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Caution Urged in Concomitant Use of Tamoxifen & CYP2D6 Inhibitors

Laino, Charlene

doi: 10.1097/01.COT.0000360989.44529.21

ORLANDO, FL—Two major studies have produced conflicting results when it comes to answering the question of whether antidepressants interfere with tamoxifen's ability to prevent recurrences of breast cancer.

A review of the medical records of nearly 1,000 US breast cancer patients showed that concomitant use of tamoxifen and antidepressant drugs that inhibit the cytochrome P450 2D6 (CYP2D6) pathway was associated with a two-fold risk of recurrence in the two years after starting tamoxifen. But Dutch investigators found no increased risk of cancer recurrence among women taking CYP2D6 inhibitors and tamoxifen.

Nevertheless, caution is warranted at this time, and concomitant use of the two classes of drugs should be avoided whenever possible, agreed both teams of researchers and outside experts who offered commentary for this article.

Also, based in part on results of the US study, the Food and Drug Administration is poised to add new information to tamoxifen's label warning physicians about potentially harmful interactions between the drug and some CYP2D6 inhibitors, according to FDA spokesperson Karen Riley, MPH. “There's no word yet on the timing though,” she said.

Both studies were presented here at the ASCO Annual Meeting (Abstracts CRA508 and CRA 509).

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CYP2D6 Antagonists

Among the best known CYP2D6 antagonists are several members of the selective-serotonin-reuptake inhibitor (SSRI) class of antidepressants, which are widely used to prevent both the depression that often strikes cancer patients and tamoxifen-induced hot flashes, said US investigator Ronald E. Aubert, PhD, MSPH, Vice President of Clinical Analytics, Outcomes, and Reporting at Medco Health Solutions, a pharmacy-benefit management company.



Three of the most commonly used SSRI antidepressants are the moderate-to-potent CYP2D6 inhibitors fluoxetine, paroxetine, and sertraline. (A moderate inhibitor is an agent that causes at least a two-fold increase or a 50% to 80% decrease in the plasma area-under-the-curve levels of the substrate drug. Strong inhibitors cause an even greater change in plasma levels of the substrate drug, while weaker inhibitors exert a smaller charge.)

In contrast, the SSRIs escitalopram, citalopram, and fluvoxamine and the serotonin-norepinephrine-reuptake inhibitor (SNRI) venlafaxine are weak CYP2D6 inhibitors, he said.

Not all CYP2D6 inhibitors are SSRI or SNRI antidepressants: Among other moderate-to-strong inhibitors are the antifungal fluconazole, the antidepressant bupropion, and the antiarrythmic agent quinidine.

Tamoxifen is metabolized into its active metabolite endoxifen by the cytochrome P450 2D6 enzyme in the liver, he explained. Research has shown that women who have reduced-function CYP2D6 polymorphisms and are poor metabolizers have lower levels of endoxifen and are at increased risk of breast cancer relapse.

Additionally, studies have suggested that the use of specific CYP2D6 inhibitor drugs lowers plasma levels of endoxifen by 45% to 58%.

“Thus, there exists a strong biologic rationale for the hypothesis that breast cancer outcomes will be worse in women taking these drugs with tamoxifen,” Dr. Aubert said.

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US Study

To determine whether the concomitant use of CYP2D6 inhibitor drugs and tamoxifen increases a woman's risk of breast cancer recurrence, Dr. Aubert and colleagues combed the medical and pharmacy records of 10.7 million members of U.S. healthcare plans in the Medco database. Inclusion criteria were women over age 50 with breast cancer who started taking tamoxifen over a 30-month period from 2003 to 2005.

The search revealed a total of 1,669 women. The first analysis involved 945 women who took tamoxifen alone and 353 who also took a moderate-to-potent CYP2D6 inhibitor while they were taking tamoxifen. A second analysis involved 137 women who were taking a weak CYP2D6 inhibitor and 213 women who were taking moderate-to-potent CYP2D6 inhibitor, all while on tamoxifen.

“On average, women took the CYP4D6 inhibitors about 30% of the time with tamoxifen, or for 340 days of the 730 days of the study. The primary reason they took them was for depression, followed by hot flashes,” Dr. Aubert said.

Results showed that 13.9% of women taking tamoxifen and a moderate-to-potent CYP2D6 inhibitor had a breast cancer recurrence at two years, compared with 7.5% among women taking tamoxifen alone. “This translates to a significant, 1.92-fold risk of recurrence among women taking a moderate-to-potent CYP2D6 inhibitor, compared with the tamoxifen-only group,” Dr. Aubert said.

In the second analysis, the two-year risk of breast-cancer recurrence was 7.5% among women taking tamoxifen alone, 8.8% among women taking tamoxifen and a weak CYP4D6 inhibitor, and 16% among women taking tamoxifen and a moderate-to-strong CYP4D6 inhibitor.

“The risk of recurrence among women taking the weaker CYP4D6 inhibitor was not significantly different than that of women taking tamoxifen alone,” Dr. Aubert said. In contrast, the two-year risk of recurrence was 2.2-fold times higher among women taking tamoxifen and a moderate-to-potent CYP4D6 inhibitor, compared with those taking tamoxifen alone.

“Our findings add to existing evidence indicating that the combined use of tamoxifen and specific moderate-to-potent CYP2D6 inhibitors can reduce the effectiveness of tamoxifen in preventing breast-cancer recurrence,” Dr. Aubert said.

During the question-and-answer time, an attendee noted that women with late-stage cancer are more likely to be depressed and take an antidepressant. “This is a wonderful example of confounding factors,” she said.

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Dutch Study

The Dutch study had a similar observational design, with the researchers reviewing pharmacy data on 1,962 breast cancer patients treated with tamoxifen from 1994 to 2006. Of those, 213 women also took a CYP2D6 inhibitor; 150 were labeled frequent users because they took a CYP2D6 inhibitor for 60 days or longer while on tamoxifen.

About 70% of women taking a CYP2D6 inhibitor were taking [the moderate-to-strong SSRIs] fluoxetine or paroxetine, said Vincent O. Dezentjé, MD, a trainee in the Department of Oncology at Leiden University Medical Center.

During a follow-up period of 4.1 years, the recurrence rate was 13.3% among women who took tamoxifen and a CYP2D6 inhibitor, compared with 14.6% among women who took tamoxifen alone or who took a CYP2D6 inhibitor for less than 60 days while on tamoxifen, a non-significant difference.

“Surprisingly, despite a strong biologic rationale, and in contrast to the last study, we didn't find any difference in event-free survival rates,” Dr. Dezentjé said. “However, caution in using the two drugs together is warranted. Maybe the effect was too small to detect with our sample size. Other limitations are that we had no data on side effects or CD4 genotype.”

The study did confirm the seemingly obvious hypothesis that adherence to a tamoxifen regimen is associated with a reduced risk of breast cancer recurrence. Though intuitive, the association had not previously been demonstrated, Dr. Dezentjé said.

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‘Better-Designed Studies Ongoing’

Study Discussant Vered Stearns, MD, Associate Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins School of Medicine, said that limitations of both studies include their retrospective design, relatively small sample sizes, limited follow-up, and lack of CD4 genetic analysis.

“Better designed studies are ongoing. Until such data are available, the concomitant use of tamoxifen and CYP2D6 inhibitors should be limited whenever possible. Alternative therapy should be considered,” she said.

Others agreed: “There are other options [besides the stronger CYP2D6 inhibitors], so why not use them?” asked Julie R. Gralow, MD, Director of Breast Medical Oncology at Seattle Cancer Care Alliance and the moderator of a news conference at the meeting that highlighted both studies. “We should err on the side of caution even if we view these studies as not being definitive,” she said.

Dr. Gralow said that if an antidepressant is needed, she recommends that her patients take venlafaxine (Effexor). “We have a lot of information on Effexor's effectiveness against hot flashes and depression, so that's the one I use,” she explained.

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Graduate Program in Cancer Metastasis to Begin at M. D. Anderson

This fall The University of Texas M. D. Anderson Cancer Center will open a graduate program on cancer metastasis. The program, supported by a grant from The University of Texas System, will be offered through The University of Texas Graduate School of Biomedical Sciences (GSBS) at Houston, a combined program of M. D. Anderson and The University of Texas Health Science Center at Houston.

“Metastasis is far and away the major killer of cancer patients, and this doctoral program is the first to treat the study of metastasis as a separate discipline,” said the program organizer, Gary E. Gallick, PhD, Professor and Director of Education in M. D. Anderson's Department of Genitourinary Medical Oncology and a member of the GSBS faculty.

The University of Texas System has allocated $485,250 to the metastasis program over three years and its Board of Regents allocated $5 million for the initiative to cultivate innovative programs that will attract high-quality graduate students to UT System institutions.

Students admitted to the program will be designated I.J. Fidler Fellows in Metastasis Research in honor of Isaiah J. Fidler, DVM, PhD, Director of M. D. Anderson's Cancer Metastasis Research Center and a longstanding leader in research and translational programs in the area of metastasis.

“It's crucial that we improve our basic understanding of the underlying mechanisms for the spread of cancer to distant sites,” said M. D. Anderson Provost and EVP Raymond DuBois, MD PhD, Immediate Past President of AACR. “This program will enhance the training of future scientists who will advance metastasis research.”

© 2009 Lippincott Williams & Wilkins, Inc.
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