caa a22 4500 555285278 20200410031629.0 cr unu---uuuuu 190206s2018 xx s 000 0 eng 1932-6203 10.1371/journal.pone.0193640 doi (BORIS)oai:boris.unibe.ch:124099 610 ddc 29522543 pmid NOS2 polymorphisms in prediction of benefit from first-line chemotherapy in metastatic colorectal cancer patients [Elektronische Daten] [Marta Schirripa, Wu Zhang, Dongyun Yang, Shu Cao, Satoshi Okazaki, Fotios Loupakis, Martin Dave Berger, Yan Ning, Yuji Miyamoto, Mitsukuni Suenaga, Giulia Alberti, Jordan D West, Sara Lonardi, Taline Khoukaz, Francesca Bergamo, Francesca Battaglin, Carlotta Antoniotti, Alfredo Falcone, Sebastian Stintzing, Volker Heinemann, Heinz-Josef Lenz] publishedVersion openAccess eu-repo 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. Schirripa Marta joint author Zhang Wu joint author Yang Dongyun joint author Cao Shu joint author Okazaki Satoshi joint author Loupakis Fotios joint author Berger Martin Dave joint author Ning Yan joint author Miyamoto Yuji joint author Suenaga Mitsukuni joint author Alberti Giulia joint author West Jordan D. joint author Lonardi Sara joint author Khoukaz Taline joint author Bergamo Francesca joint author Battaglin Francesca joint author Antoniotti Carlotta joint author Falcone Alfredo joint author Stintzing Sebastian joint author Heinemann Volker joint author Lenz Heinz-Josef joint author PLoS ONE 13(3), e0193640 1932-6203 https://boris.unibe.ch/124099/1/pone.0193640.pdf text/html WWW-Backlink auf das Repository 1 info:eu-repo/semantics/article boris PeerReviewed boris peerstatus BORIS 856 40 https://boris.unibe.ch/124099/1/pone.0193640.pdf text/html WWW-Backlink auf das Repository BORIS 700 1- Schirripa Marta joint author BORIS 700 1- Zhang Wu joint author BORIS 700 1- Yang Dongyun joint author BORIS 700 1- Cao Shu joint author BORIS 700 1- Okazaki Satoshi joint author BORIS 700 1- Loupakis Fotios joint author BORIS 700 1- Berger Martin Dave joint author BORIS 700 1- Ning Yan joint author BORIS 700 1- Miyamoto Yuji joint author BORIS 700 1- Suenaga Mitsukuni joint author BORIS 700 1- Alberti Giulia joint author BORIS 700 1- West Jordan D. joint author BORIS 700 1- Lonardi Sara joint author BORIS 700 1- Khoukaz Taline joint author BORIS 700 1- Bergamo Francesca joint author BORIS 700 1- Battaglin Francesca joint author BORIS 700 1- Antoniotti Carlotta joint author BORIS 700 1- Falcone Alfredo joint author BORIS 700 1- Stintzing Sebastian joint author BORIS 700 1- Heinemann Volker joint author BORIS 700 1- Lenz Heinz-Josef joint author BORIS 773 0- PLoS ONE 13(3), e0193640 1932-6203 BK010053 XK010053 XK010000 BORIS BORIS BORIS info:eu-repo/semantics/article openAccess