Abstract Background: Antibody-drug conjugates (ADC) are increasingly utilized to treat a variety of solid tumor and hematologic malignancies. Fam-trastuzumab deruxtecan-nxki (T-DXd) is an ADC that combines the anti-HER2 monoclonal antibody, trastuzumab, to a highly potent topoisomerase I inhibitor payload. It is indicated in the treatment of metastatic HER2-positive and HER2-low and ultralow breast cancer. While veno-occlusive disease (VOD) is commonly described in patients with hematologic malignancies, it is rarely seen in patients with solid tumors but has been documented with other ADCs. We present a rare case of VOD that occurred in a patient with breast cancer receiving T-DXd. Case Presentation: A 45-year-old female with triple-negative breast cancer developed a rapid metastatic recurrence following neoadjuvant chemo-immunotherapy, then rapid progression while on first-line sacituzumab govitecan. Given the tumor was HER2-low (IHC 2+, FISH negative), she received second-line T-DXd. After cycle 4 of T-DXd, she developed rapid elevations of total and direct bilirubin as well as transaminases. Abdominal imaging was negative for progression in the liver. Due to further elevations in bilirubin, a liver biopsy was conducted and revealed venous outflow obstruction consistent with VOD. Defibrotide was considered for treatment, however the patient ultimately pursued hospice care. Discussion: VOD results from damage to the small blood vessels in the liver, leading to obstruction of blood flow, volume overload, and potentially liver failure. It can rapidly progress to multiorgan failure if untreated. VOD presents with tender hepatomegaly, rapid weight gain, ascites, and jaundice, often accompanied by elevations in total and direct bilirubin, as well as transaminases. VOD occurs most commonly after hematopoietic stem cell transplantation, and more rarely can occur secondary to treatment with ADCs. The two most implicated ADCs are gemtuzumab ozogamicin and inotuzumab ozogamicin, utilized in hematologic malignancies. Management of VOD includes defibrotide, a thrombolytic agent that stabilizes the endothelium. On review of the literature, there are reports of VOD occurring after treatment with trastuzumab emtansine, another ADC used in breast cancer. However, to our knowledge, there are no reports of VOD occurring after treatment with T-DXd in breast cancer patients. The most commonly reported adverse effects of T-DXd include edema, cytopenias, GI upset, peripheral neuropathy, alopecia, and elevated liver function tests. Rarely, T-DXd can cause decreased ventricular function, pneumonitis, and febrile neutropenia. Our patient received prior chemotherapy in the neoadjuvant and adjuvant setting, which is a well-described risk factor in the development of VOD. VOD is likely underrecognized in the breast cancer population given overlapping symptoms with the metastatic disease itself, such as elevations in serum liver function tests, ascites, jaundice, pain, and weight fluctuations. There is limited data regarding the optimal management and prognosis of patients with breast cancer who develop VOD after treatment with an ADC. Conclusion: We present a rare case of VOD after receipt of T-DXd in a heavily pretreated patient with metastatic breast cancer. Citation Format: K. N. Koehler, K. Noce, S. Kelly, G. Bader, M. Cherian, A. Davenport, K. C. Johnson, N. Lopetegui-Lia, A. Roy, D. Quiroga, S. Sardesai, D. Stover, R. Wesolowski, N. Williams, S. Vasu, M. E. Gatti-Mays. A case report of veno-occlusive disease (VOD) in a patient with metastatic triple-negative breast cancer receiving trastuzumab deruxtecan abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-06-07.
Koehler et al. (2026) studied this question.