Trastuzumab deruxtecan versus standard therapy for early-stage HER2-positive or HER2-low breast cancer

Breast cancer (mammary carcinoma) develops when cells in the breast gland grow uncontrollably. In the early stages, the tumor is usually confined to the breast or nearby lymph nodes and can often be surgically removed. Depending on the stage, size, and characteristics of the disease, standard treatment usually consists of surgery, followed by chemotherapy and radiation therapy if necessary, as well as—depending on the tumor’s characteristics—targeted therapies such as antibody/HER2 therapies, immunotherapy, PARP inhibitors (e.g., olaparib), or anti-hormone therapy.

The characteristics of the cancer cells can vary from patient to patient. Often, the tumor cells express the HER2 receptor on their surface (“HER2-positive”). However, there are also patients whose tumor cells do not express the receptor (“HER2-negative”) or express it only in small amounts (“HER2-low”). Drugs have therefore been developed that can specifically recognize this receptor and thus target the cancer cells. These drugs include, for example, trastuzumab and pertuzumab. The study drug trastuzumab deruxtecan (T-DXd) is what is known as an antibody-drug conjugate, in which the antibody trastuzumab is linked to a chemotherapeutic agent (deruxtecan). This allows the cancer cells to be specifically targeted and killed. The drug is already approved for use in patients with HER2-positive and HER2-low breast cancer at the advanced and metastatic stages—but not yet for early-stage breast cancer, as in this study.

After surgery and drug therapy, very small tumor remnants may remain in the body. These can be detected via cell-free tumor DNA (ctDNA) in the blood and serve as an early warning sign of a possible recurrence. This follow-up is also called a “liquid biopsy” and is often not yet part of standard follow-up care. It is conducted, for example, as part of the SURVIVE study. Prior participation in the SURVIVE study is a prerequisite for inclusion in this study.

The goal of this Phase 3 study is to investigate whether treatment with trastuzumab deruxtecan (T-DXd) improves ctDNA clearance compared to standard treatment. To this end, patients will be randomly assigned to two groups in a 2:1 ratio. Patients and the medical staff know which group they belong to. Group 1 receives T-DXd every 3 weeks for up to 16 cycles or until relapse; for hormone receptor-positive tumors, anti-hormone therapy may be administered concurrently. Arm B receives continuous, physician-selected standard therapy (e.g., anti-hormone therapy, CDK4/6 inhibitors, T-DM1, olaparib, trastuzumab, pertuzumab, capecitabine, or neratinib). The primary endpoint is the proportion of patients in whom ctDNA is no longer detectable after 12 months (ctDNA “clearance”).

Eligible participants include women and men between the ages of 18 and 75 with early-stage, HER2-positive or HER2-low breast cancer without metastases, in whom measurable tumor DNA (“molecular relapse”) was detected in the blood after completion of standard treatment. There must be no distant metastases (as shown by imaging within 8 weeks prior to enrollment). The cancer must have been completely surgically removed prior to study enrollment (so-called R0 resection). If applicable, specific waiting periods (“washout periods”) following previous treatments must be observed. In addition, patients must have previously been enrolled in the SURVIVE study.