Genes involved in pericyte-driven tumor maturation predict treatment benefit of first-line FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer

N. B. Volz, S. Stintzing, W. Zhang, D. Yang, Y. Ning, T. Wakatsuki, R. E. El-Khoueiry, J. E. Li, Adel Kardosh, F. Loupakis, C. Cremolini, A. Falcone, S. J. Scherer, H. J. Lenz

Research output: Contribution to journalArticle

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Abstract

Pericytes are crucial for angiogenesis. The impact of pericyte function to bevacizumab efficacy in mCRC treatment has not been comprehensively examined. This retrospective study investigated germline polymorphisms in genes related to early pericyte maturation to predict bevacizumab efficacy in 424 patients of two clinical trials treated first line with FOLFIRI+bevacizumab. Eight single-nucleotide polymorphisms (SNPs) were tested for potential biomarker value: RGS5 (regulator of G-protein signaling 5; rs1056515, rs2661280), PDGFR-β (platelet-derived growth factor receptor-β; rs2229562, rs2302273), CSPG4 (chondroitin sulfate proteoglycan NG2; rs8023621, rs1127648) and RALBP1 (RalA binding protein 1; rs10989, rs329007). For progression-free survival (PFS), PDGFR-β (rs2302273) was able to define significantly different patient cohorts in uni- and multivariate testing. RALPB1 (rs329007) showed predictive value for tumor response. The C allele in RGS5 (rs2661280) predicted longer overall survival and CSPG4 rs1127648 was associated with differences in PFS, but for both value was lost when multivariate analysis was applied. A comprehensive statistical analysis revealed that the biomarker value of the SNPs was dependent on primary tumor location. This is the first study to identify pericyte germline polymorphisms associated with clinical outcome in mCRC patients treated first line with FOLFIRI+bevacizumab. The differences seen with regard to primary tumor location may lead to further research to understand the clinical outcome differences seen in right- and left-sided colon cancer.

Original languageEnglish (US)
Pages (from-to)69-76
Number of pages8
JournalPharmacogenomics Journal
Volume15
Issue number1
DOIs
StatePublished - Feb 28 2015
Externally publishedYes

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Pericytes
Colorectal Neoplasms
Genes
Disease-Free Survival
Single Nucleotide Polymorphism
Neoplasms
Biomarkers
GTP-Binding Protein Regulators
Chondroitin Sulfate Proteoglycans
Platelet-Derived Growth Factor Receptors
Therapeutics
Colonic Neoplasms
Carrier Proteins
Multivariate Analysis
Retrospective Studies
Alleles
Clinical Trials
Survival
Bevacizumab
Research

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Genes involved in pericyte-driven tumor maturation predict treatment benefit of first-line FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer. / Volz, N. B.; Stintzing, S.; Zhang, W.; Yang, D.; Ning, Y.; Wakatsuki, T.; El-Khoueiry, R. E.; Li, J. E.; Kardosh, Adel; Loupakis, F.; Cremolini, C.; Falcone, A.; Scherer, S. J.; Lenz, H. J.

In: Pharmacogenomics Journal, Vol. 15, No. 1, 28.02.2015, p. 69-76.

Research output: Contribution to journalArticle

Volz, NB, Stintzing, S, Zhang, W, Yang, D, Ning, Y, Wakatsuki, T, El-Khoueiry, RE, Li, JE, Kardosh, A, Loupakis, F, Cremolini, C, Falcone, A, Scherer, SJ & Lenz, HJ 2015, 'Genes involved in pericyte-driven tumor maturation predict treatment benefit of first-line FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer', Pharmacogenomics Journal, vol. 15, no. 1, pp. 69-76. https://doi.org/10.1038/tpj.2014.40
Volz, N. B. ; Stintzing, S. ; Zhang, W. ; Yang, D. ; Ning, Y. ; Wakatsuki, T. ; El-Khoueiry, R. E. ; Li, J. E. ; Kardosh, Adel ; Loupakis, F. ; Cremolini, C. ; Falcone, A. ; Scherer, S. J. ; Lenz, H. J. / Genes involved in pericyte-driven tumor maturation predict treatment benefit of first-line FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer. In: Pharmacogenomics Journal. 2015 ; Vol. 15, No. 1. pp. 69-76.
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abstract = "Pericytes are crucial for angiogenesis. The impact of pericyte function to bevacizumab efficacy in mCRC treatment has not been comprehensively examined. This retrospective study investigated germline polymorphisms in genes related to early pericyte maturation to predict bevacizumab efficacy in 424 patients of two clinical trials treated first line with FOLFIRI+bevacizumab. Eight single-nucleotide polymorphisms (SNPs) were tested for potential biomarker value: RGS5 (regulator of G-protein signaling 5; rs1056515, rs2661280), PDGFR-β (platelet-derived growth factor receptor-β; rs2229562, rs2302273), CSPG4 (chondroitin sulfate proteoglycan NG2; rs8023621, rs1127648) and RALBP1 (RalA binding protein 1; rs10989, rs329007). For progression-free survival (PFS), PDGFR-β (rs2302273) was able to define significantly different patient cohorts in uni- and multivariate testing. RALPB1 (rs329007) showed predictive value for tumor response. The C allele in RGS5 (rs2661280) predicted longer overall survival and CSPG4 rs1127648 was associated with differences in PFS, but for both value was lost when multivariate analysis was applied. A comprehensive statistical analysis revealed that the biomarker value of the SNPs was dependent on primary tumor location. This is the first study to identify pericyte germline polymorphisms associated with clinical outcome in mCRC patients treated first line with FOLFIRI+bevacizumab. The differences seen with regard to primary tumor location may lead to further research to understand the clinical outcome differences seen in right- and left-sided colon cancer.",
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