ASCO 2009-AVOID SSRIs WITH TAMOXIFEN

June 2, 2009 (Orlando, Florida) — Until there are more data, patients who are taking tamoxifen to reduce their risk for breast cancer recurrence should avoid concomitant use of selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft).

This was the advice from experts here at the American Society of Clinical Oncology 45th Annual Meeting, even though 2 presentations on the topic reported contradictory results.

As well as being used for the treatment of depression, SSRIs are used for hot flashes, which can be an adverse effect of tamoxifen therapy. However, some of these drugs are potent inhibitors of the cytochrome P450 2D6 enzyme that converts tamoxifen to its active metabolite, endoxifen. By inhibiting the enzyme, these drugs reduce the blood levels of this active metabolite, and so reduce the efficacy of tamoxifen in protecting against breast cancer recurrence.

Adverse Effect of SSRIs

One of the studies presented at the meeting showed that women who were taking SSRIs that were moderate to potent inhibitors of the 2D6 enzyme had a 2-fold increase in the risk for breast cancer recurrence, compared with women who were not taking these drugs concomitantly.

he difference was significant — the risk for breast cancer recurrence was 7% in women who were not taking SSRIs and 16% in women who were taking SSRIs that were moderate to potent inhibitors of the 2D6 enzyme (hazard ratio, 2.2, P = .0002). These drugs include fluoxetine, paroxetine, and sertraline.

However, SSRIs that had only a weak inhibitory effect on the enzyme did not have a significant effect; in this instance, the risk for breast cancer recurrence was 8.8%, not significantly different from the 7.5% seen in women who did not take these drugs. Weak inhibitors of the 2D6 enzyme include citalopram (Celexa), escitalopram (Lexapro), and fluvoxamine (Luvox).

"The implication from these findings is that women on tamoxifen should avoid the SSRIs that are moderate to potent inhibitors, as they interfere with the beneficial effects of tamoxifen, but the SSRIs that are weak inhibitors are probably okay," said senior author Robert Epstein, MD, chief medical officer at Medco Health Solutions, a pharmacy benefit management company in the United States.

The study, conducted in collaboration with researchers from Indiana University, used Medco's 11 million member database to identify 945 women older than 50 years and who were at least 70% compliant with tamoxifen therapy for 2 years or more. The researchers identified an additional 353 such women were also taking an SSRI (most commonly paroxetine or fluoxetine); the median overlap during which they were taking both drugs was 255 days.

No Effect of SSRIs

However, a similar study, also presented at the meeting, showed no effect of SSRIs on the risk for breast cancer recurrence in women taking tamoxifen. This study was conducted in the Netherlands, and involved 1962 women who were taking tamoxifen after surgery for early-stage breast cancer. About 11% had also taken an SSRI (most commonly fluoxetine and paroxetine) at some point.

Although this study showed no difference in the risk for breast cancer recurrence between women who took SSRIs and those who did not, lead author Vincent Dezentje, MD, a trainee in oncology at Leiden University Medical Center in the Netherlands, said "doctors and patients should be cautious about using these drugs together."

The number of women who used both drugs in the Dutch study was small, so the study could have been underpowered to show a significant effect, said Julie Gralow, MD, assistant professor of oncology at the University of Washington School of Medicine in Seattle

Dr. Gralow, who moderated the press conference at which the 2 studies were highlighted, told reporters that the message she will be taking back to her clinic is to avoid the SSRIs that could interfere with tamoxifen's action. She noted that the Medco study suggested the risk for breast cancer recurrence was 2-fold higher in women who were taking these drugs concomitantly. There are other drugs that that can be used instead, so "it's better to play it safe," she said.

The same message was given by the discussant of these 2 papers, Vered Stearns, MD, from the Johns Hopkins University School of Medicine in Baltimore, Maryland. Despite the contradictory presentations, and also previous studies that have produced conflicting results, Dr. Stearns said that the use of SSRIs and other drugs with potent inhibitory effects on this enzyme should be limited in this patient population, if at all possible, and alternative drugs should be used.

However, a major limitation of both of these studies, she said, was that neither took into account the individual genetic variation in the 2D6 enzyme. Some women are poor metabolizers of tamoxifen, and they may already have reduced blood levels of the active metabolite because of their genetic predisposition.

"Ironically, it is the women who are good metabolizers of tamoxifen and who are getting the most benefit from the drug in terms of protection against breast cancer recurrence who are also the most likely to experience side effects from the drug, such as hot flashes. So these women are likely to take an SSRI for those hot flashes, but this drug interferes with the metabolism of tamoxifen and reduces its efficacy," Dr. Epstein told Medscape Oncology.

Dr. Epstein also noted that SSRIs are commonly used for hot flashes in the United States, with about 30% of women on tamoxifen taking these drugs. This is a different scenario from Europe, where these drugs are used mainly for the treatment of depression and appear to be used less commonly, he said, noting that the Dutch study found that only 11% of women taking tamoxifen were also taking these drugs.

Dr. Gralow added that the findings are important because tamoxifen is "a good drug and is still in clinical use." Although it has been superseded to some extent by aromatase inhibitors in the postmenopausal patient population, many women taking aromatase inhibitors develop adverse effects and consider switching to tamoxifen; for premenopausal women with breast cancer, tamoxifen remains the only option.

Dr. Epstein is employed by Medco Health Solutions. Dr. Dezentje has disclosed no relevant financial relationships. Dr. Gralow reports receiving honoraria from Genentech, Novartis, and Roche; and research funding from Amgen, Bayer, Bristol-Myers Squibb, Genentech, Novartis, Roche, and Sanofi-Aventis.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstracts CRA508 and CRA509. Presented May 30, 2009.