Studies indicate tamoxifen does not prevent breast cancer recurrence for 1 in 5 people.
Tamoxifen is used to prevent the return of ER+ breast cancer (recurrence) by blocking the effects of estrogen. However, research studies suggest that tamoxifen works differently based on specific DNA changes to a gene, CYP2D6. Approximately 20% of women may not respond to tamoxifen as expected due to changes in CYP2D6 that make them resistant to the medication which could result in an increased risk of ER+ breast cancer recurring.
How Kailos can help you
With the Kailos test, you will discover what DNA changes have been shown to be related to how medications are metabolized. If you are just beginning therapy, this information can be information that a treating physician incorporates into the selection process. These DNA changes could also provide physicians insights into reasons why treatments may not be working as effectively as expected or are producing more side effects than expected. At Kailos Genetics, we sequence DNA and compare it to research and clinical study data so a physician can make genetics a part of their decision making.
What is Tamoxifen?
It is a drug most commonly used to treat women with estrogen receptor (ER)-positive early-stage breast cancer in an attempt to reduce the risk of recurrence. Studies show that it reduces recurrence and mortality by greater than 30%. Tamoxifen is metabolized into it’s active form called endoxifen by a gene called CYP2D6. There have been investigations that have identified genetic changes, or variants, of CYP2D6 that can affect how well CYP2D6 works.
What Kind of Metabolizers are Affected?
The ability of the CYP2D6 gene to change tamoxifen to endoxifen, turning it into the active medicine to prevent cancer recurrence, depends on the specific changes in the CYP2D6 gene. Everyone has 2 copies of CYP2D6 in their DNA. If a person has 2 non-functioning copies of CYP2D6, it is considered a poor metabolizer of tamoxifen. According to some of the studies, poor metabolizers have an increased risk for relapse of breast cancer. At ~10%, caucasians are found to carry the CYP2D6 poor metabolizer variants more often than other ethnic populations. Also according to some studies, intermediate metabolizers (between poor and normal) may also have an increased risk of relapse of breast cancer. In this case, tamoxifen is still changed to endoxifen but much less efficiently. Importantly, intermediate metabolizers may want to avoid the use of CYP2D6 inhibitors during tamoxifen treatment as the already impaired CYP2D6 gene’s activity could be further reduced by inhibitors. Resources for information on CYP2D6 inhibitors can be found at the FDA: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers and Indiana University School of Medicine: Drug Interactions Flockhart Table
PharmGKB summary: tamoxifen pathway, pharmacokinetics. Pharmacogenetics and Genomics. 2013;23:643-647.
Association Between CYP2D6 Genotypes and the Clinical Outcomes of Adjuvant Tamoxifen for Breast Cancer. Pharmacogenomics. 2014;15(1):49-60.
Prediction of tamoxifen outcome by genetic variation of CYP2D6 in post-menopausal women with early breast cancer. Br J Clin Pharmacol. 2013;77(4):695-703.
Loss of Heterozygosity at the CYP2D6 Locus in Breast Cancer: Implications for Tamoxifen Pharmacogentic Studies. J Natl Cancer Inst. 2015;107(2):dju437.
WHAT STUDIES HAVE BEEN REVIEWED FOR BREAST CANCER PREVENTION MEDICATIONS?
A variety of scientific and clinical research groups around the world have studied the relationships between many genes and cancer prevention medications. From those studies, one gene has been identified for extensive studies: CYP2D6. In many of these studies, different forms of this gene was related, although not necessarily causative, of how effective cancer prevention medications performed. Guidelines issued by the Clinical Pharmacogenomics Implementation Consortium contain extensive information on the studies reviewed:
Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6 and Tamoxifen Therapy (January 2018) doi: 10.1002/clpt.1007
This and other cancer prevention medications have studies that, while informative on metabolism rates, are not supported by FDA communications at this time.