International Harmonization of Provisional Diagnostic Criteria for <i>ERBB2</i>-Amplified Metastatic Colorectal Cancer Allowing for Screening by Next-Generation Sequencing Panel.
prospective_cohort · Level II
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- Also identified by DOI 10.1200/PO.19.00154.
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Abstract
<i>ERBB2</i> amplification (human epidermal growth factor receptor 2 positivity [HER2<sup>+</sup>]) 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<sup>+</sup> mCRC among 3 groups (GI-SCREEN-Japan, NCTN-SWOG-USA, and Korea). We assessed HER2 status by immunohistochemistry (IHC), <i>ERBB2/CEP17</i> 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. Consensus diagnostic criteria among the 3 groups for HER2<sup>+</sup> mCRC were established as follows: IHC 3+ or IHC 2+ and <i>ERBB2/CEP17</i> 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<sup>+</sup> patients were 10.9 and 27.7 compared with 2.5 (<i>P</i> < .0001) and 3.5 (<i>P</i> < .0001), respectively, in HER2-negative patients. These findings were validated in a validation cohort (GCN, 16.2 <i>v</i> 2.4 [<i>P</i> = .0002]; CNV, 42.5 <i>v</i> 2.0 [<i>P</i> = .0003]). GCN correlated with CNV in both cohorts (exploratory, <i>r</i> = 0.90; validation, <i>r</i> = 0.97; <i>P</i> < .0001). CNV in cross-validation of the 2 NGS panels also showed a strong correlation (<i>r</i> = 0.98; <i>P</i> < .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. We have established and verified harmonized diagnostic criteria for HER2<sup>+</sup> and demonstrated consistency between IHC/FISH and CNV determined by NGS in mCRC.