Trastuzumab

Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer.[11][12][13] It is specifically used for cancer that is HER2 receptor positive.[11] It may be used by itself or together with other chemotherapy medication.[11] Trastuzumab is given by slow injection into a vein and injection just under the skin.[11][14]

Common side effects include fever, infection, cough, headache, trouble sleeping, and rash.[11] Other severe side effects include heart failure, allergic reactions, and lung disease.[11] Use during pregnancy may harm the baby.[15] Trastuzumab works by binding to the HER2 receptor and slowing down cell replication.[11]

Trastuzumab was approved for medical use in the United States in September 1998, and in the European Union in August 2000.[16][17] It is on the World Health Organization's List of Essential Medicines.[18]

Medical uses

The safety and efficacy of trastuzumab-containing combination therapies (with chemotherapy, hormone blockers, or lapatinib) for the treatment of metastatic breast cancer. The overall hazard ratios (HR) for overall survival and progression free survival were 0.82 and 0.61, respectively. It was difficult to accurately ascertain the true impact of trastuzumab on survival, as in three of the seven trials, over half of the patients in the control arm were allowed to cross-over and receive trastuzumab after their cancer began to progress.[19] Thus, this analysis likely underestimates the true survival benefit associated with trastuzumab treatment in this population.[20]

In early-stage HER2-positive breast cancer, trastuzumab-containing regimens improved overall survival (Hazard ratio (HR) = 0.66) and disease-free survival (HR = 0.60). Increased risk of heart failure (RR = 5.11) and decline in left ventricular ejection fraction (relative risk RR = 1.83) were seen in these trials as well. Two trials involving shorter term treatment with trastuzumab did not differ in efficacy from longer trials, but produced less cardiac toxicity.[21]

The original studies of trastuzumab showed that it improved overall survival in late-stage (metastatic) HER2-positive breast cancer from 20.3 to 25.1 months.

Adverse effects

Some of the common side effects of trastuzumab are flu-like symptoms (such as fever, chills and mild pain), nausea and diarrhea.[32]

One of the more serious complications of trastuzumab is its effect on the heart, although this is rare.[32] In 2–7% of cases,[33] trastuzumab is associated with cardiac dysfunction, which includes congestive heart failure. As a result, regular cardiac screening with either a MUGA scan or echocardiography is commonly undertaken during the trastuzumab treatment period. The decline in ejection fraction appears to be reversible.[34]

Trastuzumab downregulates neuregulin-1 (NRG-1), which is essential for the activation of cell survival pathways in cardiomyocytes and the maintenance of cardiac function. NRG-1 activates the MAPK pathway and the PI3K/AKT pathway as well as focal adhesion kinases (FAK).

Mechanism of action

The HER2 gene (also known as HER2/neu and ErbB2 gene) is amplified in 20–30% of early-stage breast cancers.[25] Trastuzumab is a monoclonal antibody targeting HER2, inducing an immune-mediated response that causes internalization and recycling of HER2. It may also upregulate cell cycle inhibitors such as p21Waf1 and p27Kip1.[38]

The HER2 pathway promotes cell growth and division when it is functioning normally; however, when it is overexpressed, cell growth accelerates beyond its normal limits. In some types of cancer, the pathway is exploited to promote rapid cell growth and proliferation and hence tumor formation.[39] The EGF pathway includes the receptors HER1 (EGFR), HER2, HER3, and HER4; the binding of ligands (e.g. EGF etc.) to HER receptors is required to activate the pathway.[39] The pathway initiates the MAP kinase pathway as well as the PI3 kinase/AKT pathway, which in turn activates the NF-κB pathway.[40]

Predicting response

Trastuzumab inhibits the effects of overexpression of HER2. If the breast cancer does not overexpress HER2, trastuzumab will have no beneficial effect (and may cause harm). Doctors use laboratory tests to discover whether HER2 is overexpressed. In the routine clinical laboratory, the most commonly employed methods for this are immunohistochemistry (IHC) and either silver, chromogenic or fluorescent in situ hybridisation (SISH/CISH/FISH). HER2 amplification can be detected by virtual karyotyping of formalin-fixed paraffin embedded tumor. Virtual karyotyping has the added advantage of assessing copy number changes throughout the genome, in addition to detecting HER-2 amplification (but not overexpression). Numerous PCR-based methodologies have also been described in the literature.[49] It is also possible to estimate HER2 copy number from microarray data.[50]

There are two FDA-approved commercial kits available for HER2 IHC; Dako HercepTest[51] and Ventana Pathway.[52]

Resistance

One of the challenges in the treatment of breast cancer patients by herceptin is our understanding towards herceptin resistance. In the last decade, several assays have been performed to understand the mechanism of Herceptin resistance with/without supplementary drugs. Recently, all this information has been collected and compiled in form of a database HerceptinR.[55]

History

The drug was first discovered by scientists including Axel Ullrich and H. Michael Shepard at Genentech, Inc. in South San Francisco, CA.[56] Earlier discovery about the neu oncogene by Robert Weinberg's lab [57] and the monoclonal antibody recognizing the oncogenic receptor by Mark Greene's lab [58] also contributed to the establishment of HER2 targeted therapies. Dr. Dennis Slamon subsequently worked on trastuzumab's development. A book about Dr. Slamon's work was made into a television film called Living Proof, that premiered in 2008. Genentech developed trastuzumab jointly with UCLA, beginning the first clinical trial with 15 women in 1992.[59] By 1996, clinical trials had expanded to over 900 women, but due to pressure from advocates based on early success, Genentech worked with the FDA to begin a lottery system allowing 100 women each quarter access to the medication outside the trials.[60]

Society and culture

Further reading

External links