title: Expression levels of ROS1/ALK/c-MET and therapeutic efficacy of cetuximab plus chemotherapy in advanced biliary tract cancer.
abstract: Aberrant expression of ROS1, ALK or c-MET (RAM) is implicated in carcinogenesis and cancer drug resistance. We retrospectively evaluated the effect of RAM expression on outcomes for advanced biliary tract cancer patients, who were treated with gemcitabine plus oxaliplatin (GEMOX), with or without cetuximab, in a randomized phase II trial. RAM expression levels on archived tissue sections were scored using immunohistochemistry (IHC). Of 110 tumors with IHC staining for all three markers, 18 were RAM(high) (IHC intensity 3+ for any markers). Ninety-two tumors were RAM(low) (IHC intensity <3+ for all markers). All RAM(high) tumors were intra-hepatic cholangiocarcinomas (IHCC). Of the patients with IHCC (n = 80), median overall survival (OS) of RAM(high) group was inferior to that of the RAM(low) group (5.7 vs. 11.7 months, p = 0.021). In multivariate analysis RAM(high) remained an independently adverse prognostic factor, with a hazard ratio of 2.01 (p = 0.039). In the RAM(low) group, GEMOX treatment with cetuximab significantly improved the disease control rate (68% vs. 41%, p = 0.044), median progression-free survival (7.3 vs. 4.9 months, p = 0.026), and marginally prolonged median OS (14.1 vs 9.6 months, p = 0.056), compared to GEMOX treatment alone. Future trials of anti-EGFR inhibitors for IHCC may consider RAM expression as a patient stratification factor.
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Nai-Jung
authors.initials: NJ
authors.lastname: Chiang
authors.affiliation: Department of Oncology, National Taiwan University Hospital, and National Taiwan University Cancer Center, Taipei, Taiwan.|Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chiun
authors.initials: C
authors.lastname: Hsu
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jen-Shi
authors.initials: JS
authors.lastname: Chen
authors.affiliation: Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.|Graduate Institute of Biostatistics, College of Public Health, China Medical University, Taichung, Taiwan.
authors.forename: Hsiao-Hui
authors.initials: HH
authors.lastname: Tsou
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Shen
authors.affiliation: Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yee
authors.initials: Y
authors.lastname: Chao
authors.affiliation: Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Department of Surgery, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Yan-Shen
authors.initials: YS
authors.lastname: Shan
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Shiu-Feng
authors.initials: SF
authors.lastname: Huang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.|Institute of Clinical Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
mesh_terms: D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000068818:Cetuximab / Q000008:administration & dosage* / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D011518:Proto-Oncogene Proteins; D003841:Deoxycytidine; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000068818:Cetuximab; D000093542:Gemcitabine