title: Single nucleotide polymorphisms in the IGF-IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE-3 trial.
abstract: The Insulin-like growth factor (IGF)/IGF-receptor pathway with its scaffolding proteins Insulin Receptor Substrate (IRS)1 and IRS2 are crucial regulators of metabolism and progression in metastatic colorectal cancer (mCRC). The goal of the study was the identification of predictive and prognostic markers among IRS1, IRS2, IGF1 and IGF-1R SNPs in mCRC patients enrolled in the FIRE-3 trial. Four SNPs of IRS (IRS1 rs1801278, rs1801123; IRS2 rs1805097, rs2289046) and four SNPs of IGF1-IGFR1 (rs6214, rs6220, rs2946834, rs2016347) were analyzed by PCR/direct-sequencing in the FIRE-3 trial. The relation of SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test in the overall population and in subgroup according to RAS status and treatment arm. In the overall population IRS1 rs1801123 C/- carriers (N= 105) achieved significantly worse OS compared to T/T (N = 464) in univariate (HR = 1.32 [95%CI 1.03-1.70], p = 0.029) and in multivariable. Similar results were observed among RAS wild type. Patients with IGF1 rs2946834 T/- variant (N= 280) achieved improved PFS compared to C/C (N = 257) in univariate (HR = 0.77 [95%CI 0.64-0.92], p = 0.004) and in multivariable. In the RAS wild-type subgroup IGF1 rs2946834 T/- carriers showed better PFS and OS compared to C/C (univariate HR for PFS = 0.65 [95%CI 0.51-0.81], p < 0.001; multivariable HR for PFS = 0.63 [95%CI 0.50-0.81], p < 0.001). IRS1 rs1801123 SNP was identified as a new prognostic marker for mCRC. IGF1 rs2946834 was confirmed as prognostic factor in the overall population and in RAS wild type patients. Our findings underline the importance of IGF downstream signaling pathway in RAS wild-type mCRC patient.
authors.affiliation: Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
authors.forename: Marta
authors.identifier: 0000-0001-8316-4411
authors.initials: M
authors.lastname: Schirripa
authors.affiliation: Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Shu
authors.initials: S
authors.lastname: Cao
authors.affiliation: Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okazaki
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.affiliation: Oncologia Medica 1, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy.
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Berger
authors.affiliation: Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ning
authors.affiliation: Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
authors.forename: Mitsukuni
authors.initials: M
authors.lastname: Suenaga
authors.affiliation: Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
authors.forename: Roel F
authors.initials: RF
authors.lastname: Gopez
authors.affiliation: Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: West
authors.affiliation: Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
authors.forename: Diana
authors.initials: D
authors.lastname: Hanna
authors.affiliation: Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Barzi
authors.affiliation: Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.affiliation: Department of Medical Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stintzing
authors.affiliation: Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068818:Cetuximab / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013002:Somatomedins / Q000235:genetics*; D016019:Survival Analysis
chemical_list: D055504:Insulin Receptor Substrate Proteins; D013002:Somatomedins; D000068258:Bevacizumab; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: IGF; IRS; RAS; SNP; metastatic colorectal cancer