The medical community has been amazed and troubled by the advances in biologic and targeted therapies such as gefitinib (Iressa), bevacizumab (Avastin), and certuximab (Erbitux). These therapies target, in a minimally toxic fashion, receptors known to predominate in specific cancers. But these drugs have not delivered the magnitude of the promise to patients that many expected, in part due to the lack of a testing process that identified patients who could respond to the therapy. This is changing. There are now a number of laboratory tests that are better able to predict the ability of these drugs to produce positive outcomes.
These new tests can help to direct clinicians to the proper treatment of disease when using these new drugs. This approach, called pharmacogenetic testing, is expanding rapidly. Pharmacogenetic testing is closely tied to but distinct from pharmacogenomics.
A basic definition of pharmacogenetics is the use of genetic information to help in the therapeutic treatment of a disease. Pharmacogenomics, on the other hand, can be defined as the study of how a person's genetic makeup determines response to a drug. The exciting part of this field is that some tests are already available commercially and the number is growing rapidly. In addition, pharmacogenetic tests are also becoming available for a number of other conditions, including viral diseases such as HIV and hepatitis C. Some tests can measure the presence and function of the cytochrome P450 enzyme system. These tests will not be confined to laboratory experiments, but will be of clinical import in the offices of practicing physicians.
The first drug that might come to mind is probably trastuzumab (Herceptin), which is associated with a positive Her2/neu test. The Her2 is a biomarker protein in the tyrosine kinase family. The protein is a product of the Her2 gene that is overexpressed in breast cancer, producing an overabundance of Her2 receptors in 25–30 percent of human breast cancers. This protein is found more commonly in higher grades of breast cancers, in particular ductal type. This family of proteins controls cellular processes by switching on or off various activities such as cell division. In particular, the Her2 receptor, when activated by the appropriate ligand and teamed up with other Her2 receptors in a complex called a dimer, acts as an amplifier for cellular division and is known to lead to cancer. Although not the cause of or present in all breast cancer, the presence of Her2 gene amplification and subsequent Her2 protein overexpression appears to be an independent, albeit poor prognostic sign.
This overexpression of Her2 also predicts relative resistance to some chemotherapy drugs such as cytoxan, methotrexate, and 5-flourouricil and relatively higher sensitivity to anthracyclines. It also predicts a poor response to tamoxifen even if a positive estrogen receptor is present.
Finally, it can be used to select patients who are eligible for the targeted therapy trastuzumab. Trastuzumab targets the Her2/neu extracellular portion of the protein and inhibits the proliferation signal. Trastuzumab's label specifically ties the presence of the Her2 receptor overexpression to the success of this antibody in the treatment of breast cancer.
A second drug that benefits from genetic testing is imatinib mesylate (Gleevec), used for the treatment of chronic myelogenous leukemia.
Definitive diagnosis of CML is established through genetic testing using a cytogenetic analysis of bone marrow aspirates for the Philadelphia chromosome, a translocation between chromosome 9 and 22 that brings together the BCR gene on chromosome 22 and the ABL gene on chromosome 9. The imatinib test will measure the presence of the receptor and its level of overexpression.
Imatinib mesylate is a small molecule protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the abnormal tyrosine kinase created by the Philadelphia chromosome. Imatinib inhibits proliferation and induces apoptosis in the BCR-ABL positive cell lines.
Gefitinib (Iressa) is another tyrosine kinase that has been approved for the treatment of non-small-cell lung cancer (NSCLC), a leading cause of cancer death in the U.S. Current conventional chemotherapy only slightly prolongs life. Gefitinib targets the epidermal growth factor receptor (EGFR) that is overexpressed in 40–80 percent of all NSCLCs.
In a recent New England Journal of Medicine article, Lynce et al demonstrated that mutations in the EGFR binding site for gefitinib were far more common in those patients responding to this drug than for those who did not respond.
The mutation was not found in those patients for whom treatment failed. The utility of a genetic test for identification of patients who may benefit most from gefitinib is obvious. Those in whom the drug is likely to work could benefit and those in whom the drug is unlikely to work could avoid delaying other therapy and avoid the cost of this relatively expensive drug. A clinically relevant test for this specific EGFR is likely in the near future.
Drug resistance testing in HIV
Finally, drug resistance testing for viral infections is now considered standard of care for HIV. The Panel on Clinical Practices of HIV Infection convened by the U.S. Department of Health and Human Services recommends drug resistance testing when there is a failure of combined antiretroviral therapy, or when there is suboptimal suppression of viral load after initiation of antiretroviral therapy. The goal is to determine whether a drug-resistant virus is the cause of the infection.
Genetic sequencing of HIV is one way to determine drug resistance. TruGene, an FDA-approved test marketed by Bayer Healthcare, offers one solution. This test can be done in a laboratory or clinic. In involves genetic sequencing of the entire virus and employs a powerful, constantly updated algorithm to guide treatment options. The reports clearly point clinicians to resistance or sensitivity of the various antiretroviral therapies.
Soon, tests will be available for many of the new biologics as well as for the small molecules that target specific receptors. Managed care decision makers should remain aware of development in this field. As tests become available, they should be considered for inclusion into approval criteria in order to improve selection of patients for specific therapies.
Health plans should encourage the FDA and manufacturers to lead the research on target testing to decrease the number of nonresponders to these innovative, targeted, but expensive therapies. There will be a continuous parade of new targeted small and large molecule therapies that will continue to provide exciting reading in Tomorrow's Medicine!