Targeted Therapy in her2-Positive Metastatic Breast Cancer: A Review of the Literature

Abstract

peers with other subtypes of the disease. Approval in 1998 of the first anti-her2 agent (trastuzumab) ushered in a new era of molecularly targeted therapies for her2-positive breast cancer and significantly improved outcomes in those patients.The anti-her2 agents now in clinical use span a number of drug classes, including the monoclonal antibodies trastuzumab and pertuzumab, which bind to the extracellular portion of the her2 protein; the small-molecule intracellular tyrosine kinase inhibitors lapatinib and neratinib, which block downstream receptor signalling; and the antibody-drug conjugate (adc) ado-trastuzumab emtansine (T-DM1), which combines her2 signalling disruption with direct cytotoxicity. These drugs have been shown to be efficacious in the treatment of her2-positive mbca in the first-line setting and beyond.In this article, we describe the natural history of her2-positive breast cancers, summarize the evidence for the currently available targeted agents from phase iii randomized clinical trials, and discuss the role of targeted agents in the current management of her2-positive mbca.The literature in PubMed from January 1990 to October 2014 was searched for published phase iii clinical trials relating to her2-positive mbca. Abstracts from major conferences, including the annual meetings of the American Society of Clinical Oncology (asco), the European Society for Medical Oncology, and the San Antonio Breast Cancer Symposium, were also examined. Key words included "her-2 positive," "metastatic breast cancer," "phase 3," and "clinical trial." Only English-language publications were reviewed. NATURAL HISTORYAs a transmembrane tyrosine kinase receptor protein, her2 belongs to the human epidermal receptor family of proteins. It is expressed in normal tissue including the gastrointestinal, respiratory, and urinary tracts, and skin, breast, and placenta 2 . Although her2 has ABSTRACTBreast tumours positive for her2 (human epidermal growth factor receptor 2) represent approximately 20% of all breast cancer cases and are associated with an aggressive natural history. The advent of targeted anti-her2 therapies has dramatically improved disease control and survival in patients with metastatic her2-positive breast cancer. Targeted agents are now considered the standard of care in the first-line setting and beyond.The present review summarizes the currently available data on targeted anti-her2 therapies from completed randomized phase iii clinical trials and briefly discusses emerging advances that will address unmet needs in metastatic her 2-positive breast cancer. KEY WORDSher2, metastatic breast cancer, targeted therapy, phase iii trials

TAS0728, A Covalent-binding, HER2-selective Kinase Inhibitor Shows Potent Antitumor Activity in Preclinical Models

“…HER2 forms homo-or heterodimers with ERBB family kinases to induce activation of HER2 signal transduction associated with enhanced survival and cell growth signals in cancer cells. Targeting of HER2 has been shown to be an effective antitumor therapy in breast and gastric cancers (6)(7)(8). Although anti-HER2 antibodies, including trastuzumab, pertsuzumab, and the antibody-drug conjugate, T-DM1, are approved for use in patients with HER2-overexpressing breast cancers, there is still a need for effective therapies in patients who are refractory to HER2targeting antibodies.…”

Dual-Receptor–Targeted Radioimmunotherapy of Human Breast Cancer Xenografts in Athymic Mice Coexpressing HER2 and EGFR Using 177Lu- or 111In-Labeled Bispecific Radioimmunoconjugates

“…Over expression of the human epidermal growth factor receptor-2 (HER2) occurs in about 20%-25% of breast cancers (BCs) (1) and is the therapeutic target for trastuzumab (Herceptin; Roche Pharmaceuticals), pertuzumab (Perjeta), and trastuzumab-emtansine (T-DM1; Kadcycla) (2). Although these HER2-targeted therapies combined with chemotherapy have improved the outcome for women with HER2-positive metastatic BC, not all patients respond and many patients with HER2-positive BC develop resistance within a year (3).…”

Engineered T cells: the promise and challenges of cancer immunotherapy

“…HER2 is also overexpressed in a variety of breast, head and neck, and nervous system cancers. Millions of women with breast cancer and other tumor histotypes have benefited from anti-HER2 antibody 89 , however monoclonal antibody localization and penetration have limited clinical response 90,91 . Further, HER2 expression on some malignancies, (eg.…”