National Cancer Center, EPOC, Chiba, Japan
Satoshi Fujii , Anthony Martin Magliocco , Emanuele Valtorta , Jihun Kim , Wataru Okamoto , Jeong Eun Kim , Kentaro Sawada , Yoshiaki Nakamura , Valter Torri , Scott Kopetz , Woong Yang Park , Katsuya Tsuchihara , Tae Won Kim , Kanwal Pratap Singh Raghav , Salvatore Siena , Takayuki Yoshino
Background: HER2 amplification (HER2+) in metastatic colorectal cancer (mCRC) is associated with resistance to anti-EGFR antibodies and response to HER2 targeted therapies. This study assessed the diagnostic criteria on HER2+ mCRC among four groups (GI-SCREEN-Japan, SWOG-USA, HERACLES-Italy, and Korea) and harmonized the criteria for patient enrollment in clinical trials that target these patients (pts). Methods: Samples from 475 and 16 pts with mCRC were used in exploratory and validation cohorts, respectively. We assessed HER2 status by immunohistochemistry (IHC) and HER2/CEP17 ratio and gene copy number (GCN) by fluorescence in situ hybridization (FISH) and copy number variations (CNV) by targeted next-generation sequencing (NGS) panel. OCA by ThemoFisher and AMC v3 by illumina were used in exploratory and validation cohorts, respectively for the cross-validation of NGS panels. Results: The consensus diagnostic criteria for HER2+ mCRC was reached; IHC 3+ or IHC 2+ and HER2/CEP17 ratio by FISH ≥ 2.0, and tumor content > 10% for surgically resected specimens (separate quantity criteria were established for biopsy specimens). The median GCN and CNV for pts who met consensus criteria for HER2+ was 10.9 and 27.7 compared to 2.5 (P< 0.0001) and 3.5 (P< 0.0001), respectively in pts who were HER2-. These findings were validated in validation cohort (GCN: 16.2 v 2.4, P= 0.0002; CNV: 42.5 v 2.0, P= 0.0003). GCN also showed strong correlation with CNV in both cohorts (r: exploratory: 0.90, validation: 0.97; P< 0.0001). CNV in cross validation of OCA and AMC v3 also showed strong correlation (r: 0.97, P< 0.0001). The CNV for pts fulfilling the consensus criteria was more than 4.0 in the two cohorts. The accuracy of the IHC/FISH criteria was validated for mCRC pts, providing cross-validation of NGS panels. Conclusions: We were able to verify the HER2 classification consistency between CNV by NGS and IHC/FISH by harmonizing diagnostic criteria for HER2+. This strategy can help establish diagnostic criteria for HER2+ cancer by allowing for different methodologies to be used for pts screening for trial eligibility.
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