There are encouraging data against HER2+ brain metastases with these HER2 ADCs81,87,140

There are encouraging data against HER2+ brain metastases with these HER2 ADCs81,87,140. approaches and agents, including strategies to harness the immune system. TP0463518 Subject terms: Breast cancer, Breast cancer The discovery of the monoclonal antibody trastuzumab almost 25 years ago revolutionized treatment and drug development for HER2+ breast cancer. Here, Swain et al. review the current standard of care for HER2+ breast cancer, describe mechanisms of drug resistance and focus on next-generation platforms and therapies for the treatment of this disease. Introduction Innovations in pathology, molecular biology and drug development have enabled HER2-positive breast cancer (BC), a historically aggressive subtype, to become one with impressive outcomes. The field was energized in 1978 when the first tyrosine kinase, epidermal growth factor receptor (EGFR), was discovered followed by the identification of the or (also known as and v-was discovered to be transforming, hence an oncogene, while v-oncogene. Mouse and non-mouse cell lines were reported to be transformed by neuroblastoma, glioma and carcinoma DNA (later named gene was homologous to (refs.241,246). Sequencing studies revealed that the tyrosine kinase receptor named HER2 had extensive homology to had different sequences but were closely related to the gene, located on chromosome 7 (ref.247). Thus, HER2 and were determined to be homologous with but different from EGFR (HER1). Eventually two other members of the HER family were described: HER3 on chromosome 12 and HER4 on chromosome 2 (refs.248,249). The tyrosine-binding domains of all but HER3 (which has no catalytic tyrosine kinase activity) are similar. A monoclonal antibody (mAb) to p185 in that decreased cell proliferation, spurred the development of a humanized mAb to HER2, humAb4D5-8, eventually named trastuzumab or Herceptin256,257 (Fig.?1). Phase I and II clinical studies demonstrating activity of trastuzumab were followed by a phase III registrational study that led to the approval of trastuzumab in 1998 by the FDA for patients with HER2+ metastatic breast cancer (MBC)258,259. Open in a separate window Fig. 1 Evolution of HER2 as a biomarker and target for treatment for breast cancer.Timeline of preclinical discovery milestones for HER2 biology and regulatory approval for anti-HER2 therapies. A, adjuvant setting; M, metastatic setting; N, neoadjuvant setting; +, approved in China only; *, M. Bishop and H. Varmus awarded Nobel Prize in 1989 for this discovery; **, S. Cohen and R. Levi-Montalcini awarded Nobel Prize in 1986 for discovery of growth TP0463518 factors and their receptors. Current standard of care for HER2+ BC As the understanding of HER2 biology has evolved (Box?1), so has the development of agents that target HER2. HER receptors contain an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Ligand binding to the HER proteins results in homodimerization or heterodimerization of these receptors, leading TP0463518 to activation of downstream signalling pathways that promote cell division and growth and inhibit apoptosis13. There is no known ligand for HER2, but it is a preferred dimerization partner for the other HER proteins, especially HER3 (ref.14). HER2 overexpression or amplification leads to ligand-independent dimerization and abnormal signalling in addition to increased signalling through ligand-dependent heterodimerization13. The efficacy of HER2-targeted agents is most prominent in these HER2-positive tumours. The TP0463518 definition of HER2 positivity according to American Society of Clinical OncologyCCollege of American Pathologists (ASCOCCAP) guidelines, includes tumours that have 3+ positive staining by immunohistochemistry (IHC) in 10% of tumour cells, or gene amplification detected by fluorescence in situ hybridization (FISH)15,16 (Box?2). Recent research has identified a subset of patients with HER2-low (HER2low) BC that is responsive to novel HER2-targeted ADCs17. HER2low is defined as HER2 IHC 1+ by itself or 2+ in the absence of gene amplification by ISH?(in situ hybridization). The cut-off for the level of HER2 expression by IHC is only a crude estimation of those who may actually benefit from anti-HER2 therapies. With the introduction of the new HER2low definition, additional diagnostic tools may need to be considered. Since the initial approval of trastuzumab for HER2+ BC, multiple agents exhibiting various mechanisms of action and safety profiles have been approved for the treatment of early-stage and metastatic disease (Fig.?1 and Box?3). Below, agents that have been approved by regulatory agencies Hs.76067 are briefly described and the advantages and limitations of each strategy are summarized. Box 2 HER2 diagnostics acts as an oncogene, and its amplification results in overexpression of the HER2 protein, a transmembrane receptor kinase. This abnormal expression leads to a cascade of constitutive activation of downstream signalling pathways that promote uncontrolled tumour cell proliferation. HER2 expression is associated with poor prognosis, including early recurrence and metastatic disease in breast cancer3,260,261. HER2 overexpression is also predictive of response to TP0463518 several HER2-targeted therapies, including monoclonal antibodies (mAbs) such as trastuzumab and pertuzumab, tyrosine kinase inhibitors (TKIs) lapatinib,.