Breast cancer, estrogen receptor-positive, tamoxifen, depression, hot flash, selective serotonin reuptake inhibitor, paroxetine hydrochloride (Paxil®). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
In a study of Ontario women who were taking tamoxifen for treatment of breast cancer, those who were also taking the antidepressant paroxetine (Paxil®) had a higher risk of dying from their disease. The risk of death increased in proportion to the length of the time that use of the two drugs overlapped.
British Medical Journal, published online February 8, 2010. (See the journal abstract.) (BMJ. 2010; 340:c693)
Women with hormone-responsive breast cancer (that is, breast cancer whose growth is fueled by the female sex hormone estrogen) frequently take the drug tamoxifen as part of their treatment. Tamoxifen blocks the effects of estrogen in the breast; studies have shown that it reduces the risk of breast cancer recurrence in women with estrogen receptor-positive early-stage breast cancer by about one-half and the risk of breast cancer death by about one-third.
As many as a quarter of women being treated for breast cancer suffer from depression. A class of drugs known as selective serotonin reuptake inhibitors (SSRIs) is commonly used to treat depression. Some women who are being treated with tamoxifen for breast cancer may also be taking an SSRI to treat depression. SSRIs may also be used to treat hot flashes, which are a common side effect of tamoxifen therapy.
To exert its anticancer effect, tamoxifen must first be metabolized (broken down) in the liver by an enzyme known as CYP2D6. However, some drugs—including some SSRIs—block the action of this enzyme. Paroxetine and fluoxetine (Prozac®) are two SSRIs that are known to block CYP2D6. This known drug interaction has raised the question of whether these SSRIs could interfere with the effects of tamoxifen.
Canadian researchers used medical and prescription records to identify 2,430 Ontario women who were at least 66 years old when they began receiving tamoxifen for breast cancer treatment between 1993 and 2005 and who were also treated with an SSRI during part of that time. The researchers used death certificates to determine how many women in the cohort died and the causes of death.
The women took tamoxifen for a median of four years. Paroxetine, taken by 25.9 percent of the women, was the most commonly prescribed SSRI. Other SSRIs prescribed included citalopram (Celexa®), fluoxetine, sertraline (Zoloft®), and venlafaxine (Effexor®).
The lead researcher for the study was David N. Juurlink, M.D., Ph.D., of Sunnybrook Health Sciences Centre in Toronto, Canada.
By the end of the study period (December 31, 2007), 1,074 women in the study had died (44.2 percent), of whom 374 (15.4 percent of the study group) had died of breast cancer. Among women who took paroxetine and tamoxifen at the same time, the risk of death from breast cancer (as well as the risk of death from any cause) was higher in women with a longer overlap in use of these drugs. The authors estimate that use of paroxetine for 41 percent of the period of tamoxifen treatment (the median overlap) would result in one additional breast cancer death within five years of stopping tamoxifen for every 20 women so treated. No increase in risk of death was observed among women who took other SSRIs at the same time as tamoxifen.
This study is a population-based study that supports the finding that certain SSRIs interfere with the metabolism of tamoxifen and thus may have an effect on the efficacy of tamoxifen therapy. However, the risk of death from breast cancer was not increased in women who took the SSRI fluoxetine in combination with tamoxifen, even though fluoxetine, like paroxetine, is known to block CYP2D6. The authors point out that because the number of women who were taking both fluoxetine and tamoxifen was small, it may have been difficult to detect any increase in the risk of breast cancer death.
“Our results should not be viewed as evidence that fluoxetine can safely be used in combination with tamoxifen,” they write. Similarly, the numbers of women taking other SSRIs in combination with tamoxifen may have been too small to reveal any adverse effect on breast cancer survival caused by those drug combinations. However, there are SSRIs that do not interfere with the metabolism of tamoxifen and may be used in women taking tamoxifen.
Information was not available on the breast cancer stage of the women in the study. If paroxetine was more likely to be prescribed for women with more advanced disease, then paroxetine use would be associated with poorer survival. However, the authors note that the specific SSRI prescribed is unlikely to be associated with the stage of breast cancer.
“Our findings indicate that the choice of antidepressant can significantly affect survival in women receiving tamoxifen for breast cancer,” the study authors write, adding: “When co-prescription of tamoxifen with an antidepressant is necessary, preference should be given to antidepressants that show little or no inhibition of CYP2D6.”
Women who are currently taking paroxetine in combination with tamoxifen should not abruptly discontinue taking paroxetine, says David R. Kohler, Pharm. D., an oncology clinical pharmacy specialist at the National Institutes of Health Clinical Center. Doing so could have adverse effects, including a recurrence of depression.
Women should talk with their health care providers about the advisability of switching to an antidepressant that does not have paroxetine’s effect on the body’s ability to break down tamoxifen, continues Dr. Kohler.
Sertraline, another SSRI prescribed for some women in this study, is a less potent blocker of CYP2D6 than paroxetine or fluoxetine, adds Dr. Kohler, but it may still inhibit the body’s ability to break down tamoxifen. The antidepressants bupropion (Wellbutrin®) and duloxetine (Cymbalta®), which are not SSRIs, are also moderately potent inhibitors of CYP2D6.
“Antidepressant drugs that would not be expected to affect tamoxifen metabolism by CYP2D6 include citalopram, escitalopram (Lexapro®), venlafaxine, and mirtazapine (Remeron®),” he says.
For women who are postmenopausal, doctors might consider recommending a switch from tamoxifen to another class of anti–breast cancer drugs known as aromatase inhibitors (AIs), adds Jo Anne Zujewski, M.D., of NCI's Cancer Therapy Evaluation Program. Rather than blocking estrogen as tamoxifen does, AIs interfere with the body's ability to produce the hormone. However, AIs are not effective in women with functioning ovaries when used alone. In premenopausal women, AIs must be given in combination with another type of drug, called a gonadotropin-releasing hormone analog, to stop ovarian production of estrogen.