p53 pathway genes' mutations as prognostic factors in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A single center study.

Abstract

771 Background: Mutations (muts) in oncosuppressor genes have been associated with poor prognosis in different solid tumors. This study aims to evaluate the prognostic impact of p53 pathway muts in mPDAC pts. Methods: For each mPDAC pt enrolled in this study a FFPE tumor tissue specimen was collected and Next Generation Sequencing (NGS) was performed by TSO500HT assay (DNA [523 genes], RNA [55 genes]). Primary endpoint was overall survival (OS). The Kaplan–Meier method was used to estimate efficacy outcome; log-rank test, Peto-Peto test and Cox-regression model were used to compare the differences, considering a statistically significant p value < 0.05. Results: A total of 149 mPDAC pts were enrolled; TP53 was mutated in 115/149 (77.2%) pts, CDKN2A in 28 (24.3%), CDKN2B in 8 (5.3%), ATM in 6 (4%), TP53BP1 and MDM2 in 2 pts each (1.3%) and ATR in 1 (0.7%). No mutations were found in MDM4, CHEK1 and CHEK2 genes. Overall, 121 (81.2%) pts had at least one mutation in a gene of p53 signaling pathway (p53sigmut) and 28 pts (19.8%) had none (p53sigwt). The most frequent TP53 alterations were single nucleotide variations (SNVs): R175 (10 pts-8.7%), R248 (9 pts-7.8%) and R273 (8 pts-7%); 27 TP53 muts (18.1%) occurred in exon 7, 26 (17.4%) in exon 5, 19 (12.8%) in exon 8 and 13 (8.7%) in exon 4. Median OS (mOS) was 15 months (mos) (CI 95%: 12.8-18.2) in TP53 mutated pts vs 24.3 mos (CI 95%: 17.3-Not reached) in TP53 wt pts, p=0.03. The site of TP53 alteration was correlated with pts’ survival: mOS was 34.9 mos (CI 95%: 31-Nr) in exon 4-mutated pts, 16.9 mos (CI 95%: 11.2-21.2) in exon 7-mut, 13.8 mos (CI 95%: 11.2-17.8) in exon 5-mut and 10.7 mos (CI 95%: 8.2-Nr) in exon 8-mut, p= 0.018. CDKN2A mutations were also associated with survival: mOS was 17.9 mos (CI 95%: 15.9-24.1) in wt pts vs 13.4 (CI 95%: 10.7-22.2) in mutated pts, p= 0.04. CDKN2B, ATM, TP53BP1, MDM2 and ATR mutations were not associated with OS. Overall, patients with at least one mutation in one of the genes of p53 pathway had a mOS of 15 mos (CI 95%: 12.8-18.2) vs 19.6 months (mos) (CI 95%: 17.3-Not reached) in p53sigwt patients. In terms of comutations, TP53 wt pts had a higher frequency of KRAS mutations: 94% vs 64.5%, p<0.001. Conclusions: Our study suggests an important prognostic role of p53 signaling muts in mPDAC pts; wt pts resulted in a longer OS than mutated pts, although some mutations seem to be associated with a longer survival. Further studies are needed to investigate these findings, including an in-depth analysis of structural proteogenomic.