Role of trastuzumab in the management of HER2-positive metastatic breast cancer

Abstract

Breast cancer is a major health issue in developed countries. Overexpression of HER2, a member of epidermal growth factor receptor family, occurs in 20%-30% of breast cancers. HER2 drives the cancer cells to develop a more aggressive phenotype, to metastasize to viscera and central nervous system, and to be less sensitive to chemotherapeutic agents. Trastuzumab (Herceptin  ) is a monoclonal antibody directed against the extracellular domain of HER2. As single agent or with chemotherapy, trastuzumab improves survival of HER2-positive breast cancers. In the past years, trastuzumab has completely revolutionized the scenario of the treatment of HER2-positive breast cancer, representing one of the most remarkable examples of targeted therapy in oncology. However, issues such as the best chemotherapeutic companion to associate with trastuzumab, cardiac toxicities, and clinical resistance still require tremendous efforts by researchers. Here, we review pharmacology, efficacy studies, and toxicities of trastuzumab in metastatic breast cancer. Moreover, we provide some insights on resistance to therapy. Finally, we briefly discuss trastuzumab's place in the clinical setting.

The Clinical Efficacy and Safety of Neratinib in Combination with Capecitabine for the Treatment of Adult Patients with Advanced or Metastatic HER2-Positive Breast Cancer

“…In the last twenty years, since the introduction of trastuzumab, the first HER2-directed monoclonal antibody, the natural history of HER2 positive breast cancer has improved considerably. 5 …”

“…In the last twenty years, since the introduction of trastuzumab, the first HER2-directed monoclonal antibody, the natural history of HER2 positive breast cancer has improved considerably. 5 Fueled by further exploiting the therapeutic potential of HER2 targeting and to overcome pharmacological resistance, the armamentarium of new drugs is in constant expansion, resulting in significant improvements in the outlook of women bearing this subset of breast cancer.…”

Actein Inhibits Tumor Growth and Metastasis in HER2-Positive Breast Tumor Bearing Mice via Suppressing AKT/mTOR and Ras/Raf/MAPK Signaling Pathways

“…However, one of the major challenges in the treatment of HER2-positive metastatic breast cancer is brain metastases, in which a previous study demonstrated that up to 50% of the metastatic HER2-positive breast cancer patients eventually died of central nervous system (CNS) progression (10). This may due to the fact that trastuzumab and pertuzumab are unable to penetrate the blood-brain-barrier (BBB) because of the large molecular weight (11)(12)(13). Patients with metastatic HER2-positive breast cancer receiving front-line therapeutics have higher incidences of CNS metastases ranging from 28 to 43% (10) than those reported historically (9).…”

Dual targeting of HER2-positive breast cancer with trastuzumab emtansine and pertuzumab: understanding clinical trial results

“…Several preclinical studies have not shown substantial down-regulation of cell surface HER2 by anti-ectodomain antibodies in HER2-overexpressing cells [ 24 – 26 ]. However, competitive binding and steric interference could represent potential mechanisms of resistance to this drug combination [ 27 ]. These pre-clinical results might explain the disappointing efficacy results of T-DM1-P observed in the KRISTINE and MARIANNE trials.…”