title: Germline polymorphisms as biomarkers of tumor response in colorectal cancer patients treated with anti-EGFR monoclonal antibodies: a systematic review and meta-analysis.
abstract: Studies of germline polymorphisms as predictors of tumor response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody agents in metastatic colorectal cancer have reported inconsistent results. We performed a systematic review of studies from 1990 to September 2015, followed by random-effects meta-analyses for polymorphisms examined in at least three studies. Of 87 studies, 40 passed the criteria for systematic review and 23 for meta-analysis. The polymorphisms suitable for meta-analysis were CCND1 (rs17852153), COX2 (rs20417), EGF (rs4444903), EGFR (rs712829, rs11543848, 3'UTR CA repeat), FCGR2A (rs1801274), FCGR3A (rs396991), IL8 (rs4073), KRAS (rs61764370) and VEGFA (rs3025039). Meta-analysis yielded nominal significance (at α=0.05) for rs4444903 and rs11543848, but showed no significant results after multiple testing correction; this was unchanged by sensitivity analyses to address subgroups, funnel-plot asymmetries, and study quality. This highlights a tendency for lack of replication in the face of initial positive results, and possibly the unsuitability of relying on tumor response as a surrogate marker in this setting.
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Pathobiology and Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: E K
authors.initials: EK
authors.lastname: Morgen
authors.affiliation: USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: D J
authors.initials: DJ
authors.lastname: Jonker
authors.affiliation: Canadian Cancer Trials Group, Queen's University, Kingston, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Tu
authors.affiliation: Laboratoire d'Oncopharmacologie EA 3836, Centre Antoine Lacassagne, Nice, France.
authors.forename: G
authors.initials: G
authors.lastname: Milano
authors.affiliation: Division of Medical Oncology, Azienda "Ospedali Riuniti Marche Nord", Pesaro, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Graziano
authors.affiliation: Cancer Research Program, School of Public Health and Preventive Medicine, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Zalcberg
authors.affiliation: Flinders University and Flinders Medical Centre, Adelaide, South Australia, Australia.
authors.forename: C S
authors.initials: CS
authors.lastname: Karapetis
authors.affiliation: Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.|School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.|Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Dobrovic
authors.affiliation: Canadian Cancer Trials Group, Queen's University, Kingston, Ontario, Canada.
authors.forename: C J
authors.initials: CJ
authors.lastname: O'Callaghan
authors.affiliation: Departments of Medicine and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Liu
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D011110:Polymorphism, Genetic; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; C512478:EGFR protein, human; D066246:ErbB Receptors