Aiming at a Tailored Cure for ERBB2 -Positive Metastatic Breast Cancer: A Review

Importance: Metastatic breast cancer (MBC) has traditionally been considered incurable. Accordingly, current treatment algorithms are aimed at maintaining quality of life and improving overall survival, rather than at complete eradication of the disease. Attempts to achieve cure with high-dose chemotherapy were conducted in the 1990s, with no observed long-term benefit compared with conventional chemotherapy. Nonetheless, Erb-B2 receptor tyrosine kinase 2 (ERBB2, formerly HER2)-targeted biologic treatments, developed in the past 2 decades, are currently challenging this paradigm. Indeed, a fraction of patients with ERBB2-positive MBC achieve long-lasting responses to chemotherapy and ERBB2-blockade, resembling a cure. In this setting, the challenge of identifying the optimal curable population has emerged, including identifying populations in whom treatment escalation strategies may be beneficial, while avoiding overtreatment in patients with incurable disease. Observations: A number of clinical and pathologic features allow physicians to identify patients with ERBB2-positive MBC who are more likely to experience a long-lasting response to chemotherapy and ERBB2-blockade. Long-term responders tend to be de novo metastatic, have a reduced disease burden, and tend to show deep responses to systemic treatment. In pathologic terms, features associated with long-term response are high ERBB2 expression, lack of detrimental genomic aberrations, and antitumor immune activation. This population of patients may potentially derive benefit from a tailored escalation of frontline treatment with novel anti-ERBB2 drugs, such as trastuzumab deruxtecan, tucatinib, or margetuximab. Additional recent therapeutic and diagnostic advancements could further aid in the path toward a cure for ERBB2-positive MBC. Conclusions and Relevance: Careful implementation of novel diagnostic and treatment tools could potentially expand the population of patients with ERBB2-positive MBC experiencing long-lasting disease response. Trials are in preparation to confirm this paradigm, and hopefully lead to a new era of precision therapy for breast cancer.