title: EGFR gene copy number predicts response to anti-EGFR treatment in RAS wild type and RAS/BRAF/PIK3CA wild type metastatic colorectal cancer.
abstract: Anti-EGFR antibodies are used for the treatment of RAS wild type metastatic colorectal cancer. We previously showed that EGFR gene copy number (GCN) predicts response to anti-EGFR therapy in KRAS exon 2 wild type metastatic colorectal cancer. The aim of our study was to analyse the predictive role of EGFR GCN in RAS/BRAF/PIK3CA wild type metastatic colorectal cancer. The material included 102 patients with KRAS exon 2 wild type metastatic colorectal cancer treated with anti-EGFR ± cytotoxic therapy. Next generation sequencing was used for KRAS, NRAS, BRAF and PIK3CA gene mutation analyses. EGFR GCN was analysed by EGFR immunohistochemistry guided automated silver in situ hybridisation. Increased EGFR GCN (≥4.0) predicted a better response and prolonged progression free survival in anti-EGFR treated RAS/BRAF/PIK3CA wild type patients (Log-rank test, p = 0.0004). In contrast, survival of RAS/BRAF/PIK3CA wild type, EGFR GCN below 4.0 patients did not differ from patients with mutant RAS, BRAF or PIK3CA. Our study indicates that EGFR GCN predicts anti-EGFR treatment efficacy in patients with RAS/BRAF/PIK3CA wt metastatic CRC. Tumours with EGFR GCN below 4.0 appear to be as refractory to anti-EGFR treatment as tumours with mutation in any of the RAS/RAF/PIK3CA pathway genes.
authors.affiliation: Department of Oncology, Turku University Hospital, Hämeentie 11, Turku, 20521, Finland.|MediCity Research Laboratory, University of Turku, Tykistökatu 6 A, Turku, 20520, Finland.
authors.forename: Annika
authors.initials: A
authors.lastname: Ålgars
authors.affiliation: Department of Pathology, University of Turku, Kiinamyllynkatu 10, Turku, 20520, Finland.|Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, Turku, 20520, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Sundström
authors.affiliation: Department of Pathology, University of Turku, Kiinamyllynkatu 10, Turku, 20520, Finland.|Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, Turku, 20520, Finland.
authors.forename: Minnamaija
authors.initials: M
authors.lastname: Lintunen
authors.affiliation: MediCity Research Laboratory, University of Turku, Tykistökatu 6 A, Turku, 20520, Finland.|Department of Pathology, University of Turku, Kiinamyllynkatu 10, Turku, 20520, Finland.|Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, Turku, 20520, Finland.
authors.forename: Terhi
authors.initials: T
authors.lastname: Jokilehto
authors.affiliation: HUSLAB, Division of Pathology and Genetics, Helsinki University Hospital, Topeliuksenkatu 32, Helsinki, 00029 HUS, Finland.
authors.forename: Soili
authors.initials: S
authors.lastname: Kytölä
authors.affiliation: HUSLAB, Division of Pathology and Genetics, Helsinki University Hospital, Topeliuksenkatu 32, Helsinki, 00029 HUS, Finland.
authors.forename: Milja
authors.initials: M
authors.lastname: Kaare
authors.affiliation: HUSLAB, Division of Pathology and Genetics, Helsinki University Hospital, Topeliuksenkatu 32, Helsinki, 00029 HUS, Finland.
authors.forename: Reetta
authors.initials: R
authors.lastname: Vainionpää
authors.affiliation: HUSLAB, Division of Pathology and Genetics, Helsinki University Hospital, Topeliuksenkatu 32, Helsinki, 00029 HUS, Finland.
authors.forename: Arto
authors.initials: A
authors.lastname: Orpana
authors.affiliation: Department of Oncology, Helsinki University Hospital, Haartmaninkatu 4, P.O. Box 180, Helsinki, 00290, Finland.|Clinicum/Oncology, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, Helsinki, 00014, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Österlund
authors.affiliation: Pathology, Research Programs Unit and HUSLAB, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, P.O. Box 21, Helsinki, 00014, Finland.
authors.forename: Ari
authors.initials: A
authors.lastname: Ristimäki
authors.affiliation: Department of Pathology, University of Turku, Kiinamyllynkatu 10, Turku, 20520, Finland.|Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, Turku, 20520, Finland.|Pathology, Research Programs Unit and HUSLAB, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, P.O. Box 21, Helsinki, 00014, Finland.|Auria Biobank, University of Turku and Turku University Hospital, Kiinamyllynkatu 8, Turku, 20521, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Carpen
authors.affiliation: Department of Oncology, Turku University Hospital, Hämeentie 11, Turku, 20521, Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Ristamäki
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D018628:Gene Dosage; D011905:Genes, ras; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D000077544:Panitumumab; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D047428:Protein Kinase Inhibitors; D000077544:Panitumumab; D000077146:Irinotecan; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000068818:Cetuximab; D005472:Fluorouracil; D002166:Camptothecin
keywords: BRAF-; EGFR gene copy number; PIK3CA mutations; RAS-; anti-EGFR treatment; metastatic colorectal cancer