Clinical and biomarker predictors of side effects from tamoxifen

Abstract

Tamoxifen decreases breast cancer recurrence, mortality, and breast cancer risk in high-risk women. Despite these proven benefits, tamoxifen use is often limited due to side effects. We identified predictors of tamoxifen-induced side effects based on clinical variables and serum tamoxifen metabolite biomarkers in a cross-sectional study of patients taking tamoxifen. We enrolled 241 women and collected data on demographics, tamoxifen use and side effects, as well as potential clinical and serum predictors. We used logistic regression models and adjusted for age, body mass index, ethnicity, education, prior post-menopausal hormone therapy, tamoxifen duration, and endoxifen levels to identify factors associated with side effects. Common tamoxifen attributed side effects were hot flashes (64%), vaginal dryness (35%), sleep problems (36%), weight gain (6%), and depression, irritability or mood swings (6%). In multi-variate models, tamoxifen duration, age, prior post-menopausal hormone therapy, and endoxifen levels all predicted side effects. Women who had been on tamoxifen for >12 months were less likely to report side effects (OR 0.15, 95% CI, 0.04–0.58) or severe side effects (OR 0.05, 95% CI, 0.005–0.58) compared to women on tamoxifen for <12 months. Compared to women younger than 50, women who were age 60–70 and older than 70 were less likely to report side effects (OR 0.22, 95% CI, 0.03–1.35; OR 0.13, 95% CI, 0.01–0.99; respectively). Women who previously took post-menopausal hormone therapy were more likely to report severe side effects. Women with higher endoxifen levels were more likely to report side effects (OR 1.67, 95% CI, 1.01–2.77 per standard deviation increase in endoxifen). Clinicians should consider closely monitoring adherence in women taking tamoxifen, especially in younger women, and women who previously took hormone therapy. The association between endoxifen levels and side effects is consistent with the data that suggest that endoxifen is the most highly active metabolite of tamoxifen.

Breast reconstruction after mastectomy: does it decrease depression at the long-term?

“…Household type, highest level of education and hormonal/endocrine therapy predicted higher risk of depression. These predictive values are consistent with literature where a married status showed a lower risk of depression when compared to a nonmarried status (30), lower social economic status (SES), that often includes low educational level, appears a predictor of developing depression (31)(32)(33) and depression is a known side-effect of hormonal therapy (34,35).…”

Dose Escalation of Tamoxifen in Patients with Low Endoxifen Level: Evidence for Therapeutic Drug Monitoring—The TADE Study

“…The potential links between interindividual variations in tamoxifen metabolism, endoxifen level, vasomotor side effects, and clinical outcome have remained contentious. There have been discordant reports relating metabolite levels to hot flashes, with one reporting an association (32), another an inverse correlation (33) and others an absence thereof (28,34). We found no correlation between hot flash score and CYP2D6 genotype, any tamoxifen metabolite or specifically with endoxifen level in our patient group.…”

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

“…Few of the pharmacogenomic studies reviewed herein incorporated information on tamoxifen adherence (45,83,84), and only 1 considered comprehensive genotype, adherence, and concomitant medicationwith adherence being the dominant contributor (45). If genotype is a predictor of tamoxifen discontinuation (83), then adherence may be a key intermediate factor in the causal pathway between CYP2D6 genotype and breast cancer recurrence or mortality (23).…”