IN JANUARY 2025, the Food and Drug Administration (FDA) approved Enhertu (trastuzumab deruxtecan or T-DXd) to treat people with metastatic breast cancer that had minimal levels of HER2 proteins, now known as HER2-ultralow breast cancer. The new approval expands treatment options for those with hormone receptor-positive metastatic breast cancer that was previously considered HER2-negative.
Hormone receptor-positive, HER2-negative breast cancer, the most common subtype of the disease, accounts for 70% of all breast cancer diagnoses. Until recently, HER2-negative status on patients’ pathology reports indicated that treatments targeting HER2, a protein found on the surface of breast cancer cells that can help the cells grow faster, would not be effective. But the HER2-negative status did not capture the full picture of HER2 presence in breast cancer.
“The majority of patients with HER2-negative disease will have some HER2 expression, but not enough to be classified as HER2-positive,” says Aditya Bardia, director of the breast oncology program at UCLA Health Jonsson Comprehensive Cancer Center in Los Angeles. The distinction is important because patients with hormone receptor-positive metastatic breast cancer with any degree of HER2 expression may now be candidates for treatment with Enhertu.
HER2-low and HER2-ultralow Breast Cancer
Enhertu, an antibody-drug conjugate (ADC), binds to cancer cells that express HER2 proteins and delivers a payload of chemotherapy. The FDA originally approved Enhertu to treat metastatic HER2-positive breast cancer in 2019 then approved the ADC for patients with HER2-low breast cancer in 2022. HER2-low cancers have a score of 1+ or 2+, indicating some HER2 expression, on an immunohistochemical (IHC) test. An IHC score of 3+ is considered HER2-positive, as are some 2+ scores found positive through additional testing. In January 2025, the FDA expanded Enhertu’s approval to include patients with HER2-ultralow metastatic breast cancer, cases with faint signs of HER2 expression that are scored 0 on IHC tests.
The expanded approval was based on a phase III trial called DESTINY-Breast06, which was published Sept. 15, 2024, in the New England Journal of Medicine. The study evaluated whether patients with hormone receptor-positive metastatic breast cancer that was found to be HER2-low or HER2-ultralow would benefit from Enhertu. In the open-label trial, 866 patients with metastatic breast cancer who had received one or more lines of endocrine-based therapy, including 713 with HER2-low disease and 153 with HER2-ultralow disease, were randomized to receive Enhertu or physician’s choice of standard chemotherapy.
Recent FDA approvals have led to new labels for HER2 expression in breast cancer diagnoses.
HER2 status is determined by scores on one or two common pathology tests: the immunohistochemical (IHC) test, which measures HER2 expression with antibodies, and the fluorescence in situ hybridization (FISH) test, which measures the number of copies of the HER2 gene present. While breast cancer was once characterized as HER2-positive or HER2-negative, the approval of Enhertu has created new categories:
- HER2-null: HER2 protein is undetectable. “Only 10% to 15% of patients with breast cancer will be truly null,” says Dana-Farber medical oncologist Sara Tolaney. Patients with HER2-null breast cancer are not candidates for HER2-targeted therapies.
- HER2-low: Breast cancer cells have some level of HER2 expression, but the use of certain HER2-targeted therapies requires a higher level of expression. Enhertu has been approved to treat HER2-low breast cancer.
- HER2-ultralow: Breast cancer cells have very low levels of HER2 protein. Some HER2-targeted therapies are not used in these cases, but Enhertu has been approved for metastatic HER2-ultralow breast cancer that is also hormone receptor-positive.
Patients who were given Enhertu had no cancer growth or progression for a median of 13.2 months versus 8.1 months for patients given chemotherapy, with similar results seen in the subgroup of people with HER2-ultralow breast cancer. Moreover, 60% of all patients in the trial who were given Enhertu had tumors that responded to treatment compared with a 30% tumor response rate in the chemotherapy group. “Benefits were seen in all subgroups of patients receiving Enhertu, including those with low, moderate and high disease burden and those with liver metastasis,” says Bardia, the study’s lead investigator. “It’s exciting to have this drug now available for a broader patient population. It gives physicians and patients another option in the arsenal in the fight against cancer.”
Revisiting HER2 Statuses
The expanded FDA approval has implications for most people with HER2-negative metastatic breast cancer going forward. “If you’re a patient with metastatic breast cancer that is not currently HER2-positive, you should have a discussion with your oncologist about asking the pathologist to relook at your biopsy slide to see if there’s a little bit of HER2 protein there,” says Sara Tolaney, a medical oncologist at Dana-Farber Cancer Institute in Boston. You might also ask to get another biopsy, she adds. “Tumors evolve over time. If your biopsy was a year ago, it’s possible that the tumor may now have a little bit of HER2 protein. If it does, you could be a candidate for Enhertu. The expanded FDA approval is allowing more patients to have access to a highly effective therapy.”
Enhertu is delivered through IV infusion and is administered once every three weeks. Nausea is a common side effect, which can be managed with anti-nausea medication. Hair loss can occur in up to 40% of patients. “We also monitor patients carefully for interstitial lung disease and treat if it arises,” Tolaney says. The study found 11.3% of patients experienced interstitial lung disease or pneumonitis, an inflammation of the lungs. These lung conditions can be deadly if not treated.
Cancer Today magazine is free to cancer patients, survivors and caregivers who live in the U.S. Subscribe here to receive four issues per year.
