Metastatic breast cancer demonstrates HER2/neu amplification approximately 15% of the time. However, HER2 mutations, which often stimulate tumor growth, occur in only 3% to 5% of patients, and are seen more frequently in metastatic versus primary tumors. They are more frequent in lobular carcinoma, including triple-negative lobular cancer. Many of these variants are resistant to trastuzumab and lapatinib. However, neratinib can be efficacious, and recent data suggest that antibody–drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan may also be helpful. Laboratory and clinical data raise the possibility that simultaneous treatment with ADCs plus neratinib may be even more efficacious. Tucatinib, which has demonstrated significant activity in the central nervous system, has also been shown in vitro to be active against a number of these HER2 variants. This report describes a patient with metastatic estrogen receptor–positive, HER2-nonamplified breast cancer with an activating HER2 mutation whose tumor became resistant to neratinib as well as capecitabine, but whose subsequent leptomeningeal disease had a dramatically successful response to tucatinib plus capecitabine. As the frequency of HER2 mutations increases during the evolution of metastatic breast cancer, it is important to obtain genomic evaluation on these tumors with either repeat tissue or liquid biopsy as they progress over time.
Recent advances in bioengineering and manufacturing have catapulted Antibody–drug conjugates (ADCs) to broader clinical applications. ADCs take advantage of the exquisite specificity of monoclonal antibodies (mAb) to deliver a highly potent cytotoxic agent to a specifically targeted cell expressing a selected antigen. HER2-positive breast cancer has served as a testing ground for ADC development in solid tumors that over-express HER2/neu by linking trastuzumab to a payload agent. With the current advances, ADCs leverage the selective targeting of monoclonal antibodies to deliver highly potent agents which otherwise have a narrow therapeutic index. Ado-trastuzumab emtansine (T-DM1) was the first ADC approved for patients with HER2-postive metastatic breast cancer (MBC) and fam-trastuzumab deruxtecan-nxki (T-DXd) was recently approved as well. Sacituzumab govitecan-hziy (SG) was approved in 2020 for patients with triple negative breast cancer (TNBC). Studies focusing on utilizing ADCs in earlier stages of breast cancer in the neoadjuvant or adjuvant setting, and central nervous system (CNS) disease are in progress. New ADCs and bispecific antibodies (bAbs) are also in development.
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