Evolution of HER2 Targeting in Metastatic Breast Cancer

[摘要] As early as 1987, HER2 overexpression was identifiedas a strong negative prognostic marker, thus defining ahigh-risk breast cancer subtype [1]. Clinical reality, however, changed dramatically over time with the followingapproval of HER2-directed drugs. Already with the introduction of trastuzumab, the first monoclonal antibody inbreast oncology, a major improvement of outcome, andspecifically overall survival, was observed [2]. At first believed to act mainly via inhibition of downstream growthfactor signalling, trastuzumab was soon found to harbourimmunotherapeutic properties as well [3, 4], and to date,this drug remains the backbone of HER2-directed treatment both in the early and the metastatic settings. Asteady flow of novel agents was introduced over the next15 years, among them the tyrosine kinase inhibitors lapatinib and neratinib, pertuzumab, another monoclonal antibody targeting a distinct epitope of the extracellular domain, and finally, trastuzumab-emtansine (T-DM1), thefirst antibody-drug conjugate (ADC) to become clinically available in the field. While this development has further improved patients’ outcomes, the fundamental problem of ultimate disease progression after initial responsepersisted. This and the broad application of these drugsas (neo)adjuvant therapy indicated the need for noveltreatment approaches. Last but not least, with growingincidence and awareness, the problem of brain metastasesin HER2-positive breast cancer patients became a specific scientific focus of interest.

[学科分类] 泌尿医学