TP53 variant allelic frequency is associated with differential outcomes in endometrial cancer

Abstract

Objectives: Endometrial cancers with TP53 mutations (mTP53) are a poor prognosis group, most often comprised of high-grade carcinomas with high somatic copy number alterations (sCNA). A recent sub-analysis of PORTEC-3 demonstrated that patients with TP53 mutant tumors, based on immunohistochemistry, benefit from treatment escalation with systemic chemotherapy. Herein we demonstrate that outcomes may vary dependent on variant allelic frequency (VAF) of TP53 missense mutations, not just the presence of a mutation alone. Methods: De-identified clinical data from the TCGA endometrial cancer cohort was obtained via cbioportal.org. Only patients with information regarding stage, histology, somatic copy-number burden, TP53 sequencing with variant allelic frequency, and exposure to RT were included. Patients with multiple TP53 alterations and stage IV disease were excluded from the analysis. T-test was performed to test for differences in sCNA burden, age, and stage between groups. Kaplan-Meieir analyses were performed to determine progression free survival (PFS) on each cohort, stratified into a VAF high or low using a 0.5 cutoff. Cox regression analysis was used to calculate hazard ratios. Download : Download high-res image (131KB) Download : Download full-size image Results: In total, 389 had genomic and treatment data available for analysis. Of these, 133 (34%) had a TP53 missense mutation. The average age was 64 years, with no significant difference between the RT and not RT groups (p=0.3). The mean sCNA for the RT and no RT, groups were 0.19 and 0.18, respectively (p=0.65). When analyzing the impact of TP53 status on PFS, mTP53 patients who did not receive RT had worse outcomes compared to wild-type TP53 (HR 3.5 [1.8-6.9], p Conclusions: This data highlights that TP53 VAF is a valuable prognostic marker and may be predictive of poor outcomes after radiotherapy alone. Residual wild-type p53 signaling in tumors with a low VAF may help explain outcomes similar to wild-type tumors. This genomic signal could help stratify patients with mTP53 tumors to multimodal therapy or de-escalation of therapy to radiotherapy alone. Further work remains to be done to determine a functional and biologic explanation for these findings.