Prevalence and prognostic role of mismatch repair gene defect in endometrial cancer patients

Abstract

The study was to evaluate the prevalence of mismatch repair gene defect among Thai patients with endometrial cancer and its association with clinico-pathological features and survivals. The formalin fixed paraffin-embedded blocks of EMC tissue from hysterectomy specimens of patients having surgery in our institution between 1 Jan 1995 and 31 December 2016 were assessed for the immunohistochemical expression of 4 mismatch repair proteins (MLH1, PMS, MSH2, MSH 6). Mismatch repair gene defect was determined by a negative expression of at least 1 protein. Among 385 EMC patients included in the study, mean age was 57.3 ± 10.8 years with 62.3% aged ⩽ 60 years. The most frequent mismatch repair gene defect was MSH6 (38.7%), followed by PMS2 (34.3%), MLH1 (33.2%), and MSH2 (16.4%). Overall, 55.1% showed negative expression of at least one protein. We found significantly higher mismatch repair gene defect in patients aged ⩽ 60 years, with early stage disease, and negative lymph node status than the other comparative groups: 59.2% vs 48.3% for age (p = 0.037), 58.2% vs 45.2% (p = 0.027) for stage, and 58.1% vs 44.6% (p = 0.048) for nodal status. The 5-year progression-free survival, overall survival, and endometrial cancer-specific survival of patients with mismatch repair gene defect was higher than those without gene defect. The differences were statistically significant for only progression-free survival and endometrial cancer-specific survival: 87.7% (95% confidence interval = 83.0%-92.4%) vs 81.5% (95% confidence interval = 75.4%-87.6%) (p = 0.049) for progression-free survival and 91.0% (95% confidence interval = 86.9%-95.1%) vs 85.5% (95% confidence interval = 80.0%-91.0%) (p = 0.044) for endometrial cancer-specific survival, respectively. In conclusion, more than half of Thai endometrial cancer patients had mismatch repair gene defect. The patients with mismatch repair gene defect had significantly younger age (⩽ 60 years) and better prognosis in terms of early stage, negative nodal status, and longer survivals.

Endometrial cancer risk and survival by tumor MMR status

“…Findings have varied from subsequent studies of varying design assessing survival using multivariate analysis: no association was detected between tumor MMR-deficiency and survival from analysis of 109 EC patients (endometrioid and non-endometrioid subtypes; MSI-H=0.46; 95% CI=0.05–4.77) [ 33 ], improved survival (HR=0.2; 95% CI=0.1–0.7) was reported for MMR-deficient EC based on IHC results from 191 EC patients [ 24 ]; no association between tumor MMR class and outcome was observed for 1,024 patients designated as epigenetic MMR defective EC (HR=0.78; 95% CI=0.43–1.41) or “probable MMR mutation” (HR=0.91; 95% CI=0.40–2.07) [ 18 ]. The most recent study of 466 women reported that endometrioid MLH1 -methylated MMR-deficient EC cases had significantly reduced recurrence-free survival in univariate analysis (p<0.001) [ 22 ]; a recent study of 385 Thai women reported improved survival for patients exhibiting tumor MMR deficiency [ 34 ], although it should be noted that MMR loss of function was observed for a relatively large proportion of their cohort (55%, 33% ascribed to loss of MLH1 function) compared to what has been previously reported for largely Caucasian cohorts.…”

Mismatch repair deficiency identifies patients with high‐intermediate–risk (HIR) endometrioid endometrial cancer at the highest risk of recurrence: A prognostic biomarker

“…Although dMMR has been associated with a better prognosis in CRC, its prognostic significance in EC is unclear. 21 Whereas many studies have reported worse survival and/or shorter disease-free survival among patients dMMR or microsatellite instability (MSI), 10,14,[22][23][24][25] other studies have demonstrated improved survival [26][27][28][29] or no association. [30][31][32][33] A recent meta-analysis also demonstrated no association between MMR status and OS or RFS.…”

Trends of uterine cancer incidence: a projection from the past to the future

“…Such risks are well recognized in Western populations [11]. Notably, only few studies in Asia have been published [12131415]. Our study found the prevalence of MMR gene defect in Thai patients as high as 55% [15].…”

“…Notably, only few studies in Asia have been published [12131415]. Our study found the prevalence of MMR gene defect in Thai patients as high as 55% [15]. This should alert the gynecologic oncologist to assess this particular risk by comprehensive history taking focused on previous and family history.…”