Jager Nynke G L, Koornstra Rutger H T, Vincent Andrew D, van Schaik Ron H N, Huitema Alwin D R, Korse Tiny M, Schellens Jan H M, Linn Sabine C, Beijnen Jos H
Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands.
BMC Cancer. 2013 Dec 28;13:612. doi: 10.1186/1471-2407-13-612.
Tamoxifen has dramatically reduced the recurrence and mortality rate of estrogen receptor positive breast cancer. However, the efficacy of tamoxifen varies between individuals and 40% of patients will have a recurrence despite adjuvant tamoxifen treatment. Factors that predict tamoxifen efficacy would be helpful for optimizing treatment. Serum concentrations of the active metabolite, endoxifen, may be positively related to treatment outcome. In addition, hot flashes are suggested to be positively associated with tamoxifen treatment outcome.
We investigated in a series of 109 patients whether the frequency and severity of hot flashes were related to concentrations of tamoxifen and its metabolites. A serum sample of all patients was analyzed for the concentration of tamoxifen, N-desmethyltamoxifen, endoxifen and 4-hydroxytamoxifen, as well as for estradiol concentrations and several single nucleotide polymorphisms in CYP2D6. Additionally, these patients completed a questionnaire concerning biometric data and treatment side effects.
We found no evidence supporting an association between concentrations of tamoxifen or metabolites and either the frequency or severity of hot flashes in the covariate unadjusted analyses. However, including interactions with menopausal status and pre-treatment hot flash (PTHF) history indicated that post-menopausal women with PTHF experienced an increasing frequency of hot flashes with increasing serum concentrations of tamoxifen and its metabolites. This finding was not altered when adjusting for potential confounding factors (duration of tamoxifen treatment, CYP2D6 phenotype, estradiol serum concentration, age and body mass index). In addition we observed a positive association between body mass index and both hot flash frequency (p = 0.04) and severity (p < 0.0001). We also observed that patients with lower estradiol levels reported more severe hot flashes (p = 0.02).
No univariate associations were observed between concentrations of active tamoxifen metabolites and either the frequency or severity of hot flashes during treatment. However, the frequency of hot flashes may be exacerbated by higher serum concentrations of tamoxifen and its metabolites in post-menopausal women with a history of hot flashes prior to tamoxifen treatment.
他莫昔芬显著降低了雌激素受体阳性乳腺癌的复发率和死亡率。然而，他莫昔芬的疗效存在个体差异，40%的患者在接受辅助他莫昔芬治疗后仍会复发。预测他莫昔芬疗效的因素将有助于优化治疗。活性代谢产物内昔芬的血清浓度可能与治疗结果呈正相关。此外，潮热被认为与他莫昔芬治疗结果呈正相关。
我们在109例患者中研究了潮热的频率和严重程度是否与他莫昔芬及其代谢产物的浓度相关。分析了所有患者血清样本中他莫昔芬、N-去甲基他莫昔芬、内昔芬和4-羟基他莫昔芬的浓度，以及雌二醇浓度和CYP2D6中的几个单核苷酸多态性。此外，这些患者完成了一份关于生物特征数据和治疗副作用的问卷。
在未调整协变量的分析中，我们没有发现证据支持他莫昔芬或其代谢产物浓度与潮热频率或严重程度之间存在关联。然而，纳入与绝经状态和治疗前潮热（PTHF）病史的相互作用表明，有PTHF的绝经后女性潮热频率随着他莫昔芬及其代谢产物血清浓度的增加而增加。在调整潜在混杂因素（他莫昔芬治疗持续时间、CYP2D6表型、血清雌二醇浓度、年龄和体重指数）后，这一发现没有改变。此外，我们观察到体重指数与潮热频率（p = 0.04）和严重程度（p < 0.0001）均呈正相关。我们还观察到雌二醇水平较低的患者报告的潮热更严重（p = 0.02）。
在治疗期间，未观察到活性他莫昔芬代谢产物浓度与潮热频率或严重程度之间存在单变量关联。然而，在他莫昔芬治疗前有潮热病史的绝经后女性中，较高的他莫昔芬及其代谢产物血清浓度可能会加剧潮热频率。
