進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-0107201820481500
論文名稱(中文) 中藥當歸暴露對於女性乳癌發生率之影響
論文名稱(英文) A population-based case-control study on the associations of Angelica sinensis with breast cancer
校院名稱 成功大學
系所名稱(中) 公共衛生研究所碩士在職專班
系所名稱(英) Graduate Institute of Public Health(on the job class)
學年度 106
學期 2
出版年 107
研究生(中文) 陳忠淵
研究生(英文) Jhong-Yuan Chen
學號 SB7051044
學位類別 碩士
語文別 中文
論文頁數 56頁
口試委員 指導教授-李中一
召集委員-顏宏融
口試委員-簡玉雯
口試委員-陳忠仁
中文關鍵字 當歸  植物性雌激素  乳癌  健保資料庫  流行病學研究 
英文關鍵字 Angelica  Phytohormone  Breast cancer  Health insurance database  Epidemiological studies 
學科別分類
中文摘要 研究背景:
自從荷爾蒙補充療法被發現會提高乳癌發生風險後,學界對於中藥中所含的植物性荷爾蒙同樣會有乳癌的顧慮,尤其是最常使用在改善婦科更年期症狀的當歸。在當歸相關研究中,早期有些學者發現當歸萃取液會刺激乳癌細胞的增生。但後續試驗中所觀察到的結果卻非呈現一致性,甚至有觀察到當歸萃取物有抑制雌激素活性或促進乳癌細胞凋亡等抑癌作用。也因為缺乏關鍵性的人體對照實驗佐證,因此在當歸與乳癌風險的議題上,目前學界還是無共識,因此臨床工作者與患者對於當歸的使用亦無所適從。
研究目的:
  本研究希望能利用台灣健保資料庫的人群回溯性資料,利用其大樣本的特性,進一步來探討當歸等含植物性荷爾蒙藥材對於女性乳癌發生之關聯性,期待以本研究結果能夠為這個多年爭論不休的議題提供較佳的流行病學證據。
材料和方法:
本研究將採用病例對照研究設計,資料來源為國衛院所發行全民健康保險資料中之2000-2008年全人口癌症特殊需求檔和2005年承保抽樣歸人檔。病例組為2005-2008年全人口癌症特殊需求檔中新診斷為乳癌之患者;對照組則為2005年承保抽樣歸人檔中追蹤至2008年期間未罹患乳癌,本研究以時間密度選樣方法,以病例/對照1:3的比例,匹配乳癌確診日及年齡選擇對照組個案。確認個案組與對照組後,從2000/1/1回溯至乳癌診斷日觀察當歸及其他潛在干擾因子的暴露狀況,比較病例組與對照組經當歸暴露後乳癌發生風險是否存在差異。統計方法採邏輯斯迴歸;統計套裝軟體使用SAS 9.4執行。
結果:
本研究經控制潛在干擾因子後發現:當歸劑單複方使用與乳癌風險結果呈現弱但顯著的保護效應,調整後乳癌發病勝算比為0.93(95%信賴區間0.90-0.96;P值<0.0001)。進一步分析劑量反應關係亦顯示其保護效應與當歸單複方劑量增加正相關,趨勢分析亦達統計學意義。另外,在當歸暴露期分析依然顯示其保護效應與當歸劑暴露期增加正相關,亦可見當歸暴露五年後其保護效應才明顯達到統計學意義。且本研究中亦發現當歸的保護效應在47-55歲更年期間達到高峰,其調整後勝算比為0.89(95%信賴區間0.85-0.93;P值<0.0001)。亦嘗試分析臨床較少與當歸共用的含植物性荷爾蒙中藥-葛根與山藥,調整後乳癌發病勝算比亦與當歸相同呈現弱保護效應或無影響。
結論:
  這個以族群為基礎的病例對照研究結果顯示,當歸劑暴露對於女性乳癌風險並呈現微弱但顯著的保護效應。且經本研究中所提出數個否證與敏感度分析的反複驗證亦獲得相同的結論。
英文摘要 A population-based case-control study on the association of herbal Angelica sinensis exposure with risk of breast cancer

Jhong-Yuan Chen
Chung-Yi Li
Department of Public Health & College of Medicine National Cheng Kung University

SUMMARY

This case-control study, including 34,262 women with breast cancer diagnosis and 102,786 matched controls identified from medical claims of 1-million Taiwan’s National Health Insurance program beneficiaries in 2005-2008, was conducted to investigate the relationships between Angelica sinensis and breast cancer. After controlling potential confounding factors, we found that the use of single and compound prescription of Angelica sinensis and breast cancer risk showed a weak but significant protective effect. Further analysis of the dose-response relationship also showed that the protective effect was positively correlated with the increase in the dose of the single and compound prescription of Angelica sinensis, and the trend test also revealed statistically significant. In addition, the analysis of the induction period of Angelica still showed that the protective effect was positively correlated with the increase of the induction period of Angelica sinensis. Besides, we found that the protective effect of Angelica reached related peak under the first Angelica exposure during the 47-55 years old. In the end, we also attempted to analyze other herbs which was known contained phytohormone include Pueraria and Dioscorea polystachya. And the adjusted odds ratio of breast cancer was similar to the exposure of Angelica sinensis revealed statistically weak protective effect or no statistical difference.



INTRODUCTION

Since hormone replacement therapy had been found to increase the risk of breast cancer, the scientists also had concerns about the breast cancer carcinogenic effect of phytohormone contained in herbs of traditional Chinese medicines, especially Angelica, which is commonly used to improve gynecological menopausal symptoms. In the related research of Angelica, some researchers found that Angelica extract could stimulate the proliferation of breast cancer cells. However, the results observed in the subsequent experiments were not consistent. It was even observed that some Angelica extract had anti-cancer effects such as inhibiting estrogen activity or promoting apoptosis of breast cancer cells. By far, there is no consensus on the issue of angelica and breast cancer risk relationship. Therefore, the study was conducted to investigate the association of Angelica sinensis with breast cancer risk in women by retrospective use of Taiwan's health insurance database. It was expected that the results of this study can provide better epidemiological evidence for the long-term debate over the putative link between angelica and breast cancer risk.

MATERIAL AND METHODS

We conducted a case-control study design based on Taiwan’s National Health Insurance claim data (medical claims of all cancer patients and of a random sample of 1-million people registgered in 2005) released by the National Health Research Institutes. The case series was all newly diagnosed breast cancer patient with catastrophic illness registration in Taiwan between 2005-2008; the control group was randomly selected from the 1-million beneficiaries who registered with the National Health Insurance program in 2005 who had no breast cancer diagnosis between 2000 and 2008. We employed the time density sampling method to select controls who were matched to case on date of breast cancer diagnosis and age, with a case/control ratio of 1/3. Exposure of angelica and other potential confounders was retrospectively retrieved between 2000/1/1 and date of breast cancer diagnosis. Logistic regression models were used in the analysis with SAS 9.4.

RESULTS

After controlling for potential confounders, we found that the use of single and compound prescription of Angelica sinensis and breast cancer risk showed a weak but significant protective effect, the covariate adjusted odds ratio of breast cancer incidence was 0.93 (95% confidence interval 0.90-0.96; P value <0.0001). Further analysis of the dose-response relationship also showed that the protective effect was positively correlated with the dose of single and compound prescription of Angelica sinensis; and the trend test was statistically significant. In addition, the analysis of the induction period of Angelica showed that the protective effect was positively correlated with the duration of exposure to Angelica sinensis. And we found that the protective effect of Angelica sinensis became statistically significant after five years of exposure. Besides, we found that the protective effect of Angelica reached related peak for the first Angelica exposure at 47-55 years of age, with an adjusted odds ratio of 0.89 (95% confidence interval 0.85-0.93; P value <0.0001). We also attempted to analyze other herbs which was known to contain phytohormone including Pueraria and Dioscorea polystachya. Similar to the effect of Angelica sinensis, the aOR of breast cancer associated with Pueraria and Dioscorea also suggested null or weak but significantly protective effect.

CONCLUSION

This population-based case-control study suggested that exposure to Angelica sinensis showed a weak but significant protective effect on breast cancer risk. The results remained intact after various falsification approaches and sensitivity analyses.
論文目次 摘要 III
英文摘要 V
誌謝 VIII
目次 IX
表目次 XI
第1章 前言 1
1.1 研究目的 2
第2章 文獻回顧 3
2.1 當歸之簡介 3
2.2 當歸與乳癌之相關研究 3
2.2.1乳癌細胞刺激與雌激素相關作用研究 3
2.2.2乳癌細胞抑制與否定雌激素作用研究 4
2.2.3表觀遺傳學研究 4
2.2.4台灣當歸製劑使用情形 5
2.3 當歸相關研究小結 5
2.4 乳癌之簡介 6
2.5 乳癌之危險因子 6
2.5.1 乳癌病史 6
2.5.2 乳癌家族史 6
2.5.3 年齡 7
2.5.3.1 初經與更年期年齡 7
2.5.3.2未產婦與初產年齡 7
2.5.4 肥胖 8
2.5.5外源性荷爾蒙 8
2.5.6 內源性荷爾蒙 9
2.5.6.1 雌激素 9
2.5.6.2雄性素 9
2.5.7 其他危險因子 9
2.5.7.1 骨質密度 9
2.5.7.2 身高 10
2.5.7.3 良性乳腺疾病 10
2.5.7.4不良生活習慣與常見致癌因子 10
2.5.8 台灣健保資料庫乳癌風險研究 10
2.6 乳癌文獻小結 11
第3章 材料與方法 12
3.1 研究問題 12
3.2資料來源 12
3.3 研究設計 14
3.3.1 研究對象定義與選取 15
3.3.2 當歸暴露的操作型定義 16
3.3.3 各類危險因子操作型定義 16
3.3.4 人口基本資料定義與擷取 17
3.4 資料分析 17
3.4.1 描述性統計 17
3.4.2 分析性統計 17
3.4.3 敏感度分析 18
第4章 結果 20
4.1 基本資料 20
4.2 當歸暴露與乳癌發生之勝算比 21
4.3 當歸暴露與乳癌發生之劑量反應關係 22
4.4 當歸暴露期時間長短與乳癌風險 23
4.5 否證分析 – 針灸暴露與乳癌風險 24
4.6 更年期與當歸對乳癌發病風險之影響 25
4.7 敏感度分析 – 黃體酮 25
4.8 敏感度分析 – 乳房良性腫瘤 26
4.9 含植物性荷爾蒙中藥與乳癌風險觀察 27
第5章 討論 29
5.1 當歸的乳癌風險分析結果 29
5.2 過去文獻比較與相關機轉討論 29
5.3 研究優勢與限制 31
5.3.1 研究優勢 31
5.3.1 研究限制 31
第6章 結論 33
參考文獻 35
附錄 52
參考文獻 1. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet, 1997. 350(9084): p. 1047-59.
2. Rossouw, J.E., et al., Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA, 2002. 288(3): p. 321-33.
3. Amato, P., S. Christophe, and P.L. Mellon, Estrogenic activity of herbs commonly used as remedies for menopausal symptoms. Menopause, 2002. 9(2): p. 145-50.
4. Lau, C.B., et al., Use of dong quai (Angelica sinensis) to treat peri- or postmenopausal symptoms in women with breast cancer: is it appropriate? Menopause, 2005. 12(6): p. 734-40.
5. Zhang, C.Z., et al., In vitro estrogenic activities of Chinese medicinal plants traditionally used for the management of menopausal symptoms. J Ethnopharmacol, 2005. 98(3): p. 295-300.
6. Godecke, T., et al., Integrated standardization concept for Angelica botanicals using quantitative NMR. Fitoterapia, 2012. 83(1): p. 18-32.
7. Zhou, W.J., et al., Angelica sinensis polysaccharides promotes apoptosis in human breast cancer cells via CREB-regulated caspase-3 activation. Biochem Biophys Res Commun, 2015. 467(3): p. 562-9.
8. Du, J., et al., Ligustilide inhibits spontaneous and agonists- or K+ depolarization-induced contraction of rat uterus. J Ethnopharmacol, 2006. 108(1): p. 54-8.
9. Su, Y.W., et al., Ligustilide prevents LPS-induced iNOS expression in RAW 264.7 macrophages by preventing ROS production and down-regulating the MAPK, NF-kappaB and AP-1 signaling pathways. Int Immunopharmacol, 2011. 11(9): p. 1166-72.
10. Piersen, C.E., Phytoestrogens in botanical dietary supplements: implications for cancer. Integr Cancer Ther, 2003. 2(2): p. 120-38.
11. Hajirahimkhan, A., B.M. Dietz, and J.L. Bolton, Botanical modulation of menopausal symptoms: mechanisms of action? Planta Med, 2013. 79(7): p. 538-53.
12. Liu, J., et al., Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem, 2001. 49(5): p. 2472-9.
13. Circosta, C., et al., Estrogenic activity of standardized extract of Angelica sinensis. Phytother Res, 2006. 20(8): p. 665-9.
14. Qi, H., et al., Sensitization of tamoxifen-resistant breast cancer cells by Z-ligustilide through inhibiting autophagy and accumulating DNA damages. Oncotarget, 2017. 8(17): p. 29300-29317.
15. Ma, H., et al., Z-ligustilide restores tamoxifen sensitivity of ERa negative breast cancer cells by reversing MTA1/IFI16/HDACs complex mediated epigenetic repression of ERa. Oncotarget, 2017. 8(17): p. 29328-29345.
16. Hsieh, S.C., et al., The prescribing of Chinese herbal products in Taiwan: a cross-sectional analysis of the national health insurance reimbursement database. Pharmacoepidemiol Drug Saf, 2008. 17(6): p. 609-19.
17. Lin, Y.H. and J.H. Chiu, Use of Chinese medicine by women with breast cancer: a nationwide cross-sectional study in Taiwan. Complement Ther Med, 2011. 19(3): p. 137-43.
18. Lai, J.N., C.T. Wu, and J.D. Wang, Prescription pattern of chinese herbal products for breast cancer in taiwan: a population-based study. Evid Based Complement Alternat Med, 2012. 2012: p. 891893.
19. Torre, L.A., et al., Global cancer statistics, 2012. CA Cancer J Clin, 2015. 65(2): p. 87-108.
20. DeSantis, C., et al., Breast cancer statistics, 2013. CA Cancer J Clin, 2014. 64(1): p. 52-62.
21. Liu, L., et al., Invasive breast cancer incidence trends by detailed race/ethnicity and age. Int J Cancer, 2012. 130(2): p. 395-404.
22. Gomez, S.L., et al., Hidden breast cancer disparities in Asian women: disaggregating incidence rates by ethnicity and migrant status. Am J Public Health, 2010. 100 Suppl 1: p. S125-31.
23. Wu, A.H., et al., Body size, hormone therapy and risk of breast cancer in Asian-American women. Int J Cancer, 2007. 120(4): p. 844-52.
24. Shin, H.R., et al., Recent trends and patterns in breast cancer incidence among Eastern and Southeastern Asian women. Cancer Causes Control, 2010. 21(11): p. 1777-85.
25. Shen, Y.C., et al., Significant difference in the trends of female breast cancer incidence between Taiwanese and Caucasian Americans: implications from age-period-cohort analysis. Cancer Epidemiol Biomarkers Prev, 2005. 14(8): p. 1986-90.
26. Nichols, H.B., et al., Declining incidence of contralateral breast cancer in the United States from 1975 to 2006. J Clin Oncol, 2011. 29(12): p. 1564-9.
27. Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet, 2001. 358(9291): p. 1389-99.
28. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer Statistics, 2017. CA Cancer J Clin, 2017. 67(1): p. 7-30.
29. Kelsey, J.L., M.D. Gammon, and E.M. John, Reproductive factors and breast cancer. Epidemiol Rev, 1993. 15(1): p. 36-47.
30. Colditz, G.A. and B. Rosner, Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses' Health Study. Am J Epidemiol, 2000. 152(10): p. 950-64.
31. Rosner, B., G.A. Colditz, and W.C. Willett, Reproductive risk factors in a prospective study of breast cancer: the Nurses' Health Study. Am J Epidemiol, 1994. 139(8): p. 819-35.
32. Bruzzi, P., et al., Short term increase in risk of breast cancer after full term pregnancy. Bmj, 1988. 297(6656): p. 1096-8.
33. Lauby-Secretan, B., et al., Body Fatness and Cancer--Viewpoint of the IARC Working Group. N Engl J Med, 2016. 375(8): p. 794-8.
34. Eliassen, A.H., et al., Adult weight change and risk of postmenopausal breast cancer. Jama, 2006. 296(2): p. 193-201.
35. van den Brandt, P.A., et al., Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol, 2000. 152(6): p. 514-27.
36. Nelson, H.D., et al., Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Ann Intern Med, 2012. 156(9): p. 635-48.
37. Beral, V. and C. Million Women Study, Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet, 2003. 362(9382): p. 419-27.
38. Nyante, S.J., et al., Risk factors for specific histopathological types of postmenopausal breast cancer in the NIH-AARP Diet and Health Study. Am J Epidemiol, 2013. 178(3): p. 359-71.
39. Clemons, M. and P. Goss, Estrogen and the risk of breast cancer. N Engl J Med, 2001. 344(4): p. 276-85.
40. Beattie, M.S., et al., Endogenous sex hormones, breast cancer risk, and tamoxifen response: an ancillary study in the NSABP Breast Cancer Prevention Trial (P-1). J Natl Cancer Inst, 2006. 98(2): p. 110-5.
41. Farhat, G.N., et al., Sex hormone levels and risks of estrogen receptor-negative and estrogen receptor-positive breast cancers. J Natl Cancer Inst, 2011. 103(7): p. 562-70.
42. Key, T., et al., Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst, 2002. 94(8): p. 606-16.
43. Lippman, M.E., et al., Indicators of lifetime estrogen exposure: effect on breast cancer incidence and interaction with raloxifene therapy in the multiple outcomes of raloxifene evaluation study participants. J Clin Oncol, 2001. 19(12): p. 3111-6.
44. Missmer, S.A., et al., Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst, 2004. 96(24): p. 1856-65.
45. Sieri, S., et al., Sex hormone levels, breast cancer risk, and cancer receptor status in postmenopausal women: the ORDET cohort. Cancer Epidemiol Biomarkers Prev, 2009. 18(1): p. 169-76.
46. Eliassen, A.H., et al., Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst, 2006. 98(19): p. 1406-15.
47. Dorgan, J.F., et al., Prospective case-control study of premenopausal serum estradiol and testosterone levels and breast cancer risk. Breast Cancer Res, 2010. 12(6): p. R98.
48. Wysowski, D.K., et al., Sex hormone levels in serum in relation to the development of breast cancer. Am J Epidemiol, 1987. 125(5): p. 791-9.
49. Thomas, H.V., et al., A prospective study of endogenous serum hormone concentrations and breast cancer risk in premenopausal women on the island of Guernsey. Br J Cancer, 1997. 75(7): p. 1075-9.
50. Chen, Z., et al., Hip bone density predicts breast cancer risk independently of Gail score: results from the Women's Health Initiative. Cancer, 2008. 113(5): p. 907-15.
51. Qu, X., et al., Bone mineral density and risk of breast cancer in postmenopausal women. Breast Cancer Res Treat, 2013. 138(1): p. 261-71.
52. Ahlgren, M., et al., Growth patterns and the risk of breast cancer in women. N Engl J Med, 2004. 351(16): p. 1619-26.
53. Lahmann, P.H., et al., Body size and breast cancer risk: findings from the European Prospective Investigation into Cancer And Nutrition (EPIC). Int J Cancer, 2004. 111(5): p. 762-71.
54. Green, J., et al., Height and cancer incidence in the Million Women Study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk. Lancet Oncol, 2011. 12(8): p. 785-94.
55. Ritte, R., et al., Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer: a cohort study. Int J Cancer, 2013. 132(11): p. 2619-29.
56. Dupont, W.D. and D.L. Page, Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med, 1985. 312(3): p. 146-51.
57. London, S.J., et al., A prospective study of benign breast disease and the risk of breast cancer. Jama, 1992. 267(7): p. 941-4.
58. Hartmann, L.C., et al., Benign breast disease and the risk of breast cancer. N Engl J Med, 2005. 353(3): p. 229-37.
59. Gram, I.T., et al., Smoking and Risk of Breast Cancer in a Racially/Ethnically Diverse Population of Mainly Women Who Do Not Drink Alcohol: The MEC Study. Am J Epidemiol, 2015. 182(11): p. 917-25.
60. Hansen, J. and R.G. Stevens, Case-control study of shift-work and breast cancer risk in Danish nurses: impact of shift systems. Eur J Cancer, 2012. 48(11): p. 1722-9.
61. Guibout, C., et al., Malignant breast tumors after radiotherapy for a first cancer during childhood. J Clin Oncol, 2005. 23(1): p. 197-204.
62. Chuang, S.C., et al., Associations between Medical Conditions and Breast Cancer Risk in Asians: A Nationwide Population-Based Study in Taiwan. PLoS One, 2015. 10(11): p. e0143410.
63. Alberts, J.F., et al., Socioeconomic inequity in health care: a study of services utilization in Curacao. Soc Sci Med, 1997. 45(2): p. 213-20.
64. Wu, A.H., et al., Epidemiology of soy exposures and breast cancer risk. Br J Cancer, 2008. 98(1): p. 9-14.
65. Gilani, G.S., Phytoestrogens and health. 2002: Champaign, Ill. : AOCS Press,.
66. Tsai, N.M., et al., The natural compound n-butylidenephthalide derived from Angelica sinensis inhibits malignant brain tumor growth in vitro and in vivo. J Neurochem, 2006. 99(4): p. 1251-62.
67. Chen, Y.L., et al., The induction of orphan nuclear receptor Nur77 expression by n-butylenephthalide as pharmaceuticals on hepatocellular carcinoma cell therapy. Mol Pharmacol, 2008. 74(4): p. 1046-58.
68. Kan, W.L., et al., Study of the anti-proliferative effects and synergy of phthalides from Angelica sinensis on colon cancer cells. J Ethnopharmacol, 2008. 120(1): p. 36-43.
69. Cao, W., et al., [Structural analysis and anti-tumor activity in vivo of polysaccharide APS-2a from Angelica sinensis]. Zhong Yao Cai, 2008. 31(2): p. 261-6.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2021-07-31起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2021-07-31起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw