title: HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer.
abstract: BACKGROUND
  Patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS benefit from epidermal growth factor receptor (EGFR)-targeted therapy. However, patients who are treated with anti-EGFR antibodies will eventually develop the resistance to those agents. HER2 amplification is one of the mechanisms conferring resistance to anti-EGFR antibody therapy and could therefore be a potential therapeutic target. The aim of this study was to detect HER2 amplification in circulating tumor DNA (ctDNA) from patients with CRC and acquired resistance to anti-EGFR antibody therapy.
  
  
  RESULTS
  Our data showed that 22% (4/18) of patients in the cohort exhibited HER2 amplification. One of these patients was found to be positive for HER2 amplification in matched tumor specimens collected after cetuximab therapy, at which point the patient had acquired cetuximab resistance, despite being negative for HER2 amplification prior to therapy.
  
  
  METHODS
  We analyzed plasma ctDNA using digital polymerase chain reaction (PCR) from 18 patients with CRC, who had been treated with anti-EGFR antibody-based therapy (cetuximab) and subsequently acquired resistant cetuximab. HER2 gene copy number was analyzed using fluorescence in situ hybridization in tumor samples before and after acquisition of resistance to cetuximab-based therapy.
  
  
  CONCLUSIONS
  Analysis of plasma ctDNA by digital PCR could be useful for detecting HER2 amplification in patients with CRC who were resistant to anti-EGFR antibody therapy.
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takegawa
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Kimio
authors.initials: K
authors.lastname: Yonesaka
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Yoshikane
authors.initials: Y
authors.lastname: Nonagase
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Pathology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Maenishi
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Tsurutani
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Taroh
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Center for Clinical and Translational Research, Kyushu University, Kyushu, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis; D000068818:Cetuximab / Q000494:pharmacology*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D004273:DNA, Neoplasm / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000068818:Cetuximab; D004273:DNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: acquired resistance; cetuximab; colorectal cancer; ctDNA; human epidermal growth factor receptor 2