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Background: Tamoxifen is oxidized by cytochrome-P450 enzymes (e.g., CYP2D6) to two active metabolites, which are eliminated via glucuronidation by UDP-glucuronosyl transferases (UGT). We measured the association between functional polymorphisms in key UGTs (UGT2B15*2, UGT2B7*2, and UGT1A8*3) and the recurrence rate among breast cancer survivors., Methods: We used the Danish Breast Cancer Cooperative Group registry to identify 541 cases of recurrent breast cancer among women with estrogen receptor-positive tumors treated with tamoxifen for at least 1 year (ER(+)/TAM(+)), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER(-)/TAM(-)). We matched one control to each case on ER status, menopausal status, stage, calendar period, and county. UGT polymorphisms were genotyped from archived primary tumors. We estimated the recurrence OR for the UGT polymorphisms by using logistic regression models, with and without stratification on CYP2D6*4 genotype., Results: No UGT polymorphism was associated with breast cancer recurrence in either the ER(+)/TAM(+) or ER(-)/TAM(-) groups [in the ER(+)/TAM(+) group, compared with two normal alleles: adjusted OR for two UGT2B15*2 variant alleles = 1.0 (95% CI, 0.70-1.5); adjusted OR for two UGT2B7*2 variant alleles = 0.96 (95% CI, 0.65-1.4); adjusted OR for one or two UGT1A8*3 variant alleles = 0.95 (0.49-1.9)]. Associations were similar within strata of CYP2D6*4 genotype., Conclusions: Functional polymorphisms in key tamoxifen-metabolizing enzymes were not associated with breast cancer recurrence risk., Impact: Our results do not support the genotyping of key metabolic enzyme polymorphisms to predict response to tamoxifen therapy.

Background: Cytochrome P450 2D6 (CYP2D6) inhibition reduces the concentration of 4-hydroxylated tamoxifen metabolites, but the clinical relevance remains uncertain., Methods: We conducted a large case-control study nested in the population of 11 251 women aged 35-69 years at diagnosis of stage I-III breast cancer between 1985 and 2001 on Denmark's Jutland Peninsula and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent or contralateral breast cancers among women with estrogen receptor-positive (ER+) disease treated with tamoxifen for at least 1 year and 300 cancers in women with ER-negative (ER-) disease never treated with tamoxifen. We matched one control subject per case patient on ER status, menopausal status, stage, calendar time, and county, genotyped the CYP2D6*4 allele to assess genetic inhibition, and ascertained prescription history to assess drug-drug inhibition. We estimated the odds ratio (OR), associating CYP2D6 inhibition with breast cancer recurrence and adjusted for potential confounding with logistic regression. To address bias from incomplete information on CYP2D6 function, we used Monte Carlo simulation to complete a record-level probabilistic bias analysis. All statistical tests were two-sided., Results: The frequency of the CYP2D6*4 minor allele was 24% in case patients with ER+ tumors, 23% in case patients with ER- tumors, and 22% each in control subjects with ER+ and ER- tumors. In women with ER+ tumors, the associations of one functional allele with recurrence (OR = 0.99; 95% confidence interval = 0.76 to 1.3) and no functional allele with recurrence (OR = 1.4; 95% confidence interval = 0.84 to 2.3) were near null, as were those for women with ER- tumors. The near-null associations persisted when evaluated by intake of medications, by combining genotype with medication history, in the probabilistic bias analysis, or by restricting the analysis to women with ER expression confirmed by re-assay., Conclusion: The association between CYP2D6 inhibition and recurrence in tamoxifen-treated patients is likely null or small.

Background: Up to one-quarter of breast cancer patients suffer clinically significant depression in the year after diagnosis, which may respond to intervention. About half may be prescribed a psychotropic medication, such as a selective serotonin reuptake inhibitor (SSRI), while completing breast cancer therapy. Cytochrome P-450 2D6 (CYP2D6) metabolizes SSRIs and also metabolizes tamoxifen to more active forms. Therefore, concurrent use of SSRIs may reduce tamoxifen's effectiveness at preventing breast cancer recurrence. The SSRI citalopram has limited potency to inhibit CYP2D6 activity, so has been recommended for breast cancer patients taking tamoxifen. This study provides epidemiologic evidence to support this recommendation., Material and Methods: We conducted a case-control study of breast cancer recurrence nested in the population of female residents of Denmark who were diagnosed with non-metastatic estrogen-receptor positive breast cancers between 1994 and 2001 and who took tamoxifen for at least one year. We ascertained complete prescription histories by linking cases' and controls' civil registration numbers to the Danish national prescription registry. We estimated the association between SSRI use while taking tamoxifen and risk of recurrent breast cancer., Results: About the same proportion of recurrent cases (37 of 366) and matched controls (35 of 366) received at least one prescription for citalopram or its s-stereoisomer while taking tamoxifen (adjusted odds ratio = 1.1, 95% confidence interval = 0.7, 1.7). Breast cancer patients taking other SSRIs were also at no increased risk of recurrence (adjusted odds ratio = 0.9, 95% confidence interval = 0.5, 1.8)., Discussion: Breast cancer patients with indications for an SSRI may be prescribed citalopram - and possibly other SSRI - without adversely affecting the outcome of adjuvant therapy with tamoxifen.

Tamoxifen remains an important adjuvant therapy to reduce the rate of breast cancer recurrence among patients with oestrogen-receptor-positive tumours. Cytochrome P-450 2D6 metabolizes tamoxifen to metabolites that more readily bind the oestrogen receptor. This enzyme also metabolizes selective serotonin reuptake inhibitors (SSRI), so these widely used drugs - when taken concurrently - may reduce tamoxifen's prevention of breast cancer recurrence. We studied citalopram use in 184 cases of breast cancer recurrence and 184 matched controls without recurrence after equivalent follow-up. Cases and controls were nested in a population of female residents of Northern Denmark with stages I-III oestrogen-receptor-positive breast cancer 1985-2001 and who took tamoxifen for 1, 2, or most often for 5 years. We ascertained prescription histories by linking participants' central personal registry numbers to prescription databases from the National Health Service. Seventeen cases (9%) and 21 controls (11%) received at least one prescription for the SSRI citalopram while taking tamoxifen (adjusted conditional odds ratio=0.85, 95% confidence interval=0.42, 1.7). We also observed no reduction of tamoxifen effectiveness among regular citalopram users (>or=30% overlap with tamoxifen use). These results suggest that concurrent use of citalopram does not reduce tamoxifen's prevention of breast cancer recurrence.