title: Polymorphisms in Genes Involved in EGFR Turnover Are Predictive for Cetuximab Efficacy in Colorectal Cancer.
abstract: Transmembrane receptors, such as the EGFR, are regulated by their turnover, which is dependent on the ubiquitin-proteasome system. We tested in two independent study cohorts whether SNPs in genes involved in EGFR turnover predict clinical outcome in cetuximab-treated metastatic colorectal cancer (mCRC) patients. The following SNPs involved in EGFR degradation were analyzed in a screening cohort of 108 patients treated with cetuximab in the chemorefractory setting: c-CBL (rs7105971; rs4938637; rs4938638; rs251837), EPS15 (rs17567; rs7308; rs1065754), NAE1 (rs363169; rs363170; rs363172), SH3KBP1 (rs7051590; rs5955820; rs1017874; rs11795873), SGIP1 (rs604737; rs6570808; rs7526812), UBE2M (rs895364; rs895374), and UBE2L3 (rs5754216). SNPs showing an association with response or survival were analyzed in BRAF and RAS wild-type samples from the FIRE-3 study. One hundred and fifty-three FOLFIRI plus cetuximab-treated patients served as validation set, and 168 patients of the FOLFIRI plus bevacizumab arm served as controls. EGFR FISH was done in 138 samples to test whether significant SNPs were associated with EGFR expression. UBE2M rs895374 was significantly associated with progression-free survival (log-rank P = 0.005; HR, 0.60) within cetuximab-treated patients. No association with bevacizumab-treated patients (n = 168) could be established (P = 0.56; HR, 0.90). rs895374 genotype did not affect EGFR FISH measurements. EGFR recycling is an interesting mechanism of secondary resistance to cetuximab in mCRC. This is the first report suggesting that germline polymorphisms in the degradation process predict efficacy of cetuximab in patients with mCRC. Genes involved in EGFR turnover may be new targets in the treatment of mCRC.
authors.affiliation: USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California. Department for Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany. sebastian.stintzing@med.uni-muenchen.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stintzing
authors.affiliation: USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department for Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany. German Cancer Consortium (DKTK); German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
authors.affiliation: Institute of Pathology, Paracelsus Medical University, Salzburger Landeskliniken (SALK), Salzburg, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.affiliation: Institute of Pathology, Paracelsus Medical University, Salzburger Landeskliniken (SALK), Salzburg, Austria. Medizinisches Versorgungszentrum für Histologie, Zytologie und Molekulare Diagnostik, Trier, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kemmerling
authors.affiliation: German Cancer Consortium (DKTK); German Cancer Research Centre (DKFZ), Heidelberg, Germany. Institute of Pathology, University of Munich, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.affiliation: Institute of Pathology, University of Munich, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jung
authors.affiliation: Department of Preventive Dentistry and Periodontology, University of Munich, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Folwaczny
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.affiliation: USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ning
authors.affiliation: USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sebio
authors.affiliation: USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stremitzer
authors.affiliation: USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sunakawa
authors.affiliation: USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsusaka
authors.affiliation: USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California. Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yamauchi
authors.affiliation: U.O. Oncologia Medica 2-Aziendo Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: U.O. Oncologia Medica 2-Aziendo Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.affiliation: U.O. Oncologia Medica 2-Aziendo Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.affiliation: USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016022:Case-Control Studies; D000068818:Cetuximab / Q000494:pharmacology* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D059748:Proteolysis; D016896:Treatment Outcome; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D044763:Ubiquitin-Conjugating Enzymes; C512478:EGFR protein, human; D066246:ErbB Receptors; C000596156:UBE2M protein, human; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin