One of the first major breakthroughs in the treatment of breast cancer was the discovery of the HER2 protein. It was HER2 that became one of the first successful targets of modern oncology.
The monoclonal antibody trastuzumab, and later pertuzumab, virtually transformed the treatment of HER2-positive breast cancer. Today, the combination of these drugs is widely used for the treatment of both early and metastatic HER2-positive disease.
However, despite significant progress, over time some tumors become resistant to treatment. This is where a new idea emerged: was it possible to attach a chemotherapeutic agent to a HER2-directed antibody so that the drug could deliver the cytotoxic substance directly to the tumor cell?
Thus began the era of antibody-drug conjugates in the treatment of breast cancer.
One of the first successful ADCs was trastuzumab emtansine (T-DM1). The EMILIA and KATHERINE trials showed that the drug was effective in both metastatic and early HER2-positive breast cancer. It was particularly interesting that patients’ quality of life was better preserved during treatment. Trastuzumab emtansine was less associated with the development of some severe side effects that often accompany standard chemotherapy. In the setting of metastatic disease, where treatment is a long-term process, this is especially important for patients.
In recent years, the development of trastuzumab deruxtecan (T-DXd) is considered one of the most significant milestones. The DESTINY-Breast03 and DESTINY-Breast04 trials demonstrated that trastuzumab deruxtecan significantly improved both disease control and overall survival in metastatic breast cancer with HER2-positive and HER2-low expression.
It was particularly notable that in the analysis of the trials, patients maintained their quality of life for a prolonged period during treatment—including physical activity, pain control, and daily functioning. Emotional and social functioning were also better preserved, which is especially important in the context of an oncological disease.
ADCs Beyond HER2
Today, ADCs are no longer limited to the treatment of HER2-positive breast cancer.
Modern research has shown that the use of these drugs is effective in other breast cancer subtypes as well, including hormone receptor-positive HER2-negative and triple-negative disease.
One of the most important directions has been the development of ADCs targeting the TROP2 protein. TROP2 is a protein that is often present in high amounts across various subtypes of breast cancer, particularly in HER2-negative disease.
Sacituzumab govitecan is directed precisely at this target, having shown efficacy in both triple-negative and hormone receptor-positive HER2-negative metastatic breast cancer. The ASCENT and TROPiCS-02 trials demonstrated that the drug significantly improved treatment outcomes compared to standard chemotherapy. Trial analyses also noted a better preservation of quality of life, including in terms of pain management, physical functioning, and the control of daily activities.
In recent years, another TROP2-directed ADC—datopotamab deruxtecan (Dato-DXd)—has come into the spotlight. The TROPION-Breast01 and TROPION-Breast02 trials showed its efficacy across various subtypes of HER2-negative breast cancer, including both hormone receptor-positive and triple-negative disease. Existing data indicate that datopotamab deruxtecan can improve disease control while simultaneously maintaining the patient’s quality of life.
Today, ADCs are considered one of the fastest-growing fields in modern oncology. Although the full spectrum of these drugs is not yet entirely available in Georgia, some significant steps have already been taken: trastuzumab emtansine (T-DM1) is already actively used in clinical practice; additionally, trastuzumab deruxtecan (T-DXd) has now been registered in Georgia. All of this indicates that modern targeted treatments are gradually becoming more accessible to Georgian patients as well.
Author: Salome Kordzaia, MD, Clinical Oncologist at the “Consilium Medulla” Clinic; PhD student at Ivane Javakhishvili Tbilisi State University.
