Case Report: Case studies evaluating anti-HER2 therapy as a tumor-agnostic strategy in rare malignancies

Despite the success of HER2-targeted antibody-drug conjugates (ADCs) in common cancers, there is a lack of real-world evidence regarding their role in rare tumors where ERBB2 gene amplification by next-generation sequencing (NGS) may serve as a more precise driver than traditional protein expression. In this retrospective case series at Bumrungrad International Hospital, we describe three patients with ERBB2-amplified rare tumors-periampullary carcinoma (immunohistochemistry [IHC] 2+, 77 copies by NGS), salivary duct carcinoma (IHC 3+, 33.7 copies), and poorly differentiated carcinoma (IHC 1+, 16.8 copies)-treated with trastuzumab emtansine (T-DM1) and/or trastuzumab deruxtecan (T-DXd). Despite heterogeneous histology and low-to-equivocal IHC scores, all achieved meaningful objective responses: a 301-day partial remission, a complete intracranial and systemic response using sequential ADC therapy (T-DXd followed by T-DM1 after toxicity), and a near-complete response in an IHC 1+ (HER2-low) tumor. These results demonstrate that high-level gene amplification can predict ADC efficacy regardless of IHC status or rare histology. Our findings underscore the value of integrating NGS into diagnostic workflows at the point of care to identify 'hidden' responders and support the feasibility of ADC sequencing in the management of treatment-limiting toxicities.