title: HER2 Amplification and Cetuximab Efficacy in Patients With Metastatic Colorectal Cancer Harboring Wild-type RAS and BRAF.
abstract: Cetuximab has shown clinical benefit in patients with metastatic colorectal cancer (mCRC) harboring wild-type RAS. Human epidermal growth factor receptor 2 (HER2) amplification may be a mechanism of cetuximab resistance. We evaluated the association between HER2 amplification and cetuximab efficacy in patients with mCRC harboring wild-type RAS and BRAF.
  
  
  
  Between December 2003 and June 2013, we identified 142 patients with mCRC whose tumors harbored both wild-type exons 2, 3, and 4 in KRAS and NRAS, and wild-type exon 15 in BRAF using high throughput sequencing (OncoMap version 4.0). All patients received cetuximab after oxaliplatin, irinotecan, and fluoropyrimidine failure. HER2 status was determined using immunohistochemistry and silver in situ hybridization (SISH) and correlated with cetuximab efficacy.
  
  
  
  Of 142 RAS and BRAF wild-type tumors, we observed 7 cases (4.9%) of HER2 amplification by SISH. After a median follow-up of 13.2 months (range, 1.4-78.1 months), median progression-free survival (PFS) was significantly different according to HER2 status: 3.1 months in patients with HER2 amplification compared with 5.6 months in those with non-amplified HER2 (hazard ratio, 2.73; 95% confidence interval, 1.18-6.31; P = .019). Overall survival (OS) was not significantly different between groups, although there was a tendency towards shorter OS in patients with HER2-amplified tumors (hazard ratio, 1.31; 95% confidence interval, 0.61-2.82; 10.1 vs. 13.5 months; P = .488).
  
  
  
  HER2 amplification is predictive of shorter PFS after cetuximab treatment in patients with mCRC harboring wild-type RAS and BRAF. Further study is warranted for this patient population.
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jihun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Hong
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Dalyong
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Kyu-Pyo
authors.initials: KP
authors.lastname: Kim
authors.affiliation: Clinical Research Center, Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Young-Kwang
authors.initials: YK
authors.lastname: Yoon
authors.affiliation: Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Deokhoon
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Chun
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Yangsoon
authors.initials: Y
authors.lastname: Park
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Jang
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: twkimmd@amc.seoul.kr.
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D000068818:Cetuximab / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D000074322:Antineoplastic Agents, Immunological; D000068818:Cetuximab; D048493:Proto-Oncogene Proteins B-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; D018631:ras Proteins; C508053:ERBB2 protein, human; C482119:BRAF protein, human
keywords: Chemotherapy; HER2 copy-number; Resistant; Survival; Target agent