eNOS polymorphisms as predictors of efficacy of bevacizumab-based chemotherapy in metastatic colorectal cancer: Data from a randomized clinical trial

Paola Ulivi, Emanuela Scarpi, Alessandro Passardi, Giorgia Marisi, Daniele Calistri, Wainer Zoli, Marzia Del Re, Giovanni Luca Frassineti, Davide Tassinari, Stefano Tamberi, Bernadette Vertogen, Dino Amadori

Research output: Contribution to journalArticle

Abstract

Background: Bevacizumab plus chemotherapy is a widely used therapeutic option for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of bevacizumab efficacy have not yet been identified. We analyzed vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) polymorphisms in relation to response to bevacizumab. Methods: Two hundred and thirty-seven patients with mCRC enrolled onto the phase III prospective multicentre randomized "Italian Trial in Advanced Colorectal Cancer (ITACa)" trial were evaluated. One hundred fourteen patients received chemotherapy plus bevacizumab (CT + B) and 123 received chemotherapy (CT) alone. Five single nucleotide polymorphisms (SNPs) (-2578, -1498, -1154, -634 and +936) for VEGF and 2 SNPs (-786, +894) and one variable number tandem repeat in intron 4 for eNOS were analyzed for each patient. The polymorphisms were assessed in relation to progression-free survival (PFS), objective response rate (ORR) and overall survival (OS). Results: VEGF 936C/T, eNOS +894 G/T and VNTR were significantly correlated with outcome in CT + B patients, but not in CT-only patients. In particular, patients with a specific haplotype combination of the 2 eNOS polymorphisms (defined eNOS Haplo1/Haplo1 and eNOS Haplo 2/Haplo2) showed significantly longer PFS (15.0 vs 9.1 months, P = 0.001) and OS (34.5 vs 20.5 months P = 0.002), and a higher ORR (71 vs 45.9%, P = 0.013) than those with the other genotypes, respectively. Conclusions: Specific eNOS polymorphisms may be capable of identifying a subset of mCRC patients who are more responsive to bevacizumab-based chemotherapy. If confirmed, these results would permit individually tailored treatment with bevacizumab.

Original languageEnglish
Article number258
JournalJournal of Translational Medicine
Volume13
Issue number1
DOIs
Publication statusPublished - Aug 11 2015

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Chemotherapy
Nitric Oxide Synthase Type III
Polymorphism
Colorectal Neoplasms
Randomized Controlled Trials
Drug Therapy
Vascular Endothelial Growth Factor A
Disease-Free Survival
Single Nucleotide Polymorphism
Nucleotides
Minisatellite Repeats
Bevacizumab
Introns
Haplotypes
Therapeutics
Survival Rate
Genotype
Survival

Keywords

  • Advanced colorectal cancer
  • Bevacizumab
  • eNOS
  • SNPs
  • VEGF

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

eNOS polymorphisms as predictors of efficacy of bevacizumab-based chemotherapy in metastatic colorectal cancer : Data from a randomized clinical trial. / Ulivi, Paola; Scarpi, Emanuela; Passardi, Alessandro; Marisi, Giorgia; Calistri, Daniele; Zoli, Wainer; Del Re, Marzia; Frassineti, Giovanni Luca; Tassinari, Davide; Tamberi, Stefano; Vertogen, Bernadette; Amadori, Dino.

In: Journal of Translational Medicine, Vol. 13, No. 1, 258, 11.08.2015.

Research output: Contribution to journalArticle

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abstract = "Background: Bevacizumab plus chemotherapy is a widely used therapeutic option for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of bevacizumab efficacy have not yet been identified. We analyzed vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) polymorphisms in relation to response to bevacizumab. Methods: Two hundred and thirty-seven patients with mCRC enrolled onto the phase III prospective multicentre randomized {"}Italian Trial in Advanced Colorectal Cancer (ITACa){"} trial were evaluated. One hundred fourteen patients received chemotherapy plus bevacizumab (CT + B) and 123 received chemotherapy (CT) alone. Five single nucleotide polymorphisms (SNPs) (-2578, -1498, -1154, -634 and +936) for VEGF and 2 SNPs (-786, +894) and one variable number tandem repeat in intron 4 for eNOS were analyzed for each patient. The polymorphisms were assessed in relation to progression-free survival (PFS), objective response rate (ORR) and overall survival (OS). Results: VEGF 936C/T, eNOS +894 G/T and VNTR were significantly correlated with outcome in CT + B patients, but not in CT-only patients. In particular, patients with a specific haplotype combination of the 2 eNOS polymorphisms (defined eNOS Haplo1/Haplo1 and eNOS Haplo 2/Haplo2) showed significantly longer PFS (15.0 vs 9.1 months, P = 0.001) and OS (34.5 vs 20.5 months P = 0.002), and a higher ORR (71 vs 45.9{\%}, P = 0.013) than those with the other genotypes, respectively. Conclusions: Specific eNOS polymorphisms may be capable of identifying a subset of mCRC patients who are more responsive to bevacizumab-based chemotherapy. If confirmed, these results would permit individually tailored treatment with bevacizumab.",
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T1 - eNOS polymorphisms as predictors of efficacy of bevacizumab-based chemotherapy in metastatic colorectal cancer

T2 - Data from a randomized clinical trial

AU - Ulivi, Paola

AU - Scarpi, Emanuela

AU - Passardi, Alessandro

AU - Marisi, Giorgia

AU - Calistri, Daniele

AU - Zoli, Wainer

AU - Del Re, Marzia

AU - Frassineti, Giovanni Luca

AU - Tassinari, Davide

AU - Tamberi, Stefano

AU - Vertogen, Bernadette

AU - Amadori, Dino

PY - 2015/8/11

Y1 - 2015/8/11

N2 - Background: Bevacizumab plus chemotherapy is a widely used therapeutic option for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of bevacizumab efficacy have not yet been identified. We analyzed vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) polymorphisms in relation to response to bevacizumab. Methods: Two hundred and thirty-seven patients with mCRC enrolled onto the phase III prospective multicentre randomized "Italian Trial in Advanced Colorectal Cancer (ITACa)" trial were evaluated. One hundred fourteen patients received chemotherapy plus bevacizumab (CT + B) and 123 received chemotherapy (CT) alone. Five single nucleotide polymorphisms (SNPs) (-2578, -1498, -1154, -634 and +936) for VEGF and 2 SNPs (-786, +894) and one variable number tandem repeat in intron 4 for eNOS were analyzed for each patient. The polymorphisms were assessed in relation to progression-free survival (PFS), objective response rate (ORR) and overall survival (OS). Results: VEGF 936C/T, eNOS +894 G/T and VNTR were significantly correlated with outcome in CT + B patients, but not in CT-only patients. In particular, patients with a specific haplotype combination of the 2 eNOS polymorphisms (defined eNOS Haplo1/Haplo1 and eNOS Haplo 2/Haplo2) showed significantly longer PFS (15.0 vs 9.1 months, P = 0.001) and OS (34.5 vs 20.5 months P = 0.002), and a higher ORR (71 vs 45.9%, P = 0.013) than those with the other genotypes, respectively. Conclusions: Specific eNOS polymorphisms may be capable of identifying a subset of mCRC patients who are more responsive to bevacizumab-based chemotherapy. If confirmed, these results would permit individually tailored treatment with bevacizumab.

AB - Background: Bevacizumab plus chemotherapy is a widely used therapeutic option for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of bevacizumab efficacy have not yet been identified. We analyzed vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) polymorphisms in relation to response to bevacizumab. Methods: Two hundred and thirty-seven patients with mCRC enrolled onto the phase III prospective multicentre randomized "Italian Trial in Advanced Colorectal Cancer (ITACa)" trial were evaluated. One hundred fourteen patients received chemotherapy plus bevacizumab (CT + B) and 123 received chemotherapy (CT) alone. Five single nucleotide polymorphisms (SNPs) (-2578, -1498, -1154, -634 and +936) for VEGF and 2 SNPs (-786, +894) and one variable number tandem repeat in intron 4 for eNOS were analyzed for each patient. The polymorphisms were assessed in relation to progression-free survival (PFS), objective response rate (ORR) and overall survival (OS). Results: VEGF 936C/T, eNOS +894 G/T and VNTR were significantly correlated with outcome in CT + B patients, but not in CT-only patients. In particular, patients with a specific haplotype combination of the 2 eNOS polymorphisms (defined eNOS Haplo1/Haplo1 and eNOS Haplo 2/Haplo2) showed significantly longer PFS (15.0 vs 9.1 months, P = 0.001) and OS (34.5 vs 20.5 months P = 0.002), and a higher ORR (71 vs 45.9%, P = 0.013) than those with the other genotypes, respectively. Conclusions: Specific eNOS polymorphisms may be capable of identifying a subset of mCRC patients who are more responsive to bevacizumab-based chemotherapy. If confirmed, these results would permit individually tailored treatment with bevacizumab.

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KW - Bevacizumab

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KW - SNPs

KW - VEGF

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