Speaking of breast cancer - we’re on a roll this month! - there are very important happenings at the FDA next week. On October 18, the FDA will to evaluate recent research regarding 2D6 gene variants and response to the breast cancer drug, tamoxifen, and whether this research warrants any warnings or changes to the tamoxifen package insert.
In concert with the hearing, DNA Direct is launching our first drug metabolism test: 2D6 testing with personalized test results interpretation for tamoxifen. (Testing can be ordered online at the Genes&Drugs website.) Below is DNA Direct’s backgrounder, which explains the test, the research and why we’re offering 2D6 Tamoxifen testing to certain patient populations.
TAMOXIFEN & 2D6 BACKGROUNDER
Recent research on tamoxifen has shown that potentially up to 7-10% of women with breast cancer may not receive the full medical benefit from taking tamoxifen, because of their unique genetic make-up. These women have a special version of a gene (CYP2D6, commonly referred to as 2D6), which may reduce the effectiveness of tamoxifen and increase their chance of breast cancer recurrence. With over 500,000 women currently taking tamoxifen, this research has wide-reaching implications.
FDA and Tamoxifen: What’s Happening? Given the recent research, the FDA has taken action and is closely examining the clinical evidence regarding 2D6 genotype as an indicator of tamoxifen efficacy. The FDA’s Clinical Pharmacology Subcommittee is scheduled to review the research and the package insert for tamoxifen on October 18, 2006 in Washington, D.C. The Subcommittee will then decide whether to recommend revising the tamoxifen label to include information about 2D6 testing for post-menopausal women considering tamoxifen therapy.
Why Hasn’t This Information Come Out Before? The decoding of the human genome has made it possible to explore disease and treatment through a new, molecular lens. Although tamoxifen has been in use for over two decades, it has only recently been possible to research the genetic relationship between the drug and the 2D6 gene. In fact it was just last June that important new information was presented at the annual meeting of the American Society of Clinical Oncology.
Scientific Background on Tamoxifen and 2D6 A group of genes called the cytochrome P450s play an important role in how drugs and toxins are metabolized in the liver. One particular gene, called CYP2D6 (pronounced “sip-2-d-6″), and commonly referred to as 2D6, is present in different forms in different people. The 2D6 enzyme is responsible for metabolizing tamoxifen to its most active form, endoxifen. Endoxifen is the active agent that helps prevent hormone-positive breast cancer from recurring. It is 100 times more potent than tamoxifen itself.
Seven to ten percent of Caucasians have a form of 2D6 that produces an inactive enzyme, which means the drug doesn’t metabolize as it should. These people are known as “poor metabolizers.”
Studies have shown that people who are “poor metabolizers” produce endoxifen at very low levels. Retrospective data on 250 patients presented at the ASCO Clinical Science Symposium this year suggest that certain forms of the 2D6 gene correlate with worse relapse-free survival and disease-free survival in hormone-positive, tamoxifen-treated patients. Supporting data for this exists in the published literature.
Tamoxifen and Paxil: Contraindications Other factors besides genetics may play a role in the way a patient can metabolize tamoxifen. The FDA is also evaluating the research indicating that some serotonin reuptake inhibitors (SSRIs) interfere with the metabolism and efficacy of tamoxifen.
SSRIs, such as Paxil, are frequently prescribed to women to reduce hot flashes and other uncomfortable side effects or to treat depression. Many of these same women are taking tamoxifen. Recent research has shown that certain SSRI antidepressants interfere with the body’s ability to metabolize tamoxifen. As a result, taking these medications can “cancel out” the cancer-preventing benefits of taking tamoxifen.
If the enzymatic process that converts tamoxifen to endoxifen is interrupted — either because someone is a poor metabolizer or because they are taking SSRI antidepressants — the therapeutic effects of tamoxifen are significantly reduced.
Not all antidepressants affect the 2D6 enzyme in the same way, which means they don’t all have the same effect on tamoxifen. While Paxil has been shown to interfere with tamoxifen metabolism, other drugs such as Effexor do not inhibit 2D6 enzymes and therefore may provide alternatives for women on tamoxifen.
What Can Women Taking Tamoxifen Do? Women who are taking (or considering taking) tamoxifen will be particularly interested in this latest research and the FDA hearings. While the FDA deliberates, it is possible for women to consider being tested for the 2D6 gene. The test isn’t useful for everyone, but there is a target population that could significantly benefit from this type of genetic knowledge.
Who is Appropriate for 2D6 Testing? The 2D6 test for tamoxifen is only appropriate for postmenopausal women who are taking or considering taking tamoxifen to prevent the recurrence of breast cancer. Knowing their genetic status, women can work with their physician to perhaps take into consideration other equally effective treatments, such as aromatase inhibitors.
Testing is not appropriate for pre- or perimenopausal women because knowing their genetic status at this time would not change the treatment recommendation. This is because there are no hormonal treatments that are equally as effective as tamoxifen for these women. (It is possible that this may change as more data is gathered about 2D6 and tamoxifen.)
Testing is not appropriate for women with hormone-negative cancers, because tamoxifen is not a recommended treatment for these cancers. Test results will not provide helpful information regarding treatment options for these cancers.
Testing is not appropriate for women who have not had breast cancer but are considered high-risk, since there is not enough data about this situation to make recommendations at this time.
Who is DNA Direct? DNA Direct, a web-based genetic testing and counseling service, has been monitoring recent developments in science related to genetic testing and pharmacogenomic labeling. DNA Direct will begin offering a Tamoxifen Test (2D6) beginning October 19, 2006 for $300 to provide postmenopausal women with genetic information needed to make informed treatment decisions.
The Ethics of Testing and Informed Choice DNA Direct’s ethical responsibility to our patients and customers is to provide them with currently reliable scientific and medical information. We believe that when adequately informed, people can carefully balance risks and benefits to make informed treatment decisions. For postmenopausal women, 2D6 testing information can help patients and their healthcare providers optimize medical management and consequently decrease their risk of breast cancer recurrence. Thus we advocate providing 2D6 testing for this group of patients.
However, because pharmacogenetics is a relatively new and growing area of research, information on tamoxifen is not available for all categories of patients. For pre- and perimenopausal women we believe more research is still needed before 2D6 is a valuable tool for optimizing therapy for this population. Until that time, we err on the side of caution and recommend waiting for more evidence is available.
Tamoxifen Testing Women can order testing directly from DNA Direct via the website, Genes & Drugs (www.genesanddrugs.com). Physicians can also order testing for their patients via this website. A cheek swab is all that is needed to obtain a DNA sample for testing. Our Customer Service department can be reached at 1-877-646-0222 and email@example.com.