Abstract HER2-18: HER2-18 Determination of HER2-low status in tumors of patients with unresectable and/or metastatic breast cancer in DESTINY-Breast04
Authors: Prat Aleix , Modi Shanu , Tsurutani Junji , Cameron David , Harbeck Nadia , Garrido Charo , Karnoub Maha , Hsu Ching , Feng Wenquin , Yung Lotus , Wang Yibin , Gambhire Dhiraj , Ford Shirin K. , Vitazka Patrik , Ueno Naoto T. 
Published: March 2023

Abstract
Background In DESTINY-Breast04, the HER2-targeted antibody drug conjugate trastuzumab deruxtecan (T-DXd) demonstrated significant survival benefit vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable or metastatic breast cancer (mBC) (Modi et al. N Engl J Med 2022). These results emphasize the importance of accurately identifying HER2 expression in breast tumor tissue. Here, we describe concordance between previously determined (historical) HER2 scores and central HER2 scores, and tumor sample characteristics for pts with mBC screened and enrolled in DESTINY-Breast04. Methods DESTINY-Breast04 was a randomized, open-label, phase 3 study in pts with centrally determined HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+ with negative in situ hybridization [ISH]) mBC who had previously received 1-2 lines of chemotherapy. Pts were randomized 2:1 to T-DXd or TPC. HER2 scores were determined via central testing of tumor specimens by the investigational Ventana PATHWAY 4B5 IHC assay, using the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) testing guidelines HER2 scoring algorithm, and Ventana INFORM HER2 dual ISH assay (as applicable). Results 1340 pts identified as having HER2-low mBC per historical data submitted tumor samples for central HER2-low testing. Of those, 557 pts met all eligibility criteria and were enrolled in DESTINY-Breast04. The proportion of samples from metastatic vs primary tumors was 59% vs 41% for all submitted tumor samples and 65% vs 35% for enrolled patients. Of those with available data, most were biopsy specimens (995 [74%] vs 344 [26%] resection/excisions) and were submitted as archived formalin-fixed, paraffin-embedded tissue (1183 [88%] vs 157 [12%] freshly collected samples); historical testing dates ranged from 2000-2020. Of samples with data on the historical HER2 IHC test used (31%), most were scored using local Ventana 4B5 (63%) or Agilent HercepTest (32%) assays. Tumor distribution characteristics were similar between screened and enrolled pts. For samples with historical and central HER2 results (N = 1108), 849/1108 (77%) were centrally scored as HER2-low. Of the samples that were not centrally scored as HER2-low, 88% were scored as HER2 IHC 0. Historical and central HER2 score concordance was assessed by sample region of origin (North America, Europe, China, or Asia without China) and collection date (2013 or earlier, 2104-2018, or 2019 or after) and scoring agreement was associated with these factors. Efficacy of T-DXd vs TPC for pts in DESTINY-Breast04 was consistent across all tumor sample characteristics (primary vs metastatic, specimen type, archival vs fresh, and tissue collection date). Conclusions Despite the lack of prior clinical utility and training in distinguishing HER2 IHC 0 from HER2-low (IHC 1+, 2+/ISH–), evolving guidelines since historical HER2 status provision, differences in local testing methods, and differences in key sample characteristics (primary vs metastatic; archived vs fresh; widely variable sample biopsy and testing dates), there was a 77% agreement between historical and central HER2-low status using the Ventana PATHWAY 4B5 IHC assay and Ventana INFORM HER2 Dual ISH assay. This rate is comparable to the reported initial concordance rates for HER2 overexpression IHC testing (range 74-82%; Roche J. Natl Cancer Inst 2002, Perez. J Clin Oncol 2006). Moreover, consistent benefit of T-DXd vs TPC was generally seen across patient groups with various tumor sample characteristics in DESTINY-Breast04. Determination of HER2-low status using the Ventana PATHWAY 4B5 IHC assay (and ISH when applicable) demonstrated the ability of the test, analyzed by pathologists using current ASCO/CAP guidelines, to identify pts who benefit from T-DXd. Funding This study was funded by Daiichi Sankyo and AstraZeneca.
Citation Format: Aleix Prat, Shanu Modi, Junji Tsurutani, David Cameron, Nadia Harbeck, Charo Garrido, Maha Karnoub, Ching Hsu, Wenquin Feng, Lotus Yung, Yibin Wang, Dhiraj Gambhire, Shirin K. Ford, Patrik Vitazka, Naoto T. Ueno. HER2-18 Determination of HER2-low status in tumors of patients with unresectable and/or metastatic breast cancer in DESTINY-Breast04 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr HER2-18.