p53abn EC were BRCA wildtype and HRDsig+; alterations in HRR genes RAD51C and PALB2 were enriched in these samples (FDR

Conclusions

HRDsig prevalence ranged from 11% in p53abn EC to ≤2% in NSMP, MMRd and POLE alt EC. Biallelic BRCA loss strongly associated with HRDsig (90% HRDsig+ in p53abn). Unlike ovarian and breast cancers, a significant fraction of BRCA loss in EC was not biallelic (37% of p53abn) likely accounting for a lower rate of HRDsig in BRCA alt EC (66% in p53abn). Furthermore, a greater proportion of EC with HRDsig do not harbor a BRCA alt (8% vs 3% of p53abn). Further study of the efficacy of PARPi in HRDsig+ EC patients (BRCA alt and wildtype) is warranted.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Foundation Medicine, Inc.

Funding

Foundation Medicine Inc.

Disclosure

B. Pothuri: Financial Interests, Personal, Advisory Role: Eisai, AstraZeneca, GSK, Merck, Lilly, ImmunoGen, Mersana, Seagen, Signatera, Sutro Biopharma, Celsion, Curio Science, GOG Foundation, Imvax, Incyte, InxMed, Onconova Therapeutics, Peerview, R-Pharm, Regeneron, WebMD; Financial Interests, Personal, Speaker, Consultant, Advisor: GOG Foundation, Merck, Seagen; Financial Interests, Personal, Other: Society of Gynecologic Oncoology, Projects In Knowledge, Bio Ascend, PER, OncLive, Yale University; Financial Interests, Institutional, Research Funding: Tesaro, Clovis Oncology, Genentech, Takeda, Celsion, Celgene, AstraZeneca, ImmunoGen, Merck, GSK, NRG Oncology, Eisai, Karyopharm Therapeutics, Incyte, Agenus, Mersana, VBL Therapeutics, Novocure, Seagen, InxMed, Sutro Biopharma, Toray Industries, Acrivon Therapeutics, Xencor, Onconova Therapeutics. B. Decker: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks or ownership: Roche, Vaccitech. E.S. Sokol, D.I. Lin, N.A. Danziger, J. Elvin: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks or ownership: Roche. A.B. Schrock: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. M.A. Levy: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks or ownership: Roche; Financial Interests, Personal, Licencing Fees or royalty for IP: GenomOncology. H. Tukachinsky: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine.