Interpreting homologous recombination deficiency in rare gynecological cancers: A case of primary mucinous endometrial adenocarcinoma of gastrointestinal type.

Mucinous endometrial carcinoma of gastric type (MCG) is a rare and aggressive malignancy with no established standard of care. Biomarkers of homologous recombination deficiency (HRD), including BRCA1/2 alterations and genomic signatures, are increasingly used to predict sensitivity to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), but their utility in rare gynecologic cancers remains unclear. We report a 52-year-old female with metastatic TP53-abnormal endometrial MCG. Whole-genome and transcriptome analysis identified a pathogenic germline BRCA1 mutation with somatic loss of heterozygosity (LOH), resulting in biallelic BRCA1 loss. A high HRDetect score (0.96) further supported an HRD phenotype. The patient achieved an initial partial response to frontline platinum-based chemotherapy. However, despite genomic evidence predicting PARPi sensitivity, she experienced rapid disease progression within three months of completion of platinum and starting maintenance niraparib. Retrospective copy-number signature analysis classified the tumor as a non-HRD signature characterized by high ploidy rather than classic BRCA-associated genomic scarring. To further investigate treatment response, a patient-derived xenograft (PDX) model was established. The model faithfully recapitulated the clinical phenotype, showing response to cisplatin but intrinsic resistance to the PARP inhibition. This case demonstrates a discordance between genomic HRD biomarkers and therapeutic response. Despite germline BRCA1 mutation, somatic LOH, and a high HRDetect score, platinum response was not durable and PARPi sensitivity was not observed. These findings highlight the limitations of current HRD biomarkers in rare gynecologic cancers and support integrating functional and genomic approaches to guide precision oncology.