Difference in serum cytokines between metastatic colorectal cancer patients with mutant and wild type RAS in response to targeted treatment with monoclonal antibodies

Abstract

Cytokines and chemokines play dual – pro- and antioncogenic – roles in tumor progression. Targeted medications of monoclonal antibodies, anti-VEGF (bevacizumab) and anti-EGFR (cetuximab, panitumumab), are widely used in treatment of metastatic colorectal cancer (mCRC) and are prescribed in dependence upon presence or absence of mutations in the RAS gene. The aim of the study was to assess mCRC heterogeneity in the dependence upon presence or absence of mutation in RAS gene according to serum cytokine composition and its dynamics in the response to antitumor therapy using targeted medications of monoclonal antibodies. Levels of 20 cytokines were estimated by Multiplex analysis in serum of 50 patients with mCRC (25 KRAS+ and 25 KRAS- , who received anti-VEGF therapy, bevacizumab and anti EGFR therapy, cetuximab/ panitumumab respectively) before and after 4 courses of treatment. The results were analyzed separately in patients with complete, partial response and progression of the disease. The results showed that before the treatment in KRAS+ patients the levels of GM-CSF, IL-2, IL-5, IL-6, IL-7, IL-10, and IL-13 exceeded the ones in KRAS- patients; on the contrary, they had lower amounts of IL-8, IP-10, MIG, and MIP-1α. In patients who received anti-EGFR therapy and developed complete response, the increase of IL-15 and MIG along with a 2 to 3-fold decrease in GM-CSF, IL-2, IL-4, IL-6, IL-8, IL-17А, and МСР-1 was noted. Progression of the disease was observed in patients with initially low levels of the vast majority of the studied cytokines with dramatically elevation after non-effective anti-EGFR treatment. In patients having received anti-VEGF therapy, progression was followed by decrease in all of the studied cytokine and chemokine levels, while complete response resulted in decreases in IL-6, IL-5 and IL-10 (the last ones up to 0) and the increase of MIG. Thus, serum levels of cytokines in patients with mCRC were shown to be different in dependence of KRAS mutation; different response to targeted monoclonal antibodies may be reflected by the dynamics of serum cytokines` composition. Prevailing of many prooncogenic and proangiogenic cytokines in KRAS+ mCRC patients may be considered in terms of their unfavorable prognosis.