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研究生： 錢叙芝
Chien, Hsu-Chih
論文名稱： Trastuzumab於臺灣乳癌患者之心臟毒性評估
Trastuzumab Related Cardiotoxicity in Taiwanese Breast Cancer Women
指導教授： 高雅慧
Yang, Yea-Huei Kao
學位類別： 博士
Doctor
系所名稱： 醫學院 - 臨床藥學與藥物科技研究所
Institute of Clinical Pharmacy and Pharmaceutical sciences
論文出版年： 2016
畢業學年度： 104
語文別： 英文
論文頁數： 144
中文關鍵詞： trastuzumab 、乳癌 、心臟毒性
外文關鍵詞： trastuzumab, breast cancer, cardiotoxicity
相關次數： 點閱：83  下載：2 
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    • 研究背景及目的：亞洲乳癌患者佔全世界新診斷乳癌患者的百分之四十，然而目前的治療指引乃至藥品仿單中所刊載的資訊，皆以西方族群為觀察對象所得之證據為主。癌症治療旨在延長壽命，改善生活品質。然而，全身性腫瘤治療相關的副作用，卻可能影響患者情緒及生活品質，衍生醫療費用、生活照護等公共衛生議題。本研究將針對治療HER2 (human epidermal growth factor receptor type 2)蛋白表現陽性乳癌的首選藥品trastuzumab，分析其藥品使用型態，用藥後心臟毒性的發生率、風險及相關危險因子等。

    研究方法：本研究以全民健保研究資料庫特殊需求檔及重大傷病檔為材，研究族群為2006年1月1日至2012年12月31日首次被診斷乳癌的患者。針對化療後心衰竭危險因子，我們納入2006年1月1日至2011年12月31日首次被診斷乳癌並開始接受化療的患者，分析於開始接受化療後二年內發生心衰竭的危險因子。針對trastuzumab用藥後心衰竭危險因子評估，我們納入2006年1月1日至2012年12月31日開始使用trastuzumab的乳癌患者，評估開始用藥後一年內發生心衰竭的危險因子。
    針對使用trastuzumab發生心衰竭的風險評估，我們以傾向分數(propensity score)與開始接受化療的年度為配對條件，選取未使用trastuzumab但接受化療的乳癌患者為對照組，評估trastuzumab發生心衰竭的風險。在此評估模式中，我們納入化療藥品(包括anthracyclines, taxanes及cyclophosphamides)的累積劑量，以校正其他有心毒性藥品的使用對trastuzumab風險評估的影響。

    結果：在2006年到2012年共有65,135位新診斷乳癌患者。其中有7,333使用trastuzumab。使用trastuzumab後發生心衰竭的粗發生率為2.58 %。
    於開始接受化療後二年內發生心衰竭的危險因子包括年齡，使用有心毒性的標靶治療藥品或化療藥品(包括trastuzumab, anthracyclines及taxanes)。接受化療前一年使用降血壓藥品(包括beta-blockers, diuretics及angiotensin converting enzyme inhibitors)，alpha-glucosidase inhibitors及statins的乳癌患者，相較於未使用者於化療後二年罹患心衰竭的風險較高。相較於為接受乳癌篩檢者，確診為乳癌前曾接受乳癌篩檢者，於化療後二年罹患心衰竭的風險較低。化療前接受電腦斷層掃描(computed tomography, CT)者，於化療後二年罹患心衰竭的風險較高。
    在6,337使用trastuzumab且於用藥後存活至少一年的乳癌女性中，於開始接受治療的一年內，心衰竭的發生率為1.40%。相較於用藥前未接受心臟功能監測者，接受心臟功能監測者罹患心衰竭的風險較高。其他使用trastuzumab後發生心衰竭的危險因子包括年齡，高血壓及心律不整的病史。
    相對於未使用trastuzumab的乳癌女性，使用trastuzumab一年後心衰竭的風險增加了71% (aHR: 1.71; 95% CI, 1.02-2.86 )。

    結論：臺灣乳癌患者使用trastuzumab後心衰竭的粗發生率僅西方族群的五分之一。臺灣乳癌患者接受化療後發生心衰竭的危險因子與西方乳癌患者相似。使用trastuzumab後發生心衰竭的風險與危險因子皆與西方乳癌患者相似。

    Scope and Objective: Asian women accounted for 40% of newly diagnosed breast cancer cases worldwide but real-world evidence regarding the cardiac safety of trastuzumab in the Asian population is limited.
    This thesis is thus aimed to describe the prescribing pattern of trastuzumab, to evaluate the rate and the risk factors related to heart failure and/or cardiomyopathy (HF/CM) among Taiwanese breast cancer women and trastuzumab users and to estimate the risk of HF/CM Taiwanese trastuzumab users.

    Methods: Using National Health Insurance Research Database (NHIRD), we described the prescribing pattern of trastuzumab and estimated the incidence and risk factors for HF/CM among breast cancer women within 2 years after chemotherapy initiation and trastuzumab related HF/CM within the first year of treatment course in all trastuzumab users during 2006 to 2012.
    We also evaluated the risk of trastuzumab related HF/CM among all incident breast cancer women that were diagnosed during 2006 to 2009. The median follow-up duration was 5.29 years. We applied a land mark design and matched trastuzumab user with nonusers using the year of breast cancer diagnosis and propensity score (PS) with caliper widths of 0.25 standard deviation of PS, and allowing up to 4 nonusers per trastuzumab user. We applied cause-specific hazard model, using trastuzumab as a time dependent variable and cumulative courses of chemotherapy agents with known cardiotoxicity (including anthracyclines, taxanes, and cyclophosphamide) as time dependent covariates in the analysis model, to evaluate the risk of HF/CM in the matched cohort. We also examined the robustness of our finding by performing 8 sensitivity analyses.

    Results: Among 65,135 incident breast cancer patients from January 1, 2006 to December 31, 2012, there were 7,333 trastuzumab users in our cohort. The crude HF/CM incident rate of trastuzumab users was 2.58%. Risk factors of HF/CM in Taiwanese breast cancer women that received chemotherapy were age, receiving cardiotoxic chemotherapy agents (including trastuzumab, anthracyclines and taxanes), hypertensive agents (including beta-blockers, diuretics and angiotensin converting enzyme inhibitors), alpha-glucosidase inhibitors and statins. Women with a breast cancer screening within 2 years prior to the diagnosis were at a lower risk of HF/CM while those who received computed tomography (CT) prior chemotherapy initiation had higher risks to have HF/CM.
    In 6,337 women that survived at least one year after trastuzumab initiation, 89 (1.40%) women had HF/CM within a year after trastuzumab initiation. Receiving a baseline cardiac monitoring, diagnosed as hypertension and arrhythmia prior trastuzumab were risk factors for trastuzumab related HF/CM.
    Compared with non-users, the 1-year cumulative HR for HF/CM in trastuzumab users was 1.71 (95% CI, 1.02-2.86). Our sensitivity analyses yielded similar results.

    Conclusion: Compared to the published results, our cohort was approximately 10 years younger; the trastuzumab-related HF/CM rate was 5-fold lower. Nonetheless, our cohort had a similar trastuzumab-related HF/CM risk. Our results provide the critical cardiac safety information of trastuzumab for the Asian patient population.

    1. Introduction 1 1.1. Roles of Trastuzumab in Breast Cancer Treatment 1 1.2. Indication, Usage and Cardiac Monitoring of Trastuzumab in Breast Cancer Women 2 1.2.1. Indication 2 1.2.2. Usage 3 1.2.3. Cardiac Monitoring 3 1.3. Reimbursement Criteria of Trastuzumab Under Taiwan National Health Insurance 4 1.4. Cardiovascular Risks among Breast Cancer Patients 5 1.5. Trastuzumab Related Cardiotoxicity from Clinical Trials 6 1.5.1. Systematic Review 6 1.5.2. Herceptin Adjuvant (HERA) Trial 7 1.5.3. National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 Trial 9 1.5.4. North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer (NCCTG N9831) Trial 10 1.6. Trastuzumab Related Cardiotoxicity from Settings Other Than Clinical Trials 12 1.7. Risk Factors of Trastuzumab Related Cardiotoxicity 14 1.8. Implication for Asian patients 16 1.9. Quality of Care Among Breast Cancer Patients in Taiwan 16 1.10. Knowledge Gap 18 1.11. Impact of Nationwide Reimbursement Criteria on The Cardiovascular Risk Assessment of Trastuzumab and Challenges We Met 18 1.11.1. Challenge in Comparability 18 1.11.2. The risk of competing events 19 1.12. Aims and Objectives 21 2. Method 23 2.1 Data Source 23 2.2 Objective 1: Trastuzumab Utilization Pattern 24 2.2.1. Study Population 24 2.2.2. Analytic Variables and Definition 24 2.3. Objective 2: The Incidence and The Risk Factors of Trastuzumab-related HF/CM 25 2.3.1. Study Population 25 2.3.2. Outcome Definition 26 2.3.3. Analytic Variables and Definition 26 2.3.4. Comorbid Status and Concurrent Medication 26 2.3.5. Medical Records Related to Breast Cancer Treatment 28 2.3.6. Chemotherapy Course Definition 29 2.3.7. Analytical Approach 30 2.4. Objective3: The Risk of Trastuzumab-related HF/CM 31 2.4.1. Study Population 31 2.4.2. Analytic Variables and Definition 31 2.4.3. Target Therapy, Chemotherapy and Radiation Therapy Exposure 32 2.4.4. Propensity Score (PS) Model 33 2.4.5. Statistical Analysis 34 2.4.6. Subgroup Analysis & Sensitivity Analysis 35 3. Results 37 3.1. Objective 1: Prescribing Pattern of Trastuzumab 37 3.1.1. Cohort Characteristics 37 3.1.2. Utilization of Trastuzumab 38 3.2. Objective 2-1: Incidence of HF/CM 39 3.2.1. Cohort Characteristics 39 3.2.2. Incidence of HF/CM 41 3.3. Objective 2-2: Risk Factors for HF/CM Among Breast Cancer Women That Treated with Chemotherapy 42 3.3.1. Cohort Characteristics 42 3.3.2. Risk Factors for HF/CM among Breast Cancer Women That Treated with Chemotherapy 43 3.4. Objective 2-3: Risk Factors for HF/CM Among Trastuzumab Users 44 3.4.1. Cohort Characteristics 44 3.4.2. Risk Factors for HF/CM Among Trastuzumab Users 45 3.5. Objective3: The Risk of Trastuzumab-related HF/CM 46 3.5.1. Study Cohort 46 3.5.2. Baseline Characteristics 47 3.5.3. Utilization of Trastuzumab 47 3.5.4. Incidence of HF/CM 48 3.5.5. Matched Cohort 48 3.5.6. Risk of HF/CM 49 4. Discussion 51 4.1. Taiwanese Breast Cancer Cohort 51 4.2. Prescribing Patterns of Trastuzumab Among Taiwanese Breast Cancer Women 52 4.2.1. Time to Initiate Trastuzumab 52 4.2.2. Treatment Duration of Trastuzumab 53 4.2.3. Dosage and Frequency 53 4.3. Incidence of Cardiac Adverse Events Among Taiwanese Breast Cancer Women That Were Treated with Chemotherapy 54 4.4. Selection Criteria for Cohorts to Evaluate the Risk Factors for HF/CM among Breast Cancer Women That Treated with Chemotherapy and Those among Trastuzumab Users 56 4.4.1. The Rationale of Cohort and Analytical Model Selection for Objective 2-2 56 4.4.2. The Rational of Cohort and Analytical Model Selection for Objective 2-3 57 4.5. Risk Factors for HF/CM among Breast Cancer Women That Treated with Chemotherapy (Objective 2-2) 58 4.5.1. Computed Tomography 58 4.5.2. Cumulative Counts for Courses of Cardiotoxic Agents 59 4.5.3. Age 63 4.5.4. Medication for Cardiovascular Comorbidities 63 4.5.5. Breast Cancer Screening 65 4.5.6. The Year Diagnosed as Breast Cancer 66 4.6. Risk Factors for Trastuzumab Related Cardiotoxicity Among Trastuzumab Users (Objective 2-3) 67 4.6.1. Baseline Cardiac Monitoring 67 4.6.2. Cardiovascular Comorbidities 68 4.6.3. Age 69 4.6.4. Health Consciousness 70 4.6.5. Cardiotoxic Agents/ Therapy to Treat Breast Cancer 70 4.6.6. Limitation 71 4.7. The Risk of Trastuzumab-related HF/CM (Objective 3) 72 4.7.1. HF/CM Incidence 72 4.7.2. Low HF/CM Incidence in Asian Trastuzumab Users 73 4.7.3. Evaluation of Health Behavior Bias 74 4.7.4. Consideration of Exposed Periods 75 4.7.5. Consideration of Follow-up Periods 75 4.7.6. Consideration of Comparators 76 4.7.7. The Impact of the Overexpressed Status of HER2 on Cardiotixicity 77 4.7.8. Consideration on the Risk of Competing Event 77 4.7.9. Limitation 77 5. Future Direction 80 6. Conclusions 83 REFERENCES 136

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