研究重要性：在過去二十多年來，研究發現乳癌病患使用tamoxifen與子宮內膜癌的關係，但甚少將死亡率、其他干擾因素、以及使用藥物可能會隨時間有動態變化等的情況納入分析討論。
研究目標：瞭解臺灣乳癌病患使用tamoxifen與子宮內膜癌發生的關係。
研究設計：本研究為全人口世代研究。研究起始點為第一次使用tamoxifen後的第180天。
資料來源：本研究使用全民健保資料庫及重大傷病檔。
研究對象：從2000年1月1日至2012年12月31日期間初次診斷為乳癌的女性病患共99,895位。研究期間有使用tamoxifen的乳癌女性病患為實驗組，將符合研究條件的實驗組乳癌病患根據出生年、乳癌初診年、共病症(如高血壓、糖尿病、肥胖和多囊性卵巢症候群)以及社會經濟指標(如投保薪資和投保單位城鄉別)以1:1的配對比進行配對，最後得到實驗組與對照組病患各20,875位。
研究暴露：從2000年1月1日追蹤至2013年12月31日為止，女性乳癌病患使用tamoxifen的情形，藥物定義採WHO(Anatomical Therapeutic Chemical (ATC))藥物分類系統對tamoxifen的ATC 編碼為L02BA01，其Define Daily Dose(DDD)為20mg。
主要結果測量：重大傷病檔中ICD-9編碼為182.xx的子宮內膜癌病患。
統計分析：利用T檢定及卡方檢定來分析實驗組(暴露tamoxifen)與對照組(未暴露tamoxifen)兩組在配對後其基本特性是否有差異。再將接受子宮切除手術、其他癌症及死亡作為競爭風險，並利用Competing risk adjusted Cox regression model(模式一)及Time-dependent Competing risk adjusted Cox regression model(模式二)來分析乳癌病患使用tamoxifen與子宮內膜癌風險的關係。
研究結果：臺灣乳癌病患在追蹤期間內控制其他研究變項下，模式一分析結果顯示乳癌病患平均每年使用少於或超過238 DDD在罹患子宮內膜風險分別高於未使用者(HR:2.49,95%CI:1.23-5.03,p=0.011；HR: 16.46, 95%CI:8.46-31.99,p<0.001)；以年齡分層分析，乳癌病患在20至49歲使用tamoxifen與子宮內膜癌風險無關，在50歲以上使用tamoxifen罹患子宮內膜癌風險高於未使用者(HR:6.3,95%CI:2.91-13.65,p<0.001)；考慮tamoxifen、芳香環抑制劑與子宮內膜癌風險關係發現，曾使用tamoxifen及芳香環抑制劑其子宮內膜風險高於未使用者(HR:4.06, 95%CI:2.37-6.96,p<0.001)，但單獨使用芳香環抑制劑(aromatase inhibitors)與子宮內膜癌風險無關。進一步以年齡分層分析顯示50歲以上曾使用過此兩種藥物在子宮內膜癌上風險較未使用者高(HR: 6.76, 95%CI: 3.09-14.79,p<0.001)。
模式二分析結果顯示乳癌病患在追蹤期間內使用超過336 DDD在罹患子宮內膜風險高於未使用者(HR:3.12,95%CI:1.65-5.93,p=0.001)，而研究起始日前180天每增加100 DDD tamoxifen其子宮內膜癌風險上升16%(HR:1.16,95%CI:1.01-1.34,p=0.040)；以年齡分層分析，乳癌病患在20至49歲使用tamoxifen與子宮內膜癌風險無關，在50歲以上使用tamoxifen罹患子宮內膜癌風險則高於未使用者(HR:2.55,95%CI:1.41-4.61,p=0.002)；考慮tamoxifen、芳香環抑制劑與子宮內膜癌風險關係發現，曾使用tamoxifen及芳香環抑制劑其子宮內膜風險高於未使用者(HR:7.3,95%CI:4.23-12.59,p<0.001)，但單獨使用芳香環抑制劑與子宮內膜癌風險無關；進一步以年齡分層分析不論在20-49歲或50歲以上曾使用過此兩種藥物在子宮內膜癌上風險都較未使用者高(HR:5.38,95%CI:2.33-12.44,p<0.001；HR:11,95%CI:4.97-24.53,p<0.001)。
結論：利用全民健保資料庫進行全人口回溯性的世代研究，觀察臺灣乳癌病患使用tamoxifen與子宮內膜癌關係，考慮干擾因素並依競爭風險模式(模式一)和時間相依設計競爭風險模式(模式二)分析，臺灣乳癌病患使用tamoxifen會增加子宮內膜癌風險，尤其是50歲以上使用者；再者，50歲以上曾使用tamoxifen和芳香環抑制劑會增加子宮內膜癌的風險，但單獨使用芳香環抑制劑卻與子宮內膜癌風險無關，其子宮內膜癌的風險可能來自於tamoxifen的影響；最後，從整個追蹤期(模式一)及劃分每一年為個別追蹤期(模式二)的分析結果比較得知，tamoxifen的使用量與子宮內膜癌風險有關。本研究也發現在開始使用tamoxifen的180天內，其使用量就與子宮內膜癌風險有關。

Importance: Although data from a number of studies over the last 20 years have discovered association between tamoxifen and endometrial cancer among breast cancer women, there is still rare study discussing this issue taking the mortality, other confounding factors and the dynamic use of drug into account.
Objective: The aim of this study is to investigate the association between tamoxifen and endometrial cancer among breast cancer women.
Design: This is a population-based retrospective cohort study. The index date is set as the first prescription of tamoxifen + 180 days.
Setting: We conduct this study by using the National Health Insurance Database (NHID) and Serious Disabling Diseases (SDD) database in Taiwan.
Participants: Female patients with newly-diagnosis of breast cancer during Jan 1, 2000 to Dec 31, 2012 are recruited from registry for SDD in this study (n=99,895). Using exact matching, control (n=20,875) is matched per case by newly-diagnosis year of breast cancer, year of birth, comorbidity and socioeconomic index.
Exposure: Female patients with newly-diagnosis of breast cancer and use tamoxifen during Jan 1, 2000 to Dec 31, 2013 include in this study. Tamoxifen defines as Anatomical Therapeutic Chemical (ATC) by WHO is L02BA01, and its Define Daily Dose (DDD) is 20mg
Main Outcome Measure: Endometrial cancer classify according to the ICD-9 code is 182.xx from Registry for SDD.
Statistics analysis: Chi-square or t tests use to examine differences of women with newly-diagnosis breast cancer in demographic and characteristics between tamoxifen exposure cases and controls. Hysterectomy、other cancer (malignant) and death are taken as competing risks. Using competing risk adjusted Cox regression model (model 1) and Time-dependent competing risk adjusted Cox regression model (model 2), we will evaluate the association between tamoxifen and endometrial cancer among breast cancer patients in Taiwan.
Result：This study in model 1 showed that breast cancer patients in Taiwan use less or over 238 DDD tamoxifen per year during follow-up, the risk in endometrial cancer was higher than that of non-users (HR:2.49,95%CI:1.23-
5.03,p=0.011；HR: 16.46, 95%CI: 8.46-31.99, p<0.001). Over 50 years old users by age stratification, the risk was higher than that of non-users (HR: 6.3, 95%CI: 2.91-13.65, p<0.001). The risk of endometrial cancer in patients who use tamoxifen and aromatase inhibitors was higher than those non-users (HR: 4.06, 95%CI: 2.37-6.96, p<0.001), especially for over 50 years old users. (HR: 6.76, 95%CI: 3.09-14.79, p<0.001); however, using aromatase inhibitors alone had no correlation with the risk of endometrial cancer.
In model 2, breast cancer patients in Taiwan use over 336 DDD tamoxifen per year during follow-up, the risk in endometrial cancer was higher than that of non-users (HR:3.12,95%CI:1.65-5.93,p=0.001). With an increase of each additional 100 DDD of tamoxifen during 180 days prior to index date, the risk of endometrial cancer increased by 16%(HR:1.16,95%CI:
1.01-1.34,p=0.040). Over 50 years old users by age stratification, the risk was higher than that of non-users (HR: 2.55, 95%CI: 1.41-4.61, p=0.002). The risk was also higher with using of tamoxifen and aromatase inhibitors than with non-users in endometrial cancer (HR: 7.3, 95%CI: 4.23-12.59, p<0.001). The risk in 20-49 years and 50 years of age with using of tamoxifen and aromatase inhibitors was higher than in non-users(HR:5.38,95%CI:2.33-12.44,p<0.001；HR: 11,95%CI:4.97-24.53,p<0.001); however, the use of aromatase inhibitors alone was not association with the risk of endometrial cancer among breast cancer patients.
Conclusion：This was a population-based retrospective cohort study from the National Health Insurance Database. In this study, we observed the association between tamoxifen and endometrial cancer among breast cancer patients in Taiwan. Taking the mortality, other confounding factors and the dynamic use of drug into account, we designed the competition risk model (model 1) and time-dependent analysis- competition risk model (model 2). Our data suggested that the use of tamoxifen in breast cancer patients among Taiwan increased the risk of endometrial cancer, especially for those who were over 50 years of age. Furthermore, using tamoxifen and aromatase inhibitors over 50 years of age increased the risk of endometrial cancer; however, the use of aromatase inhibitors alone was not association with the risk, which may come from the effect of tamoxifen. Finally, to analyze two models in this study, we found the risk in endometrial cancer among breast cancer patients who use tamoxifen was association with dosage. Besides, the initial dose of tamoxifen during 180 days prior to index date was also association with the risk of endometrial cancer.

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