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

Marta Schirripa, Wu Zhang, Dongyun Yang, Shu Cao, Satoshi Okazaki, Fotios Loupakis, Martin D 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 & 1 others Heinz-Josef Lenz

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)e0193640
JournalPLoS One
Volume13
Issue number3
DOIs
Publication statusPublished - 2018

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Chemotherapy
Polymorphism
colorectal neoplasms
drug therapy
Colorectal Neoplasms
Macrophages
Immune system
genetic polymorphism
Drug Therapy
prediction
Tumors
Genes
immune system
Chemical activation
Immune System
DNA
macrophage activation
neoplasms
Macrophage Activation
DNA Sequence Analysis

Keywords

  • Aged
  • Bevacizumab/pharmacology
  • Clinical Trials as Topic
  • Cohort Studies
  • Colorectal Neoplasms/diagnosis
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Nitric Oxide Synthase Type II/genetics
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Treatment Outcome

Cite this

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 D; 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; Lenz, Heinz-Josef.

In: PLoS One, Vol. 13, No. 3, 2018, p. e0193640.

Research output: Contribution to journalArticle

Schirripa, M, Zhang, W, Yang, D, Cao, S, Okazaki, S, Loupakis, F, Berger, MD, Ning, Y, Miyamoto, Y, Suenaga, M, Alberti, G, West, JD, Lonardi, S, Khoukaz, T, Bergamo, F, Battaglin, F, Antoniotti, C, Falcone, A, Stintzing, S, Heinemann, V & Lenz, H-J 2018, 'NOS2 polymorphisms in prediction of benefit from first-line chemotherapy in metastatic colorectal cancer patients', PLoS One, vol. 13, no. 3, pp. e0193640. https://doi.org/10.1371/journal.pone.0193640
Schirripa, Marta ; Zhang, Wu ; Yang, Dongyun ; Cao, Shu ; Okazaki, Satoshi ; Loupakis, Fotios ; Berger, Martin D ; 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 ; Lenz, Heinz-Josef. / NOS2 polymorphisms in prediction of benefit from first-line chemotherapy in metastatic colorectal cancer patients. In: PLoS One. 2018 ; Vol. 13, No. 3. pp. e0193640.
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abstract = "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.",
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author = "Marta Schirripa and Wu Zhang and Dongyun Yang and Shu Cao and Satoshi Okazaki and Fotios Loupakis and Berger, {Martin D} and Yan Ning and Yuji Miyamoto and Mitsukuni Suenaga and Giulia Alberti and West, {Jordan D} and Sara Lonardi and Taline Khoukaz and Francesca Bergamo and Francesca Battaglin and Carlotta Antoniotti and Alfredo Falcone and Sebastian Stintzing and Volker Heinemann and Heinz-Josef Lenz",
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pages = "e0193640",
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TY - JOUR

T1 - NOS2 polymorphisms in prediction of benefit from first-line chemotherapy in metastatic colorectal cancer patients

AU - Schirripa, Marta

AU - Zhang, Wu

AU - Yang, Dongyun

AU - Cao, Shu

AU - Okazaki, Satoshi

AU - Loupakis, Fotios

AU - Berger, Martin D

AU - Ning, Yan

AU - Miyamoto, Yuji

AU - Suenaga, Mitsukuni

AU - Alberti, Giulia

AU - West, Jordan D

AU - Lonardi, Sara

AU - Khoukaz, Taline

AU - Bergamo, Francesca

AU - Battaglin, Francesca

AU - Antoniotti, Carlotta

AU - Falcone, Alfredo

AU - Stintzing, Sebastian

AU - Heinemann, Volker

AU - Lenz, Heinz-Josef

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Aged

KW - Bevacizumab/pharmacology

KW - Clinical Trials as Topic

KW - Cohort Studies

KW - Colorectal Neoplasms/diagnosis

KW - Female

KW - Genotype

KW - Humans

KW - Male

KW - Middle Aged

KW - Neoplasm Metastasis

KW - Nitric Oxide Synthase Type II/genetics

KW - Polymorphism, Single Nucleotide

KW - Prognosis

KW - Treatment Outcome

U2 - 10.1371/journal.pone.0193640

DO - 10.1371/journal.pone.0193640

M3 - Article

VL - 13

SP - e0193640

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

ER -