Merve Kaya

Molecular and Clinicopathologic Characterization of Mismatch Repair-Deficient Endometrial Carcinoma Not Related to MLH1 Promoter Hypermethylation

Universal tumor screening in endometrial carcinoma (EC) is increasingly adopted to identify individuals at risk of Lynch syndrome (LS). These cases involve mismatch repair-deficient (MMRd) EC without MLH1 promoter hypermethylation (PHM). LS is confirmed through the identification of germline MMR pathogenic variants (PV). In cases where these are not detected, emerging evidence highlights the significance of double-somatic MMR gene alterations as a sporadic cause of MMRd, alongside POLE/POLD1 exonuclease domain (EDM) PV leading to secondary MMR PV. Our understanding of the incidence of different MMRd EC origins not related to MLH1-PHM, their associations with clinicopathologic characteristics, and the prognostic implications remains limited. In a combined analysis of the PORTEC-1, -2, and -3 trials (n = 1254), 84 MMRd EC not related to MLH1-PHM were identified that successfully underwent paired tumor-normal tissue next-generation sequencing of the MMR and POLE/POLD1 genes. Among these, 37% were LS associated (LS-MMRd EC), 38% were due to double-somatic hits (DS-MMRd EC), and 25% remained unexplained. LS-MMRd EC exhibited higher rates of MSH6 (52% vs 19%) or PMS2 loss (29% vs 3%) than DS-MMRd EC, and exclusively showed MMR-deficient gland foci. DS-MMRd EC had higher rates of combined MSH2/MSH6 loss (47% vs 16%), loss of >2 MMR proteins (16% vs 3%), and somatic POLE-EDM PV (25% vs 3%) than LS-MMRd EC. Clinicopathologic characteristics, including age at tumor onset and prognosis, did not differ among the various groups. Our study validates the use of paired tumor-normal next-generation sequencing to identify definitive sporadic causes in MMRd EC unrelated to MLH1-PHM. MMR immunohistochemistry and POLE-EDM mutation status can aid in the differentiation between LS-MMRd EC and DS-MMRd EC. These findings emphasize the need for integrating tumor sequencing into LS diagnostics, along with clear interpretation guidelines, to improve clinical management. Although not impacting prognosis, confirmation of DS-MMRd EC may release patients and relatives from burdensome LS surveillance.

Efficacy of PD-(L)1 inhibition in the treatment of endometrial cancer across molecular classes: a systematic review and meta-analysis

PD-(L)1 inhibitors have shown benefit in mismatch repair-deficient (MMRd) endometrial cancer. However, their efficacy in mismatch repair-proficient endometrial cancer (comprising POLE-mutated (POLEmut), p53-abnormal (p53abn), and no-specific-molecular-profile (NSMP) molecular classes) remains unclear. This systematic review and meta-analysis evaluated the efficacy of PD-(L)1 inhibitors, as monotherapy or combined with chemotherapy, across the 4 molecular classes. Systematic searches were conducted across Embase, PubMed, Cochrane, and Web of Science, with manual searches of reference lists and conference websites. A total of 7 reports on 5 clinical trials were identified, with 3 included in the meta-analysis. Overall survival and progression-free survival were assessed. In patients with primary advanced or recurrent MMRd endometrial cancer (n=215), adding a PD-(L)1 inhibitor to platinum-based chemotherapy significantly improved overall (HR 0.36, 95% CI 0.21 to 0.62) and progression-free survival (HR 0.35, 95% CI 0.23 to 0.53). In patients with p53abn endometrial cancer, no significant benefits in overall (HR 0.91, 95% CI 0.26 to 3.22; n=135) or progression-free survival (HR 0.84, 95% CI 0.41 to 1.70; n=326) were observed, but both were affected by significant heterogeneity. In patients with NSMP endometrial cancer, a significant benefit was observed for progression-free survival (HR 0.73, 95% CI 0.57 to 0.95; n=373), but no overall survival benefit (HR 0.93, 95% CI 0.63 to 1.39; n=242). Insufficient data were available for patients with POLEmut endometrial cancer (n=12), with no events reported in 2 of 3 clinical trials comprising the majority of patients (n=11). PD-(L)1 inhibition demonstrated significant efficacy in patients with advanced or recurrent MMRd endometrial cancer. In NSMP endometrial cancer, adding a PD-(L)1 inhibitor to platinum-based chemotherapy showed potential benefit, whereas in p53abn endometrial cancer, such benefit was not found. POLEmut endometrial cancer, although rare in recurrent or metastatic settings, was associated with a favorable prognosis, regardless of treatment. These findings underscore the relevance of the molecular classification of endometrial cancer and highlight the importance of prioritizing molecular analyses in clinical trials to guide personalized PD-(L)1 inhibition strategies.