Tamoxifen use is often limited in some patients due to adverse effects including severe hot flash symptoms.
Tamoxifen undergoes hepatic bioactivation by
CYP2D6 and
CYP3A4 to form the active metabolite
endoxifen. It remains unclear whether the extent of attained
endoxifen level or genetic polymorphisms in drug metabolizing
enzymes is associated with the frequency and severity of
hot flashes. We conducted a prospective study using self-reported surveys to assess
tamoxifen side effects experienced during the week prior to
clinic visits of 132 female
breast cancer patients on
tamoxifen therapy, and hot flash severity scores were tabulated. At the time of
clinic visit, blood samples were obtained to determine
tamoxifen and its metabolite levels and to determine
CYP2D6 and
CYP3A4 genotypes. The majority of participants (77 %) experienced
hot flashes, with 11 % experiencing severe or very severe symptoms. We observed an inverse correlation between
endoxifen concentration and hot flash severity score following adjustment for age, BMI, and menopausal status in patients with non-zero scores (p < 0.001). Interestingly,
CYP2D6 genotype was not significantly associated with hot flash scores in patients on no known inhibitory medications. However,
CYP3A4*22 carriers were less likely to have
hot flashes with an odds ratio of 8.87 (p < 0.01) even when compared to a cohort with similar
endoxifen levels. Our data demonstrate that patients with higher
endoxifen levels tended to predict lower hot flash severity scores. Importantly, this is the first study to show
CYP3A4*22 genotype as an independent predictor of hot flash severity during
tamoxifen therapy.