trastuzumab

trastuzumab is a monoclonal antibody used to treat breast cancer and gastric cancer that tests positive for the HER2 protein. Developed by Genentech, it is marketed under the brand name Herceptin and works by binding to the HER2/neu receptor to inhibit the growth of cancer cells. Its introduction marked a significant advancement in targeted therapy for oncology, transforming the prognosis for a specific subset of patients.

Medical uses

trastuzumab is indicated for the treatment of HER2-positive breast cancer, including in the adjuvant, neoadjuvant, and metastatic settings. It is also approved for HER2-positive gastric or gastroesophageal junction adenocarcinoma. Treatment typically follows confirmation of HER2 status through diagnostic tests like immunohistochemistry or fluorescence in situ hybridization, as recommended by guidelines from the American Society of Clinical Oncology and the College of American Pathologists. It is often combined with chemotherapy agents such as paclitaxel, docetaxel, or carboplatin, and in metastatic disease, it may be used with pertuzumab and docetaxel as part of the CLEOPATRA regimen.

Mechanism of action

The drug exerts its effects by specifically binding to the extracellular domain of the HER2/neu receptor, a member of the epidermal growth factor receptor family that is overexpressed in certain cancers. This binding inhibits the dimerization of HER2 with other receptors like HER3, thereby blocking the activation of downstream signaling pathways such as the MAPK/ERK pathway and the PI3K/AKT/mTOR pathway that promote cell proliferation and survival. Additionally, trastuzumab mediates antibody-dependent cellular cytotoxicity by recruiting immune effector cells like natural killer cells, and it may inhibit angiogenesis and promote apoptosis.

Adverse effects

Common adverse effects include fever, chills, and infusion-related reactions, which often occur with the first administration. Cardiotoxicity, manifesting as a reduction in left ventricular ejection fraction or congestive heart failure, is a significant concern, particularly when used with anthracycline chemotherapy like doxorubicin; monitoring by echocardiogram is standard. Other potential effects include pulmonary toxicity, neutropenia, and diarrhea. The U.S. Food and Drug Administration maintains a black box warning regarding cardiomyopathy, infusion reactions, and embryo-fetal toxicity.

History

The development of trastuzumab was pioneered by scientists at Genentech, including Dennis J. Slamon of the University of California, Los Angeles, following research into the HER2/neu oncogene by Robert A. Weinberg. The pivotal clinical trial, published in the New England Journal of Medicine in 2001, demonstrated a survival benefit in metastatic breast cancer. It received accelerated approval from the U.S. Food and Drug Administration in 1998, becoming one of the first targeted therapies in oncology. Subsequent studies, such as the HERA trial and the NSABP B-31 trial, established its efficacy in the adjuvant setting.

Society and culture

The high cost of trastuzumab has sparked significant debate over drug pricing and access to cancer treatments globally, with advocacy by groups like the World Health Organization. It is included on the WHO Model List of Essential Medicines. The drug's development story was featured in the BBC documentary "The Cancer Emperor" and influenced narratives in books like "The Emperor of All Maladies" by Siddhartha Mukherjee. Legal battles over patents, such as those involving Roche and biosimilar manufacturers like Mylan, have also been prominent in the pharmaceutical industry.

Category:Monoclonal antibodies Category:Antineoplastic drugs Category:Genentech