The heterogeneous impact of targeted therapy on the prognosis of stage III/IV colorectal cancer patients with different subtypes of TP53 mutations

Abstract

Background: The relationship between molecular characteristics and the prognosis of colorectal cancer (CRC) patients has not been fully understood. This study explored the impact of targeted therapy on the prognosis of CRC patients with different TP53 mutations, in the context of comprehensive treatment.

Methods: This study included patients with stage III/IV primary CRC from the electronic medical record system. TP53 mutations were detected via next-generation sequencing (NGS) using formalin-fixed paraffin-embedded (FFPE) tissues. Applying two methods, we classified TP53 mutations as gain of function (GOF)/non-GOF mutations or known/likely loss of function (LOF) mutations. Kaplan-Meier plot and parametric survival analysis were performed to evaluate the prognosis of CRC patients and identify potential predictors.

Results: There were 286 patients included, of which 166 (58.04%) patients received targeted therapy and 120 (41.96%) did not. There were 286 patients in the TP53 GOF classification set and 247 in the TP53 LOF classification set. Parametric survival analysis, adjusted for sex, onset, KRAS mutation, sidedness, stage, and surgery, showed that receiving targeted therapy predicted better overall survival (OS) among patients who harbored TP53 GOF mutations (HR 0.40, 95% confidence interval (CI) [0.21, 0.76], p = 0.005) or known LOF mutations (HR 0.21, 95% CI [0.07, 0.60], p = 0.002). However, there was no significant impact of receiving targeted therapy on OS among patients harboring TP53 non-GOF mutations (HR 1.68, 95% CI [0.50, 5.63], p = 0.403) or likely LOF mutations (HR 0.90, 95% CI [0.34, 2.39], p = 0.837).

Conclusions: Receiving targeted therapy had a heterogeneous impact on the prognosis of CRC patients harboring different TP53 mutations. These results provide promising value for future personalized treatment and precision medicine.

Keywords: colorectal neoplasms; genomic medicine; high-throughput nucleotide sequencing; mutation; survival analysis.