Study Suggests Earlier Research on CYP2D6 Is Flawed
A study by researchers at the Mayo Clinic suggests that the large studies on the link between CYP2D6 and tamoxifen's effectiveness may be flawed because the studies did the genetic testing on samples of tissue from the breast cancer rather than on healthy tissue.
Tamoxifen is a hormonal therapy medicine that is used in several different ways to treat different types of breast cancer:
- It’s used to lower the risk of breast cancer coming back (recurrence) in men and women diagnosed with early-stage, hormone-receptor-positive breast cancer after surgery. Doctors call tamoxifen used in this way adjuvant hormonal therapy.
- Tamoxifen also is used to treat women and men diagnosed with advanced-stage or metastatic hormone-receptor-positive disease.
- Finally, tamoxifen is used to reduce breast cancer risk in women who haven’t been diagnosed but are at higher-than-average risk.
The body uses an enzyme called CYP2D6 to convert tamoxifen into its active form. The CYP2D6 enzyme is made by the CYP2D6 gene. About 10% of people have a CYP2D6 genotype (a classification of the CYP2D6 gene) that doesn’t function as it should and so doesn’t make enough of the CYP2D6 enzyme. Some smaller studies found that people with certain CYP2D6 genotypes might not get all the benefits of tamoxifen. After these smaller studies were published, some doctors and women began to ask for CYP2D6 genetic testing.
But CYP2D6 testing is controversial because several large studies then found no link between CYP2D6 genotypes and the effectiveness of tamoxifen.
A new study by researchers at the Mayo Clinic suggests that the large studies on CYP2D6 may be flawed because the studies did the genetic testing on samples of tissue from the breast cancer rather than on healthy tissue.
The study is published in The Journal of the National Cancer Institute, vol. 107, issue 2. Read the abstract of “Loss of Heterozygosity at the CYP2D6 Locus in Breast Cancer: Implications for Germline Pharmacogenetic Studies.”
Researchers call the CYP2D6 gene “highly variable.” This means that certain sections of its DNA are structured differently in different people. So there are many different CYP2D6 genotypes. Most people carry two copies of the CYP2D6 gene, one inherited from each parent.
In this study, the researchers looked at more than 1,000 breast cancer tissue samples and did genetic testing on them. They found that more than 40% of the breast cancers had lost one copy of the CYP2D6 gene. Researchers call this “loss of heterozygosity.” Having only one copy of the CYP2D6 gene means that results of CYP2D6 genetic testing could incorrectly classify a person’s CYP2D6 genotype. In other words, your CYP2D6 testing might classify you as someone who produces enough CYP2D6 enzyme when you really don’t, and vice versa.
The researchers then looked at samples of normal tissue as well as breast cancer tissue from about 200 women in the NCCTG 89-30-52 trial and did CYP2D6 genetic testing on them.
When they compared CYP2D6 genotypes that came from healthy tissue that had been removed along with the breast cancer and CYP2D6 genotypes that came from a cheek swab, the researchers found that the genotypes matched perfectly.
Still, when the researchers compared CYP2D6 genotypes that came from breast cancer tissue to CYP2D6 genotypes that came from healthy tissue, they found that about 20% of the genotypes were misclassified.
“The potential benefit of CYP2D6 testing is obvious, but has been difficult to establish,” said Matthew Goetz, M.D., a Mayo Clinic oncologist and senior author of the study. “We found that if you use tumor tissue to determine the CYP2D6 genotype a patient was born with, you are going to get it wrong a substantial portion of the time.”
Right now, CYP2D6 gene testing isn't routinely done. Based on the results of this study, CYP2D6 testing may help decide if tamoxifen is a good adjuvant hormonal therapy choice for a specific woman. For women with genotypes that produce low levels of the CYP2D6 enzyme, an aromatase inhibitor might be a better hormonal therapy choice because aromatase inhibitors don't depend on the CYP2D6 enzyme.
The aromatase inhibitors are:
- Arimidex (chemical name: anastrozole)
- Aromasin (chemical name: exemestane)
- Femara (chemical name: letrozole)
It may be some time before CYP2D6 testing is used to help guide hormonal therapy medicine choices. Still, you might want to talk to your doctor about this study if you're considering tamoxifen treatment or are already taking tamoxifen.
It's also important to know that some medicines also can affect how the CYP2D6 enzyme functions and may reduce tamoxifen's effectiveness. These medicines include some antidepressants known as serotonin-specific reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Other commonly prescribed medicines such as Cardioquin (chemical name: quinidine), Benadryl (chemical name: diphenhydramine), and Tagamet (chemical name: cimetidine) can block CYP2D6 activity. Most doctors recommend avoiding any medicine that can affect CYP2D6 function while you're taking tamoxifen. If you have to take a medicine that may reduce CYP2D6 activity, you and your doctor should discuss hormonal therapy options that aren't affected by CYP2D6 activity.
Editor’s Note: In 2018, the Clinical Pharmacogenetics Implementation Consortium, an international group of scientists that issues guidelines on the effects of genetic factors on reactions to drugs, issued a guideline on using CYP2D6 genotype information to make decisions about prescribing tamoxifen after surgery to treat hormone-receptor-positive breast cancer. The guideline strongly recommends that people with an abnormal CYP2D6 genotype that makes them less able to metabolize tamoxifen be treated with a different type of hormonal therapy, such as an aromatase inhibitor.
— Last updated on February 22, 2022, 10:03 PM
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