HER2 as a therapeutic target in bladder cancer

Background: HER2 (encoded by the ERBB2 gene) is a non-ligand-binding member of this family that exerts its activity through homo- or heterodimerization with other ERBB proteins. While multiple HER2-targeted therapies are FDA-approved for breast cancer, the clinical utility of targeting HER2 in bladder cancer patients remains undefined. Therefore, we leveraged a prospective sequencing initiative and a new collection of patient-derived organoid (PDO) and xenograft (PDX) models to explore the prevalence and biologic role of HER2 in bladder cancer pathogenesis and the potential clinical utility of HER2-targeted therapies. Material and methods: To define the landscape of HER2 alterations in bladder cancer patients, we leveraged data generated by The Cancer Genome Atlas (TCGA), and 2230 bladder cancer patients enrolled in a prospective tumor genomic profiling initiative at Memorial Sloan Kettering Cancer Center (MSK). We generated 41 PDOs that genetically and phenotypically reflect the human disease. Those proprietary models were characterized through various genomic sequencing and used to understand HER2 activation potential and sensitivity to multiple anti-HER2 targeted agents. Results: 17% of bladder cancer patients in TCGA and 16% in the prospective MSK bladder cancer cohorts had oncogenic HER2 mutations and/or gene amplification. HER2 alterations were more common in tumors of higher grade and stage, and also varied significantly as a function of histology with the highest frequency in the micropapillary subtype (37% vs 19% in UC, NOS). Analysis of 119 patients with paired primary/metastatic tumors noted discordance in 37.5% of patients with HER2 alterations. Compared to breast cancer patients, the mean ERBB2 copy number in HER2 amplified bladder cancers was significantly lower (2.69 vs 3.30, p-value = 0.004), with a lower correlation between ERBB2 linear copy number and mRNA expression. Of 41 PDX/PDO models, we identified HER2 alterations in 10. HER2 altered PDX models were significantly more sensitive to the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) than the HER kinase inhibitor neratinib. Neratinib resistance was associated with lacking AKT dependence on upstream HER2 activation. Conclusion: In sum, HER2 mutations/amplification in bladder cancer are associated with higher grade and stage and enriched in patients with micropapillary histology. In addition, we observed frequent discordance in HER2 status between primary/metastatic pairs and a lower correlation between HER2 expression and gene copy number versus breast cancers. Preclinical evaluation of HER2 altered PDO/PDXs indicated significantly greater sensitivity to the HER2-directed ADC T-DXd compared to the HER kinase inhibitor neratinib, which provided justification for clinical trials of HER2 ADCs in bladder cancer patients. Conflict of interest: Advisory Board: D.B.S. has served as a consultant for/received honorarium from Pfizer, Loxo/Lilly Oncology, Vividion Therapeutics, Scorpion Therapeutics, Fore Therapeutics and BridgeBio. H.A.A provided consultation to AstraZeneca, Janssen Biotech, Bristol-Myers-Squibb and Paige.ai. M.B. has served as a consultant for Eli Lilly and PetDx.