Genetic testing may hold the key to improving these odds. About two-thirds of newly diagnosed breast cancer patients are ER (estrogen-receptor) positive and are candidates for hormonal therapy. Tamoxifen is a likely choice of treatment in these cases but one third of breast cancer patients currently fail tamoxifen treatment. Genetic testing identifies patients that are at risk for failure. This vital information gives medical providers a tool to better manage treatment and drug regimens.
Tamoxifen is converted to the active compound endoxifen in the liver by an enzyme called CYP2D6 (CytochromeP450 2D6). Endoxifen is 30-100 times more effective than tamoxifen. A DNA test can determine a person’s genetic ability to create levels of this enzyme. The more of the 2D6 enzyme a woman has the better she can absorb tamoxifen and convert it, thereby avoiding relapse.
About 7-10% of women are CYP2D6 poor metabolizers with absent or greatly reduced levels of this enzyme. Another 35% are intermediate metabolizers that have slightly lowered levels of the enzyme. Intermediate metabolizers and even normal metabolizers can also be at an increased risk of relapse when certain other medications are taken at the same time.A common side effect of tamoxifen treatment is hot flashes, commonly treated with anti-depressants such as Paxil. A few years ago several doctors wondered if the anti-depressants were making Tamoxifen less effective. That is, were they preventing the enzyme 2D6 from doing its job?
The answer is yes. Many anti-depressants such as Paxil reduce the ability of the 2D6 enzyme to work, so women taking the medication – espcially those that were poor or intermediate metabolizers of 2D6 – were not getting the needed benefit from tamoxifen.
This suggests that widespread genetic testing and careful analysis of overall drug regimens could result in successful outcomes for many of the 35% of ER positive breast cancer patients who currently fail tamoxifen treatment. With more than 500,000 women currently taking tamoxifen, this research has wide-reaching implications.
“I hope that this technology is quickly adopted in the medical community. This is a simple and fairly inexpensive test that can help physicians improve breast cancer survival rates,” stated Howard Coleman, Genelex CEO.
Who Should Be Tested?
The CYP2D6 test for tamoxifen is considered appropriate for postmenopausal women who are currently taking or considering tamoxifen to prevent the recurrence of breast cancer. It is especially important if the patient is also taking or considering co-administration with anti-depressants.
Filed under: Cytochrome P450, Personalized Medicine, Pharmacogenetics Tagged: | 2D6, breast cancer, CYP2D6, cytochrome P450 2D6, tamoxifen
Here are some additional reference Dr Oesterheld recommends:
J Clin Oncol. 2007 Nov 20;25(33):5187-93.Click here to read Links
Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes.
Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, Simon W, Eichelbaum M, Brauch H.
Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany. hiltrud.brauch@ikp- stuttgart.de
PURPOSE: The clinical outcome of tamoxifen-treated breast cancer patients may be influenced by the activity of cytochrome P450 enzymes that catalyze the formation of antiestrogenic metabolites endoxifen and 4-hydroxytamoxifen. We investigated the predictive value of genetic variants of CYP2D6, CYP2C19, and three other cytochrome P450 enzymes for tamoxifen treatment outcome. PATIENTS AND METHODS: DNA from 206 patients receiving adjuvant tamoxifen monotherapy and from 280 patients not receiving tamoxifen therapy (71 months median follow-
up) was isolated from archival material and was genotyped for 16 polymorphisms of CYP2D6, CYP2C19, CYP2B6, CYP2C9, and CYP3A5 by matrix-assisted, laser desorption/ionization, time-of-flight mass spectrometry, and by copy number quantification. Risk and survival estimates were calculated using logistic regression, Kaplan-Meier, and Cox regression analyses. RESULTS: Tamoxifen-treated patients carrying the CYP2D6 alleles *4, *5, *10, *41-all associated with impaired formation of antiestrogenic metabolites-had significantly more recurrences of breast cancer, shorter relapse-free periods (hazard ratio [HR], 2.24; 95% CI, 1.16 to 4.33; P = .02), and worse event-free survival rates (HR, 1.89; 95% CI, 1.10 to 3.25; P = .02) compared with carriers of functional alleles. Patients with the
CYP2C19 high enzyme activity promoter variant *17 had a more favorable clinical outcome (HR, 0.45; 95% CI, 0.21 to 0.92; P = .03) than carriers of *1, *2, and *3 alleles. CONCLUSION: Because genetically determined, impaired tamoxifen metabolism results in worse treatment outcomes, genotyping for CYP2D6 alleles *4, *5, *10, and *41 can identify patients who will have little benefit from adjuvant tamoxifen therapy. In addition to functional CYP2D6 alleles, the CYP2C19 *17 variant identifies patients likely to benefit from tamoxifen.
PMID: 18024866
Ann Oncol. 2007 Oct 18 [Epub ahead of print]Click here to read Links
Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism.
Gjerde J, Hauglid M, Breilid H, Lundgren S, Varhaug JE, Kisanga ER, Mellgren G, Steen VM, Lien EA.
The Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen.
BACKGROUND: Tamoxifen is hydroxylated by cytochrome P450 (CYP)
2D6 to the potent metabolites 4-hydroxytamoxifen (4OHtam) and 4- hydroxy-N-demethyltamoxifen (4OHNDtam), which are both conjugated by sulphotransferase (SULT)1A1. Clinical studies indicate that CYP2D6 and SULT1A1 genotypes are predictors for treatment response to tamoxifen. Therefore, we examined the relationship between CYP2D6 genotype, SULT1A1 genotype, SULT1A1 copy number and the pharmacokinetics of tamoxifen. PATIENTS AND METHODS: The serum levels of tamoxifen and metabolites of 151 breast cancer patients were measured by high-pressure liquid chromatography-tandem mass spectrometry. The CYP2D6 and SULT1A1 polymorphisms and SULT1A1 copy number were determined by long PCR, PCR-based restriction fragment length polymorphism, DNA sequencing and fluorescence-based PCR.
RESULTS: The levels of 4OHtam, 4OHNDtam and N-demethyltamoxifen were associated with CYP2D6 predicted enzymatic activity (P < 0.05). The
SULT1A1 genotype or copy number did not influence the levels of tamoxifen and its metabolites. However, the ratios of N- demethyltamoxifen/tamoxifen and N-dedimethyltamoxifen/N- demethyltamoxifen were related to SULT1A1 genotype. CONCLUSION:
CYP2D6 and SULT1A1 genotypes may partly explain the wide inter- individual variations in the serum levels of tamoxifen and its metabolites. We propose that therapeutic drug monitoring should be included in studies linking CYP2D6 and SULT1A1 genotypes to clinical outcome.
PMID: 17947222
Clin Pharmacol Ther. 2007 Sep 19 [Epub ahead of print]Click here to read Links
Tamoxifen Pharmacogenomics: The Role of CYP2D6 as a Predictor of Drug Response.
Goetz MP, Kamal A, Ames MM.
1Department of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Tamoxifen continues to be a standard endocrine therapy for the prevention and treatment of estrogen receptor (ER)-positive breast cancer. Tamoxifen can be considered a classic “pro-drug,” requiring metabolic activation to elicit pharmacological activity. CYP2D6 is the rate-limiting enzyme catalyzing the conversion of tamoxifen into metabolites with significantly greater affinity for the ER and greater ability to inhibit cell proliferation. Both genetic and environmental (drug-induced) factors that alter CYP2D6 enzyme activity directly affect the concentrations of the active tamoxifen metabolites and the outcomes of patients receiving adjuvant tamoxifen. The a priori knowledge of the pharmacogenetic variation known to abrogate CYP2D6 enzyme activity may provide a means by which the hormonal therapy of breast cancer can be individualized.Clinical Pharmacology & Therapeutics advance online publication 19 September 2007; doi:10.1038/sj.clpt.6100367.
PMID: 17882159
Personalized Cancer Medicine Is Here, Now
As we enter the era of “personalized” medicine, it is time to take a fresh look at how we evaluate treatments for cancer patients. More emphasis is needed matching treatment to the patient. Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival.
Findings presented at the 41st Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden and the Annual Meeting of the American Assoication for Cancer Research (AACR) in San Diego, CA concluded that “functional profiling” with cell-based assays is relevant for the study of both “conventional” and “targeted” anti-neoplastic drug agents (anti-tumor and anti-angiogenic activity) in primary cultures of “fresh” human tumors.
Cell-based Assays with “cell-death” endpoints can show disease-specific drug activity, are useful clinical and research tools for “conventional” and “targeted” drugs, and provide unique information complementary to that provided by “molecular” tests. There have been more than 25 peer-reviewed publications showing significant correlations between cell-death assay results and patient response and survival.
Many patients are treated not only with a “targeted” therapy drug like Tarceva, Avastin, or Iressa, but with a combination of chemotherapy drugs. Therefore, existing DNA or RNA sequences or expression of individual proteins often examine only one compenent of a much larger, interactive process. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.
There is a tactic of using biopsied cells to predict which cancer treatments will work best for the patient, by taking pieces of live “fresh” tumor tissue, applying different chemotherapy treatments to it, and examining the results to see which drug or combination of drugs does the best job killing the tumor cells. A cell-based assay test with “functional profiling,” using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive).
Funtional profiling measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected, functional profiling is measuring them through the surrogate of measuring if the cell is alive or dead.
For example, the epidermal growth factor receptor (EGFR) is a protein on the surface of a cell. EGFR-inhibiting drugs certainly do target specific genes, but even knowing what genes the drugs target doesn’t tell you the whole story. Both Iressa and Tarceva target EGFR protein-tyrosine kinases. But all the EGFR mutation or amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don’t tell you if Iressa is better or worse than Tarceva or other drugs which may target this. There are differences. The drugs have to get inside the cells in order to target anything. So, in different tumors, either Iressa or Tarceva might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.
As an example of this testing, researchers have tested how well a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast, and colorectal cancers. The pre-test can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer.
The funtional profiling technique makes the statistically significant association between prospectively reported test results and patient survival. It can correlate test results that are obtained in the lab and reported to physicians prior to patient treatment, with significantly longer or shorter overall patient survival depending upon whether the drug was found to be effective or ineffective at killing the patient’s tumor cells in the laboratory.
This could help solve the problem of knowing which patients can tolerate costly new treatments and their harmful side effects. These “smart” drugs are a really exciting element of cancer medicine, but do not work for everyone, and a pre-test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.
Literature Citation:
Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007
Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)