Targeting HER2 in breast cancer: beyond trastuzumab

Excerpt

Trastuzumab has altered the natural history of HER2⁺ breast cancer. In the metastatic setting, it has improved progression-free and overall survival. In patients with operable breast cancer, adjuvant trastuzumab, when added to chemotherapy, has improved disease-free and overall survival. Unfortunately, virtually all patients with metastatic breast cancer develop disease that is at least partially resistant to trastuzumab. In these patients, there is still value in continuing trastuzumab in combination with other treatments, but trastuzumab alone is unable to fully suppress tumor growth. Multiple mechanisms of resistance to trastuzumab have been suggested including activation of other growth factor receptors, preferential finding of HER2 to HER3, loss of the extracellular domain of HER2, and activation of the PI3 kinase pathway as a result of PTEN loss or a PIK3CA mutation. It is unknown to what extent these mechanisms are relevant in individual patients, but it is probable that many different mechanisms of resistance are clinically important. Over the past decade, a number of treatments have been developed for patients with trastuzumab-resistant disease. At present, only lapatinib, a small-molecule inhibitor of HER1 and HER2, is commercially available. It is active when administered with either chemotherapy or trastuzumab. A variety of other therapies are under investigation in phase III clinical trials. Pertuzumab, a monoclonal antibody that inhibits HER2-HER3 heterodimers, appears to be effective when combined with trastuzumab ± chemotherapy. T-DM1, an antibody-drug conjugate, has also displayed remarkable activity in the setting of refractory disease and has limited toxicity. It is presently under investigation in multiple randomized trials. Neratinib is an oral irreversible tyrosine kinase inhibitor that targets HER1, HER2, and HER4. As a single agent, it appears to be more active than lapatinib, but is associated with more significant toxicity. It, too, is under evaluation in phase III trials in the adjuvant and metastatic settings. A variety of other agents are under active study including the mTOR inhibitors, the PI3kinase inhibitors, angiogenesis inhibitors, and IGFR antagonists. It is likely that a number of new agents will be available for the treatment of HER2⁺ breast cancer in the next several years, and outcomes for this group of patients will continue to improve. …