- Catherine M Kelly, medical oncology fellow 15,
- David N Juurlink, division head, clinical pharmacology123457,
- Tara Gomes, epidemiologist7,
- Minh Duong-Hua, analyst6,
- Kathleen I Pritchard, professor1235,
- Peter C Austin, senior statistician57,
- Lawrence F Paszat, senior scientist12357
- 1Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Canada
- 2Sunnybrook Research Institute, Toronto,
- 3Department of Medicine, University of Toronto, Toronto
- 4Department of Pediatrics, University of Toronto
- 5Department of Health Policy, Management, and Evaluation, University of Toronto
- 6Canadian Institute for Health Information, Toronto
- 7The Institute for Clinical Evaluative Sciences, Ontario, Canada
- Correspondence to: D Juurlink, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada M4N 3M5
- Accepted 1 February 2010
Objective To characterise whether some selective serotonin reuptake inhibitor (SSRI) antidepressants reduce tamoxifen’s effectiveness by inhibiting its bioactivation by cytochrome P450 2D6 (CYP2D6).
Design Population based cohort study.
Participants Women living in Ontario aged 66 years or older treated with tamoxifen for breast cancer between 1993 and 2005 who had overlapping treatment with a single SSRI.
Main outcome measures Risk of death from breast cancer after completion of tamoxifen treatment, as a function of the proportion of time on tamoxifen during which each SSRI had been co-prescribed.
Results Of 2430 women treated with tamoxifen and a single SSRI, 374 (15.4%) died of breast cancer during follow-up (mean follow-up 2.38 years, SD 2.59). After adjustment for age, duration of tamoxifen treatment, and other potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine (an irreversible inhibitor of CYP2D6) were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P<0.05 for each comparison). By contrast, no such risk was seen with other antidepressants. We estimate that use of paroxetine for 41% of tamoxifen treatment (the median overlap in our sample) would result in one additional breast cancer death within five years of cessation of tamoxifen for every 19.7 (95% confidence interval 12.5 to 46.3) patients so treated; the risk with more extensive overlap would be greater.
Conclusion Paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer, supporting the hypothesis that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer.
We thank David Henry, John Horn, and Steven Shumak for comments on an earlier draft of this manuscript, and we thank Ashif Kachra for assistance with manuscript preparation.
Participants: CMK (guarantor): study concept, design, data extraction, analysis, manuscript writing. DNJ: study concept, design, analysis, supervision, manuscript writing. TG: study design, analysis of data. MD-H: data extraction and analysis. KIP: study design, supervision. PCA: study design and analysis of data. LFP: study concept, design, analysis, supervision. CMK and DNJ had full access to the data (including statistical reports and tables) in the study. CMK takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding: CMK was supported by a fellowship award from the Sunnybrook Hospital Foundation. DNJ was supported by a New Investigator award from the Canadian Institutes of Health Research. PCA is supported by a Career Investigator award from the Heart and Stroke Foundation of Ontario. LFP is supported by a Clinician Scientist award from the Ontario Ministry of Health and Long-Term Care. This research was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The study was supported in part by the Ontario Drug Policy Research Network, funded by the Ontario Drug Innovation Fund. The funder had no role in the design, analysis, conduct or reporting of the study. The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred.
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org_disclosure.pdf (available on request from the corresponding author. During the past three years KIP has been a consultant for Sanofi-Aventis, AstraZeneca, Roche, Pfizer, Ortho-Biotech, YM Biosciences, Novartis, Abraxis, Amgen, and GlaxoSmithKline (GSK). KIP has received research funding either directly through per case funding for studies, or indirectly through the National Cancer Institute of Canada Clinical Trials Group, contracted with pharmaceutical companies including AstraZeneca, YM Biosciences, Bristol Myers, Squibb, Sanofi-Aventis, Amgen, Ortho-Biotech, Pfizer, Novartis, GlaxoSmithKline, and Ortho Biotech. KIP has received honorariums or been part of speaker’s bureaux from Sanofi-Aventis, AstraZeneca, Pfizer, Roche, YM Biosciences, and Novartis. KIP has given paid expert testimony for Sanofi-Aventis, AstraZeneca, and GlaxoSmithKline. KIP has been a member of Advisory Committees for Sanofi-Aventis, AstraZeneca, Ortho-Biotech, Roche, Pfizer, Novartis, YM Biosciences, and GlaxoSmithKline. All other authors declare (1) no support from any company for the submitted work; (2) no relationships with any companies that might have an interest in the submitted work in the previous 3 years; (3) their spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and (4) no non-financial interests that may be relevant to the submitted work.
Ethical approval: The study was approved by the research ethics board of Sunnybrook Health Sciences Centre, Toronto, Canada.
Data sharing: No additional data available
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