KRAS-mutated patients with liver-only metastatic colorectal cancer treated with Bevacizumab and chemotherapy. Functional analysis of TP53 mutations and outcomes

A42 Background: TP53 missense mutations (MMs) may confer sensitivity to anti-angiogenics via cross-talk mechanisms between p53, vascular endothelial growth factor (VEGF) and VEGF receptors. Recently, we observed that in a population of patients affected by metastatic gastric adenocarcinoma, treated with Ramucirumab plus chemotherapy, those who had a p53 loss of function mutation showed an improvement in terms of survival1. In this context, here we present the results of a study conducted on a homogeneous subgroup of KRAS-mutated colorectal cancer (CRC) patients with liver-only metastases, treated with first-line 5-Fluorouracil/Irinotecan (FOLFIRI) chemotherapy plus Bevacizumab. The aim of the study was to assess whether TP53 MMs were associated with the patients’ clinical outcomes. Material (patients) and Methods: TP53 MMs were detected in primary tumors by next-generation sequencing of 62 patients. TP53 MMs were classified by mutant-specific residual transcriptional activity scores (TP53 RTAS) as transcriptionally inactive (TP53Inactive = TP53 RTAS < 1%) or transcriptionally active (TP53Active = TP53 RTAS ≥ 1%)2,3. TP53 RTAS results were used for categorizing patients to perform progression-free survival (PFS), response rate (RR) and overall survival (OS) analyses. Results: The study population consisted of 62 KRAS-mutated colorectal cancer patients with liver-only metastases, who underwent first-line systemic therapy with FOLFIRI regimen combined with Bevacizumab. TP53 MMs were found in 39 patients (62%): 16 had TP53Inactive and 23 TP53Active MMs. The 16 patients with TP53Inactive MMs showed better PFS compared to those with wild-type TP53 or TP53Active (p=0.007). This effect was retained in the multivariate model (p=0.02) and a similar clinical impact was also observed in the OS analysis (p=0.04). Moreover, we observed a statistically significant difference in terms of overall RR (p=0.03) and rate of post-treatment resection of liver metastases between the 16 patients with TP53Inactive and those with wild-type TP53 or TP53 MMs (p=0.02). Conclusions: Our study suggests that TP53 MMs could help in identifying those patients who may benefit the most from Bevacizumab-based systemic therapy.