Mismatch repair in endometrioid endometrial cancer: Increasing our therapeutic proficiency by capitalizing on molecular deficiency

Endometrial cancer (EC) remains the only gynecologic malignancy with a rising incidence and mortality. Although patients with early stage disease have excellent oncologic outcomes, those with high-intermediate–risk (HIR) features (including age, grade 2 or 3 tumor, the presence of lymphovascular space invasion [LVSI], and ≥50% myometrial invasion) have a local/distant 4-year failure rate of 15% to 20%, highlighting the importance of effective therapy. Both Gynecologic Oncology Group study 249 (GOG249) and the Postoperative Radiation Therapy in Endometrial Carcinoma 3 (PORTEC-3) trial were developed in an effort to improve outcomes in patients with HIR endometrial cancer by the incorporation of systemic therapy. Unfortunately, despite the integration of carboplatin and paclitaxel in the adjuvant setting, no significant differences in recurrence-free survival (RFS) or overall survival (OS) were identified between cohorts. In the advanced stage, metastatic, and recurrent settings, limited therapeutic advancements have been made, with long-term survival approaching 15%. These findings highlight an unmet clinical need and reinforce the importance of mismatch repair (MMR) as a novel therapeutic target. MutL homolog 1 (MLH1), mutS homolog 2 (MSH2), MSH6, and postmeiotic segregation (PMS2) are the primary proteins involved in MMR, with deficiency resulting in DNA replication errors at microsatellite repeats and a phenotype with high microsatellite instability (MSI-H). This phenotype is associated with a 100-fold to 1000-fold increase in mutations, giving rise to tumor-specific neoantigens, which can be recognized by the immune system as nonself-molecules. The clinical relevance of immunotherapy in the treatment of solid malignancies is firmly established, and checkpoint inhibitors are approved for the treatment of several solid tumors. Recently, immunotherapy has emerged as an appealing therapeutic strategy in patients with EC and may be particularly relevant in the setting of deficient MMR (dMMR). During the evaluation of specimens from NRG Oncology/GOG210, Goodfellow and colleagues identified MSI-H status in nearly 30% of patients. Expanding on that assessment, McMeekin et al explored the clinicopathologic significance of dMMR in an alternate cohort of patient samples abstracted from NRG Oncology/GOG210 and identified dMMR in 42% of patients with stage III or IV EC. Furthermore, immunohistochemical studies on EC specimens have detailed programmed cell death 1 (PD-1) and PD-1 ligand (PD-L1) expression levels surpassing those observed in ovarian and cervical carcinoma. In this issue of Cancer, Backes and colleagues detail the impact of dMMR on oncologic outcomes in patients with HIR endometrioid EC who received treatment at a single institution. It is noteworthy that, in their cohort, dMMR was associated with an increase in the risk of disease recurrence, independent of the type of adjuvant therapy received. Moreover, the rate of distant recurrences was nearly 5 times greater in the dMMR group compared with patients who had intact MMR. Unfortunately, because of the small sample size, the few recurrences (n = 32), and heterogeneous treatment plans, it remains difficult to determine the impact of MMR status on outcome based on adjuvant therapy. In addition, nearly one-half of the patients in each cohort did not receive adjuvant treatment despite meeting HIR criteria, potentially impacting disease recurrence rates. In future observational studies exploring the clinical relevance of MMR status on EC outcomes, propensity score matching may help mitigate baseline differences between cohorts. Furthermore, the prognostic implications of dMMR in patients with EC are discordant from those identified in colon cancer, in which dMMR appears to be associated with improved cancer outcomes.