Discussion
breast cancer, depression, weight gain
BREAST CANCER
In our comprehensive analyses of tamoxifen side effects in 1175 healthy women, five symptoms demonstrated an association with tamoxifen in both pre- and postmenopausal women. When comparing these side effects in women randomised to low-dose (2.5 and 5 mg) versus high-dose (10 and 20 mg) tamoxifen, the difference of severity from start to end of treatment was 34% lower in the low-dose group, a finding restricted to premenopausal women.Few studies describe tamoxifen-induced side effects [In our study, 34 of the total 48 predefined symptoms were not significantly associated with tamoxifen. Ten questions covered psychological well-being whereof only ‘feeling nervous’ was associated with tamoxifen use, but unexpectedly with a negative direction. These findings contrast patient information, where mood swings and depression are described as common tamoxifen side effects [The clinical belief is that tamoxifen induces weight gain. The FACT-ES questionnaire only includes questions about weight gain and not about weight change or loss [We found several symptoms strongly associated with menopausal status not previously described. The interaction of menopausal status on tamoxifen symptoms has not been studied extensively. In the NSABP P-1 trial, women of age 50–59 years reported more tamoxifen-associated symptoms compared to younger women. However, women <50 years reported the greatest relative increase in proportion of women reporting hot flashes at each examination during the study (36 months) [Interestingly, we found that postmenopausal women discontinued treatment at nearly a twofold higher rate compared to premenopausal women. This finding contradicts earlier studies suggesting lower adherence in younger women [Importantly, we did not observe any reduction in severity of the top five symptoms when lowering the dose in postmenopausal women. The biological mechanisms behind the menopausal-dependent difference in tamoxifen side effects have not previously been addressed in detail. Three main factors probably influence the tamoxifen effect: tamoxifen metabolites, ER tissue expression, and hormone plasma concentrations. In the present study, there was no difference in tamoxifen metabolite (endoxifen) concentrations comparing pre- and postmenopausal women (data not published). We have previously shown that the expression of ER in the epithelial breast tissue of healthy women increases with increasing age [From a clinical perspective, menopausal status is essential when assessing risk-benefit of the therapy of choice. In the U.S., tamoxifen is the only FDA-approved drug for breast cancer risk reduction among high-risk premenopausal women. However, high-risk postmenopausal women also have the option of raloxifene and aromatase inhibitors for preventive treatment.The KARISMA trial has several strengths and weaknesses. Strengths include the fact that it is the only low-dose trial so far using the 20 mg standard dose as reference. Also, the double-blinded randomised study design with healthy participants, detailed information on side effects and high adherence with an overall compliance of 85.3%. We found few differences in baseline characteristics between treatment arms. With the exception of questions related to sexuality, the response rate for the remaining questions was close to 100%.The major limitation of the study is that the treatment lasted for only six months. As the KARISMA trial was a dose-determination study, the trial was not designed for studying the long-term effects of tamoxifen. In a clinical setting, both risk-reducing and adjuvant tamoxifen therapy is recommended for at least five years [