HER2-directed therapy in metastatic vulvar empd—a report of two cases and narrative review

Background: Extramammary Paget's disease (EMPD) is a rare malignancy of the skin arising in apocrine gland-rich areas, most commonly the vulva, scrotum, and perianal region. Often misdiagnosed due to resemblance to benign dermatologic conditions, EMPD presents diagnostic and therapeutic challenges. While localized disease usually has a favorable prognosis after surgery, metastatic EMPD is rare, with poor outcomes and limited options. Recent molecular profiling has identified human epidermal growth factor receptor 2 (HER2) overexpression as a potential therapeutic target. We present a clinical series of HER2-positive EMPD treated with targeted therapies and review the literature to assess their role in disease control and outcomes. Case Description: We report two cases of metastatic HER2-amplified vulvar EMPD treated with HER2-directed agents, including trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (T-DXd), and integrate our findings into a narrative review of reported cases. Both patients achieved clinical benefit from HER2-targeted therapy with disease control across sequential regimens. Conclusions: We describe one of the first documented real-world cases of vulvar EMPD treated with T-DXd, showing a meaningful clinical response. HER2-positive metastatic vulvar EMPD may respond to targeted therapy, and T-DXd appears promising for disease control. Molecular HER2 testing should be incorporated into the diagnostic workup to guide therapy selection in this rare malignancy.