ORLANDO — There's still no clear answer to whether CYP2D6 inhibitors—including some leading antidepressants—reduce the effectiveness of tamoxifen and increase the risk of breast cancer recurrence, based on the conflicting results of two retrospective database studies presented at the annual meeting of the American Society of Clinical Oncology.
Ronald Aubert, Ph.D., and his colleagues found that concomitant use of a CYP2D6 inhibitor increased the risk of recurrence at 2 years among 1,659 women identified through a large combined U.S. medical and pharmacy claims database. The increased risk was even greater for drugs deemed to be moderate or potent CYP2D6 inhibitors.
Dr. Vincent Dezentjé and his colleagues, however, found no increased risk in a study of 1,962 women identified through three large Dutch databases of hospital admissions, pharmacy claims, and pathologic data. Even when they looked at drugs deemed to be strong CYP2D6 inhibitors, the Dutch researchers saw no greater risk of recurrence.
“Additional studies that incorporate both genetic variants and use of inhibitors are required,” said Dr. Vered Stearns of Johns Hopkins University in Baltimore in a discussion of the studies. Until further data are available, “concomitant use of CYP2D6 inhibitors should be limited,” and noninhibitor alternative drugs should be considered.
Hepatic cytochrome P450 2D6 (CYP2D6) is key to the metabolic activation of tamoxifen to its active metabolite, endoxifen. Several previous studies have shown that women receiving tamoxifen have lower levels of endoxifen and are at greater risk of breast cancer recurrence if they have reduced-function CYP2D6 polymorphisms (poor metabolizers). Likewise, previous small studies with CYP2D6 inhibitors and tamoxifen have shown reductions in endoxifen, but have not clearly delineated their impact on breast cancer recurrence.
In their retrospective cohort analysis, Dr. Aubert and his colleagues mined medical and pharmacy claims from the 10 million member integrated database of Medco Health Solutions Inc. They used ICD-9 and CPT-4 codes to define the clinical end points. Dr. Aubert said he and several of his coinvestigators are employed by Medco Health Solutions.
The study population included women who initiated tamoxifen therapy between July 1, 2003, and Dec. 31, 2005. In all, 1,659 women met the criteria for tamoxifen adherence and breast cancer diagnosis. Of these, 945 women had no CYP2D6 inhibitor therapy, 359 women were considered to be exposed to a moderate or potent CYP2D6 inhibitor while on tamoxifen, and 355 women had either no overlap of CYP2D6 inhibitor and tamoxifen therapy or were on CYP2D6 inhibitors that were considered to be weak. Follow-up measurement started 6 months after the initiation of therapy and continued through Dec. 31, 2007.
“When we looked at the distribution of the types of CYP2D6 inhibitors, 79% were antidepressants, with the majority of those being an SSRI (52%),” said Dr. Aubert. In addition, 6% of women were on a serotonin-norepinephrine reuptake inhibitor, 34% were on some other type of antidepressant, 12% were on an antifungal, and 18% were on seven other drugs in unique classes. The mean duration of overlap with tamoxifen was 340 days; the median was 287 days.
Women on CYP2D6 inhibitors had an almost doubled incidence of breast cancer recurrence. For women not on a CYP2D6 inhibitor, the incidence was 7.5% vs. 13.9% in women on a moderate or potent CYP2D6 inhibitor (hazard ratio, 1.92; P less than .001).
“Moderate to severe CYP2D6 inhibitors used concomitantly with tamoxifen were associated with a 92% greater risk of breast cancer recurrence vs. tamoxifen alone,” said Dr. Aubert. Moderate to potent CYP2D6 inhibitor SSRIs (fluoxetine, paroxetine, and sertraline) were associated with a 120% increase in the risk of breast cancer recurrence, whereas weak CYP2D6 inhibitor SSRIs (citalopram, escitalopram, and fluvoxamine) were not associated with an increased risk.
Dr. Dezentjé of Leiden (the Netherlands) University Medical Center and his coinvestigators also performed a retrospective follow-up study. They used three large linked databases: a pharmacy database (PHARMO), a pathology database (PALGA), and a hospital admissions database (Dutch Medical Register) to look at nine CYP2D6 inhibitors: bupropion, paroxetine, fluoxetine, quinidine, duloxetine, terbinafine, amiodarone, cimetidine, and sertraline.
Patients were included if they had a pathology report of a breast cancer resection specimen between 1994 and 2006 and had used tamoxifen in the same period. In all, 3,147 patients were identified with primary breast cancer, of which 1,962 were eligible for this analysis. Most (89%) were on tamoxifen alone, leaving 213 women on tamoxifen and a CYP2D6 inhibitor. Only 150 women met the criteria (at least 60 days) for concomitant use, however, and about 70% were on either paroxetine or fluoxetine.