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Background  Macrophages play a crucial role in the interaction between tumor and immune system, and iNOS is known as a surrogate marker of M1 macrophages activation. The goal of the study was to investigate the role of iNOS polymorphisms as prognostic marker in mCRC patients.    Materials and methods  Functional significant polymorphisms in the promoter of  INOS  gene were analyzed by PCR-based and direct DNA sequencing in 4 cohorts of patients receiving bevacizumab based first-line chemotherapy: two evaluation cohorts (TRIBE ARM A and ARM B) and two validation cohorts (FIRE 3 arm A and MOMA). The relation of the SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test. Subgroup analyses according to  RAS  status were preplanned.    Results  In the exploratory cohort 1 (TRIBE A), patients with CCTTT  any>13repeats  (N = 57) showed improved median PFS compared with patients carrying the  ≤13/≤13 repeats  variant (N = 152) (HR, 0.64; 95%CI 0.44–0.92,  p  = 0.010). Similar results were shown adopting the  >26repeats / ≤26 repeats  (HR, 0.56; 95%CI 0.36–0.87,  p  = 0.005). In  RAS  mutant, patient with  any>13 repeats  (N = 24) had improved PFS results compared with those carrying the  ≤13/≤13 repeats variant  (N = 81) (HR, 0.51; 95%CI 0.30–0.87,  p  = 30.009). Similar results were found adopting the  >26 repeats/≤26 repeats  cut off: (HR, 0.52; 95%CI 0.27–0.98,  p  = 0.035). These data were partially confirmed in the exploratory cohort 2 (TRIBE B): a better median PFS was observed in patients with  >26 repeats  vs ≤26  repeats  (N = 205) patients. However, these data were not confirmed in the two validation cohorts.    Conclusion  We failed to replicate the exploratory findings in both validation sets. The CCTTT polymorphic region of the INOS gene does not predict outcome in mCRC receiving bevacizumab based first line chemotherapy. Further investigations are needed to reveal mechanisms between tumor, immune system and chemotherapy response.

NOS2 polymorphisms in prediction of benefit from first-line chemotherapy in metastatic colorectal cancer patients