Occasionally, one patient changes medicine. In 1998, a 45-year-old woman with breast cancer walked into a clinic at Georgetown University's Lombardi Cancer Center in Washington, D.C. Like many patients taking the anti-estrogen drug tamoxifen, she was suffering from severe hot flashes and was desperate for help. On a hunch, her doctor put her on the antidepressant paroxetine (Paxil), and the hot flashes disappeared almost completely within a few days.
"It was like the silver bullet," said pharmacologist David Flockhart, M.D., Ph.D., now at Indiana University. "Far, far too fast for any ... psychiatric effect of that drug to have worked." Her response to the drug left researchers wondering, is it possible that paroxetine cured this patient's hot flashes overnight?
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In the last 6 years, Flockhart's group has helped elaborate on the metabolism of tamoxifen, along the way revealing that gene variations may be crucial to how individuals respond to tamoxifen therapy for their cancers. (The data on this question are preliminary.) The tamoxifen work is just one example of pharmacogenetics, the study of genetic variability in the way people respond to medicines. But cancer pharmacogenetics, despite some advances in recent years, continues to be almost completely ignored by clinical oncologists.
Last November, a U.S. Food and Drug Administration advisory committee declined to recommend that doctors test patients for a genetic variant that predisposes them to severe side effects from irinotecan, a chemotherapy drug for colorectal cancer. "The obstacles for integrating pharmacogenetics into routine practice are still there," said Howard McLeod, Pharm.D., of Washington University in St. Louis. Despite much hype about a future of individualized medicine, the field of cancer pharmacogenetics still awaits a breakthrough.
A Tamoxifen Response Gene?
When Flockhart and his graduate student, James Rae, Ph.D., searched 6 years ago for tamoxifen metabolites in the blood of the breast cancer patient with hot flashes, they observed that one chromatography peak declined dramatically after her paroxetine treatment. Flockhart expected the peak to be the metabolite 4-hydroxy-tamoxifen, which had been described in 1980 by Craig Jordan, Ph.D., D.Sc., now at the Fox Chase Cancer Center in Philadelphia, and was assumed to be the most active tamoxifen metabolite. But, it turned out, the peak was something completely unknown. Over the next few years, Rae purified, identified, and synthesized the substance, a little-studied metabolite the group dubbed "endoxifen." Endoxifen "turns out to be 10 times more potent than the most potent active metabolite previously reported," said Flockhart.
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If endoxifen is the most important metabolite of tamoxifen, then patients with wild-type CYP2D6 should benefit much more from tamoxifen than patients who have variants in the gene. This appears to be the case, according to data presented at December's San Antonio Breast Cancer Symposium. Genotyping tumor samples from an old tamoxifen clinical trial, the Flockhart group found that 5-year disease-free survival for patients homozygous for inactivating 2D6 mutations was only 46%, compared with 83% for patients without the mutations. (Overall survival, however, did not differ.)
The poor 2D6 metabolizers "are not converting tamoxifen to endoxifen, and since our hypothesis is that endoxifen is the most important anti-estrogenic molecule ... perhaps they don't get as big an anti-estrogenic kick," said Daniel Hayes, M.D., of the University of Michigan in Ann Arbor, and one of Flockhart's collaborators. But, Hayes cautioned, "we don't know if this changes whether these drugs are effective against breast cancer." An overall survival benefit must first be demonstrated. "We want [to do] a larger study to confirm these results and to find out if there is an effect on overall survival," said Rae.
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Even if a trial confirms that endoxifen levelsand CYP2D6 genotypesare crucial for individual patient response to tamoxifen, that information may come too late for practical use. Aromatase inhibitors are gradually replacing tamoxifen in the wake of clinical trials, showing a slight but statistically significant survival advantage. Tamoxifen thus may eventually become obsolete, so the field of tamoxifen pharmacogenetics may have a finite amount of time to prove its worth and provide a rationale for genetic testing.
But tamoxifen may still be more effective than aromatase inhibitors in patients with wild-type CYP2D6, because they have high endoxifen levels. "Our goal is to ... predict which patients should still get tamoxifen, and which patients should definitely get aromatase inhibitors," said Flockhart. "You can imagine a situation where you have a pattern of genetic variants that allows you to select tamoxifen and another that allows you to select aromatase inhibitors [that] would notably improve the efficacy and reduce the toxicity of both."
Before such testing can happen, the survival implications of endoxifenand 2D6 genotypemust be proven. "It has a chance of being a true story," said McLeod. "I have no clue which way it'll shake out." Flockhart expects to have the answer within a few years, but timing is crucial. "To get someone to stop using aromatase inhibitors, to go back to tamoxifen, would be a very hard sell, regardless of the data," said McLeod.
Success, by showing that genes can predict individual drug therapy outcome, would help a lot of breast cancer patients. Predictive testing "is something we badly need in cancer," said Flockhart. Unlike heart disease medications, whose effects can be predicted from patient cholesterol count, blood pressure, and C-reactive protein levels, "in cancer there's nothingyou're shooting completely in the dark, as to who's going to get the best effects from a drug."
Solid pharmacogenetic data on toxicity does exist for certain cancer treatments. The best known example is thiopurine methyltransferase (TPMT) and childhood leukemia. Children treated with thiopurine chemotherapy drugs are very vulnerable to toxic overdose if they don't have any functional TPMT, the metabolizing enzyme. (About one in 10 people has intermediate enzyme activity, and one in 300 has little or no enzyme activity.) Because the consequence of treating children with nonfunctional TPMT using these drugs could be death from drug overdose, it seems on its surface like a good case for genetic testing.
But such testing is still rarely done by oncologists. In July 2003, the pediatric subcommittee of the FDA's Oncologic Drugs Advisory Committee declined to require TPMT genotyping of childhood leukemia patients. The committee received advice from several experts, who warned that genotyping could endanger patients by causing delays in therapyor by underdosing. Many doctors "won't necessarily know how to respond and arguably might overreact and cut doses fairly dramatically," said Naomi Winick, M.D., of the University of Texas Southwestern in Dallas, at the hearing.
It's clear that oncologists don't want to cut doses now, at least not based on a gene test. To convince them, "what we need are prospective clinical trials to determine the optimal dose adjustment based on genotype," said Rae. McLeod would like to see more TPMT testing now, and blames clinical oncologists for resisting change. "If you're an oncologist who's used to managing toxicity, you have no incentive to reduce toxicity," he said. "It's really only patients who want toxicity avoidance, and therefore [TPMT testing] has been very slow to be integrated in a broad fashion."
Whether doctors will also resist gene testing for drug efficacy, as opposed to toxicity, remains to be seen. The tamoxifen story, if it plays out, would be one test case. In demonstrating patient benefit from pharmacogenetics, "the bar is incredibly low," said McLeod. He points out that the response rate for Herceptin (trastuzumab) is only 25%, even when given to only those patients who overexpress the Her-2/neu gene. "So it's not like we have to hit a home run all the time," he said. "All we have to do is get it right three out of 10 times, or better, and we're going to be improving the current state of affairs."
Before individualized cancer treatments based on pharmacogenetic information finally gain acceptance, researchers must first peel away layers of biological complexity to find the gene variants that affect drug response. In their breast cancer work, Flockhart and Hayes are now looking at polymorphisms in the estrogen receptor, in addition to variants in drug metabolizing enzymes, in hopes of predicting response to both tamoxifen and aromatase inhibitors. They also must consider variants in the aromatase gene itself, as well as coactivators and corepressors for the estrogen receptor, all of which may harbor polymorphisms that affect patient response.
All this effort is restricted to endocrine therapy so far. "The whole field of pharmacogenetics is in its infancy," said Hayes. "We've bitten off a very small piece to study. You know, you've got to walk before you can run."
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