SSRIs and Tamoxifen
Over the past couple of years, there has been attention paid to the possible negative interaction of tamoxifen and some SSRIs (medications used to treat depression). Since both tamoxifen and anti-depressants are commonly prescribed to women who have had breast cancer, this has been taken very seriously. This situation is a good example of the importance of working with doctors who are well educated about breast cancer treatment and medications. If you are taking medication for depression and are taking tamoxifen, talk with the prescribing doctor about this to be sure that the particular combination is safe.
On a related note, if you are seeking or seeing a therapist to process the many issues related to breast cancer, it is also very important to work with someone who is experienced in this area. Many excellent therapists don't know much about cancer and its treatment, and you don't want to waste your valuable time and money educating your therapist about the issues. When you make initial contact with a possible therapist, in addition to the other basic questions (availability, insurance, location), as whether s/he has worked with other women who have had breast cancer.
This is a long posting but important:
Best Evidence Interview: Use of Some SSRIs With Tamoxifen Increases Mortality in Breast Cancer Patients
A Best Evidence Interview With Catherine Kelly, MD
The Best Evidence Study
Dr. Kelly was the lead author of: Kelly CM, Juurlink DN, Gomes T, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women
receiving tamoxifen: a population based cohort study. BMJ. 2010;340:c693. doi: 10.1136/bmj.c693.
About the Interviewee
At the time that this study was performed, Dr. Kelly was a medical oncology fellow at the Odette Cancer Center of the Sunnybrook Health Sciences Center in Toronto, Ontario, Canada. The study was based on her thesis in clinical epidemiology, conducted at the Department of Health Policy, Management, and Evaluation at the University of Toronto.
Currently, she is a Susan G.. Komen fellow in the Department of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
Tamoxifen is an established treatment for hormone receptor-positive breast cancer in pre- and postmenopausal women. As a prodrug, tamoxifen is metabolized into its most active metabolite, endoxifen, by the cytochrome P450 isoenzyme 2D6 (CYP2D6). This metabolism is blocked in women who carry loss-of-function variant CYP2D6 alleles or
who take drugs that inhibit CYP2D6 function. Presence of the variant alleles is associated with an increased risk for breast cancer recurrence and a shorter time to recurrence during tamoxifen therapy. Observational studies have been carried out to determine whether drugs that inhibit CYP2D6 have the same effects. The results of these earlier studies were inconclusive, mainly because they were underpowered statistically or they used weak inhibitors.[1-3]
Among the drugs that inhibit CYP2D6 are the selective serotonin reuptake inhibitor (SSRI) antidepressants. It has been estimated that up to 25% of patients with breast cancer experience a major depressive disorder. A commonly prescribed antidepressant is the SSRI paroxetine, which potently inhibits CYP2D6. At last year's annual meeting of the American Society of Clinical Oncology (ASCO), 2 observational studies in breast cancer patients taking tamoxifen and an SSRI reported conflicting results. Investigators from the United States found an increased risk for recurrence,
whereas investigators from The Netherlands found no such association.
Dr. Kelly and her colleagues in Toronto carried out a study to investigate the interaction between tamoxifen and SSRIs by linking data from prescribing records with clinical data from a large population-based cancer registry and other population-based healthcare datasets in the Canadian province of Ontario. They identified 24,430 women at least 66
years of age who were treated with tamoxifen for breast cancer between 1993 and 2005. Among these women, 2430 had overlapping treatment with a single SSRI (paroxetine, fluoxetine, sertraline, fluvoxamine, citalopram, or venlafaxine).
By the end of follow-up (mean duration, 2.38 years), 1074 (44.2%) of these women had died, including 374 (15.4%) who died of breast cancer.
After adjustment for potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine were associated with 24%, 54%, and 91% increases in the risk for death from breast cancer, respectively, which represented a significant difference for each comparison (P < .05). By contrast, no such increased risk was seen with other antidepressants. The investigators calculated that use of paroxetine for 41% of tamoxifen treatment (the median overlap in the study sample) would result in 1 additional breast cancer death within 5 years of cessation of tamoxifen for every 19.7 (95% confidence interval, 12.5-46.3) patients treated. The risk with more extensive overlap would be greater, the investigators noted. These results supported the hypothesis that
SSRIs can reduce or abolish the benefit of tamoxifen in women with breast cancer. Dr. Kelly and colleagues concluded that breast cancer patients taking tamoxifen who are treated for depression or hot flashes should be prescribed antidepressants that show little or no inhibition of CYP2D6.
The results of the study, which were first presented at the 32nd Annual San Antonio Breast Cancer Symposium,December 9-13, 2009, were published in BMJ earlier this year. Dr. Kelly spoke with Linda Brookes on behalf of Medscape Oncology to discuss the study and some of its clinical implications for Medscape's readers.
Medscape: Dr. Kelly, your study was the first to demonstrate a clinical effect of long-term CYP2D6 inhibition during tamoxifen treatment. How did your study differ from previous studies that looked at the effects of CYP2D6 inhibition in patients taking tamoxifen?
Dr. Kelly: Our study differed from previous studies in a number of key areas. We had a large cohort of women -- almost 2500 -- who were exposed to a single SSRI during tamoxifen therapy. We excluded patients who received more than 1 SSRI for a number of reasons. We had reviewed the literature in order to get a sense of which SSRIs were
considered potent, moderate, or weak, and we found the data variable. Often a particular SSRI had not been studied specifically in tamoxifen-treated patients. So we decided not to group drugs into categories but to examine the effects of each drug individually by including only patients exposed to 1 SSRI while receiving tamoxifen. In that way, we grouped patients who received only paroxetine or only citalopram during tamoxifen therapy. We were then able to compare breast cancer mortality among women who took paroxetine for a very short period of time compared with
women who took it for a longer period during tamoxifen therapy. We repeated these analyses for all 6 SSRIs included in our study. We were able to show that increasing overlap of paroxetine with tamoxifen therapy was associated with an increased risk for breast cancer mortality that correlated with the duration of overlap.
Most other studies have used a case-control design, but we felt that a cohort study would be better to examine this particular drug interaction, which is somewhat unusual in that the event (breast cancer death) occurs many years after the exposure (SSRI use during tamoxifen). Another important characteristic and strength of our study was that it
included women who started tamoxifen therapy anytime over a 13-year period between 1993 until 2005, and we continued following patients through 2007. Unlike other studies, we chose breast cancer mortality as our primary outcome, knowing that we would have complete capture of this event. About 15% of patients died of breast cancer
during follow-up. In our Cox model, patients were followed from the date they stopped taking tamoxifen, because most deaths from breast cancer occur after completion of therapy. Finally, we were extremely privileged to have access to Ontario population-based healthcare datasets, which are used extensively and are well validated for this kind of research.
Medscape: Why didn't you have a group taking just tamoxifen and no other drug?
Dr. Kelly: I believe what we did was better in that women who are prescribed an antidepressant may be systematically different from women who never receive an antidepressant, whereas women who have had a very short course of
paroxetine are probably similar in many respects to women who have a longer duration of therapy. So, in a way, our controls were built into each drug group.
Medscape: The studies presented at ASCO in 2009 reported conflicting results. Your findings were more consistent with those of the US study. Did that reflect any similarities between Canada and the United States,
or differences between the North American studies and the European study, which did not find any association between CYP2D6 inhibitor use and breast cancer recurrence?
Dr. Kelly: No; I think the differences were not due to geography but probably reflect differences in study design, statistical power, and length of follow-up. When these studies are published, we will be able to examine them more closely.
Medscape: Are there any differences in prescribing of SSRIs between these parts of the world?
Dr. Kelly: I am not aware of differences in prescribing patterns, but I suspect there are probably some SSRIs prescribed more often in different countries for various reasons, such as availability through provincial drug formularies and cost.
Medscape: How do you explain the result with fluoxetine, which in your study showed no association with increased risk for death from breast cancer?
Dr. Kelly: We expected to see an increased risk for breast cancer mortality in women taking fluoxetine during tamoxifen therapy. The literature consistently shows that fluoxetine is a potent inhibitorof CYP2D6. I think the reason we did not see an increase in risk was probably because not enough women were taking fluoxetine. It is not prescribed very often anymore. The other reason for our finding could be that paroxetine and fluoxetine inhibit CYP2D6 in slightly different ways; paroxetine is an irreversible or mechanism-based inhibitor (it used to be called a "suicide" inhibitor), and
fluoxetine is not. Either way, as I think we made clear in the discussion part of our paper, our results should not exonerate fluoxetine, and we would still advise that fluoxetine along with other potent CYP2D6 inhibitors be avoided in women taking tamoxifen.
Medscape: The result for the main outcome, which was adjusted for confounders -- age, year that tamoxifen was started, duration of tamoxifen treatment, timing of tamoxifen in relation to date of breast cancer diagnosis,
socioeconomic status, comorbidity in the year before completion of tamoxifen treatment, and co-prescription of other CYP2D6 inhibitors -- was increased risk for death from breast cancer. Could you tell anything about recurrence?
Dr. Kelly: It is very hard to capture disease recurrence with these types of data. Often when a patient presents with recurrence of disease, she is not necessarily admitted to hospital. A patient may be switched to a different hormonal agent and not necessarily admitted to hospital. Also, not all patients have a biopsy at the time of recurrence, particularly patients who started tamoxifen in the earlier years of our study. As an outcome or an endpoint, breast cancer mortality is better than recurrence. We could capture it completely and it is definitive. We also conducted a sensitivity analysis
that included death from any cause, including breast cancer, and found an increased risk associated with paroxetine.
This is because the most frequently recorded cause of death was breast cancer, and it is also because sometimes an individual can die from the remote effects of their cancer and the death may not be ascribed to breast cancer. This would have happened equally across all antidepressant groups.
Medscape: You have said quite definitively that if a breast cancer patient is taking tamoxifen then she shouldn't be on paroxetine or fluoxetine. What are the equivalent medications that patients can switch to?
Dr. Kelly: There are alternative medications that patients can take for the treatment of depression, anxiety, and hot flashes. These include drugs that do not inhibit CYP2D6, like the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine or gabapentin or drugs that have minimal inhibitory activity, like citalopram. It is important, though, that if a
patient is taking paroxetine during tamoxifen therapy, that the drug is not stopped abruptly; it should be tapered over time. I have discussed our findings with psychiatry colleagues, and they stress the absolute necessity of antidepressant
therapy, particularly in patients with severe depression in whom it can be lifesaving. However, they also advise that some women, after a certain period of time, may no longer need to continue an antidepressant, and discontinuing it may be appropriate.
Medscape: Is the interaction between tamoxifen and SSRIs widely understood by the physicians who prescribe antidepressants for breast cancer patients?
Dr. Kelly: I think, as a result of our study and others, that there is definitely increased awareness, certainly among medical oncologists who regularly prescribe tamoxifen. There have also been some excellent reviews in a number of psychiatry and oncology journals.[9-11] We were happy that our research was published in BMJ, because the journal has an open-access policy and a wide readership across many different medical specialties, which is important for promoting awareness of this drug interaction. Wide exposure is welcome because often antidepressant therapy is initiated by someone other than a medical oncologist or psychiatrist, such as a family physician.
Medscape: The editorial that was published alongside your study pointed out inconsistencies in the information contained in the summaries of product characteristics, which in some countries do not mention the
possibility of reduced tamoxifen efficacy with concurrent use of CYP2D6 inhibitors. Do you know of any plan to include information about this interaction on drug labels in the United States?
Dr. Kelly: That is correct. As pointed out in the editorial, differences exist in product summaries for tamoxifen, with some manufacturers listing reduced efficacy caused by concurrent use of CYP2D6 inhibitors and others not. The same applies for paroxetine. I believe this issue is being addressed, and we agree with the statement in the editorial that there should be promotion of this drug interaction among healthcare professionals and harmonization of product characteristics.
Medscape: What about other drugs, beside SSRIs, that could interfere with the metabolism of tamoxifen taken by breast cancer patients?
Dr. Kelly: Many drugs can inhibit CYP2D6 to varying degrees. As I mentioned earlier, I performed an extensive review of the literature at the beginning of this work. There were many drugs listed by different sources as having the potential to inhibit CYP2D6. Some sources ranked a drug as potent while others ranked it as weak. In the study, we adjusted for drugs that we felt were clinically relevant, such as amiodarone, quinidine, thioridazine, bupropion. In practice, I find the online resource from Indiana University a very useful guide.
Medscape: As you mentioned in your paper, about 7% of women are poor metabolizers of tamoxifen because of the CYP2D6 variants they carry. These patients are not getting benefit with tamoxifen even without taking a
CYP2D6 inhibitor, such as an SSRI. So, do you think that, in the emerging era of personalized medicine, genetic testing for CYP2D6 of breast cancer patients is warranted? I imagine that most patients would want to know whether there is a chance that they might not respond to tamoxifen, even if it is small.
Dr. Kelly: There are about 13 published studies specifically addressing the association between CYP2D6 loss-offunction variants and outcome among patients taking tamoxifen. Most indicate that polymorphisms in CYP2D6 are important predictors of prognosis for patients with breast cancer who are taking tamoxifen. However, the data are not entirely consistent and are limited by the inclusion of small numbers of patients. In addition, few data have accounted for use of concomitant CYP2D6-inhibiting medication during tamoxifen therapy.
Our study supports the hypothesis that functioning CYP2D6 is necessary to derive benefit from tamoxifen, and it is relatively straightforward, in most cases, to discontinue a potent CYP2D6 inhibitor in preference for an alternative agent. Given the high prevalence of depression and hot flashes among breast cancer patients, avoidance of this drug interaction should have the greatest public health impact. In regard to whether patients starting tamoxifen should have CYP2D6 genotype testing, this is an area of active research, and we expect to know the answer in the next year or so. At the present time, CYP2D6 testing is not recommended until we have consistent, well-validated data.
Medscape: For women who are poor metabolizers of CYP2D6, would starting therapy with an aromatase inhibitor be preferable to tamoxifen on the basis that an aromatase inhibitor would not interact with CYP2D6?
Also, if a patient cannot tolerate or does not respond to SSRIs other than paroxetine, would switching from tamoxifen to an aromatase inhibitor be an option?
Dr. Kelly: For postmenopausal women with hormone receptor-positive breast cancer, an aromatase inhibitor is recommended at some time during adjuvant therapy. However, some women may not tolerate an aromatase inhibitor,and others may have severe osteoporosis that is exacerbated by an aromatase inhibitor. For premenopausal women
with hormone receptor-positive breast cancer, aromatase inhibitors are contraindicated, and the standard of care is to give these women tamoxifen for 5 years. The alternative would be to suppress ovarian function, which has long-term consequences in young women in terms of risk to bone and cardiovascular health.
Medscape: What do you think needs to be done in the clinic now and in the future to further address how CYP2D6 inhibition affects the effectiveness of tamoxifen?
Dr. Kelly: Because tamoxifen remains globally one of the most important and effective drugs for the treatment of hormone receptor-positive breast cancer, and because antidepressant use in combination with tamoxifen therapy is
common, promoting awareness of this avoidable drug interaction takes priority. The direct effect of many commonly prescribed antidepressants that are considered weak or moderate inhibitors has not been studied directly with respect to their effects on tamoxifen metabolism, so studies are needed to address this. We did not consider the effects of varying doses of antidepressant, and this requires investigation. Ongoing studies will provide data that will enable bodies such ASCO, the National Comprehensive Cancer Network, the St Gallen Oncology Conferences, and Cancer Care Ontario to
provide recommendations -- and ultimately evidence-based guidelines -- regarding the role of CYP2D6 genotyping.
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