KSR1 gene polymorphism in mCRC patients treated with first-line FOLFIRI and bevacizumab

Background Kinase suppressor of Ras (KSR) 1 is a scaffolding protein regulating the Raf/Mek/ERK cascade. Preclinical data showed that KSR1 could increase estrogen receptor transcriptional activity after exposure to estrogens. Recent retrospective analyses suggested a possible role for KSR1 rs2241906 C/T polymorphism in predicting the outcome of patients with mCRC. Methods MCRC patients receiving first-line FOLFIRI+bevacizumab prospectively enrolled in a translational research program were selected on the basis of KRAS and BRAF mutational status availability. KSR1 rs2241906 polymorphism was analyzed on DNA extracted from peripheral blood by means of PCR and direct sequencing. Taking into account the connection between estrogen pathway and KSR1, subgroup analyses according to gender were pre-planned. Results 287 patients were included. Main patients’ characteristics were the following: M/F=175/112; median age=62 (range 26-79); ECOG-PS 0/1-2=240/47; synchronous/metachronous disease=213/74; Köhne score (low/intermediate/high/data missing)=122/129/22/14; KRAS-BRAF mutational status (wt-wt/mut-wt/wt-mut)= 123/146/18. In the overall KRAS-BRAF wt population, KSR1 polymorphism did not affect the outcome. The analysis performed according to gender showed that in the KRAS-BRAF wt population females with KSR1 rs2241906 T/- achieved a significantly better PFS (median 15.9 mos) in comparison to C/C variant carriers (median 8.8 mos) (HR=0.44 [95%CI 0.21-0.91], p=0.010); meanwhile males with T/- showed a worse PFS in comparison to those carrying the C/C variant (HR=1.92 [95%CI 1.05-3.53], p=0.021). These results were significant also in a multivariate model and a significant interaction of gender with PFS according to KSR1 allelic variants was demonstrated (p=0.004). Conclusions This prospectively conceived pharmacogenetic study confims the role of KSR1 polymorphisms in affecting the outcome of mCRC KRAS-BRAF wt patients. In particular, these results indirectly indicate that estrogenic stimulation could affect the proliferation of KRAS-BRAF wt CRC cells through an interaction with KSR1. Preclinical investigations to further explore this preliminary hypothesis are ongoing.