The clinicopathology and survival characteristics of patients with POLE proofreading mutations in endometrial carcinoma: A systematic review and meta-analysis

Abstract

Background Endometrial carcinoma (EC) is classified into four distinct molecular subgroups. Patients with polymerase epsilon exonuclease domain mutated (POLE-EDM) tumors have the best prognosis of all. This meta-analysis consolidated the clinicopathology variations reported in the POLE-mutant subtype and survival parameters in patients with EC. Methods The following internet data bases were searched: PubMed, Web of science, Embase and Scimage directory. Data was extracted from eligible studies including sample size, number of positive POLE-mutant cases, EDM sequencing information, clinicopathologic, and survival data. Meta-analysis and a random-effects model produced pooled estimates of POLE prognostic parameters using 95% confidence intervals (CI), hazard ratios (HR), and odds ratios (OR). Results The meta-analysis included 11 cohort studies comprising 5508 EC patients (442 POLE EDM tumors). Patients with POLE mutant EC were associated with improved disease specific survival (HR = 0.408, 95% CI: 0.306 to 0.543) and progression-free survival (HR = 0.231, 95% CI: 0.117 to 0.456). POLE-mutated tumors were mostly endometrioid histology (84.480%; 95% CI: 77.237 to 90.548), although not significantly more than wild type tumors (OR = 1.386; p = 0.073). The POLE mutant tumors significantly present (p<0.001) at Federation of International of Gynecologists and Obstetricians (FIGO) lower stages I-II (OR = 2.955, p<0.001) and highest grade III (OR = 1.717, P = 0.003). The tumors are significantly associated with invasion less than half (<50%) of the myometrium (OR = 1.765, p = 0.001), but not deeply invasive EC (MI>50%, OR = 0.83, p = 0.34). POLE mutations significantly protected against lymph node metastases (OR = 0.202, p = 0.001), and have no clear association with lymph-vascular space invasion (OR = 0.967, 95% 0.713–1.310, p = 0.826). The tumors are predominantly of low ESMO risk stratification distribution (40.356%; 95% CI: 27.577 to 53.838). Conclusions POLE mutations serve as an important biomarker of favorable prognosis in EC. The tumors are characteristically high grade, early stage, and remain localized in the endometrium with reduced likelihood of lymph node metastasis for improved survival prospects and the lowest risk classification. These findings have implications for medical management of EC.

Molecular Profiling of Endometrial Cancer From TCGA to Clinical Practice

“…20,25 Individual patient data meta-analysis of all published and available international reports on POLEmut ECs showed that patients with confirmed pathogenic POLE mutations have almost no recurrence or disease-specific death events, even when their tumors appear to have unfavorable clinicopathologic or molecular characteristics, and adjuvant treatment was not associated with outcomes. 14 Excellent survival outcomes in POLEmut ECs were also confirmed in a more recent meta-analysis, 26 and in a 2022 publication from a Danish database in which patients with high-grade POLEmut ECs who received no adjuvant treatment encountered no recurrence events. 15 Taken together, these data support de-escalation of therapy in this molecular subtype.…”

Sentinel lymph node biopsy in high-risk endometrial cancer: performance, outcomes, and future avenues

“…Therefore, efforts are required to minimize unnecessary adjuvant chemotherapy. The presence of POLE mutations in high-risk patients is an excellent example of this [ 58 ]. These patients may not need adjuvant chemotherapy even if SLN mapping identifies macroscopic lymph node metastasis; they may not require SLN mapping at all.…”

“…Longitudinal studies on patient-reported outcomes of adjuvant chemotherapy revealed that in patients with endometrial cancer, adjuvant chemotherapy is independently associated with increased fatigue, lymphedema, and neuropathy even after two years of treatment [58]. Therefore, efforts are required to minimize unnecessary adjuvant chemotherapy.…”

Nab-Paclitaxel-Based Systemic Approach to Achieving Complete Remission for Relapsed Stage III Endometrial Carcinoma: Insights From the Indian Subcontinent

“…The patient underwent molecular analysis with immunohistochemistry, depicting positive POLE gene mutation and negative wild-type P53 and MSI. The presence of POLE demonstrates favorable prognostic possibilities, despite rare and high-grade tumours [7,8].…”