HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer

Abstract

// Naoki Takegawa 1 , Kimio Yonesaka 1 , Kazuko Sakai 2 , Hiroto Ueda 1 , Satomi Watanabe 1 , Yoshikane Nonagase 1 , Tatsuya Okuno 1 , Masayuki Takeda 1 , Osamu Maenishi 3 , Junji Tsurutani 1 , Taroh Satoh 4 , Isamu Okamoto 5 , Kazuto Nishio 2 , Takao Tamura 1 , and Kazuhiko Nakagawa 1 1 Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan 2 Department of Genome Biology, Kinki University School of Medicine, Osaka, Japan 3 Department of Pathology, Kinki University School of Medicine, Osaka, Japan 4 Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, Japan 5 Center for Clinical and Translational Research, Kyushu University, Kyushu, Japan Correspondence to: Kimio Yonesaka, e-mail: yonesaka@sakai.med.kindai.ac.jp Keywords: colorectal cancer, cetuximab, acquired resistance, human epidermal growth factor receptor 2, ctDNA Received: August 21, 2015      Accepted: November 21, 2015      Published: December 02, 2015 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. Conclusion: 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.