Abstract Introduction: The role of definitive treatment for the primary tumor in de novo stage IV breast cancer remains contentious, with most randomized trials demonstrating no survival advantage. However, contemporary HER2-targeted therapies often achieve durable systemic control. In clinical practice, there is limited evidence about the optimal management strategy for patients with HER2+ metastatic breast cancer (MBC) who have isolated local progression of their primary breast tumor and/or regional lymph nodes. Methods: We performed a retrospective cohort study between January 2007 and June 2025 of sequential patients with HER2+ MBC at our institution who experienced isolated local progression and were treated with definitive local therapy while continuing the same systemic HER2-targeted therapy. Descriptive characteristics of these cases are presented. The outcome of interest included time on unchanged systemic treatment after local therapy. Results: We identified nine patients with HER2+MBC who experienced isolated progression in the breast and/or axilla despite sustained systemic disease control and subsequently underwent definitive local therapy (see Table 1 for patient characteristics). All patients received taxane-based chemotherapy. Six were treated with a combination of trastuzumab (H) and pertuzumab (P) as concurrent HER2-targeted therapy, while 3 were treated with H alone. This was followed by maintenance H+/-P. A complete radiological response was observed in seven of the nine patients, representing the best systemic response. Five patients had local progression; 3 had locoregional progression; one had regional progression only. Surgical management consisted of mastectomy in 7 patients and lumpectomy in 2 patients. Axillary dissection or sentinel lymph node biopsy was performed in 6 cases. Four patients received adjuvant radiotherapy. In one patient, only ductal carcinoma in situ was identified at the time of surgery. All invasive tumors retained HER2 positivity at the time of local progression, and ER status remained unchanged in all but one case. Following surgery, all patients continued the same maintenance systemic therapy with durations ranging from 8 to 144 months. At last follow-up, all patients remained on maintenance therapy without evidence of systemic progression except for one patient who transitioned to T-Dxd after developing intracranial disease. Conclusion: This case series of patients with HER2+ MBC who developed isolated locoregional progression and received definitive local therapy were able to continue first-line maintenance treatment for an extended period, thereby avoiding increased toxicity associated with later-line systemic therapies. These findings suggest that in select patients, progression limited to the primary tumor may be effectively managed with local treatment alone without the need to alter HER2-targeted therapy. Citation Format: Y. Berner-Wygoda, M. Li, M. Elliot, J. Savill, N. Pathak, M. B. Nadler, V. Kumar, P. L. Bedard, D. Cescon, E. Amir. Local progression in patients with responding metastatic HER2+ breast cancer: A Case Series 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 PS5-06-30.
Berner-Wygoda et al. (Tue,) studied this question.