International Harmonization of Provisional Diagnostic Criteria for <i>ERBB2</i>-Amplified Metastatic Colorectal Cancer Allowing for Screening by Next-Generation Sequencing Panel
Satoshi Fujii, Anthony M. Magliocco, Jihun Kim, Wataru Okamoto, Jeong Eun Kim, Kentaro Sawada, Yoshiaki Nakamura, Scott Kopetz, Woong‐Yang Park, Katsuya Tsuchihara, Tae Won Kim, Kanwal Raghav, Takayuki Yoshino
Abstract
PURPOSE ERBB2 amplification (human epidermal growth factor receptor 2 positivity [HER2 + ]) in metastatic colorectal cancer (mCRC) has important therapeutic implications that necessitate the need for accurate diagnostics. The study purpose was to establish and validate harmonized diagnostic criteria for HER2 + mCRC among 3 groups (GI-SCREEN-Japan, NCTN-SWOG-USA, and Korea). PATIENTS AND METHODS We assessed HER2 status by immunohistochemistry (IHC), ERBB2/CEP17 ratio, gene copy number (GCN) by fluorescence in situ hybridization (FISH), and copy number variation (CNV) using two targeted next-generation sequencing (NGS) panels. Tumor samples from 475 and 16 patients with mCRC in exploratory and validation cohorts, respectively, were used for cross-validation of the NGS panels. RESULTS Consensus diagnostic criteria among the 3 groups for HER2 + mCRC were established as follows: IHC 3+ or IHC 2+ and ERBB2/CEP17 ratio by FISH ≥ 2.0, tumor content > 10% for surgically resected specimens, and necessary tumor content not defined for biopsy specimens. The median GCN and CNV for HER2 + patients were 10.9 and 27.7 compared with 2.5 ( P < .0001) and 3.5 ( P < .0001), respectively, in HER2-negative patients. These findings were validated in a validation cohort (GCN, 16.2 v 2.4 [ P = .0002]; CNV, 42.5 v 2.0 [ P = .0003]). GCN correlated with CNV in both cohorts (exploratory, r = 0.90; validation, r = 0.97; P < .0001). CNV in cross-validation of the 2 NGS panels also showed a strong correlation ( r = 0.98; P < .0001). CNV in patients who fulfilled the consensus criteria was > 4.0 in all, which demonstrates the accuracy of the IHC/FISH criteria and cross-validation of NGS panels. CONCLUSION We have established and verified harmonized diagnostic criteria for HER2 + and demonstrated consistency between IHC/FISH and CNV determined by NGS in mCRC.