More Data Support Genetic Test to Predict Response to Tamoxifen

Zosia Chustecka

October 07, 2009

October 7, 2009 — More data are available to support the use of a genetic test to predict a woman's response to tamoxifen, so that those who will not respond can be offered alternative therapies.

The test identifies women with an inherited deficiency in the CYP2D6 gene, which codes for an enzyme that breaks tamoxifen into its active metabolites. Women with this deficiency — about 8% to 10% of the Caucasian population — do not metabolize tamoxifen, and so do not release its active metabolites. This means that they do not benefit from the protection it offers against breast cancer recurrence.

Using the test to identify this small group would allow these patients to be offered alternative therapies that would work, such as aromatase inhibitors.

The new data, collected from 1325 women with early breast cancer and were receiving tamoxifen as adjuvant therapy, are published in the October 7 issue of the Journal of the American Medical Association.

"This large study validates our previous findings in a sufficiently powered manner," said second author Matthew Goetz, MD, from the Mayo Clinic in Rochester, Minnesota. Not only were there more patients, there was more comprehensive genotyping and an extended follow-up, he said in an interview with Medscape Oncology.

The majority of the data (n = 1100 women) come from clinical practices in Germany; the remainder (n = 225 women) come from a clinical trial in the United States, Dr. Goetz explained. Most of the women (95%) were postmenopausal, he added.

The study showed that women lacking the CYP2D6 enzyme function (poor metabolizers) had an almost 2-fold increased risk of developing breast cancer, compared with women who had full CYP2D6 function (good metabolizers).

There was also an intermediate group — women in whom only 1 of the 2 alleles on the CYP2D6 gene is functional (intermediate metabolizers). This group accounts for about 20% to 25% of the Caucasian population, and they "do slightly worse" on tamoxifen than the women who are good metabolizers, Dr. Goetz explained. What should be done about these intermediate metabolizers is currently unclear, he said, adding that more data are needed.

Testing in the Clinic

Dr. Goetz and colleagues first reported the association between CYP2D6 and tamoxifen in 2005/06, and the Mayo Clinic changed its practice then, he said. For 3 years now, they have been testing all postmenopausal women with estrogen-receptor-positive breast cancer who are being considered for tamoxifen adjuvant therapy. Women who are found to be deficient in CYP2D6 are then counseled and offered alternative therapies, he explained.

Several tests for CYP2D6 are commercially available, Dr. Goetz noted.

When asked whether he would advise all physicians to test for CYP2D6 before prescribing tamoxifen, Dr. Goetz replied: "If you have alternative therapies that are effective, why would you give a drug such as tamoxifen that has been identified as having a much higher risk of recurrence in a small subset of patients. I think that is really the crux of the issue . . . that a predictive factor is helpful when there is an alternative therapy."

He added that the aromatase inhibitors are "very effective in postmenopausal women with breast cancer; in fact, they have been shown to be more effective than tamoxifen."

The issue of tamoxifen and CYP2D6 was discussed at a US Food and Drug Administration Advisory Committee meeting in October 2006. At that meeting, the committee agreed to recommend a label change for tamoxifen to highlight the fact that poor metabolizers are at increased risk for breast cancer recurrence. However, Dr. Goetz pointed out, "it hasn't happened yet."

At that same meeting, the committee did not reach a consensus on whether to recommend that women be tested. "Some members believed that the genetic test should be recommended, whereas others believed that it should be mentioned in the label as an option for discussion between the healthcare provider and patient. However, the majority indicated that it should be included in an appropriate section of the package insert," Dr. Goetz wrote in a report (Clin Pharmacol Ther. 2008;83:160-166).

Approached for outside comment, Hyman Muss, MD, from the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill School of Medicine, said there is some controversy in this field because not all of the studies have confirmed the finding. Dr. Muss spoke to Medscape Oncology at the San Antonio Breast Cancer Symposium, where a different set of data — but the same conclusions — were reported by Dr. Goetz and colleagues.

Despite the uncertainty, Dr. Muss told Medscape Oncology that he is in favor of using the test after discussing it with the patient, if the patient agrees.

Dr. Muss explained that using the test would identify women who would not respond to tamoxifen, and would allow the physician to offer an alternative but appropriate treatment. "For example, in a postmenopausal woman, you could use an aromatase inhibitor or another drug like tamoxifen, such as toremifene," he explained. "In a premenopausal woman, you could consider ovarian suppression or possibly another selective estrogen-receptor modulator, although nothing has been tested as extensively as tamoxifen," he added.

Even if it turns out that this is all wrong, you have done no harm.

"Even it turns out that this is all wrong, you have done no harm," Dr. Muss said. "But if it turns out that this is important, then you have done some good, because otherwise 5% to 10% of women would not have been treated appropriately." Those women would have been taking tamoxifen without benefiting from it. Also, the "women who are poor metabolizers are less likely to suffer from side effects of the treatment, so they will be telling their doctor how well they are doing on tamoxifen," he said. They tolerate the drug well, and so they continue on it, but they are not getting any benefit from it, he pointed out.

"That is why I would argue in favor of using this test — if it turns out not to be important, I haven't lost anything by changing my patients to alternative effective options, but if it turns out to be true and I haven't used the test, then I will have been treating 10% of my patients with a drug that doesn't work," Dr. Muss said.

Developing Active Metabolite

Dr. Goetz noted that his group is now working with the National Cancer Institute to develop the active metabolite of tamoxifen, endoxifen, into a drug for clinical use. The team hopes to start clinical trials within the next 6 to 12 months.

Using endoxifen in place of tamoxifen would remove the need for CYP2D6 testing, Dr. Goetz said. But what began as a potential new drug for poor metabolizers might turn out to be a "better drug for all patients," he said. Preclinical tests suggest that endoxifen is about 100-fold more potent than tamoxifen; it has a higher affinity for the estrogen receptor and is better at suppressing the proliferation of breast cancer cells in vitro, he said.

Dr. Goetz and several coauthors report that they are named inventors (along with the Mayo Clinic) on nonprovisional patent applications for tamoxifen and CYP2D6. The technology is not licensed and no royalties have accrued. Dr. Goetz also reports having acted as a consultant for Roche and having received honoraria from Pfizer, Roche, and DNA Direct. Details of the financial disclosures of the other authors are listed in the paper. Dr. Muss reports acting as a consultant for Pfizer, Genentech, Amgen, Roche, Bristol-Myers Squibb, and Tragara; and receiving research funding from AstraZeneca, Pfizer, GlaxoSmithKline, Genentech, and Novartis.

JAMA 2009;302:1429-1436.

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