E373: P53 Gain/Loss of Function Status Correlates with Overall Survival in Patients with Resected Pancreatic Cancer

Pancreatic cancer is an aggressive, often lethal, GI malignancy. The P53 gene, whose normal function is critical for regulation of replication, DNA repair and apoptosis, is the most common tumor-suppressor gene mutated in pancreatic ductal adenocarcinoma (PDAC). The purpose of our study is to determine the impact of the various P53 mutation subtypes on survival in resectable PDAC.

Methods:

This was a retrospective cohort study based on an institutional database of patients with pancreatic resection. Patients that underwent curative-intent resection for PDAC between 2016-2021 were identified. Patient and tumor characteristics were recorded as well as oncologic outcome data. P53 tumor genotypes were grouped into wild-type, gain-of-function (GOF) mutations, and non-GOF mutations. P53 GOF mutations included were R175H, R248W, R248Q, R273H, R282W, and G245S, as described by previous literature. Non-GOF mutations included all other P53 mutations observed.

Results:

The study included a total of 308 patients with PDAC with a mean age of 68.5(±9.20) years, of which 53% were male. P53 mutations were found in 218 patients (70.8%) with PDAC and wild-type P53 was noted in 90 patients (29.2%). Of the patients with mutant P53, 50 patients (22.9%) had a gain of function (GOF) mutation, and 168 patients (77.1%) had a non-GOF. A Kaplan- Meier disease-free survival analysis showed GOF mutations were associated with a favorable prognosis compared to non-GOF (38.1 ± 7.3 months vs. 17.7 ±2.7 months, p = 0.01). Patients with wild-type P53 had a worse disease-free survival than GOF patients, however, this was not significant (22.4 ±6.0 months vs. 38.1 ± 7.3 months, p= ns). There was no difference in overall survival between different P53 mutation statuses. In a Cox-regression for disease-free survival, lymphovascular invasion, perivascular invasion, adjuvant chemotherapy and neoadjuvant chemotherapy were found to be independent prognostic factors (p < 0.05 for each). Additionally, although bordering on significance, the P53 mutation type was also associated with disease-free survival (p= 0.069). A Cox-regression analysis for overall survival found lymphovascular invasion, adjuvant chemotherapy, and neoadjuvant chemotherapy as independent prognostic factors (p < 0.05 for each).

Conclusions:

Our data suggest that P53 mutations, especially when grouped by gain-of-function status hold prognostic value regarding earlier recurrence. GOF mutations were found to be highly associated with favorable disease-free survival. Further investigations are required to validate these findings.