Lynn M. Lewis

Cytochrome gene polymorphisms, serum estrogens, and hot flushes in midlife women

OBJECTIVE: The purpose of this study was to evaluate whether genetic polymorphisms in selected cytochrome P450 enzymes (CYPc17α, CYP1A1, and CYP1B1), estradiol (E2) levels, and estrone levels were associated with hot flushes. METHODS: Women with hot flushes were those aged 45–54 years who reported ever experiencing hot flushes (n = 354). Women without hot flushes were those aged 45–54 years who reported never experiencing hot flushes (n = 258). Each participant completed a questionnaire and provided a blood sample for determination of genotypes, E2 levels, and estrone levels. RESULTS: Carriers of the CYP1B1 (Val432Leu) polymorphism were more likely to report having any hot flushes (risk ratio [RR] 1.16, 95% confidence interval (CI) 0.98–1.37) and at least weekly hot flushes (RR 1.29, 95% CI 0.98–1.70) than women without the polymorphism, although these associations were of borderline statistical significance. In addition, carriers of the CYP1B1 polymorphism were likely to have a statistically significant 30% increased risk of reporting moderate to severe hot flushes (RR 1.30, 95% CI 1.02–1.67) and a statistically significant 27% increased risk of reporting hot flushes lasting a year or more (RR 1.27, 95% CI 1.00–1.61) compared with women without the polymorphism. There were no associations between CYP1A1 or CYPc17α polymorphisms and hot flushes. Low E2 and estrone levels were associated with hot flushes, but they did not alter the association between the CYP1B1 polymorphism and hot flushes. CONCLUSION: These data suggest that a CYP1B1 polymorphism may be associated with severe and persistent hot flushes, independent of E2 and estrone levels. LEVEL OF EVIDENCE: III

Association of tamoxifen (TAM) and TAM metabolite concentrations with self-reported side effects of TAM in women with breast cancer.

The positive effects of tamoxifen (TAM) on breast cancer recurrence and survival as well as on overall mortality have led to its use as the predominant adjuvant therapy among women with breast cancer. However, the association of TAM intake with undesirable side effects has been reported in numerous studies. This analysis was carried out to assess whether the concentrations of TAM or TAM metabolites, N-desmethyltamoxifen (N-DMT) and 4-hydroxytamoxifen (4-OHT), were associated with self-reported side effects of TAM. Participants were 99 breast cancer patients who had been taking TAM for at least 30 days. Each participant completed a questionnaire that was used to ascertain whether she experienced certain specific symptoms while taking TAM. In addition, each woman provided a blood sample that was used to measure plasma concentrations of TAM, N-DMT, and 4-OHT by high performance liquid chromatography. Results of the analysis showed that women who experienced at least one TAM-related side effect had significantly higher levels of TAM than women not experiencing any TAM-related side effects. Furthermore, women who reported experiencing visual problems had significantly higher levels of both TAM and N-DMT compared to those women who reported experiencing no visual problems. The levels of 4-OHT were negatively associated with the occurrence of vaginal discharge. The results of this study suggest that the self-reported occurrence of certain symptoms during TAM treatment is related to TAM metabolism. Future studies should assess subgroups of women with specific TAM and TAM metabolite profiles to determine whether alternate, equally effective therapies would decrease their risk of experiencing certain undesirable side effects.

Aging May Be Associated with Concentrations of Tamoxifen and Its Metabolites in Breast Cancer Patients

BACKGROUND Although tamoxifen (TAM) is the predominant adjuvant therapy for estrogen receptor positive (ER(+)) breast tumors, 50% of breast cancer patients do not respond positively to this therapy, or they experience adverse side effects. This variability in TAM responsiveness may be due to differences in TAM metabolism that stem from differences in race, age, and body mass index (BMI). Thus, the purpose of this study was to test the hypothesis that race, age, and BMI are associated with the metabolism of TAM to two primary metabolites, N-desmethyltamoxifen (N-DMT) and 4-hydroxytamoxifen (4-OHT). METHODS The study design was cross-sectional, and data were analyzed using independent sample t tests and multiple linear regression models. Breast cancer patients (n = 99) taking TAM for at least 30 days were recruited from a local hospital clinic. Each participant provided informed consent, completed a questionnaire, and donated a blood sample. The questionnaire was used to ascertain race, age, and BMI. The blood samples were used to measure plasma concentrations of TAM, N-DMT, and 4-OHT. RESULTS Plasma concentrations of TAM, N-DMT, and 4-OHT differed among individual patients. Age, but not race and BMI, was positively associated with plasma concentrations of TAM and N-DMT, even after adjustment for potential confounders (p = 0.02 for TAM and p = 0.03 for N-DMT). CONCLUSIONS This study suggests that aging may alter the metabolism of TAM. As increased levels of TAM and TAM metabolites may provide a possible explanation for why older women taking TAM are at increased risk for adverse side effects, future studies should determine whether age-related differences in the concentrations of TAM and TAM metabolites are associated with differences in TAM toxicity or responsiveness.