Molecular profiling: Prognostic implications of POLE mutations
Church DN, Stelloo E, Nout RA, et al. Prognostic significance of POLE proofreading mutations in endometrial cancer. J Natl Cancer Inst. 2014;107(1):402.
van Gool IC, Eggink FA, Freeman-Mills L, et al. POLE Proofreading mutations elicit an antitumor immune response in endometrial cancer. Clin Cancer Res. 2015;21(14):3347 - 3355.
The TCGA identified a subgroup of endometrial carcinomas with mutations of the DNA polymerase POLE. These mutants have a high rate of proofreading error and frequent base pair substitutions. This POLE subgroup (6% to 12% of endometrial tumors) is associated with endometrioid histology and high-grade tumors. Patients with these tumors would be expected to have an aggressive course with poor survival, but often these patients survive without a recurrence. We need more understanding of why.
POLE mutations and prognosis
In a secondary analysis by Church and colleagues of the PORTEC-1 and -2 studies (2 large, randomized controlled trials evaluating postoperative external beam radiation therapy [EBRT] or vaginal brachytherapy), tumors were tested for mutations in POLE (POLE-mutant and POLE wild-type). POLE mutations were detected in 6.1% of tumors overall. Despite their high grade, POLE-mutant tumors resulted in fewer recurrences (6.2% vs 14.1%) and fewer deaths (2.3% vs 9.7%) than POLE wild-type tumors. In grade 3 tumors, 0 of 15 POLE-mutant tumors recurred.
These results indicate that, even with having poor prognostic features, endometrial cancers with mutations in POLE have an excellent prognosis.5
POLE mutations and the immune response
To explain the discrepancy in the results by Church and colleagues, van Gool and colleagues analyzed endometrial cancer specimens from PORTEC-1, -2, and the TCGA studies. Endometrial cancers were categorized as POLE-mutants, POLE wild-type, or microsatellite stable (MSS) tumors. They found that POLE-mutant endometrial cancers have an increased lymphocytic infiltrate (present in 22 of 47 POLE-mutant specimens) as compared with POLE wild-type or MSS tumors.
Also, POLE-mutants had an increased density of cytotoxic T-cells (CD8+) at the tumor center and margin that significantly exceeded that of POLE wild-type or MSS tumors. The proportion of tumors with CD8+ cells exceeding the median were also higher in POLE-mutant (60%) compared with POLE wild-type (31.3%) and MSS (7.2%) tumors. Markers LAG3, TIM-3, TIGI, as well as T-cell inhibitors PD1 and CTLA-4, confirmed evidence of T-cell exhaustion--all of which correlated with CD8 expression.
These findings suggest that POLE mutations lead to hundreds of thousands of DNA fragments stimulating the immune system through prolonged antigenic exposure.6 This immune response is so powerful that even these tumors with poor prognostic features will have excellent clinical outcomes.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
POLE-mutant endometrial cancers have mutations that stimulate the immune system with tremendous amounts of antigenic neopeptides. This robust immune response is demonstrated by tumor infiltrating lymphocytes that enhance antitumor effects and host killing in spite of traditional poor prognostic features.