POLE

This Japanese real-world study investigated comprehensive genomic profiling and tumor mutational burden (TMB) in parathyroid carcinoma, a rare endocrine malignancy. Among 25 patients, 28% exhibited elevated TMB (≥ 10 mut/Mb), with frequent alterations observed in CDC73, TP53, and MEN1 genes. POLE alterations and microsatellite instability (MSI-high) were also identified in some cases. These findings highlight the molecular heterogeneity of the disease and the value of genomic profiling for uncovering potential therapeutic opportunities.

This large genomic analysis of 2901 endometrial carcinomas refines molecular classification by addressing several clinical questions. The study confirms that all four mismatch repair genes (MLH1, MSH2, MSH6, PMS2) confer an equivalently favorable prognosis, validating dMMR status as a class-level prognostic designation. It demonstrates that the exceptional survival benefit associated with POLE-ultramutated tumors is confined to canonical exonuclease-domain hotspot mutations, excluding variants of uncertain significance. Finally, patients with TP53 mutations and high copy-number instability (CNH) are identified as having the most urgent unmet therapeutic need.

The FIGO staging system for endometrial cancer underwent a significant revision in 2023, incorporating refined anatomical criteria and molecular determinants. This update aims to optimize adjuvant treatment selection by maximizing therapeutic benefits while minimizing harm. Molecular subgroups include POLEmut, p53abn, MMRd, and NSMP. The 2025 ESGO-ESTRO-ESP recommendations further enhance this framework by mandating estrogen receptor (ER) assessment within the NSMP category, identifying early-stage disease with an increased risk of recurrence and mortality.