Real-World Data Show Trastuzumab Deruxtecan Extends Survival in HER2-Low Metastatic Breast Cancer

A new real-world study from China offers some of the clearest evidence yet that trastuzumab deruxtecan, one of the most talked-about cancer drugs of the past decade, delivers on its promise outside the carefully controlled environment of clinical trials. Researchers at Fudan University Shanghai Cancer Center followed 126 Chinese women with HER2-low metastatic breast cancer who received the drug between November 2021 and November 2024, and found that the antibody-drug conjugate kept their disease in check for a median of 9.1 months. The findings, published in BMC Cancer, provide a crucial reality check on how the therapy performs in a broader, more diverse patient population than the one enrolled in the landmark trials that first won it regulatory approval.

Trastuzumab deruxtecan, often abbreviated as T-DXd, belongs to a class of treatments known as antibody-drug conjugates, which are sometimes described as guided missiles for cancer cells. The drug pairs a monoclonal antibody that homes in on human epidermal growth factor receptor 2, or HER2, with a potent chemotherapy payload called deruxtecan, attached through a linker designed to remain stable in the bloodstream. Once the antibody binds to its target and the complex is swallowed into the tumor cell, the linker is cleaved and the cytotoxic drug is released. Critically, the payload is membrane-permeable, meaning it can diffuse into neighboring tumor cells that may express little or no HER2 themselves, a phenomenon researchers call the bystander effect. This mechanism explains why the drug works not only in tumors with high HER2 levels but also in the so-called HER2-low category, where the receptor is present at low levels that historically disqualified patients from HER2-targeted therapy.

The concept of HER2-low disease has reshaped how oncologists classify breast cancer. Roughly half of all breast cancers previously labeled HER2-negative actually show weak HER2 expression on immunohistochemistry, and the recognition that these tumors respond to T-DXd effectively created an entirely new treatment category. The pivotal DESTINY-Breast04 trial demonstrated that the drug significantly extended survival in this population compared with standard chemotherapy, leading to approvals in the United States, Europe and elsewhere. But trial populations are often younger, healthier and more ethnically homogeneous than the patients seen in everyday oncology clinics, and questions have lingered about whether the striking trial results translate to routine practice, particularly in Asian patient populations where prior real-world data were scarce.

To address that gap, the Fudan team retrospectively analyzed the medical records of every patient with HER2-low metastatic breast cancer treated with T-DXd at their center during the three-year study window. The cohort was heavily pretreated: the women had received a median of three prior lines of therapy, with some having endured as many as five or more. Their median age was 56 years. About 32 percent had metastatic disease from the moment of diagnosis, known as de novo metastatic cancer, while the remaining 68 percent had developed metastases after an initial diagnosis of earlier-stage disease. Just under two-thirds of the patients had hormone receptor-positive tumors, meaning their cancers were fueled by estrogen or progesterone, while the rest had hormone receptor-negative disease, an aggressive subtype with fewer targeted options.

The headline result was a median real-world progression-free survival, or rwPFS, of 9.1 months, measured from the start of T-DXd treatment until either disease progression or death. For context, the same patients had achieved a median progression-free survival of only 3.5 months on the treatment they received immediately before switching to T-DXd, a descriptive comparison that underscores how much the drug outperformed the therapies that preceded it. Among the 111 patients whose tumors could be radiologically assessed using the RECIST 1.1 criteria, the objective response rate was 30.63 percent, meaning nearly one in three saw their tumors shrink measurably. Add in patients whose disease remained stable, and the disease control rate climbed to 72.07 percent, a remarkable figure for a cohort this heavily pretreated.

Perhaps the most intriguing finding emerged from a subgroup analysis of hormone receptor-positive patients. The researchers discovered that women whose tumors expressed low levels of the progesterone receptor, defined as 10 percent or less of tumor cells staining positive, fared dramatically better on T-DXd than those with high progesterone receptor expression. Their median real-world progression-free survival was 17.77 months, nearly triple the 6.13 months observed in the high-expression group, a difference that was highly statistically significant. The biological explanation remains speculative, but progesterone receptor expression is a marker of a more intact, hormone-driven tumor biology, and tumors with low PR expression may be more genomically unstable and more dependent on cell-kill mechanisms that antibody-drug conjugates exploit. If confirmed, the finding could help oncologists identify which hormone receptor-positive patients are most likely to benefit from early T-DXd treatment.

Taking the analysis a step further, the team built an exploratory prognostic score using multivariable Cox regression, a statistical technique that estimates the independent contribution of multiple clinical factors to survival outcomes. The resulting model, based on age, HER2 status and hormone receptor status, split patients into low-score and high-score groups with strikingly different trajectories: median real-world progression-free survival of 12.4 months in the low-score group versus just 5.13 months in the high-score group. The authors are careful to frame this score as hypothesis-generating rather than a validated clinical tool. Derived from a single-center cohort of 126 patients, it would need to be confirmed in independent, ideally prospective, populations before it could guide treatment sequencing decisions in the clinic. Still, it represents a first step toward personalizing the use of an expensive and sometimes toxic therapy.

The study’s real-world design is both its strength and its limitation. On one hand, it captures the messy complexity of routine clinical care, including patients with poorer performance status, unusual prior treatments and comorbidities that would have excluded them from trials. On the other hand, the retrospective, single-center design means the results are vulnerable to selection bias, and the lack of a control group makes it impossible to draw definitive causal conclusions. The authors also note that detailed safety data, including rates of adverse events such as interstitial lung disease, a known and potentially serious risk of T-DXd, were collected in supplementary analyses rather than forming the primary endpoint. Longer follow-up will be needed to estimate overall survival, which was not yet mature in this cohort.

For patients and clinicians, the significance of the study lies in its confirmation that the extraordinary results seen in clinical trials are reproducible in ordinary practice. T-DXd has already transformed the treatment landscape for HER2-low metastatic breast cancer, offering meaningful extra months of disease control to women who once had little beyond conventional chemotherapy. This new evidence from Shanghai suggests that Chinese patients, who were underrepresented in the pivotal trials, benefit just as substantially, and it hints at biological markers like progesterone receptor expression that could one day refine who receives the drug and when. As antibody-drug conjugates multiply across oncology, studies like this one serve as an essential bridge between the idealized world of clinical research and the real-world clinics where the drugs must ultimately prove their worth.

Subject of Research: Real-world effectiveness of trastuzumab deruxtecan in HER2-low metastatic breast cancer

Article Title: Real-world clinical outcomes of trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer

Article References: Zhang, K.-Y., Zhu, X.-Z., Ying, X.-H., Chen, L., & Wang, Z.-H. (2026). Real-world clinical outcomes of trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer. BMC Cancer. https://doi.org/10.1186/s12885-026-17096-7

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17096-7

Keywords: trastuzumab deruxtecan, HER2-low, metastatic breast cancer, antibody-drug conjugate, real-world evidence, progression-free survival, progesterone receptor, RECIST, prognostic score, BMC Cancer, oncology, drug response