Transcriptional signatures indicating RB function correlate with response to CDK4/6 inhibition in endometrial cancer

PURPOSE: CDK4/6 inhibitors (CDK4/6is) are being investigated in endometrial cancer (EC) clinical trials with some patients showing a significant response. However, there are few biomarkers to predict which EC patients will respond to CDK4/6is. Current inclusion criteria include EC histology and/or lack of certain genetic alterations. We hypothesize that instead, EC patients should be included or excluded from CDK4/6i clinical trials based on the RB functional status of the tumor defined by the activity of RB function-predictive transcriptional signatures. EXPERIMENTAL DESIGN: We analyzed RB1 and TP53 mutation status, RB protein expression, baseline transcriptional profiles, and RB function-predictive transcriptional signatures in EC samples from 39 patients who participated in two combination clinical trials of the CDK4/6i abemaciclib, one testing letrozole/abemaciclib and the other letrozole/metformin/abemaciclib (NCT03675893). All patients had estrogen receptor positive ECs of varying molecular subtypes with the majority of cases being of endometrioid histology. We statistically assessed for correlation of the results of these analyses with objective response to the CDK4/6i in the clinical trials. RESULTS: We show that RB protein expression levels and RB1 mutation status do not correlate with CDK4/6i response. Rather, we show that decreased activity of multiple RB function-predictive transcriptional signatures, which suggests that RB is functional, corresponds to response to the CDK4/6i. We show that reduced expression of specific E2F family members correlates with CDK4/6i response. CONCLUSIONS: These results suggest that RB function-predictive transcriptional signatures may be a relevant biomarker for CDK4/6i response in EC and merit further refinement and validation in the clinical setting.