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

Schirripa, Marta; Zhang, Wu; Yang, Dongyun; Cao, Shu; Okazaki, Satoshi; Loupakis, Fotios; Berger, Martin Dave; Ning, Yan; Miyamoto, Yuji; Suenaga, Mitsukuni; Alberti, Giulia; West, Jordan D; Lonardi, Sara; Khoukaz, Taline; Bergamo, Francesca; Battaglin, Francesca; Antoniotti, Carlotta; Falcone, Alfredo; Stintzing, Sebastian; Heinemann, Volker; ... (2018). NOS2 polymorphisms in prediction of benefit from first-line chemotherapy in metastatic colorectal cancer patients. PLoS ONE, 13(3), e0193640. Public Library of Science 10.1371/journal.pone.0193640

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Berger, Martin Dave

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1932-6203

Publisher:

Public Library of Science

Language:

English

Submitter:

Rebeka Gerber

Date Deposited:

05 Feb 2019 14:15

Last Modified:

24 Oct 2019 00:05

Publisher DOI:

10.1371/journal.pone.0193640

PubMed ID:

29522543

BORIS DOI:

10.7892/boris.124099

URI:

https://boris.unibe.ch/id/eprint/124099

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