Breast Surgery Linked to Longer Survival in HER2-Positive Metastatic Breast Cancer, Study Finds

For decades, women diagnosed with breast cancer that had already spread to distant organs at first detection—so-called de novo metastatic breast cancer—were generally considered beyond the reach of surgery on the primary tumor. The disease was systemic, the thinking went, so removing the breast would add risk without benefit. That doctrine is now under renewed scrutiny, and a new study published in Breast Cancer Research and Treatment adds a striking data point for one of the most treatment-responsive subtypes: HER2-positive de novo metastatic breast cancer.

The retrospective study, led by Malia Brennan and colleagues at the University of Washington and the Fred Hutchinson Cancer Center in Seattle, examined 103 patients diagnosed with HER2-positive de novo metastatic breast cancer between 2011 and 2023. The researchers asked two questions that have divided surgical oncologists for years: which patients in this population actually undergo breast surgery, and does the operation change the trajectory of local and distant disease progression or survival compared with systemic therapy alone?

The answer to the first question was clear. Nearly 43 percent of the cohort—42.7 percent—underwent breast surgery, and the choice was far from random. Patients who received surgery tended to be younger, with a median age at diagnosis of 48 years compared with 56 years among those managed without an operation, although that difference did not reach statistical significance. More telling, the surgery group carried a lower metastatic burden: an average of 1.3 sites of distant disease versus 1.9 sites in the non-surgery group, a difference that was statistically significant. In other words, surgeons and their patients were selecting the operations for those with less extensive spread.

The surgical details reveal how practice has evolved. Among those operated on, 70.5 percent underwent mastectomy and 29.5 percent lumpectomy. Axillary surgery was performed in 72.7 percent of surgical patients, but the mix of procedures shows the influence of modern, less invasive staging: 38.6 percent received a full axillary lymph node dissection, 27.3 percent a sentinel lymph node biopsy, and 6.8 percent a targeted axillary dissection—a technique that allows de-escalation of surgery after effective systemic treatment. The high rate of axillary intervention in a metastatic setting underscores how thoroughly the regional nodes were still being evaluated, even when distant disease was present.

Local disease progression emerged as a key selection factor. Before surgery, 39 percent of the surgical group had exhibited local progression at the primary site, compared with 23.5 percent of the non-surgery group—a difference that approached significance. This suggests that uncontrolled disease in the breast itself was one of the triggers pushing clinicians toward operative management. Yet after the operation, the tables turned: only 17.1 percent of surgical patients experienced subsequent local progression, versus 23.5 percent of those treated with systemic therapy alone, a difference that was not statistically significant. Surgery, in this dataset, did not decisively outperform modern drug therapy at controlling the primary site.

The survival signal, however, was dramatic. After adjusting for age, sites of metastases, and the number of metastatic sites in Cox proportional hazards models, patients who underwent breast surgery had significantly improved overall survival, with a hazard ratio of 0.33—meaning roughly a two-thirds reduction in the risk of death—compared with those treated without surgery. Kaplan-Meier analyses supported the same conclusion. On its face, that is the kind of result that could reshape guidelines overnight.

But the authors themselves urge restraint, and the statistical architecture of the study explains why. This was a single-institution retrospective review, not a randomized trial. Logistic regression and multivariable adjustment can account for measured confounders such as age and metastatic burden, but they cannot eliminate selection bias—the inherent tendency for healthier, lower-burden patients to be offered surgery in the first place. The very factors that predicted who got the operation, particularly the lower number of metastatic sites, are also factors that independently predict longer survival. The hazard ratio of 0.33 therefore represents an association, not proof of causation, and the authors state explicitly that the significant association between surgery and improved survival must be interpreted with caution.

The study arrives in a field crowded with competing evidence. Randomized trials have tested primary tumor resection in metastatic breast cancer for a decade: the 2015 Lancet Oncology trial by Badwe and colleagues found no survival benefit for locoregional treatment of the primary tumor, while the MF07-01 protocol by Soran and colleagues reported improved survival with surgery in stage IV disease. The EA2108 trial led by Khan and colleagues found that early local therapy for the primary site in de novo stage IV breast cancer did not improve survival overall. More recently, the Japanese JCOG1017 PRIM-BC trial and a 2024 meta-analysis of randomized controlled trials have added further nuance, and a 2025 Cochrane review systematically assessed breast surgery for metastatic breast cancer. Notably, prior analyses specifically focused on HER2-positive stage IV patients in the era of targeted therapy—such as work by Mudgway and colleagues and by Lu and colleagues—have suggested that the subtype may behave differently, which is precisely the niche this new single-institution study addresses.

What makes the HER2-positive question especially compelling is the transformation of the subtype’s prognosis by HER2-targeted therapy. Drugs directed against the human epidermal growth factor receptor 2 have significantly improved survival in de novo metastatic HER2-positive breast cancer, converting one of the most aggressive diagnoses into a chronic, manageable condition for many patients. As systemic therapy grows more effective, the calculus around local interventions shifts: if the drugs can hold distant disease at bay for years, the question of whether removing the breast adds incremental benefit—or merely risk—becomes empirically testable rather than doctrinal. The Seattle data suggest that in carefully selected patients with limited metastatic burden, surgery is being deployed, and that its association with survival deserves rigorous prospective testing.

The findings also intersect with a parallel movement in early-stage disease: trials such as those led by Kuerer and colleagues have explored eliminating breast surgery entirely for exceptional responders to neoadjuvant systemic therapy, showing that as drug treatment improves, the role of the scalpel is being renegotiated in both directions—expanded for some metastatic patients, withdrawn for some early-stage ones. For now, the practical takeaway for patients with HER2-positive de novo metastatic breast cancer is that surgery remains an option on the table, most often pursued in those with fewer sites of metastatic spread and uncontrolled local disease, and that the apparent survival advantage associated with the operation must await randomized evidence before it can be prescribed with confidence. The study was approved by the University of Washington Research IRB Committee, and the authors declare no competing interests or external funding.

Subject of Research: Medicine & Public Health

Article Title: Surgical management in HER2 + de novo metastatic breast cancer: disease progression and survival

Article References: Brennan, M., Javid, S. H., Flanagan, M. R., Schmicker, R., Gwin, W. R., Fleuret, S., & Palmquist, E. (2026). Surgical management in HER2 + de novo metastatic breast cancer: disease progression and survival. Breast Cancer Research and Treatment, 220(1), Article 7. https://doi.org/10.1007/s10549-026-08108-y

Image Credits: AI Generated

DOI: 10.1007/s10549-026-08108-y

Keywords: breast cancer, HER2-positive, metastatic breast cancer, surgical oncology, de novo stage IV, systemic therapy, survival outcomes, selection bias, Surgical, management, HER2, novo