探討內分泌治療的乳癌患者與糖尿病發生風險之相關性

乳癌(breast cancer)在全球女性癌症發生率位居第一，在台灣根據國民健康署106年癌症登記報告顯示，乳癌的發生率逐年持續上升且為女性癌症首位。乳癌的治療日益進步，統計報告顯示乳癌的存活率優於其他癌症。治療的進步雖然延長患者的存活率，但也可能衍生其他健康問題而導致生活品質下降，因此降低因治療造成的共病及提升生活品質成為醫療照護上需要重視的議題。乳癌內分泌治療藥物分為(1)適用於停經前後的泰莫西芬(Tamoxifen)；(2)適用於停經後的芳香環酶抑制劑(Aromatase inhibitors)；(3)適用於停經前的促性腺激素釋放激素類似物(Gonadotrophin-releasing hormone agonists, GnRH agonists)。前兩者的作用機轉分別為抑制雌激素與受體結合與阻斷雄性素轉換為雌激素，而GnRH agonists則是直接抑制卵巢生成雌激素的功能，進而導致雌激素缺乏。雌激素與胰島素分泌、胰島素抵抗、能量平衡和葡萄糖穩定態有關。而胰島素抵抗及胰島細胞分泌功能障礙被認為是糖尿病的致病機制。上述概要顯示乳癌的內分泌治療可能與糖尿病的發生有關，但先前研究報告對兩者的相關性無一致的結果，且尚無研究探討接受GnRHa治療者與發生糖尿病的相關性。本研究使用台灣健保資料庫(National Health Insurance Research Databases 2003-2013)，篩選新診斷女性乳癌個案，分析其接受內分泌治療與糖尿病發生風險之相關性，使用SPSS 22統計軟體進行數據分析，計算糖尿病的累積發生率。使用多變量Cox回歸分析以估計糖尿病的風險比值。本研究個案數有4224位，未接受內分泌治療者占1805位，接受內分泌治療者占2419位，接受內分泌治療者以年齡正負5歲及相同乳癌診斷年的條件與未接受內分泌治療者進行1：1配對，分為(1)接受內分泌治療配對組；(2)單獨接受泰莫西芬治療配對組；(3)曾經接受泰莫西芬與芳香環酶抑制劑治療配對組；(4)單獨接受芳香環酶抑制劑治療配對組；(5)接受促性腺激素釋放激素類似物治療配對組，結果顯示糖尿病的累積發生率在各組別差異無統計上意義，但在曾經接受泰莫西芬與芳香環酶抑制劑治療配對組，治療組追蹤前二年的累積發生率高於未接受治療組，且具統計上意義，P值為0.017。糖尿病的風險比值在曾經接受泰莫西芬與芳香環酶抑制劑治療配對組，於接受治療後二年，接受治療組的糖尿病風險為未治療組的2.25倍，並達統計上的顯著意義，P值為0.013；其他組別則無統計上差異。本篇研究結果為接受過泰莫西芬與芳香環酶抑制劑治療的乳癌患者，在接受治療前兩年的糖尿病發生風險高於未接受治療者，而在接受內分泌治療的乳癌個案糖尿病的風險相較於未接受治療者，差異性無統計上顯著意義，但是在追蹤二年內仍可以看到治療組的風險比值高於未治療組，意味著內分泌治療藥物在乳癌病患接受內分泌治療早期可能是糖尿病發生的重要危險因素，因此建議接受內分泌藥物治療之乳癌病患，應早期密切監測糖尿病的發展，及時介入預防措施，以提升乳癌病患在治療過程的生活品質及用藥安全。

關鍵字

乳癌內分泌治療；糖尿病；回溯性世代研究；台灣健康保險資料庫

並列摘要

Breast cancer ranks first in the incidence of female cancer in the world. According to the 106-year cancer registration report of the National Health Bureau in Taiwan, the incidence of breast cancer continues to rise year by year and ranks first in female cancer. The treatment of breast cancer is improving day by day, and statistical reports show that the survival rate of breast cancer is better than other cancers. Although the progress of treatment prolongs the survival rate of patients, it may also lead to other health problems and lead to a decline in quality of life. Therefore, reducing co-morbidities due to treatment and improving the quality of life have become issues that need attention in medical care. Breast cancer endocrine therapy drugs are divided into (1) Tamoxifen for women before and after menopause; (2) Aromatase inhibitors for women after menopause; (3) Gonadotrophin-releasing hormone agonists (GnRH agonists) for women before menopause. The mechanism of the first two functions is to inhibit the binding of estrogen to the receptor or block the conversion of androgen to estrogen, while GnRH agonists directly inhibits the function of ovarian production of estrogen, which in turn leads to estrogen deficiency. Estrogen is related to insulin secretion, insulin resistance, energy balance and glucose homeostasis. Insulin resistance and islet cell secretion dysfunction are considered to be the pathogenic mechanism of diabetes. The above summary shows that endocrine therapy may be related to the occurrence of diabetes, but previous studies have reported inconsistent results on the correlation between the two, and there is no research to explore the correlation between GnRH agonists treatment and diabetes. This study used the National Health Insurance Research Databases 2003-2013 to screen newly diagnosed cases of female breast cancer, analyze the correlation between their endocrine therapy and the risk of diabetes, and use SPSS 22 statistical software for data analysis to calculate the cumulative incidence of diabetes. And use multivariate Cox regression analysis to estimate the hazard ratio of diabetes. The number of cases in this study was 4224, 1805 were not receiving endocrine therapy, 2419 were receiving endocrine therapy, and those receiving endocrine therapy were the same as those who did not receive endocrine therapy based on the conditions of age ±5 years and the same　breast cancer diagnosis year 1:1 paired, divided into (1) paired group receiving endocrine therapy; (2) paired group treated with tamoxifen alone; (3) paired group once treated with tamoxifen and aromatase inhibitor; (4) paired group receiving aromatase inhibitor alone ; (5) paired group receiving ovarian function suppression. The results showed that the cumulative incidence of diabetes was not statistically significant in each group, but in the paired group who had been treated with tamoxifen and aromatase inhibitors, the cumulative incidence in the first two years of follow-up was higher in the treatment group than in the unaccepted treatment group, with statistical significance. The hazard ratio of diabetes in the paired group who had been treated with tamoxifen and aromatase inhibitors after two years of follow-up, the risk of diabetes in the treated group was 2.25 times that of those who did not receive treatment, and it was statistically significant; other there is no statistical difference between the groups. The results are that breast cancer patients who have received tamoxifen and aromatase inhibitors have a higher risk of diabetes in the two years than those who have not received treatment. Breast cancer cases who have received endocrine therapy have a higher risk of diabetes than those who have not received treatment, but there is no statistically significant difference. However, within two years of follow-up, the hazard ratio of the treatment group is higher than that of the untreated group, which means that endocrine therapy may be an important risk factor for diabetes in the early stage of treatment. Therefore, it is recommended that breast cancer patients treated with endocrine therapy should closely monitor the development of diabetes and promptly intervene in preventive measures to improve the quality of life and drug safety of breast cancer patients during the treatment process.