title: Tamoxifen-associated hot flash severity is inversely correlated with endoxifen concentration and CYP3A4*22.
abstract: 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.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, LHSC-University Hospital, Western University, Room B9-132, 339 Windermere Road, London, ON, N6A 5A5, Canada.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Baxter
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Teft
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Choi
authors.forename: Eric
authors.initials: E
authors.lastname: Winquist
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D019584:Hot Flashes / Q000139:chemically induced* / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D057566:Self Report; D013629:Tamoxifen / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human