Refinement of high-risk endometrial cancer classification using DNA damage response biomarkers: a TransPORTEC initiative

The TransPORTEC consortium previouslclassified high-risk endometrial cancer including poor-risk histologies such as clear cells, into four molecular subtypes POLE mutated, microsatellite unstable, TP53 mutated, and no specific molecular profile. We evaluated whether DNA damage response biomarkers could further refine this high-risk tumors classification, in particular the heterogeneous no specific molecular profile and TP53 mutated subsets recently qualified as poor prognosis in high-risk endometrial cancer. DNA damage response biomarkers including proteins involved in DNA damage (delta-H2AX), homologous recombination (RAD51), regulators of error-prone Non Homologous End-Joining (DNA-pk, FANCD2), and PARP-1 were evaluated in 116 high-risk tumors by immunohistochemistry. CD8 and PD-1 expression by immunochemistry and mutation analyses were performed previously. Survival outcome were calculated using Kaplan-Meier and Log-rank test. None of the DNA damage response biomarkers alone were prognostic. However markers were informative within molecular subsets. Among the no specific molecular profile subset, delta-H2AX+ was significantly predictive of poor disease free survival (Hazard Ratio = 2.56; p = 0.026), and among TP53 mutated, a DNA-pk+/FANCD2-profile (favouring error-prone Non Homologous End-Joining) predicted worst disease free survival (Hazard Ratio = 4.95; p = 0.009) resulting in five distinct prognostic subgroups from best to worst prognosis: group1 POLE mutated/Microsatellite unstable > group2 no specific molecular profile with no DNA damage > group3 TP53 mutated/Non Homologous End-Joining negative > group4 no specific molecular profile with high DNA damage > group5 TP53 mutated/Non Homologous End-Joining positive; p = 0.0002). Actionable targets were also different among subsets. Group3 had significantly higher infiltration of PD-1+ immune cells (p = 0.003), segregating with group1. Group2 had frequent PI3K pathway mutations and ER positivity. While group5, with the worst prognosis, had high DNA damage and PARP-1 expression providing a rationale for PARP inhibition. Our findings have refined the TransPORTEC prognostic classification of high-risk endometrial cancer into five distinct subgroups by integrating DNA damage response biomarkers and identified molecular subtype-specific therapeutic strategies.