P53 Mutations May Reveal Viability of Different Pancreatic Cancer Therapies

Patients with PDAC and non-GOF mutations had less favorable OS and DFS outcomes in various instances compared with those who had wild-type or GOF mutations.

Results from a retrospective cohort study published in the Journal of Surgical Oncology suggested that P53 mutations, when grouped by functional status, may have differential prognostic value with regard to the survival and recurrence of patients with pancreatic ductal adenocarcinoma (PDAC).

Of the 243 patients (74%) with P53 mutations in their tumors, 87 (26%) were wild type; gain-of-function (GOF) mutations were observed in 24% of patients, and non-GOF mutations were observed in 76%. Furthermore, the most common P53 mutation was the GOF mutation R273H (4%), then R248W (4%) and R248Q (3%); the most common non-GOF mutations were R273C (5%), Y220C (5%), and G245S (3%).

The median overall survival (OS) in the entire cohort was 29.4 months (± 1.4); in the non-GOF mutation cohort, the median OS was 25.6 months (± 2.4) compared with 32.2 months (± 3.6) in the wild-type cohort (P = .040) and 36.2 months (± 4.4 months) in the GOF mutation cohort (P = .049).

The median disease-free survival (DFS) in the entire cohort was 16.3 months (± 0.83); in the non-GOF mutation cohort, the median DFS was 14.6 months (± 1.2) compared with 19.6 months (± 3.5) in the wild-type group (P = .038) and 18.3 months (± 3.6) in the GOF mutation cohort (P = .051).

Notably, the Kaplan-Meier comparison revealed that the G245S mutation cohort had a median OS of 15.8 months (± 2.4) compared with 32.2 months (± 3.6) in the wild-type cohort (P = .01). Similarly, the R273C mutation cohort had a median DFS of 9.3 months (± 3.2) compared with 19.6 months (± 3.5) in the wild-type cohort (P = .027).

Additionally, in patients who received leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) chemotherapy, those with non-GOF mutations had a lower median OS and median DFS compared with those who had wild-type or GOF mutations (P = .008 and P = .016, respectively). In an analysis of those who received gemcitabine-based therapy, there was no significant difference in median OS or median DFS when comparing mutational status.

In an assessment of radiotherapy response, it was found that no significant difference for median OS or DFS was observed based on mutational status (P = .73 and P = .58, respectively).

“Pancreatic cancer is an aggressive malignancy with improving treatments but poor OS. The P53 tumor suppressor gene, commonly mutated in PDAC, may provide prognostic clues depending on mutation function,” wrote lead study author Hui Chen, from the Jefferson Pancreas, Biliary, and Related Cancer Center in the Department of Surgery at Thomas Jefferson University, with coauthors. “We found that patients with non‐GOF P53 mutations had a higher incidence of lymphovascular invasion and shorter OS and DFS as compared [with] both GOF and WT [groups].”

A total of 330 patients with resected PDAC who received curative-intent pancreatic resection and had next-generation sequencing data at the Thomas Jefferson University Hospital between 2016 and 2022 were included in the analysis.

The mean age of patients was 68.6 years (± 8.8 years), and 50.9% of patients were male; 81.8% were White, 79.3% had received adjuvant chemotherapy, 89.1% had perineural invasion, 51.2% had tumor stage T2, and 39.2% had nodal stage N1.

Favorable survival outcomes were identified, overall, in the wild-type and GOF groups vs the non-GOF group. The investigators noted that these effects were primarily limited to the patients treated with FOLFIRINOX chemotherapy.

The investigators also ran an ad-hoc 2-arm analysis that compared patients with non-GOF tumors (n = 185) to the rest of the cohort (n = 145). Kaplan-Meier analyses showed that those with non-GOF mutations had a median OS of 25.6 months (± 2.4) vs 35.6 months (± 2.9) in the rest of the cohort (P = .01) and a median DFS of 14.6 months (± 1.2) vs 18.3 months (± 2.4), respectively (P = .01).

A Cox-regression analysis also demonstrated that non-GOF status was more associated with mortality compared with the rest of the cohort (HR, 1.3; P = .05); identified tumor factors that correlated with the increased mortality were lymphovascular invasion (HR, 1.8; P <.001), perineural invasion (HR, 1.8; P = .03), and positive margins (HR, 1.8; P = .001). Adjuvant chemotherapy was a protective factor for survival (HR, 0.59; P = .002).

In a subset of patients who received FOLFIRINOX, Cox-regression demonstrated that non-GOF status was associated with poor OS (HR, 2.0; P = .008) and worse DFS (HR, 1.7; P = .016) compared with the rest of the group. A gemcitabine-based therapy subset of patients demonstrated that there was no significant impact of P53 mutational subtype on OS (HR, 0.87; P = .47).

Reference

Chen H, Agarwal A, Yellanki S, et al. P53 function status correlates with overall survival in patients with resected pancreatic cancer. J Surg Oncol. Published online August 7, 2025. doi:10.1002/jso.70060