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PHARMACOEPIDEMIOLOGY |
From SUNY Upstate Medical University, Syracuse, New York.
Address for reprints: David Lehmann, MD, 750 Adams Street, Syracuse, NY 13210.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Selective serotonin reuptake inhibitors • tamoxifen • estrogen receptor-positive breast cancer • depression • CYP isoform inhibition
The selective serotonin reuptake inhibitors (SSRIs) are among the most potent inhibitors of one or more of the CYP isoforms involved in tamoxifen metabolism and have been in widespread use for more than 10 years. The 20% to 30% prevalence of depression in breast cancer patients is approximately two to three times greater than the general population.6-8 Since the SSRIs are the most commonly used drugs for depression, it is likely that a significant subgroup of breast cancer patients will receive long-term treatment with both an SSRI and tamoxifen. Hence, the possibility exists that the production of the potent antiestrogenic 4-hydroxy metabolite may be chronically inhibited, resulting in the attenuation of the antitumor effect of tamoxifen.
Because of these issues, the aim of this study was to investigate whether chronic administration of CYP isoform inhibitors with tamoxifen is associated with an alteration in the clinical outcome of patients with estrogen receptor-positive breast cancer.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Case-Patient Identification and Eligibility
The Regional Oncology Center at the State University of New York Upstate Medical University Hospital is a principal referral site for oncology care in central New York. Information concerning tumor status on individual patients from 1986 to present is retrievable from an electronic database in the tumor registry. Updates regarding the status of tumor recurrence for individual patients are requested from referring physicians annually.
The cohort containing the pool of potential cases in this database comprised patients on tamoxifen, initially diagnosed between 1986 to 1999 (inclusive), who had recurrences of estrogen receptor-positive breast cancer. Further eligibility for inclusion of cases was contingent on the availability of continuous annual updates and the presence of a complete medical record from the date of original tumor diagnosis until patient death or year 2003. Eligibility from this pool of 105 cases was further limited to patients with Stage II and III disease at year of diagnosis. This population was chosen to better maximize study power because Stage II/III patients account for the preponderance of relapses.1,2 To militate against bias toward the null hypothesis, charts of potential cases were reviewed and patients excluded for disease contraindications and drug-drug interactions that preclude the use of chronically administered, potent CYP 2D6, 2C9, or 3A inhibitors. These factors included liver disease, long QT and neuroleptic malignant syndromes, and use of monoamine oxidase inhibitors.5 At the end of this process, 28 patients were eligible for inclusion as cases.
Controls: Source and Matching
Controls were selected from the same cohort as the cases. Identical eligibility criteria for cases (excluding tumor recurrence) were applied to controls. That is, controls were selected from the pool of estrogen receptor-positive patients initially diagnosed between 1986 and 1999 (inclusive), without recurrences, who had annual tumor status updates and longitudinal medical records available. The same drug-related exclusions for the cases also applied to the controls. To assist with matching by year of diagnosis, the inclusion period for initial tumor diagnosis of 1986 to 1999 was divided into quartiles. Controls were then matched to cases by cancer stage at diagnosis and year of diagnosis. For purposes of study efficiency, 28 cases were matched to an equal number of controls for the initial (1:1) analysis to determine a trend toward statistical significance (greater inhibitor exposure in cases). An expansion of the study to a ratio of 1:4 was planned if we found a trend toward greater CYP inhibitor use in cases.
Data Collected
Clinical features of all patients were extracted from the charts, stored on site at University Hospital. These records include all outpatient and inpatient progress notes, orders, summaries, telephone communications, and all laboratory and radiographic reports. Variables were entered on a predesigned data form. Age, sex, ethnicity, alcohol use, cigarette use, drug allergies, and all medication history lists available at each visit were recorded. No topical dermatological preparations were recorded in any patient. Drugs prescribed for less than 1 month (e.g., antimicrobials) and those discontinued with less than a 3-month exposure were excluded from data collection and analysis since it is doubtful that such short-term modulation of tamoxifen metabolism could significantly affect an ultimate clinical outcome. Since no patient in either group was chronically exposed to an inducer, all other medications prescribed were then reviewed to determine whether they were CYP 2D6, 2C9, or 3A4 inhibitors or substrates, as described in Table I.5 Furthermore, as all of these medications are usually prescribed for indefinite periods, it was assumed that patients had continuous exposures unless discontinued in the medical record in both cases and controls.
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The date for all data extracted was limited to year of collection to comply with the Health Insurance Portability and Accountability Act (HIPAA) guidelines for studies that do not require patient informed consent. The study was approved by the Institutional Review Board for the Protection of Human Subjects at the SUNY Upstate Medical University.
Statistical Analysis
The main focus of the statistical analysis was the comparative exposure of CYP 2D6, 2C9, and 3A inhibitors between cases and controls. Although the pharmacokinetic impact from concomitant CYP 2D6, 2C9, and 3A substrate use with tamoxifen is much more speculative, comparative exposures to relevant CYP substrates were also separately analyzed for the sake of completeness. Given the significant intersubject variability in the relative contribution of each isoform to 4-hydroxy-tamoxifen generation and the variability in the Ki values among CYP inhibitors, exposures to all inhibitors and substrates were treated as discrete (yes/no) variables without weighting as to the degree of CYP isoform effect. Individual inhibitors or substrates of more than one of the isoforms involved in tamoxifen metabolism were counted more than once for analysis as a separate entity. Likewise, combinations of CYP2D6, 2C9, and 3A inhibitors or substrates used in individual patients were analyzed separately.
Patient characteristics between cases and controls were compared using the Yates-corrected chi-square test for categorical data and the Wilcoxon rank sum test for continuous data. When expected cell counts were less than 5, Fischer's exact test was used to determine differences between the groups using the EPI 6 statistical program (USD, Inc., Stone Mountain, GA). Matched pair analysis (the maximum likelihood estimate) was used to assess the association between CYP inhibitor exposure and clinical outcome to strengthen the statistics.9 The matched analysis was performed using the matched-samples component of the Pepi computer programs for epidemiologists (Version 4.0, Abramson JH, Gahlinger PM). This approach was repeated to compare CYP 2D6, 2C9, and 3A substrate exposure between cases and controls.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Table II also shows that cases and controls were identically matched for cancer stage and quartile year of initial diagnosis. However, within Stage II, more controls (10 vs. 5) were node negative, and more cases (7 vs. 2) had four to nine positive nodes. Since both observations could insert bias in favor of the alternative hypothesis, concomitant use of CYP 2D6, 2C9, and 3A inhibitors was evaluated in these 24 patients. Within these nodal subsets, 3 cases and 4 controls were exposed to relevant CYP inhibitors, favoring the null hypothesis. For Stage III, since more controls (4 vs. 1) had four to nine positive nodes, any resultant bias would favor the null hypothesis.
Table III shows the results of separate matched analyses for exposures to the relevant CYP inhibitors and substrates between cases and controls. No significant differences for either category were found. Indeed, for the primary exposure of interest (concomitant CYP inhibitor use), controls actually received a greater number of CYP 2D6 or 2C9 inhibitors, combined 2D6/2C9 inhibitors, and any inhibitor of the three isoforms. This observation of a trend toward protection from combined CYP inhibitor and tamoxifen exposure in the controls favors the null hypothesis since this concomitant use would likely produce a chronic decrease in the potent antiestrogen metabolite in the group with a better clinical outcome.
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Table III also shows no significant differences between cases and controls concerning CYP 2D6, 2C9, and 3A substrate exposure. Although a trend toward a greater exposure to concomitant CYP isoform substrates in cases was observed, the significance of this observation is unclear since there is a lack of evidence supporting either the in vitro or the clinical relevance of drug interactions involving substrate use with tamoxifen.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Several weaknesses are present in our study that could contribute to the negative results. The case control design is retrospective and particularly prone to bias.9 Indeed, due to the inexactitude of the literature on the relative contributions of the three CYP isoforms to the production of the most potent active metabolite, 4-hydroxy-tamoxifen, incorrect assumptions could have been made that could affect our analysis and conclusions. Also, a substantial and unverifiable assumption was made as to the actual duration of exposure to all coadministered drugs, thereby producing a widely variable exposure to concomitant medications throughout the study period. However, any bias entered by either of these considerations would apply to both cases and controls without preference for either subgroup, particularly since patients in both groups were derived from a cohort nested in a database that is used for purposes other than research (clinical and administrative).
Since a beta error introduced by a small sample size could also account for the lack of an association between CYP inhibitor exposure and breast cancer recurrence, we applied statistics to address this question of adequate study power. Setting the power value at 90%, an alpha of .05, an odds ratio of 1.5, and a presumed inhibitor use in cases of 30% (based on the prevalence of depression), 719 cases would be required to detect a difference if one truly existed.
Our findings strengthen the ex vivo observation that 4-hydroxy-tamoxifen accumulates in tumors extracted from estrogen receptor-positive breast cancer patients with acquired tamoxifen resistance.11 This observation, combined with our results, minimizes the likelihood that pharmacokinetic alterations in tamoxifen metabolism are of major significance in permitting tumor recurrences in breast cancer patients. It is more likely that a pharmacodynamic shift to the right in dose response, perhaps via an alteration in estrogen receptor sensitivity within tumor cells to 4-hydroxy-tamoxifen, may occur in a subgroup of patients with estrogen receptor-positive breast cancer.
In summary, it is unlikely that the effect of chronic exposure to potent CYP isoform inhibitors affects the antitumor effect of tamoxifen and its 4-hydroxy metabolite. These observations support the safety of the continued practice of treating depression with SSRIs in breast cancer patients receiving concomitant tamoxifen therapy.
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FOOTNOTES |
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Submitted for publication August 14, 2003; Revised version accepted April 20, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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1. Early Breast Cancer Trials' Collaborative Group: Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352: 930-942.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
2. Early Breast Cancer Trials' Collaborative Group: Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351: 1451-1467.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Jordan VC, Collins MM, Rowsby L, Prestwich G: A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 1977;75: 305-316.
4. Crewe HK, Ellis SW, Lennard S, Tucker GT: Variable contribution of cytochromes P450 2D6, 2C9, and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem Pharmacol 1997;53: 171-178.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Flockhart DA: Drug interactions: Defining genetics influences on pharmacological responses. Retrieved from www.drug-interactions.com
6. Narrow WE, Rae DS, Robins LN, Regier DA: Revised prevalence estimates of mental disorders in the United States. Arch Gen Psychiatry 2002;59: 115-123.
7. McDaniel JS, Musselman DL, Porter MR, Reed DA, Nemeroff CB: Depression in patients with cancer: diagnosis, biology, and treatment. Arch Gen Psychiatry 1995;52: 89-99.
8. Friedman R: Watch for depression in long-term tamoxifen use. Medscape Medical News, 2003. Retrieved from www.medscape.com/viewarticle/455908
9. Greenberg RS, Daniels SR, Flanders WD, Eley JW, Boring JR: Medical Epidemiology. Norwalk, CT: Appleton & Lange, 1993.
10. Breslow NE, Day NE: Statistical Methods in Cancer Research: Vol. 1. The Analysis of Case-Control Studies. Washington, DC: IARC Scientific Publications, 1980.
11. MacCallum J, Cummings J, Dixon JM, Miller WR: Concentrations of tamoxifen and its major metabolites in hormone responsive and resistant breast tumours. Br J Cancer 2000;82: 1629-1635.[CrossRef][Web of Science][Medline]
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