Trastuzumab deruxtecan (Enhertu) is efficacious to treat patients with hormone receptor-positive and HER2- low metastatic breast cancer
June 6, 2022
Trastuzumab deruxtecan (Enhertu) is an antibody-drug-conjugate (ADC), meaning that a chemotherapy drug, deruxtecan (topoisomerase I inhibitor) is attached to a monoclonal antibody targeting HER-2 (epidermal growth factor receptor 2) protein. Because some breast cancer cells have high numbers of HER2, the antibody binds to cancer cells more readily than to normal and healthy cells. Once it binds to cancer cells, it releases deruxtecan into cancer cells, leading to cell death.
Trastuzumab deruxtecan (Enhertu) is currently approved for the patients with metastatic HER2-positive breast cancer as well as HER2-positive gastric cancer.
In order to determine the amounts of HER2 in breast cancer cells, pathologists use the diagnostic tests called “immunohistochemistry (IHC)” and “in situ hybridization (ISH)”. Immunohistochemistry (IHC) is used to quantify the amount of the HER2 protein in cancer cells. In situ hybridization (IHC), on the other hand, is used to determine the copy numbers of the HER2 gene in cancer cells (in a normal cell, there should be only 2 copies of HER2). Currently, the metastatic breast cancer patients with HER2 - score 3 from immunohistochemistry (IHC) or higher and/or HER2- score 1 from in situ hybridization (ISH) are approved for Trastuzumab deruxtecan (Enhertu).
However, approximately 85% of breast cancer patients have HER2-negative tumor. Among them, 60% of cases can be categorized as HER2-low, which is defined as +1 or +2 IHC score and zero ISH score. The breast cancer patients with HER-2 low, unfortunately, have not benefited from the first monoclonal antibody therapy, trastuzumab (Herceptin) which targets HER2 in breast cancer cells, or from trastuzumab emtansine which was the first antibody-drug conjugate (ADC) therapy for HER2-positive breast cancer patients.
We have previously reported that the patients with HER2-low metastatic breast cancer may benefit from Trastuzumab deruxtecan (Enhertu). The investigators reported the complete results from the phase 3 DESTINY-Breast04 study (NCT03734029) in New England Journal of Medicine (1) as well as in the 2022 American Society of Clinical Oncology Annual Meeting on June 5, 2022.
The study was conducted with 557 patients with HER2-low and either hormone receptor-positive or negative metastatic breast cancer. The patients were randomly assigned to be treated with either Trastuzumab deruxtecan (Enhertu) or chemotherapy, and those who were treated with Trastuzumab deruxtecan (Enhertu) lived without disease getting worse for median 10.1 months, whereas those with chemotherapy for median 5.4 month. Overall, the patients who were treated with Trastuzumab deruxtecan (Enhertu) lived for median 23.9 months, whereas those with chemotherapy for median 17.5 months. In the end, treatment with trastuzumab deruxtecan (Enhertu) reduced the risk of death by 36% compared to chemotherapy for patients with HER2-low metastatic breast cancer patients.
Breast cancer patients with HER2- low currently have very limited choice for later lines of treatment and rely on chemotherapy, which do not effectively work most of the time. But with these recent results, those patients can have an effective care. In addition, Trastuzumab deruxtecan (Enhertu) can also treat one third of the triple negative breast cancer patients whose cancer cells show HER2-low status.
Other ADC therapies such as trastuzumab duocarmazine, and disitamab vedotin are being studied in clinical trials currently. Positive results with several new ADC therapies would mean that HER-2 low metastatic breast cancer patients and triple negative breast cancer patients would have many choices of effective treatments which may lead longer survival.
Serious side effects can occur with Trastuzumab deruxtecan (Enhertu). In the trial, 14 patients died from the treatment of trastuzumab deruxtecan (3.8%), compared to 5 people died from chemotherapy. Interstitial lung disease (ILD)/pneumonitis occurred in 45 patients treated with trastuzumab deruxtecan (12.1%), with 5 patients having a serious illness and 3 having death. Most frequently observed side effects were nausea, fatigue, skin and subcutaneous tissue disorders, including alopecia, vomiting, neutropenia, and anemia.
(1) Modi, Shanu et al. “Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer.” The New England journal of medicine vol. 382,7 (2020): 610-621. doi:10.1056/NEJMoa1914510