The Effect of CYP2C19 Polymorphisms on Breast Cancer Recurrence among a Danish Cohort of Premenopausal Tamoxifen Treated Women Open Access

Bhai, Sadaf Amin (Spring 2020)

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Tamoxifen is the guideline therapy for premenopausal women who are diagnosed with estrogen receptor positive breast cancer. Cytochrome P450 enzymes are responsible for breaking tamoxifen down to its active metabolites. The CYP2C19 enzyme is on the path for producing 4OH-TAM and its conversion to endoxifen, which are two key metabolites that compete with estrogen to bind to the estrogen receptor. However, polymorphisms in the CYP2C19 gene can affect the amount of metabolite produced. This study used 5,959 Danish premenopausal women enrolled in the Predictors of Breast Cancer Recurrence cohort to determine if there was an association between CYP2C19 genotype and breast cancer recurrence after tamoxifen treatment. Additionally, this study aimed to find if CYP2C19 inhibiting drug therapy was an effect modifier for this association. The genotypes examined were CYP2C19*2, which causes loss of enzyme function, and CYP2C19*17, which allows for gain of enzyme function. Cox proportional hazard ratios were calculated along with the corresponding 95% confidence intervals for univariate and adjusted analysis in both ER+/ TAM+ and ER-/ TAM- cohorts. The interaction assessment found that hazard ratios between women who took CYP2C19 inhibiting drugs and those who did not were not meaningfully different between genotypes in both cohorts. In the ER+/ TAM+ cohort, adjusted analysis gave hazard ratios of 1.17 (0.93, 1.49) and 1.01 (0.55, 1.86) for hetero- and homozygotes with CYP2C19*2 genotypes and hazard ratios of 1.09 (0.86, 1.39) and 0.77 (0.32, 1.86) for hetero- and homozygotes with CYP2C19*17 genotypes. In the ER-/ TAM- cohort, adjusted analysis gave hazard ratios of 1.38 (0.91, 2.11) and 1.29 (0.59, 2.24) for hetero- and homozygotes with CYP2C19*2 genotypes and hazard ratios of 1.00 (0.60, 1.66) and 0.84 (0.20, 3.50) for hetero- and homozygotes with CYP2C19*17 genotypes. The results of this analysis indicate that there is no association between CYP2C19*2 and CYP2C19*17 genotypes and breast cancer recurrence, and that CYP2C19 inhibiting drugs do not modify this association. This study utilized a large cohort of premenopausal women, which most previous studies did not do. Future studies should aim to focus on the effect different dosages of tamoxifen might have on recurrence.  


Table of Contents

I. Introduction- Page 1

II. Methods

a. Data Source and Population- Page 4

b. Analytic Variables- Page 5

c. Covariables- Page 5

d. Statistical Analysis- Page 6

III. Results

a. Study Population- Page 8

b. Effect Modification of CYP2C19 Inhibiting Therapy- Page 8

c. Survival Analysis- Page 9

IV. Discussion- Page 11

V. References- Page 14

VI. Tables

a. Table 1- Page 17

b. Tables 2a and 2b- Page 18

c. Tables 3a and 3b- Page 19

d. Tables 4a and 4b- Page 20 

VII. Supplements

a. Supplement 1- Page 21

b. Supplement 2- Page 22 


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