Statin Use Is Not Associated with Improved Progression Free Survival in Cetuximab Treated KRAS Mutant Metastatic Colorectal Cancer Patients: Results from the CAIRO2 Study

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.

Statin uses and mortality in colorectal cancer patients: An updated systematic review and meta‐analysis

“…After exclusion of unrelated articles, 47 full‐text articles were further reviewed according to preset inclusion and exclusion criteria. Finally, 14 studies involving 130 994 patients met our criteria and were included in this meta‐analysis . Detailed characteristics of the included studies were summarized in Table .…”

“…Detailed characteristics of the included studies were summarized in Table . Generally, six studies involving 86 622 patients reported survival outcomes for patients of pre‐diagnostic statin uses, while 11 studies involving 44 322 patients investigated survival outcomes related to post‐diagnostic statin uses . Eight studies were conducted in Europe (United Kingdom, Denmark, Netherland, Germany), four in North America, and two in Asia (China, Korea) .…”

“…Generally, six studies involving 86 622 patients reported survival outcomes for patients of pre‐diagnostic statin uses, while 11 studies involving 44 322 patients investigated survival outcomes related to post‐diagnostic statin uses . Eight studies were conducted in Europe (United Kingdom, Denmark, Netherland, Germany), four in North America, and two in Asia (China, Korea) . Six studies investigated patients with stages I‐IV, four with stages I‐III, two with stage III, one with stages II‐III, one with stage IV cancer .…”

“…Eight studies were conducted in Europe (United Kingdom, Denmark, Netherland, Germany), four in North America, and two in Asia (China, Korea) . Six studies investigated patients with stages I‐IV, four with stages I‐III, two with stage III, one with stages II‐III, one with stage IV cancer . One study only included patients with rectum cancer, four studies only included patients with colon cancer, while the remaining nine studies included patients with both colon cancer and rectum cancer .…”

“…While many preclinical researches on cells and animals have indicated the positive effects of statins on CRC, such as increasing intracellular oxidative stress, inducing apoptosis and augmenting chemosensitivity, whether statin uses are positively correlated with the survival of CRC patients in clinic is controversial. No consensus concerning the prognostic effects of statins on CRC has been reached so far . Therefore, we conducted this meta‐analysis to assess the overall and cancer‐specific survival benefits of statin uses on CRC patients.…”