PIK3CA Mutations in Early-Onset Appendiceal Adenocarcinoma

Approximately one in three patients with appendiceal cancer (AC) is diagnosed before age 50 years. Early-onset appendiceal cancer (EOAC) exhibits distinct clinicopathologic and demographic features compared with late-onset disease, suggesting potential biological differences. However, the molecular differences remain poorly understood. This study aims to compare EOAC and late-onset AC (LOAC, ≥50 years) mutational profiles and evaluate their impact on overall survival (OS).

A retrospective analysis was conducted using the Memorial Sloan Kettering-Metastatic Events and Tropisms database. Patients were stratified by age at the time of surgery into EOAC and LOAC groups. Logistic regression was used to assess differences in mutational profiles between these two groups. Findings were validated using data from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange project. Kaplan-Meier survival analysis and multivariable Cox proportional hazard models were used to evaluate associations with survival.

The study included 200 patients with appendiceal adenocarcinoma (median age: 55 years, IQR, 47-68), of whom 70 (35%) had EOAC and 130 (65%) had LOAC. Patients with EOAC had higher odds of harboring PIK3CA mutations compared with LOAC (17.1% v 7.7%; odd ratio, 2.65; P = .04), which was consistent when combined with the GENIE data set (12.3% v 5.9%; P < .01). PIK3CA mutations were exclusively observed in patients with metastatic disease (11.8%) and were more common in adenocarcinoma not otherwise specified (NOS) than mucinous tumors (63.6% v 36.4%; P = .04). In multivariable analysis, PIK3CA mutations were independently associated with worse OS (hazard ratio, 2.62 [95% CI, 1.32 to 5.20]; P < .01).

PIK3CA mutations are more common in EOAC and independently associated with worse OS. These findings suggest incorporating PIK3CA mutation status into prognostic assessments and warrant further investigation of PIK3CA inhibitors as a potential therapeutic strategy for appendiceal adenocarcinoma.