10-Jahres-Überlebensrate von Patienten mit kolorektalem Karzinom in Abhängigkeit vom PIK3CA- und KRAS- Mutations- und Acetylsalicylsäureeinnahmestatus

As more is known about the molecular properties that lead to the formation, growth, and metastasis of colorectal carcinoma, the greater gets the desire for individualized therapy for the individual patient. This requires molecular biomarkers that indicate whether a patient could benefit from a given therapy because of its tumor properties. In various retrospective analyzes and meta-analyzes, a survival advantage was shown by an "adjuvant" intake of acetylsalicylic acid by patients with colorectal carcinoma. The PIK3CA mutation status was considered as a molecular biomarker for the response of acetylsalicylic acid therapy. The aim of this work was to examine whether the PIK3CA mutation status and the KRAS mutation status in patients with colorectal cancer represent suitable molecular biomarkers for “adjuvant” therapy with acetylsalicylic acid, as well as suitable prognostic markers for overall survival. In this retrospective analysis, 153 patients with an initial diagnosis of colorectal cancer at the University Hospital Marburg in 2003/2004 were included. Paraffin-embedded tumor samples were deparaffinized and DNA extracted. The PIK3CA mutation status of tumor cells was determined by pyrosequencing and the KRAS mutation status by using multiplex sequencing. The acetylsalicylic acid intake status and the 10-year survival rate were assessed using patient records and reporting registers. In this study, there was a mutation in the PIK3CA gene found in 16% and a KRAS mutation in 57% of the patients. Acetylsalicylic acid was taken by 34% of the patients and overall survival 10 years after the initial diagnosis was at 44%. It was shown that patients with PIK3CA wild-type had a significant survival advantage over patients with PIK3CA mutation (log-rank-test: HR=0.59; 95% CI=0.29-0.96; p=0.04). Patients with regular intake of acetylsalicylic acid did not show significantly improved absolute 10- year survival in the total population compared to patients without regular intake of acetylsalicylic acid (log-rank-test: HR=0.77; 95% CI=0.5-1.22; p=0.29). Among all patients with regular intake of acetylsalicylic acid, patients with PIK3CA wild-type were shown to have a significant survival advantage over patients with PIK3CA mutations (log-rank-test: HR=0.33; 95% CI=0.05-0.62; p<0.01). This survival advantage was not evident among the patients without acetylsalicylic acid intake (log-rank-test: HR=0.78; 95% CI=0.38-1.51; p=0.43). Reviewing the combined PIK3CA and KRAS mutation status of patients with regular acetylsalicylic acid intake a significant survival benefit for patients with PIK3CA wild-type and KRAS mutation was observed compared to patients with other mutation status combinations (log-rank-test: HR=0.38; 95% CI=0.17-0.87; p=0.02). This survival advantage was not evident among the patients without acetylsalicylic acid intake (log-rank-test: HR=0.95; 95% CI=0.58-1.57; p=0.84). Patients with KRAS mutation, PIK3CA wild-type and acetylsalicylic acid ingestion showed a survival benefit over patients with KRAS mutation, PIK3CA wild-type without acetylsalicylic acid intake (log-rank-test: HR=0.57; 95% CI=0.30-1.08; p=0.09). In summary, the results of this work suggest that patients with the combination of PIK3CA wild-type and KRAS mutation in particular benefit from acetylsalicylic acid intake after diagnosis of colorectal cancer. The study situation is very heterogeneous in this regard. Studies by Liao et al. and Domingo et al. showed a significantly improved outcome for patients with a mutation in the PIK3CA gene compared to patients with PIK3CA wildtype when taking acetylsalicylic acid. In a study by Reimers et al. Patients with regular acetylsalicylic acid intake and PIK3CA wild-type showed a significantly longer overall survival compared to patients with PIK3CA wild-type without regular intake. Recent studies by Murphy et al. and Kothari et al. found no significant association between the PIK3CA mutation status and an overall survival prolongation when taking acetylsalicylic acid. The results of this study conclusively underline that the roles of the PIK3CA and KRAS mutation status as potential predictive markers for adjuvant therapy with acetylsalicylic acid in patients with colorectal cancer require prospective studies. Due to the current study situation and the not insignificant side effects profile of acetylsalicylic acid, in patients with colorectal carcinoma "adjuvant" therapy with acetylsalicylic acid should currently only be carried out as part of studies.