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Harvard Commentaries
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Reviewed by the Faculty of Harvard Medical School

Highlight on Drugs Highlight on Drugs

Drug Therapy And Your Genes (Part 1 of 2)

September 23, 2013

By Harold J. DeMonaco M.S.

Harvard Medical School

We have known for many years that drugs do not always work the same way in all people. Although there are many factors that may be responsible for the difference in response to a drug, your genes may play a larger role than we once believed.

In this column I will discuss benefits being discovered by researchers. Next month, I will write about the social and ethical concerns surrounding the field of genes and medicine, or pharmacogenetics.

Recent reports highlight why genetic testing will become important in the near future for all of us. Researchers at the Massachusetts General Hospital and at the Dana-Farber Cancer Center identified a gene mutation that appears to predict which patients with lung cancer will respond to a drug called gefitinib (Iressa). Prior to the discovery, scientists were puzzled by the results of the clinical studies with the drug. Only a small number of people appeared to be helped by Iressa. But when the drug worked, the results were impressive.

Women with the lung cancer adenocarcinoma who had no history of smoking appeared to do well when treated with Iressa. Curiously, people of Japanese descent also appeared to do well with the drug. By closely examining tumor samples taken from people who did and did not respond to Iressa, scientists were able to unravel the mystery. People who responded to Iressa appeared to have a very specific mutation of a gene called EGFR. In theory, you will have better results using Iressa if you have the gene mutation than if you do not. Testing for this gene mutation is now being performed in patients with this form of lung cancer at the Massachusetts General Hospital and at other institutions in an effort to find out if this is indeed true.

The science of pharmacogenetics is relatively new. One of the early findings related to genetic differences involved a chemical called phenylthiourea (PTU). PTU is an interesting chemical. Some people find its taste to be very bitter, while others cannot taste the chemical at all. When scientists looked more carefully, they recognized a pattern. The ability to taste PTU appeared to be related to heredity. For example, only about 6% of people with Chinese ancestry can taste the bitterness of PTU. About 25% of African Americans, however, find PTU to be bitter tasting. Although the early studies looked at racial differences, we now know that the differences are not limited to race.

Our genes appear to also play an important role in our response to many therapies, not just cancer treatment. For example, a combination of two older drugs (hydralazine and isosorbide) has all but been abandoned in the treatment of congestive heart failure. The drugs were shown to be of limited usefulness in several studies done in the late 1980s. But the people who were subjects in the study were almost all white. We now know that the drug combination does work in African Americans with congestive heart failure.

Another example of genes playing a role in drug response is an anticancer drug called Herceptin. Herceptin is an antibody that is used in the treatment of breast cancer. It targets the action of a gene mutation called the HER2 gene. About 20% to 30% of people with breast cancer, regardless of race, have an excess of the HER2 gene. These are the people who respond the best to Herceptin treatment for their breast cancer.

Genetic testing is now a part of many studies involving new drug therapies. Genetic differences are likely to become more important as drugs become more specific and more expensive. Differences in response to drugs used to treat asthma, high blood pressure and many other chronic diseases have been linked to genetic differences. Next month in Part 2, I will explore the social issues around genetic testing for drug response.

Harold J. DeMonaco, M.S. is senior clinical associate in the Decision Support and Quality Management Unit at the Massachusetts General Hospital and is currently a Visiting Scholar at the MIT Sloan School of Management. He is author of over 20 publications in the pharmacy and medical literature and routinely reviews manuscript submissions for eight medical journals.

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