Anti-HER2 therapy in metastatic breast cancer: many choices and future directions

Abstract

Metastatic HER2 + breast cancer is an expanding area of drug development and research, with three new drugs approved in 2020 alone. While first-line therapy is well-established for metastatic HER2 + breast cancer, the standard of care for second-line therapy will likely be changing soon based on the results of the DESTINY-Breast03 trial. In the third-line setting, many options are available. Considerations in choosing between regimens in the third-line include resistance to trastuzumab, the presence of brain metastases, and tolerability. High rates of resistance exist in this setting particularly due to expression of p95, a truncated form of HER2 that constitutively activates downstream signaling pathways. We suggest a tyrosine kinase inhibitor (TKI)-based regimen because of the activity of TKIs in brain metastases and in p95-expressing tumors. Attempts to overcome resistance to anti-HER2 therapies with PI3K inhibitors, mTOR inhibitors, and CDK 4/6 inhibitors are an active area of research. In the future, biomarkers are needed to help predict which therapies patients may benefit from the most. We review the many new drugs in development, including those with novel mechanisms of action.

Keywords: Anti-HER2 therapy; Drug resistance; HER2 + metastatic breast cancer; New drugs; Treatment.

Fig. 1

Mechanisms of action of current anti-HER2 therapies. Mechanisms of action of anti-HER2 therapy by monoclonal antibodies (trastuzumab and pertuzumab), Fc-optimized antibody (margetuximab), tyrosine kinase inhibitors (lapatinib, neratinib, and tucatinib), and antibody–drug conjugate (ado-trastuzumab emtansine and trastuzumab-deruxtecan)

Fig. 2

Current treatment algorithm for anti-HER2 therapy in the metastatic setting

Fig. 3

Pathways of resistance to anti-HER2 therapies, including p95. Important pathways involved in anti-HER2 resistance such as the PI3K/AKT/mTOR pathway and the expression of HER2 p95 lacking the extracellular trastuzumab-binding domain