Breast Cancer Symposium

Mayo study further confirms the importance of CYP2D6 for tamoxifen effectiveness building the case for genotyping and medication management

Mayo gave a presentation on December 11th at the 31st annual San Antonio Breast Cancer Symposium that further confirms the importance of the liver enzyme CYP2D6 in tamoxifen effectiveness. Tamoxifen is often prescribed to block the effects of estrogen in breast tissue to prevent breast cancer recurrence in ER+ (estrogen receptor positive) cancers which require estrogen to grow and spread. Previous studies have already revealed that tamoxifen is less effective in women with reduced CYP2D6 activity caused by genetic variations or co-administration with medications that inhibit CYP2D6, but the mechanism of action for tamoxifen was not well understood.

Tamoxifen is a pro-drug that is metabolized and converted into the metabolites endoxifen and 4HT; both previously believed to play a key role in suppressing estrogen. However, Mayo’s study shows that endoxifen degrades estrogen receptors in breast cancer cells and is the key metabolite involved in the effectiveness of tamoxifen. Since CYP2D6 is the enzyme that converts tamoxifen to endoxifen; this study further indicates that widespread genotyping and medication management can improve outcomes for many of the 35% of ER positive breast cancer patients who currently fail tamoxifen treatment.

On October 18, 2006, an FDA Advisory Subcommittee was convened to review the tamoxifen research findings to date and to make a recommendation regarding a label change. The consensus of the Subcommittee was that the label should be updated to reflect the fact that postmenopausal women with ER-positive breast cancer who are CYP2D6 poor metabolizers treated with tamoxifen (by genotype or drug interaction) are at increased risk for breast cancer recurrence. This label change has still not been made, and now the case is even stronger.
So, what can be done with this information to reduce the risk of breast cancer recurrence?
First, genotyping should be considered for every ER-positive breast cancer patient taking tamoxifen. Insurance typically covers testing, and alternative therapies exist for treatment for the 10% of patients who are CYP2D6 poor metabolizers.

Second, medication management involving the careful monitoring of tamoxifen co-administration with other medications, herbals, and over-the-counters needs to happen. For example, “hot flashes,” a common side effect of tamoxifen, are typically treated with selective serotonin reuptake inhibitors, and fluoxetine, paroxetine and high doses of sertraline are notoriously potent CYP2D6 inhibitors. Additionally, 35% of patients are CYP2D6 intermediate metabolizers and are at risk with less potent inhibitors of CYP2D6 such as the commonly used herbal goldenseal as shown in the interaction report below.

Genelex includes access to GeneMedRx drug and gene interaction software with each tamoxifen CYP2D6 test so healthcare providers and patients can quickly see if co-administration is going to reduce CYP2D6 activity.

Mayo’s study has confirmed the critical role of CYP2D6 in tamoxifen treatment. It is time to start putting this research to use in the clinic.

DID YOU KNOW?

The genetic code in your DNA breaks down into just four basic building blocks or nucleotides represented by letters: A/adenine, T/thymine, G/guanine, C/cytosine

More than 99% of human DNA sequences are the same across human populations. The main differences occur when a single nucleotide (A,T,C,or G) in the genome sequence is altered.
These single letter changes are called single nucleotide polymorphisms or SNPs (pronounced "snips"). For example a SNP might change the DNA sequence from AAGGCTAA to ATGGCTAA.
SNP’s represent about 90% of human genetic.

Only DNA Testing Can Tell. Twins- Identical? Fraternal?

Approximately one in every eighty births results in the delivery of twins. Although the misconception persists, the number of placentas cannot determine if same-sex twins are fraternal or identical - only DNA testing can. One third of identical twins have two placentas and more than 40% of fraternal twins have a single, fused placenta.

DNA testing to determine if twins are identical or fraternal is called twin zygosity testing. Twins that are dizygotic or fraternal are the result of two different sperm fertilizing two different eggs and share only the same amount of DNA as full siblings born at different times.

Monozygotic or identical twins are the result of one egg fertilized by a single sperm that splits in two and have identical DNA. Most twins have zygosity testing performed simply to satisfycuriosity. However, knowing if twins are identical or fraternal can be a safeguard for possible future medical emergencies—identical twins are perfect organ and tissue donors for one another.

Although identical twins often look so much alike that we have difficulty recognizing one from the other, many do notbecause their genes express themselves in different ways. Alternatively, fraternal twins can appear to be identical when they are not, like the famous Olsen twins. If you are a twin or know a twin that has ever wondered, DNA testing is the only way to answer the question with certainty.