Abstract 472: HER2 as a therapeutic target in bladder cancer
Authors: Tang Xinran , Chen Ziyu , Thomas Jasmine , Nagar Karan , Christin John , Rustgi Naryan , Gao Sizhi , Chu Carissa , De Stanchina Elisa , Berger Michael F. , Coleman Jonathan A. , Shen Michael M. , Al-Ahmadie Hikmat A. , Iyer Gopakumar V. , Kim Kwanghee , Solit David B. 
Published: April 2023

Abstract
Introduction: HER2 (encoded by the ERBB2 gene) is a member of the epidermal growth factor receptor (EGFR) family that exerts its activity through homo- or hetero-dimerization with other HER proteins. While multiple HER2-targeted therapies are FDA-approved for breast cancer, the clinical utility of targeting HER2 in bladder cancer patients remains undefined. We leveraged a prospective sequencing initiative and a new collection of patient-derived organoid (PDO) and xenograft (PDX) models to explore the prevalence of HER2 alterations in bladder cancers, its biologic role in bladder cancer pathogenesis and the potential clinical utility of HER2-targeted therapies.
Methods: To define the landscape of HER2 alterations in bladder cancer patients, we analyzed data generated by The Cancer Genome Atlas (TCGA) and patients enrolled in the prospective MSK-IMPACT sequencing cohort. To study the biology of HER2 alterations in a bladder cancer context, we generated PDO and PDX bladder cancer models, including ERBB2 amplified, ERBB2 hotspot mutated and ERBB2 wildtype models. Patient-derived models were characterized using a multiplatform approach and were used to study HER2 oncogenic dependence and sensitivity to multiple anti-HER2 targeted agents.
Results: The MSK-IMPACT assay revealed that ERBB2 alteration is common in bladder cancer, with a mutation frequency of 10.4% (breast cancer: 2.8%) and amplification frequency of 7.8% (breast cancer: 11.8%). ERBB2 alterations were more common in higher grade and stage bladder cancers. Among the HER2-altered PDOs, we identified some models with HER2 pathway dependence, similar to that observed in HER2 amplified breast cancer cell lines. However, most models had less dependence of downstream effector pathways such as AKT and ERK on HER2 signaling as compared to breast cancers. HER2-altered PDX models were significantly more sensitive to the HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) than to HER kinase inhibitor neratinib. We also observed a complete response of a HER2+ bladder cancer patient treated with T-DXd (based on PET at 7 weeks). Sensitivity to the T-DXd payload, an exatecan derivative (DXd), was found to play a key role in determining sensitivity of bladder cancer models to T-DXd.
Conclusion: Bladder cancer has higher ERBB2 mutation frequency than breast cancer, and HER2 alterations are more common in high grade and stage bladder cancers than in low-grade and non-invasive tumors, suggesting a role for HER2 in invasion and metastatic progression. The greater sensitivity of HER2 altered bladder cancer models to HER2-targeted ADC T-DXd and the complete response to T-DXd in a HER2+ bladder cancer patient provide justification for further clinical trials of HER2-targeted ADCs in bladder cancer. The sensitivity to ADC cytotoxic payload may be an important factor in determining patient response.
Citation Format: Xinran Tang, Ziyu Chen, Jasmine Thomas, Karan Nagar, John Christin, Naryan Rustgi, Sizhi Gao, Carissa Chu, Elisa De Stanchina, Michael F. Berger, Jonathan A. Coleman, Michael M. Shen, Hikmat A. Al-Ahmadie, Gopakumar V. Iyer, Kwanghee Kim, David B. Solit. HER2 as a therapeutic target in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 472.