Abstract 1588: Discordance of HER2 expression and/or amplification on repeat testing
Authors: DiPeri Timothy D. , Kong Kathleen , Karp Daniel D. , Ajani Jaffer A. , Pant Shubham , Piha-Payl Sarina A. , Dumbrava Ecaterina E. , Meric-Bernstam Funda 
Published: June 2022

Abstract
Purpose: Evaluation of human epidermal growth factor receptor 2 (HER2) expression/amplification status is critical when considering HER2-targeted therapies. We sought to assess discordance of HER2 status in patients with HER2-amplified/expressing solid tumors who underwent a repeat biopsy for pre-trial screening.
Methods: Consenting patients with solid tumors and documented HER2 expression by immunohistochemistry (IHC) or amplification by fluorescent in situ hybridization/next generation sequencing (FISH/NGS) on historical local testing underwent a new biopsy for central reevaluation of HER2 status. Samples were assessed for HER2 expression by IHC and ERBB2 amplification by FISH. Specimens were reviewed by a central laboratory. Patients with HER2 overexpression by IHC (3+) or ERBB2 amplification by FISH/NGS on local testing were assessed for HER2 discordance on central testing (not amplified by FISH and/or not 3+ by IHC on central reevaluation).
Results: 56 patients with HER2 expression/amplification on local testing with a median age of 59.5 years and 30 (53.6%) females underwent biopsy and repeat HER2 testing. Median time between consent and treatment for those enrolled was 26 days (range 8-83 days). Twelve cancers were represented, including 12 breast (21.4%), 6 gastroesophageal (10.7%), and 6 biliary tract (10.7%). 31 patients (55.4%) received HER2-targeted therapies between local and central testing. Local assessment of HER2 status on archival tissue was performed in 36 (64.3%) patients by IHC, 27 (48.2%) by FISH, and 18 (32.1%) by NGS. There were 23 patients who were IHC 3+ on local testing and of these, 15 (65.2%) were 3+, 4 (17.4%) were 2+ (3 FISH +), 2 (8.7%) were 1+ (FISH-), and 2 (8.7%) had 0 HER2 expression on central IHC. Of 4 patients that were 2+ without amplification on local testing, 3 were 2+ and 1 was 1+ on central IHC. In 18 patients with ERBB2 amplification on local NGS, 14 (77.8%) were 3+ on central IHC and 17 (94.4%) were ERBB2 amplified by FISH. Of the 51 patients who were 3+ by IHC or amplified by FISH/NGS on local testing, 14 (27.5%) were discordant on central reevaluation. Discordance in HER2 status was found in 5/12 (41.7%) gastroesophageal, 2/9 (22.2%) breast, and 1/7 (14.3%) colorectal tumors. Discordant HER2 status was observed in 9 (30.0%) of 30 cases who received intervening HER2-targeted therapy and in 5 (23.8%) of 21 patients who did not. Of 14 patients with HER2 discordance, 7 were potentially eligible for trial enrollment based on local testing but ineligible based on central HER2 testing.
Conclusions: Discordance in HER2 status on repeat biopsy is not infrequent in patients with tumors previously identified as HER2-positive/expressing. Discordance is not limited to patients with prior HER2-targeted therapy and could have therapeutic implications. Biomarker reevaluation may be warranted when considering HER2-targeted therapies but needs to be balanced with a slight delay in treatment initiation.
Citation Format: Timothy D. DiPeri, Kathleen Kong, Daniel D. Karp, Jaffer A. Ajani, Shubham Pant, Sarina A. Piha-Payl, Ecaterina E. Dumbrava, Funda Meric-Bernstam. Discordance of HER2 expression and/or amplification on repeat testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1588.