POLE mutations in endometrial carcinoma: Clinical and genomic landscape from a large prospective single-center cohort.

Background: To date, 11 DNA polymerase epsilon (POLE) pathogenic variants have been declared "hotspot" mutations. Patients with endometrial cancer (EC) characterized by POLE hotspot mutations (POLEmut) have exceptional survival outcomes. Whereas international guidelines encourage deescalation of adjuvant treatment in early-stage POLEmut EC, data regarding safety in POLEmut patients with unfavorable characteristics are still under investigation. On the other hand, the spread of comprehensive genome profiling programs has underscored the need to interpret POLE variants not considered to be hotspots.

Methods: This study provides a comprehensive analysis of 596 sequenced patients with EC. The genomic landscape of POLEmut EC was compared with cases harboring nonhotspot POLE mutations within the exonuclease domain. Additionally, the genomic characteristics of multiple classifiers, as well as those exhibiting unfavorable histopathological and clinical features, were examined.

Results: No significant genomic differences were observed among patients with POLEmut EC when comparing multiple classifiers to not-multiple classifiers or those with unfavorable clinical features. However, the tumor mutational burden differed in both comparisons, whereas the percentage of C>G mutations only differed in the comparison based on clinical features. Specific POLE mutations, even if not considered to be hotspots, have genomic features comparable to POLEmut.

Conclusions: The present findings confirm the absence of significant genomic differences among POLEmut patients regardless of multiple-classifier status or association with high-risk clinical features. Prognostic data will be essential to elucidate the clinical significance of POLE mutations not classified as hotspots that exhibit genomic characteristics similar to those in POLEmut patients.