Трастузумаб: Эффективность и проблемы применения при раке молочной железы и желудка.

Medication

Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. Common side effects include fever, infection, cough, headache, trouble sleeping, and rash. Trastuzumab works by binding to the HER2 receptor and slowing down cell replication. It is on the World Health Organization's List of Essential Medicines.

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. Thus, this analysis likely underestimates the true survival benefit associated with trastuzumab treatment in this population. 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). 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. Trastuzumab has had a "major impact in the treatment of HER2 positive metastatic breast cancer." The combination of trastuzumab with chemotherapy has been shown to increase both survival and response rate, in comparison to trastuzumab alone. It is possible to determine the "erbB2 status" of a tumor, which can be used to predict efficacy of treatment with trastuzumab. If it is determined that a tumor is overexpressing the erbB2 oncogene and the patient has no significant pre existing heart disease, then a patient is eligible for treatment with trastuzumab. It is surprising that although trastuzumab has great affinity for HER2 and high doses can be administered (because of its low toxicity), 70% of HER2+ patients do not respond to treatment. In fact resistance to the treatment develops rapidly, in virtually all patients. A mechanism of resistance involves failure to downregulate p27 (Kip1) as well as suppressing p27 translocation to the nucleus in breast cancer, enabling cdk2 to induce cell proliferation.

The optimal duration of add on trastuzumab treatment after surgery for early breast cancer is unknown. One year of treatment is generally accepted based on clinical trial evidence that demonstrated the superiority of one year treatment over none. However, a small Finnish trial also showed similar improvement with nine weeks of treatment over no therapy. Because of the lack of direct head to head comparison in clinical trials, it is unknown whether a shorter duration of treatment may be just as effective (with fewer side effects) than the accepted practice of treatment for one year. Debate about treatment duration has become a relevant issue for many public health policy makers because administering trastuzumab for a year is very expensive. Consequently, some countries with a taxpayer funded public health system, such as New Zealand, chose to fund limited adjuvant therapy. However, subsequently New Zealand has revised its policy and now funds trastuzumab treatment for up to 12 months.

Some of the common side effects of trastuzumab are flu like symptoms (such as fever, chills and mild pain), nausea and diarrhea. One of the more serious complications of trastuzumab is its effect on the heart, although this is rare. 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. 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). These are all significant for the function and structure of cardiomyocytes. Trastuzumab can therefore lead to cardiac dysfunction. Trastuzumab may harm a developing fetus.

The HER2 gene (also known as HER2/neu and ErbB2 gene) is amplified in 20–30% of early stage breast cancers. 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. 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. In cancer cells the HER2 protein can be expressed up to 100 times more than in normal cells (2 million versus 20,000 per cell). The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell (molecules called EGFs) to inside the cell, and turn genes on and off. The HER (human epidermal growth factor receptor) protein, binds to human epidermal growth factor, and stimulates cell proliferation. In some cancers, notably certain types of breast cancer, HER2 is over expressed and causes cancer cells to reproduce uncontrollably. HER2 is localized at the cell surface, and carries signals from outside the cell to the inside. Signaling compounds called mitogens (specifically EGF in this case) arrive at the cell membrane, and bind to the extracellular domain of the HER family of receptors. Those bound proteins then link (dimerize), activating the receptor. HER2 sends a signal from its intracellular domain, activating several different biochemical pathways. These include the PI3K/Akt pathway and the MAPK pathway. Signals on these pathways promote cell proliferation and the growth of blood vessels to nourish the tumor (angiogenesis). ERBB2 is the preferred dimerization partner for the other family members and ERBB2 heterodimers signaling is stronger and longer acting compared to heterodimers between other ERBB members. It has been reported that Trastuzumab induces the formation of complementarity determining regions (CDRs) leading to surface redistribution of ERBB2 and EGFR in CDRs and that the ERBB2 dependent MAPK phosphorylation and EGFR/ERBB1 expression are both required for CDR formation. CDR formation requires activation of both the protein regulator of actin polymerization N WASP, mediated by ERK1/2, and of the actin depolymerizing protein cofilin, mediated by EGFR/ERBB1. Furthermore, this latter event may be inhibited by the negative cell motility regulator p140Cap, as we found that p140Cap overexpression led to cofilin deactivation and inhibition of CDR formation. Normal cell division—mitosis—has checkpoints that keep cell division under control. Some of the proteins that control this cycle are called cdk2 (CDKs). Overexpression of HER2 sidesteps these checkpoints, causing cells to proliferate in an uncontrolled fashion. Trastuzumab binds to domain IV of the extracellular segment of the HER2/neu receptor. Monoclonal antibodies that bind to this region have been shown to reverse the phenotype of HER2/neu expressing tumor cells. Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferation. It has been suggested that trastuzumab does not alter HER 2 expression, but downregulates activation of AKT. Experiments in laboratory animals indicate that antibodies, including trastuzumab, when bound to a cell, induce immune cells to kill that cell, and that such antibody dependent cell mediated cytotoxicity is another important mechanism of action.

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. It is also possible to estimate HER2 copy number from microarray data. There are two FDA approved commercial kits available for HER2 IHC; Dako HercepTest and Ventana Pathway. Fluorescent in situ hybridization (FISH) is viewed as being the "gold standard" technique in identifying patients who would benefit from trastuzumab, but it is expensive and requires fluorescence microscopy and an image capture system. The main expense involved with CISH is in the purchase of FDA approved kits, and as it is not a fluorescent technique it does not require specialist microscopy and slides may be kept permanently. Comparative studies of CISH and FISH have shown that these two techniques show excellent correlation. The lack of a separate chromosome 17 probe on the same section is an issue with regards to acceptance of CISH. As of June 2011 Roche has obtained FDA approval for the INFORM HER2 Dual ISH DNA Probe cocktail developed by Ventana Medical Systems.

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.

The drug was first discovered by scientists including Axel Ullrich and H. Michael Shepard at Genentech, Inc. in South San Francisco, CA. Earlier discovery about the neu oncogene by Robert Weinberg's lab and the monoclonal antibody recognizing the oncogenic receptor by Mark Greene's lab 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. 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. Herceptin was Fast tracked by the FDA and gained approval in September 1998.

Trastuzumab costs about for a full course of treatment. Australia has negotiated a lower price of A$50,000 per course of treatment. Since October 2006, trastuzumab has been made available for Australian women and men with early stage breast cancer via the Pharmaceutical Benefits Scheme. This is estimated to cost the country over A$470 million for 4–5 years supply of the drug. Roche has agreed with Emcure in India to make an affordable version of this cancer drug available to the Indian market. Roche has changed the brand name of the drug and has re introduced an affordable version of the same in the Indian market. The new drug named Herclon would cost approximately RS75,000 INR (1,200) in the Indian market. On 16 September 2014, Genentech notified hospitals in the United States that, as of October, trastuzumab could only be purchased through their selected specialty drugs distributors not through the usual general line wholesalers. By being forced to purchase through specialty pharmacies, hospitals lost rebates from the big wholesalers and the ability to negotiate cost minus discounts with their wholesalers.