Correlation between p53 expression and clinical outcome in RAS/BRAF wild type metastatic colorectal cancer patients receiving later-line irinotecan-cetuximab

Abstract

Background: Preclinical and clinical data support that p53 might modulate the EGFR activity and as a consequence it might influence response/resistance to anti-EGFR monoclonal antibodies. However, the association between p53 status and clinical outcome has not been clarified yet. In our study we evaluated the role of p53 expression in RAS/BRAF wild type (WT) metastatic colorectal (mCRC) patients (pts) receiving irinotecan- cetuximab by using a validation cohort. Method(s): p53 immunohistochemical expression was retrospectively analysed in tumour samples of RAS/BRAFWT mCRC pts treated with second-third line irinotecan- cetuximab. Our aim was to evaluate the correlation between p53 expression and OS, PFS and RR. Statistical analysis was performed with the MedCalc package. Survival distribution was assessed by the Kaplan-Meyer method and comparison of survival curves was performed with log-rank test. Result(s): Globally 120 RAS/BRAF WTmCRC pts were included in our analysis, 88 in the exploratory cohort and 32 in the validation cohort. 36/88 and 14/32 pts had p53 normal expression, whereas 52/88 and 18/32 showed p53 overexpression. In the exploratory cohort, RR was 61.1% in pts with p53 normal expression versus (vs) 3.8% in pts overexpressing p53 (p<0.0001); median OS (mOS) was 18 months in pts with normal p53 (95% CI 17-20) vs 8 months (95% CI 5.9-9; p<0.0001) and median PFS (mPFS) was 8 months in pts with p53 normal status (95% CI 6.98-8.10) vs 3 months in pts with abnormal p53 (95% CI 2.90-3.63; p<0.0001). These results were confirmed in the validation cohort: RR was 56.2% in pts with normal p53 and 43.7% in pts with abnormal p53 (p=0.4830); mOS was 30.1 months in pts with p53 normal status (95% CI 22.42- 53.31) vs 13.4 months in pts with p53 overexpression (95% CI 12.04-24.84; p=0.03) and mPFS was 9.8 months in pts with normal p53 (95% CI 7.51-12.55) vs 7.9 months in pts with abnormal p53 (95% CI 5.32-8.21; p=0.02). Conclusion(s): In our study p53 normal expression was associated with better outcome in RAS/BRAF WTmCRC pts receiving irinotecan-cetuximab, as confirmed by the validation cohort. Further prospective studies are needed to validate the role of p53 in these pts and to investigate its cross-talk with EGFR.