Abstract 3188: Examining “Her2 low” patient populations for prediction to Her2-targeting antibody-drug conjugate response in Her2 negative patients using a novel high sensitivity immunohistochemistry assay
Authors: Krueger Joseph S. , Bloom Kenneth , Abe George , Okada Hisatake , Yokota Hiroyuki , Saito Naoya 
Published: September 2020

Abstract
The positive results for trastuzumab deruxtecan (DS-8201) in Her2+ breast cancer from the pivotal phase II DESTINY-Breast01 trial announced in May 2019 represents a pivotal change in approach to anti-Her2 therapy. Data from the phase 1 trial for DS-2801 has demonstrated tumor shrinkage even in patients with low Her2 expression (Her2 IHC 2+/1+) by Her2 immunohistochemistry using the Ventana HER2 (4B5) assay (Lancet Oncol. 2017 Nov;18(11):1512-1522). This is thought to be due to a strong bystander effect of deruxtecan (Int J Cancer. 2019 May 14. doi: 10.1002/ijc.32408) and a resulting enhancement of anti-tumor immunity (Mol Cancer Ther. 2018 Jul;17(7):1494-1503). Thus, prediction of patient response trastuzumab deruxtecan goes well beyond the past approaches of evaluating only Her2 over-expression or amplification, and potentially involves complex tumor and immune interactions which drive a potent response even in patients who do not have high Her2 expression.
This represents an emerging “Her2 low” strategy in drug development which seeks to use antibodies against Her2 to direct cytotoxic or immune-stimulating payloads to tumor cells which do not over-express Her2, but still retain some Her2 expression, even if considered diagnostically “Her2 negative” by the existing Her2 companion diagnostic strategies. Currently, there is no marketed approach to stratifying “Her2 low” patients for these therapies, as such an approach would require an improved method of Her2 detection or IHC interpretation strategy that allows better segmentation of patients with low Her2 expression. This demand is unlikely to be met through changing Her2 IHC interpretation, as the existing Her2 companion diagnostic strategy still remains challenging in clinical practice after nearly 15 years of improvements in scoring interpretations lead by ASCO/CAP for improved testing performance.
This study demonstrates how we can meet this challenge using a novel approach to Her2 protein detection in human formalin-fixed, paraffin embedded (FFPE) tissues, called Quanticell™. Quanticell™ relies on Konica-Minolta's Phosphor-Integrated Dot (PID) technology for ultra-sensitive, in situ detection of Her2 protein in FFPE tissues. This approach is capable of detecting Her2 expression in clinical tissues that are characterized as “Her2 negative” by current IHC approaches, facilitating the determination of a new approach to a diagnostic cutpoint to stratify patients between “her2 negative” and “Her2 low”; which is distinct from the current “Her2 high” paradigm.
Citation Format: Joseph S. Krueger, Kenneth Bloom, George Abe, Hisatake Okada, Hiroyuki Yokota, Naoya Saito. Examining “Her2 low” patient populations for prediction to Her2-targeting antibody-drug conjugate response in Her2 negative patients using a novel high sensitivity immunohistochemistry assay [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3188.