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

The Pharmacogenomics Journal volume 15, pages 69–76 (2015)Cite this article

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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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Acknowledgements

This study was supported by the NIH Grant 5 P30CA14089-27S1 and Nancy Bernstein Call to Cure Foundation. SS is granted a postdoctoral fellowship by the German Cancer Aid (Mildred-Scheel-Foundation).

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Author notes

  1. N B Volz and S Stintzing: These authors contributed equally to this work.

Authors and Affiliations

  1. USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboratory, Los Angeles, CA, USA

    N B Volz, S Stintzing, W Zhang, Y Ning, T Wakatsuki, R E El-Khoueiry, J E Li, A Kardosh & H-J Lenz

  2. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    D Yang & H-J Lenz

  3. Department of Gastroenterology Center, Cancer Institute Hospital, Tokyo, Japan

    T Wakatsuki

  4. UO Oncologia Medica 2 – Aziendo Ospedaliero-Universitaria Pisana, Pisa, Italy

    F Loupakis, C Cremolini & A Falcone

  5. University of Wuerzburg, Biocenter Physiological Chemistry, Wuerzburg, Germany

    S J Scherer

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  1. N B Volz
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Correspondence to H-J Lenz.

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Volz, N., Stintzing, S., Zhang, W. et al. Genes involved in pericyte-driven tumor maturation predict treatment benefit of first-line FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer. Pharmacogenomics J 15, 69–76 (2015). https://doi.org/10.1038/tpj.2014.40

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