Statin use is not associated with improved progression free survival in cetuximab treated KRAS mutant metastatic colorectal cancer patients: results from the CAIRO2 study.

Lisanne L Krens,Jara M Baas,Cornelis J A Punt,Henk-Jan Guchelaar,Hans Gelderblom,Lieke H J Simkens,Els R Koomen,Anthony W.I Lo

doi:10.1371/journal.pone.0112201

Abstract

Statins may inhibit the expression of the mutant KRAS phenotype by preventing the prenylation and thus the activation of the KRAS protein. This study was aimed at retrospectively evaluating the effect of statin use on outcome in KRAS mutant metastatic colorectal cancer patients (mCRC) treated with cetuximab. Treatment data were obtained from patients who were treated with capecitabine, oxaliplatin bevacizumab ± cetuximab in the phase III CAIRO2 study. A total of 529 patients were included in this study, of whom 78 patients were on statin therapy. In patients with a KRAS wild type tumor (n = 321) the median PFS was 10.3 vs. 11.4 months for non-users compared to statin users and in patients with a KRAS mutant tumor (n = 208) this was 7.6 vs. 6.2 months, respectively. The hazard ratio (HR) for PFS for statin users was 1.12 (95% confidence interval 0.78–1.61) and was not influenced by treatment arm, KRAS mutation status or the KRAS*statin interaction. Statin use adjusted for covariates was not associated with increased PFS (HR = 1.01, 95% confidence interval 0.71–1.54). In patients with a KRAS wild type tumor the median OS for non-users compared to statin users was 22.4 vs. 19.8 months and in the KRAS mutant tumor group the OS was 18.1 vs. 14.5 months. OS was significantly shorter in statin users versus non-users (HR = 1.54; 95% confidence interval 1.06–2.22). However, statin use, adjusted for covariates was not associated with increased OS (HR = 1.41, 95% confidence interval 0.95–2.10). In conclusion, the use of statins at time of diagnosis was not associated with an improved PFS in KRAS mutant mCRC patients treated with chemotherapy and bevacizumab plus cetuximab.

Highlights

Statins are widely prescribed to lower blood cholesterol concentration and have shown to reduce the risk of cardiovascular events and mortality [1]
Baseline patient characteristics according to statin use 795 patients were enrolled in the CAIRO2 study
A total of 529 patients from the CAIRO2 study were included in this analysis, 266 patients were excluded based on unknown KRAS mutation status, due to retrospective genotyping of the KRAS mutation status of the tumor, because the CAIRO2 study was performed in the pre KRAS era

Summary

Introduction

Statins are widely prescribed to lower blood cholesterol concentration and have shown to reduce the risk of cardiovascular events and mortality [1]. The use of statins have been associated with a reduced risk of malignancies in a variety of organ sites, such as colon, rectum, lungs and liver [2]. Statins inhibit cholesterol synthesis via inhibition of the mevalonate pathway and lower protein prenylation (Figure 1). Protein prenylation is crucial for several cancer cell growth related proteins, such as KRAS. The KRAS protein is activated by post-translational prenylation by binding farnesyl (C15) and geranylgeranyl (C17) moieties, both products of the mevalonate pathway. After prenylation the KRAS protein becomes lipophilic and translocates to the cellular membrane to exerts its function [3]

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