Objectives Molecular classification identifies >50% of endometrial cancers (ECs) as having ‘no specific molecular profile/NSMP’; without mismatch repair deficiency, p53 IHC abnormalities, or pathogenic POLE mutations. Clinical presentation and outcomes within NSMP ECs are diverse and optimal treatment unclear with new ESMO/ESTRO/ESP guidelines unchanged for this molecular subtype. Better biomarkers are needed to predict if and what adjuvant therapies are needed.

Methods We characterized the clinicopathological and molecular (IHC+NGS) profiles of 1047 NSMP ECs in women from population-based and institutional cohorts, testing for associations with treatment response and outcomes.

Results Key pathologic and molecular features associated with survival parameters (p<0.01) are tabulated below. 31% of NSMP ECs had CTNNB1 mutations, however, associations with outcomes (PFS) were observed only within Gr1/2 early-stage endometrioid ECs(p=0.03), or if restricted to ECs without substantial LVI or L1CAM overexpression (p< 0.005). TP53 mutations (with normal p53IHC) were discovered in 41 women with a trend (p=0.06) to worse survival. On multivariable analysis only grade (3vs.1/2) maintained significance. 8% of this cohort would be eligible for current molecular classification de-escalation trials. Treatment received did not impact survival within low-, intermediate-, or high-intermediate risk NSMP ECs. Within high-risk, the most favorable outcomes were observed in women who received pelvic radiation with no observed benefit of chemotherapy.

Conclusions Additional prognostic stratification of NSMP ECs can be achieved with both pathologic and molecular features. Further study within NSMP subgroups may identify conventional, hormonal or targeted therapies that are more effective.