Abstract 1086: HER2 expression in circulating tumor cells as a minimally invasive biomarker of therapeutic response to trastuzumab deruxutecan in breast cancer

Abstract Over the last decade, a variety of antibody-drug conjugates (ADCs) have entered clinical practice. The antitumor activity of some ADCs is correlated with the level of target proteins. Trastuzumab deruxutecan (T-DXd), an anti-HER2 ADC, is presently indicated for breast cancer with a wide range of HER2 expression, from ultralow to overexpresssion. However, evaluation of HER2 status in a tumor poses significant clinical challenges. First, although HER2 expression levels have been shown to change during treatment, it is not always feasible to obtain tumor samples immediately before administration of T-DXd. Second, heterogeneity of HER2 has been reported in breast cancer, both between and within tumors. Therefore, there is a need for a noninvasive method that can evaluate HER2 expression across the entire tumor, thereby ensuring that T-DXd is delivered to patients most likely to benefit from this agent. Circulating tumor cells (CTCs) can be measured by blood sampling, providing a minimally invasive approach that allows molecular information to be obtained in a timely manner and is valuable for guiding therapeutic decisions. Single-cell analysis allows for precise detection of tumor heterogeneity, offering insights into the diverse characteristics of cancer cells. We have developed a method for detecting CTCs and evaluating their HER2 expression by combining size-based CTC isolation with molecular imaging flow cytometry. In this study, we compared HER2 expression in CTCs from whole blood samples drawn from 17 patients with breast cancer who had pathological results available from biopsy tissue specimens collected within 28 days before or after blood sampling. CTC-based evaluation of HER2 expression in tissue demonstrated a sensitivity of 71% and a specificity of 33%. The positive predictive value was 83%. We also evaluated the relationship between HER2 expression in CTCs and the therapeutic effect of T-DXd in a separate cohort. CTC measurements were performed up to three times, namely, before T-DXd, one month after initiation of T-DXd, and at the time of disease progression whilst receiving T-DXd. One month after initiation of T-DXd, the number of HER2-expressing CTCs decreased in all five patients who achieved stable disease or a partial response and increased in four of five patients with progressive disease. These findings suggest that HER2 expression in CTCs may reflect that in tumors. This CTC detection method may help to address the challenges faced during treatment, such as intratumoral molecular heterogeneity and dynamic changes in molecular expression. Ultimately, this detection method could replace tissue biopsies and improve the outcomes of cancer therapy. Citation Format: Toru Mukohara, Nobuaki Matsubara, Yusuke Takahashi, Kentaro Shirai, Hiromichi Nakajima, Chikako Funasaka, Chihiro Kondoh, Kana Kawasaki, Maharjan Bishnu Devi, Fumie Kato, Hiroyuki Obinata, Taiga Ajiri, Masatoshi Yanagida, Reiko Watanabe. HER2 expression in circulating tumor cells as a minimally invasive biomarker of therapeutic response to trastuzumab deruxutecan in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1086.