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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

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Homologous recombination repair status in advanced endometrial cancer: an exploratory biomarker analysis from the

M Bartoletti¹, A Passarelli², A Fagotti³

¹Unit of Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.

|December 6, 2025

Abstract

Background:

Poly (ADP-ribose) polymerase (PARP) inhibitor use in endometrial cancer (EC) requires predictive biomarkers, currently lacking in clinical practice. This study assessed the incidence of homologous recombination deficiency (HRD) using genomic loss of heterozygosity (gLOH) and a machine learning-based HRD scar signature (HRDsig).

Patients And Methods:

MITO END 3 was a multicenter, phase II trial of advanced EC patients randomly assigned to receive platinum-based chemotherapy ± avelumab. Of 125 patients, 102 had tumor samples available for sequencing with FoundationOne®CDx. HRD was evaluated using gLOH (cut-off ≥16%, based on ARIEL3) and HRDsig (cut-off ≥0.7, validated pan-cancer).

Results:

Among 102 evaluable samples, 5 were HRDsig-positive, 90 HRDsig-negative, and 7 HRDsig unknown. gLOH was high in 10 cases, low in 53, and not assessable in 39. Most HRDsig-positive (4/5) and gLOH-high (8/10) tumors were of endometrioid histology and carried TP53 mutations. None were microsatellite instability-high.

Conclusions:

A small subgroup of advanced EC patients shows HRD positivity by gLOH or HRDsig, potentially identifying those most likely to benefit from PARP inhibitors. These tumors are typically endometrioid with TP53 mutations.

Keywords:

HRD PARPi endometrial cancer immunotherapy precision medicine

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