中医周期疗法降低乳腺癌癌前病变乳腺癌发生风险的研究
|
摘要
目的：
研究证明化学预防药物可以阻断乳腺癌癌前病变的发展,降低乳腺癌的发生风险,但是仅降低ER阳性乳腺癌的发生是目前化学预防药物的治疗盲区,同时诸多不良反应极大的限制了临床应用。中医周期疗法是林毅教授在中医天人相应理论基础上,根据女性冲任生理变化规律与现代医学研究成果所提出的治疗乳腺增生病的治疗原则,即经前疏肝活血、消滞散结以治标,经后温肾助阳、调摄冲任以治本。并在长期临床实践基础上提炼研制消癖系列口服液以配合中医周期疗法的临床应用。前期研究发现中医周期疗法能阻断由乳腺钼靶诊断疑诊的乳腺癌癌前病变的发展。本研究在此基础上,开展中医周期疗法对由病理诊断确诊的乳腺非典型增生患者乳腺癌发生风险影响的临床研究,并通过进一步实验研究比较中医周期疗法与他莫昔芬在阻断乳腺癌癌前病变发展的疗效,探讨中医周期疗法阻断/逆转乳腺癌癌前病变的可能作用机制。
方法：
分为临床研究部分和实验研究部分。
临床研究部分采用多因素分析方法,基于医院人群通过病例对照研究,回顾性调查手术确诊的乳腺非典型增生患者术后乳腺癌及乳腺手术事件的发生情况,根据术后是否发生乳腺癌及乳腺手术事件分为病例组和对照组,发生乳腺癌和/或乳腺手术事件者设为病例组,对照组则在没有发生乳腺癌和/或乳腺手术事件的研究对象中,按照与病例组确诊时间±6月为条件,进行1：4匹配选择。探讨中医周期疗法治疗对乳腺非典型增生患者乳腺癌发生风险的影响,以及对乳腺手术事件发生风险的影响。
实验研究在临床研究的基础上,进一步证明中医周期疗法能降低乳腺癌癌前病变大鼠乳腺癌的发生率,同时探讨其可能的作用机制。实验选用DMBA联合雌孕激素序贯法对SD大鼠进行癌前病变模型复制,通过观察比较接受中医周期疗法治疗、他莫昔芬治疗以及无治疗的空白对照组大鼠乳腺癌发生率的不同,证实中医周期疗法能降低乳腺癌癌前病变大鼠乳腺浸润性癌发生率,等效甚至优于他莫昔芬的治疗。通过对中医周期疗法治疗组、他莫昔芬治疗组及空白对照组大鼠乳腺组织(正常及病变组织)中Ki-67的测定,评估中医周期疗法抑制大鼠乳腺癌癌前病变的细胞增殖程度；通过对雌激素受体、孕激素受体和信号传导与转录激活因子3的检测,探讨中医周期疗法阻断／逆转大鼠乳腺癌癌前病变的雌激素作用相关通路；通过对微血管密度检测,了解大鼠乳腺癌前病变组织中微血管的形成情况,评估血管生成在乳腺癌形成过程中的作用；并通过进一步对血管内皮生长因子的检测,探索乳腺癌癌前病变组织血管生成的可能信号通路。
结果：
1.临床研究部分
乳腺非典型增生病患者手术治疗确诊后,平均术后间隔时间为104.22±30.32月内,接受中医周期疗法治疗可以降低乳腺癌和／或乳腺手术事件的发生风险(P=0.021, OR=0.143,95%CI:0.031～0.660),接受了中医周期疗法的乳腺非典型增生患者的乳腺癌和／或乳腺手术事件发生风险是接受其他疗法患者的0.143倍；但是,现有的数据没有发现中医周期疗法能降低乳腺癌癌前病变患者术后乳腺癌的发生风险。本研究纳入的病例中没有符合研究定义的接受他莫昔芬治疗的患者,因此,没能进行“中医周期疗法”和“他莫昔芬”在降低乳腺非典型增生患者乳腺癌发生风险的治疗疗效上进行比较。在对乳腺癌发生相关的生殖因素的分析中,本研究对乳腺癌癌前病变患者的月经初潮年龄、初产年龄、流产史、哺乳时间等进行分析,并没有发现这些生殖因素增加乳腺癌癌前病变患者术后的乳腺癌和／或乳腺手术事件的发生风险。研究也没有发现活检后间隔时间与乳腺癌和／或乳腺手术事件发生相关。乳腺癌癌前病变的手术范围并不会影响癌前病变患者的乳腺癌发生风险,也不会增加乳腺手术事件的发生风险。
2.实验研究部分：
(1)癌变率及肿瘤细胞增殖情况：
①癌变率
高剂量的中医周期疗法与空白对照组相比,能显著降低乳腺癌癌前病变大鼠乳腺癌的发生率(P=-0.047),疗效与他莫昔芬相比差异无显著性(P=-0.476)。
②增殖细胞核抗原(Ki-67)
高剂量的中医周期疗法能显著抑制癌前病变大鼠乳腺组织中Ki-67的阳性表达率,疗效与高剂量的他莫昔芬比较差异无显著性(P=-0.597)；中医非周期疗法不能对大鼠乳腺癌癌前病变组织中Ki-67的表达进行有效抑制,与周期疗法相比差异有显著性(P=-0.015)。
(2)雌激素介导的相关信号通路
①雌激素受体(ER)
所有治疗组的ER表达与空白对照组比较均差异无显著性(P>0.05)。高剂量的中医周期疗法组的ER表达显著高于高剂量的他莫昔芬、低剂量的中医周期疗法及中医非周期疗法,差异具有统计学意义(P<0.05)；
②孕激素受体(PR)
所有治疗组的PR表达显著高于空白对照组(P<0.05),而高剂量他莫昔芬治疗组PR表达显著高于中医周期疗法高剂量组及中医非周期疗法组(P<0.05)；
③信号传导与转录激活因子3(STAT3)
与模型组相比,中医周期疗法、中医非周期疗法以及他莫昔芬的治疗均对STAT3的表达没有显著影响(P>0.05)。
(3)血管生成相关的指标及促进因子的检测
①微血管密度(MVD)
中医周期疗法高、低级剂量组,中医非周期疗法组以及他莫昔芬高、低剂量组的MVD均显著低于空白对照组(K0.05)；低剂量中医周期疗法组的MVD低于高剂量他莫昔芬组,差异有显著性(P<0.05)；高剂量中医周期疗法组的MVD与高剂量他莫昔芬相比,差异无显著性(P>0.05)。
②血管内皮生长因子(VEGF)
中医周期疗法高、低级剂量组,中医非周期疗法组以及他莫昔芬高、低剂量组的VEGF表达,与模型组相比,差异无显著性(P>0.05)。中医周期疗法相比于他莫昔芬治疗,能显著降低大鼠乳腺癌癌前病变组织中VEGF的阳性表达率(P<0.05)。
结论：
1.临床研究部分
乳腺非典型增生病患者手术治疗确诊后10年内,接受中医周期疗法治疗可以降低乳腺癌和/或乳腺手术事件的发生风险,接受了中医周期疗法的乳腺非典型增生患者的乳腺癌和/或乳腺手术事件发生风险约是没有接受中医周期疗法患者的0.143倍；但是,现有的数据没有发现中医周期疗法与乳腺癌的发生风险相关。乳腺非典型增生患者的月经初潮年龄、初产年龄、流产史、哺乳时间、术后间隔时间与乳腺癌和/或乳腺手术事件的发生风险没有显著相关性。
2.实验研究部分
中医周期疗法阻断/逆转大鼠乳腺癌癌前病变疗效确切,与他莫昔芬的疗效相当,甚至优于他莫昔芬。中医非周期疗法也能阻断部分癌前病变的发展,但疗效低于中医周期疗法(高剂量和低剂量),尽管无显著性的差异。中医非周期疗法不能有效的抑制大鼠乳腺癌癌前病变组织中Ki-67的阳性表达,说明中医非周期疗法阻断乳腺癌癌前发展的疗效有限。中医周期疗法高剂量和低剂量的治疗没有发现显著地量效相关性,提示中医周期疗法的有效治疗剂量还有待进一步探讨。雌激素介导的STAT3通路和VEGF均不是中医周期疗法阻断癌前病变发展的直接作用机制,还需要进一步深入探讨中医周期疗法阻断／逆转乳腺癌癌前病变的可能作用机制,阻断血管生成是可利用的突破点。
Objective
Breast precancerous lesions can be blocked or reversed have been confirmed. Previous studies have found that Chinese medicine cycle therapy can block mammography diagnosis of suspicious breast precancerous lesions. Explore Whether Chinese medicine cycle therapy could block or reverse precancerous lesions of breast, reduce the risk of breast cancer, and to explore the possible mechanism of action.
Methods
There are two parts of the research:clinical research and experimental research.
Clinical Research:Using case-control study, retrospective survey the incidence of breast cancer-related adverse events of breast atypical hyperplasia after surgery. The case group composed by those patients that occurrencing breast cancer and/or breast-related operation events, the others who did not set to the control group. The proportion of cases and control groups was1:4. Explore the role of Chinese medicine cycle therapy in the prevention of breast cancer and/or breast-related operation events.
Experimental research:Precancerous lesions modeling methods is DMBA combined estrogen and progestogen sequential method. Compare the different incidence of breast cancer among TCM cycle therapy, tamoxifen treatment and blank control group. To confirmed that Chinese medicine cycle therapy can reduce the incidence of breast cancer of precancerous lesions in rats. Efficacy is equal to or even better than tamoxifen. To explore the possible mechanism of Chinese medicine cycle therapy blocking/reversal of precancerous lesions of breast cancer by testing Estrogen-mediated signaling pathways and angiogenesis-dependent index detection.
Results
Clinical Research:Breast atypical hyperplasia patients receiving traditional Chinese medicine cycle therapy can reduce the risk of breast cancer and/or breast-related operation events (P=0.021), the10years after surgery. However, the available data did not find correlation with TCM cycle therapy and breast cancer risk of ADH patients.
Experimental research:Chinese medicine cycle therapy compared with blank control group, can significantly reduce breast cancer incidence of precancerous lesions in rats (P=0.047), efficacy compared with tamoxifen was no significant difference (P=0.476). Compared with the model group, Chinese medicine cycle therapy, Chinese aperiodic therapy and tamoxifen treatment on STAT3expression did not significantly difference (P>0.05). MVD of Chinese medicine cycle therapy, Chinese aperiodic therapy, and the tamoxifen treatment were significantly lower than the control group (P<0.05). Chinese medicine cycle therapy compared to tamoxifen treatment can significantly reduce rat breast precancerous lesions of VEGF positive expression rate (K<0.05).
Conelusion
Clinical Research:Breast atypical hyperplasia patients receiving traditional Chinese medicine cycle therapy can reduce the risk of breast cancer and/or breast-related operation events.
Experimental research:Chinese medicine cycle therapy can block the development of precancerous lesions of breast cancer, to reduce breast cancer incidence of precancerous lesions in rats, similar efficacy with tamoxifen. Chinese medicine cycle therapy whether by blocking the development of precancerous lesions of estrogen-mediated STAT3signaling pathway, and the VEGF pathway has not been confirmed.
研究证明化学预防药物可以阻断乳腺癌癌前病变的发展,降低乳腺癌的发生风险,但是仅降低ER阳性乳腺癌的发生是目前化学预防药物的治疗盲区,同时诸多不良反应极大的限制了临床应用。中医周期疗法是林毅教授在中医天人相应理论基础上,根据女性冲任生理变化规律与现代医学研究成果所提出的治疗乳腺增生病的治疗原则,即经前疏肝活血、消滞散结以治标,经后温肾助阳、调摄冲任以治本。并在长期临床实践基础上提炼研制消癖系列口服液以配合中医周期疗法的临床应用。前期研究发现中医周期疗法能阻断由乳腺钼靶诊断疑诊的乳腺癌癌前病变的发展。本研究在此基础上,开展中医周期疗法对由病理诊断确诊的乳腺非典型增生患者乳腺癌发生风险影响的临床研究,并通过进一步实验研究比较中医周期疗法与他莫昔芬在阻断乳腺癌癌前病变发展的疗效,探讨中医周期疗法阻断/逆转乳腺癌癌前病变的可能作用机制。
方法：
分为临床研究部分和实验研究部分。
临床研究部分采用多因素分析方法,基于医院人群通过病例对照研究,回顾性调查手术确诊的乳腺非典型增生患者术后乳腺癌及乳腺手术事件的发生情况,根据术后是否发生乳腺癌及乳腺手术事件分为病例组和对照组,发生乳腺癌和/或乳腺手术事件者设为病例组,对照组则在没有发生乳腺癌和/或乳腺手术事件的研究对象中,按照与病例组确诊时间±6月为条件,进行1：4匹配选择。探讨中医周期疗法治疗对乳腺非典型增生患者乳腺癌发生风险的影响,以及对乳腺手术事件发生风险的影响。
实验研究在临床研究的基础上,进一步证明中医周期疗法能降低乳腺癌癌前病变大鼠乳腺癌的发生率,同时探讨其可能的作用机制。实验选用DMBA联合雌孕激素序贯法对SD大鼠进行癌前病变模型复制,通过观察比较接受中医周期疗法治疗、他莫昔芬治疗以及无治疗的空白对照组大鼠乳腺癌发生率的不同,证实中医周期疗法能降低乳腺癌癌前病变大鼠乳腺浸润性癌发生率,等效甚至优于他莫昔芬的治疗。通过对中医周期疗法治疗组、他莫昔芬治疗组及空白对照组大鼠乳腺组织(正常及病变组织)中Ki-67的测定,评估中医周期疗法抑制大鼠乳腺癌癌前病变的细胞增殖程度；通过对雌激素受体、孕激素受体和信号传导与转录激活因子3的检测,探讨中医周期疗法阻断／逆转大鼠乳腺癌癌前病变的雌激素作用相关通路；通过对微血管密度检测,了解大鼠乳腺癌前病变组织中微血管的形成情况,评估血管生成在乳腺癌形成过程中的作用；并通过进一步对血管内皮生长因子的检测,探索乳腺癌癌前病变组织血管生成的可能信号通路。
结果：
1.临床研究部分
乳腺非典型增生病患者手术治疗确诊后,平均术后间隔时间为104.22±30.32月内,接受中医周期疗法治疗可以降低乳腺癌和／或乳腺手术事件的发生风险(P=0.021, OR=0.143,95%CI:0.031～0.660),接受了中医周期疗法的乳腺非典型增生患者的乳腺癌和／或乳腺手术事件发生风险是接受其他疗法患者的0.143倍；但是,现有的数据没有发现中医周期疗法能降低乳腺癌癌前病变患者术后乳腺癌的发生风险。本研究纳入的病例中没有符合研究定义的接受他莫昔芬治疗的患者,因此,没能进行“中医周期疗法”和“他莫昔芬”在降低乳腺非典型增生患者乳腺癌发生风险的治疗疗效上进行比较。在对乳腺癌发生相关的生殖因素的分析中,本研究对乳腺癌癌前病变患者的月经初潮年龄、初产年龄、流产史、哺乳时间等进行分析,并没有发现这些生殖因素增加乳腺癌癌前病变患者术后的乳腺癌和／或乳腺手术事件的发生风险。研究也没有发现活检后间隔时间与乳腺癌和／或乳腺手术事件发生相关。乳腺癌癌前病变的手术范围并不会影响癌前病变患者的乳腺癌发生风险,也不会增加乳腺手术事件的发生风险。
2.实验研究部分：
(1)癌变率及肿瘤细胞增殖情况：
①癌变率
高剂量的中医周期疗法与空白对照组相比,能显著降低乳腺癌癌前病变大鼠乳腺癌的发生率(P=-0.047),疗效与他莫昔芬相比差异无显著性(P=-0.476)。
②增殖细胞核抗原(Ki-67)
高剂量的中医周期疗法能显著抑制癌前病变大鼠乳腺组织中Ki-67的阳性表达率,疗效与高剂量的他莫昔芬比较差异无显著性(P=-0.597)；中医非周期疗法不能对大鼠乳腺癌癌前病变组织中Ki-67的表达进行有效抑制,与周期疗法相比差异有显著性(P=-0.015)。
(2)雌激素介导的相关信号通路
①雌激素受体(ER)
所有治疗组的ER表达与空白对照组比较均差异无显著性(P>0.05)。高剂量的中医周期疗法组的ER表达显著高于高剂量的他莫昔芬、低剂量的中医周期疗法及中医非周期疗法,差异具有统计学意义(P<0.05)；
②孕激素受体(PR)
所有治疗组的PR表达显著高于空白对照组(P<0.05),而高剂量他莫昔芬治疗组PR表达显著高于中医周期疗法高剂量组及中医非周期疗法组(P<0.05)；
③信号传导与转录激活因子3(STAT3)
与模型组相比,中医周期疗法、中医非周期疗法以及他莫昔芬的治疗均对STAT3的表达没有显著影响(P>0.05)。
(3)血管生成相关的指标及促进因子的检测
①微血管密度(MVD)
中医周期疗法高、低级剂量组,中医非周期疗法组以及他莫昔芬高、低剂量组的MVD均显著低于空白对照组(K0.05)；低剂量中医周期疗法组的MVD低于高剂量他莫昔芬组,差异有显著性(P<0.05)；高剂量中医周期疗法组的MVD与高剂量他莫昔芬相比,差异无显著性(P>0.05)。
②血管内皮生长因子(VEGF)
中医周期疗法高、低级剂量组,中医非周期疗法组以及他莫昔芬高、低剂量组的VEGF表达,与模型组相比,差异无显著性(P>0.05)。中医周期疗法相比于他莫昔芬治疗,能显著降低大鼠乳腺癌癌前病变组织中VEGF的阳性表达率(P<0.05)。
结论：
1.临床研究部分
乳腺非典型增生病患者手术治疗确诊后10年内,接受中医周期疗法治疗可以降低乳腺癌和/或乳腺手术事件的发生风险,接受了中医周期疗法的乳腺非典型增生患者的乳腺癌和/或乳腺手术事件发生风险约是没有接受中医周期疗法患者的0.143倍；但是,现有的数据没有发现中医周期疗法与乳腺癌的发生风险相关。乳腺非典型增生患者的月经初潮年龄、初产年龄、流产史、哺乳时间、术后间隔时间与乳腺癌和/或乳腺手术事件的发生风险没有显著相关性。
2.实验研究部分
中医周期疗法阻断/逆转大鼠乳腺癌癌前病变疗效确切,与他莫昔芬的疗效相当,甚至优于他莫昔芬。中医非周期疗法也能阻断部分癌前病变的发展,但疗效低于中医周期疗法(高剂量和低剂量),尽管无显著性的差异。中医非周期疗法不能有效的抑制大鼠乳腺癌癌前病变组织中Ki-67的阳性表达,说明中医非周期疗法阻断乳腺癌癌前发展的疗效有限。中医周期疗法高剂量和低剂量的治疗没有发现显著地量效相关性,提示中医周期疗法的有效治疗剂量还有待进一步探讨。雌激素介导的STAT3通路和VEGF均不是中医周期疗法阻断癌前病变发展的直接作用机制,还需要进一步深入探讨中医周期疗法阻断／逆转乳腺癌癌前病变的可能作用机制,阻断血管生成是可利用的突破点。
Objective
Breast precancerous lesions can be blocked or reversed have been confirmed. Previous studies have found that Chinese medicine cycle therapy can block mammography diagnosis of suspicious breast precancerous lesions. Explore Whether Chinese medicine cycle therapy could block or reverse precancerous lesions of breast, reduce the risk of breast cancer, and to explore the possible mechanism of action.
Methods
There are two parts of the research:clinical research and experimental research.
Clinical Research:Using case-control study, retrospective survey the incidence of breast cancer-related adverse events of breast atypical hyperplasia after surgery. The case group composed by those patients that occurrencing breast cancer and/or breast-related operation events, the others who did not set to the control group. The proportion of cases and control groups was1:4. Explore the role of Chinese medicine cycle therapy in the prevention of breast cancer and/or breast-related operation events.
Experimental research:Precancerous lesions modeling methods is DMBA combined estrogen and progestogen sequential method. Compare the different incidence of breast cancer among TCM cycle therapy, tamoxifen treatment and blank control group. To confirmed that Chinese medicine cycle therapy can reduce the incidence of breast cancer of precancerous lesions in rats. Efficacy is equal to or even better than tamoxifen. To explore the possible mechanism of Chinese medicine cycle therapy blocking/reversal of precancerous lesions of breast cancer by testing Estrogen-mediated signaling pathways and angiogenesis-dependent index detection.
Results
Clinical Research:Breast atypical hyperplasia patients receiving traditional Chinese medicine cycle therapy can reduce the risk of breast cancer and/or breast-related operation events (P=0.021), the10years after surgery. However, the available data did not find correlation with TCM cycle therapy and breast cancer risk of ADH patients.
Experimental research:Chinese medicine cycle therapy compared with blank control group, can significantly reduce breast cancer incidence of precancerous lesions in rats (P=0.047), efficacy compared with tamoxifen was no significant difference (P=0.476). Compared with the model group, Chinese medicine cycle therapy, Chinese aperiodic therapy and tamoxifen treatment on STAT3expression did not significantly difference (P>0.05). MVD of Chinese medicine cycle therapy, Chinese aperiodic therapy, and the tamoxifen treatment were significantly lower than the control group (P<0.05). Chinese medicine cycle therapy compared to tamoxifen treatment can significantly reduce rat breast precancerous lesions of VEGF positive expression rate (K<0.05).
Conelusion
Clinical Research:Breast atypical hyperplasia patients receiving traditional Chinese medicine cycle therapy can reduce the risk of breast cancer and/or breast-related operation events.
Experimental research:Chinese medicine cycle therapy can block the development of precancerous lesions of breast cancer, to reduce breast cancer incidence of precancerous lesions in rats, similar efficacy with tamoxifen. Chinese medicine cycle therapy whether by blocking the development of precancerous lesions of estrogen-mediated STAT3signaling pathway, and the VEGF pathway has not been confirmed.
引文
[1]Wellings SR, Jensen HM. On the origin and progression of ductal carcinoma in the human breast[J]. J Natl Cancer Inst 1973:50:1111-1118.
[2]Wellings SR, Jensen HM, Marcum RG. An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions[J].J Natl Cancer Inst 1975:55:231-243.
[3]Shaaban AM, Sloane JP, West CR, et al. Histopathologic types of benign breast lesions and the risk of breast cancer:case-control study [J]. Am J surg Pathol 2002:26:421-430.
[4]Page DL,Zwaag RV, Rogers LW, et al. Relation between component parts of fibrocystic disease comples and breast cancer[J].J Natl Cancer Inst 1978:61:1055-1063.
[5]Page DL, Dupont WD, Rogers LW, et al. Intraductal carcinoma of the breast:follow-up after biopsy only [J]. Cancer 1982:49:751-758.
[6]Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease[J].N Engl J Med 1985:312:146-151.
[7]Palli D, del Turco MR, Simonciini R, et al. Benign breast disease and breast cancer:a case-cantrol study in a cohort in Italy[J]. Int J Cancer 1991:47:703-706.
[8]London SJ, Connolly JL, Schnitt SJ, et al. A prospective study of benign breast disease and the risk of breast cancer[J]. JAMA 1992:267:941-944.
[9]Dupont WD, Parl FF, Hartmann WH, et al. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia[J]. Cancer 1993:71:1258-1265.
[10]0'Connell P, Pekkel V, Fuqua SAW, et al. Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci[J].J Natl Cancer Inst 1998:90:697-703.
[11]Thompson HJ. Rat modles of premalignant breast disease[J].J Mammary Gland Biol Neoplasia 2000:5:409-420.
[12]Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease[J].N Engl J Med 1985:312:146-151.
[13]Dupont WD, Parl FF, Hartmann WH, et al. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia[J]. Cancer 1993:71:3896-3907.
[14]Page DL, Dupont WD, Rogers LW, et al. Atypical hyperplastic lesions of the female breast: a long-term follow-up study[J].Cancer 1985:55:2698-2708.
[15]Dupont WD, Page DL. Relative risk of breast cancer varies with time since diagnosisi of atypical hyperplasia[J].Hum Pathol 1989:20:723-725.
[16]Dupont WD, Parl FF, Hartmann WH, et al. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia[J].Cancer 1993:71:3896-3907.
[17]Bernsterin L, Epidemiology of endocrine-related risk factors for breast cancer[J]. J Mammary Gland Biol Neoplasia 2002:7:3.
[18]Russo IH, Russo J. Role of hormones in mammary cancer initiation and progression [J]. J Mammry Gland Biol Neoplasia 1998;3:49.
[19]Wagner JD, Kaplan JR, Burkman RT. Reproductive hormones and cardiovascular disease mechanism of acrion and clinical implications[J]. Obstet Gynecol Clin North Am 2002:29:475.
[20]Bernard Fisher, Joseph P. Costantino, D. Lawrence Wickerham, et al. Tamoxifen for the Prevention of Breast Cancer:Current Status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study[J]. Journal of the National Cancer Institute,2005,12; (97): 22:1652-1662.
[21]Day R, Ganz PA, Costantino JP, et al. Health-realted quality of life and tamoxifen in breast cancer prevention:a report from the National Surgical Adjuvant Breast and Bowel project P-1 Study[J]. J Clin Oncol 1999:17:2659-2669.
[22]Cuzick J, Forbes J, Edwards R, et al. First results from the international Breast Cancer Intervention Study:a randomized prevention trial [J]. Lancet,2002,360:817-823. [23] Vogel VG, Costantino JP, Wickerham DL, et al. The study of tamoxifen and raloxifene:preliminary enrollment data from a randomized breast cancer risk reduction trial[J]. Clin Breast Cancer 2002;3:153.
[24]林毅,唐汉均.现代中医乳房病学[M].人民卫生出版社2003年第1版：122-123.
[25]司徒红林,陈前军.消癖1-6号口服液干预治疗乳腺癌癌前病变的研究[J].肿瘤防治杂志,2002,9(2)：176-179.
[26]司徒红林,周劬志,卓睿,等.消癖口服液治疗乳腺良性病变不典型增生的临床研究[J].甘肃中医,2001；2：53-57.
[27]陈前军,徐飚,司徒红林,等.“消癖颗粒”阻断SD大鼠乳腺癌癌变及其对EGFR-STAT3通路影响研究[J].辽宁中医药大学学报,2012；14(8)：19-21.
[28]Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer. Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study[J]. J Natl Cancer Inst 1998:90:1371.
[29]Tekmal RR, Liu YG, Nair HB, et al. Estrogen receptor alpha is required for mammary development and the induction of mammary hyperplasia and epigenetic alterations in the aromatase transgenic mice [J]. JSteroid Biochem Mol Biol,2005,95(1-5):9-15.
[30]Leung G, Tsao SW, W ong YC. Sex hormone-induced mammary carcinogenesis in female Noble rats:detection of differentially expressed genes [J]. Breast Cancer Res Treat, 2003,77(1):49-63.
[31]Liu W L, Guo X, Guo ZG. Estrogen prevents bovine aortic endothelial cells from TNF-alpha—induced apoptosis via opposing effects on P38 and P44/42 CCDPK[J]. Acta Pharmacol Sin,2002,23:213-225.
[32]Plotkin LI, Aguirre JI, Kousteni S, et al. Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal--regulated kinase activation[J]. J Biol Chem,2005,'280:7317-7324.
[33]HAURA EB, TURKSON J, JOVE R. Mechanisms of disease:Insights into the emerging role of signal transducers and activators of transcription in cancer[J]. Nat Clin Pract Oncol, 2005,2(6):315-324.
[34]Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer [J]. BiochemBiophys ges Common,2005,335 (2):292-299.
[35]Haura EB, Turkson J, Jove R. Mechanisms of disease:Insights into the emerging role of signal transducers and activators of transcription in cancer [J]. Nat Clin Pratt Oncol, 2005,2(6):315-324.
[36]Sordella R, Bell DW, Haber DA, et al. Geftinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways[J]. Science,2004; 305(5687):1163-1167.
[37]Ford A C, Grandis J R. Targeting epidermal growth factor receptor in head and neck cancer[J]. Head Neck,2003,25(1); 67-73.
[38]Folkman J.What is the evidence that tumours are angiogenesis dependent [J]. J Natl Cancer Inst 1990;82:4-6.
[39]Ottinetti A, Sapino A. Morphometric evaluation of microvessels surrounding hyperplastic and nroplastic mammary lesions [J]. Breast Cancer Res Treat 1988; 11:241-248.
[40]Fregene TA, Kellog C, Pienta KJ. Microvessel quantitation as a measure of angiogenic activity in benign breast tissues lesions:a marker for precancerous disease [J]. Int J Oncol 1994:4:1199-1202.
[41]Guidi A,Fischer L, Harris J, et al. Microvessel density and distribution in ductal carcinoman in situ of the breast[J]. J Natl Cancer Inst 1994:86:614-619.
[42]Engels K,Fox SB. Whitehouse RM, et al. Up-regulation of thymidine phosphorylase expression is associated with high-grade in situ ductal carcinomas of the breast[J]. J Pathol 1997:181:207-212.
[43]Aberg UW, Saarinen N, Abrahamsson A, et al. Tamoxifen and flaxseed alter angiogenesis regulators in normal human breast tissue in vivo. PLOS One.2011;6(9):e25720. doi:10.1371/journal. pone.0025720,2011.9.30.
[44]Allred DC,Medina D. Introduction:models of premalignant breast disease[J].J Mary Gland Biol Neoplasia,2000,5(4):339-340.
[45]Henry J. Thompson, Meenakshi Singh. Rat models of premalignant breast disease[J].J Mammary Gland Biol Neoplasia.2000,5(4):409-420.
[46]李静蔚,宋爱莉,张敬涛等.DMBA诱导大鼠乳腺癌癌前病变的组织病理学研究[J].中华中医药学刊,2008,(3)：505-508.
[47]王峰,马忠兵,方允治等.乳腺癌癌前病变大鼠模型的建立.中国现代普通外科进展[J],2009,5：12(5)：38-41.
[48]宋爱莉,叶林,李静蔚等.乳复汤对乳腺非典型增生病证结合造模大鼠微循环的影响[J].山东中医杂志,2003,10；22(10)：622-626.
[49]Dawson PJ, Wolman SR, Tait L, et al.A models for the evolution of cancer from proliferative breast disease [J]. AM J Path.1996,148:313-319.
[50]PJ Dawson, SR Wolman, L.Tait, et al. MCF10AT:a model for the evolution of cancer from proliferative breast disease[J]. Am J Pathol.1996 January; 148(1):313-319.
[51]孙敬方.动物实验方法学[M].北京：人民卫生出版社,2001：424—-426.
[52]Russo J, Irma H. Atlas and histologie classifcation of tumors of the rat mammary gland [J]. J Mammary Gland Biol Neoplasia,2000,5(2):187-200.
[53]Weidner N. Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors[J]. Breast Cancer Res Treat,1995,36:169.
[54]Tanaka K, lwamoto S, Con G, et al. Expression of surviving and its relationship to loss of apotosis in breast carcinomas[J]. Clin Cancer Res,2000,6(1),127-134.
[55]Kanda N, Seno H, Konda Y, et al. STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells [J]. Oncogene, 2004,23(28):4921-4929.
[56]陈婷婷,王岳君,杨苗苗等.pSTAT3和SOCS3在人乳腺癌组织中的表达及意义[J].中国组织化学与细胞化学杂志.2012,6；(21)3：295-299.
[57]国外期刊摘译[J].现代泌尿外科杂志.2010,5;15(3)：52.
[58]Yon Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvantchemotherapy and Bevacizumab for HER2—negative breast cancer [J]. N Engl J Med,2012,366(4):299-309.
[59]Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer[J]. N Engl J Med,2012,366(4):310-320.
[60]师永红.乳腺癌与癌前期病变[J].内蒙古医学杂志,2007；39(7)：769-770.
[61]Tavassoli FA, Devilee P WHO classification of tumours. Pathology and genetics. Tumours of the breast and female genital organs. Lyon:IARC Press,2003:63-67.
[62]沈镇宙.乳腺肿瘤学[M].上海：世纪出版集团上海科学技术出版社.2005：22.
[63]Well ings SR, Jensen HM. On the origin and progression of ductal carcinoma in the human breast[J]. J Natl Cancer Inst 1973;50:1111-1118.
[64]Wellings SR, Jensen HM, Marcum RG. An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions[J].J Natl Cancer Inst 1975:55:231-243.
[65]龚西瑜.WHO乳腺肿瘤组织学分类(2003)简介[J].临床与实验病理学杂志.2004,2；20(1)：5-10.
[66]Dupont WD, Page DL. Rsik factors for breast cancer in women with proliferative breast disease[J].N Engl J Med 1985:312:146-151.
[67]Dupont WD, Parl FF, Hartmann WH, et al. Breast cancer risk associated with proliferative breast disease an atypical hyperplasia[J]. Cancer 1993:71:1258-1265.
[68]Dupont WD, Page DL. Relative risk of breast cancer varies with time since diagnosis of atypical hyperplasia[J]. Hum Pathol 1989:20:723-725.
[69]Dupont WD, Parl FF, Hartmann WH, et al. Breast cancer risk associated with proliferative breast disease an atypical hyperplasia[J]. Cancer 1993:71:1258-1265.
[70]王峰,马忠兵,方允治,等.乳腺癌癌前病变大鼠模型的建立[J].中国现代普通外科进展.2009,5；12(5)：387-390.
[71]杨世杰,杨宝峰,颜光美,等.药理学[M].北京：人民卫生出版社,2010：7-9.
[72]韦史利,赵学军.逍遥丸对高架十字迷宫小鼠行为影响的实验研究[J].辽宁中医药大学学报,2010,12(6)：265-266.
[73]侯素春,刘晓明,林熙然,等.不同剂量凉血活血复方对小鼠上皮细胞增殖、表皮细胞分化、血浆内皮素1及血清可溶性E-选择素的影响[J].中国中西医结合皮肤性病医学杂志,2003,2(2)：76-79.
[74]唐迅.病例-对照研究：实施转化医学研究的承前启后[J].北京大学学报(医学版).2010,12；42(6)：687-689.
[75]Lean ME, Mann JI, Hoek JA, et al. Translational research [J]. BMJ,2008,337(7672):a863.
[76]周业勤.论慢病管理的对象及方法[J].中国卫生事业管理-2011(10).788-790.
[77]葛卫红,谢菡.慢病管理现状[J].药学与临床研究-2012.20(6).479-484.
[78]江泽飞,于世英,孙燕.CSCO乳腺癌骨转移临床诊疗专家共识(200版)[J].丹东医药-2007(4)：45-49.
[79]Powles T, Eeles R, Ashley S, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomized chemoprevention trial [J]. Lancet 1998:352:98-101.
[80]Powles TJ. The Royal Marsden Hospital(RMH) trial:key points and remaining questions[J]. Ann N Y Acad sci 2001:949:109-112.
[81]Veronesi U, Maisonneuve P, Costa A, et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomized trial among hysterectomised women[J]. Lancet 1998:352:93-97.
[82]Veronesi U, Maisonneuve P, Rotmensz N, et al. Italian randomized trial among women with hysterectomy:tamoxifen and hormone-dependent breast cancer in high-risk women[J]. J Natl Cancer Inst 2003:95:160-165.
[83]Vogel VG. Raloxifene:a second-generationg selective estrogen receptor modulator for reducing the risk of invasive breast cancer in postmenopausal women [J]. Women's Health 2007; 3:139-153.
[84]Land SR, Wickerham DL, Costantino JP, et al. Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention:The NSABP study of Tamoxifen and Raloxifene (STAR) P-2 Trial [J]. JAMA 2006:295:2742-2751.
[85]Baum M, Buzdar A, Cuzik M, et al. Anastrozole alone or in combination with tamoxifen versus alone for adjuvant treatment of postmenopausal women with early stage breast cancer:result of the ATAC(arimides, tamoxifen alone or in combination) trail efficacy and safety up date analyses[J]. Cancer 2003:98:1802-1810.
[86]Howell A, et al. Results of the ATAC(arimides, tamoxifen alone or in combination) trail after completion of 5 year's adjuvant treatment for breast cancer[J]. Lancet 2005:365:60-62.
[87]The Arimidex, Tamoxifen, Alone or in Combination(ATAC) Trialist's Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer:100-month analysis of the ATAC trial [J]. Lancet Oncol 2008:9:45-53.
[88]Ingle JN. Endocrine therapy trials of aromatase inhibitors for breast cancer in the adjuvant and prevention settings[J]. Clin Cancer Res 2005;11:900s-905s.
[89]杜凤香,王淑斌.中药周期疗法治疗乳腺增生病830例[J].中国中医药科技.2006,5；13(3)：195-196.
[90]贾香坡.中医药周期疗法治疗乳腺增生病216例[J].河南中医.2006,9；26(9)：44-45.
[91]刘凤琳.乳腺增生病中药周期疗法的临床观察[J].四川中医.2007；25(10)：80.
[92]洪宋贞,蔡芳英,朱华宇.消癖口服液系列治疗乳腺增生病的疗效[J].实用医学杂志.2007；23(20)：3276-3277.
[2]Wellings SR, Jensen HM, Marcum RG. An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions[J].J Natl Cancer Inst 1975:55:231-243.
[3]Shaaban AM, Sloane JP, West CR, et al. Histopathologic types of benign breast lesions and the risk of breast cancer:case-control study [J]. Am J surg Pathol 2002:26:421-430.
[4]Page DL,Zwaag RV, Rogers LW, et al. Relation between component parts of fibrocystic disease comples and breast cancer[J].J Natl Cancer Inst 1978:61:1055-1063.
[5]Page DL, Dupont WD, Rogers LW, et al. Intraductal carcinoma of the breast:follow-up after biopsy only [J]. Cancer 1982:49:751-758.
[6]Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease[J].N Engl J Med 1985:312:146-151.
[7]Palli D, del Turco MR, Simonciini R, et al. Benign breast disease and breast cancer:a case-cantrol study in a cohort in Italy[J]. Int J Cancer 1991:47:703-706.
[8]London SJ, Connolly JL, Schnitt SJ, et al. A prospective study of benign breast disease and the risk of breast cancer[J]. JAMA 1992:267:941-944.
[9]Dupont WD, Parl FF, Hartmann WH, et al. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia[J]. Cancer 1993:71:1258-1265.
[10]0'Connell P, Pekkel V, Fuqua SAW, et al. Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci[J].J Natl Cancer Inst 1998:90:697-703.
[11]Thompson HJ. Rat modles of premalignant breast disease[J].J Mammary Gland Biol Neoplasia 2000:5:409-420.
[12]Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease[J].N Engl J Med 1985:312:146-151.
[13]Dupont WD, Parl FF, Hartmann WH, et al. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia[J]. Cancer 1993:71:3896-3907.
[14]Page DL, Dupont WD, Rogers LW, et al. Atypical hyperplastic lesions of the female breast: a long-term follow-up study[J].Cancer 1985:55:2698-2708.
[15]Dupont WD, Page DL. Relative risk of breast cancer varies with time since diagnosisi of atypical hyperplasia[J].Hum Pathol 1989:20:723-725.
[16]Dupont WD, Parl FF, Hartmann WH, et al. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia[J].Cancer 1993:71:3896-3907.
[17]Bernsterin L, Epidemiology of endocrine-related risk factors for breast cancer[J]. J Mammary Gland Biol Neoplasia 2002:7:3.
[18]Russo IH, Russo J. Role of hormones in mammary cancer initiation and progression [J]. J Mammry Gland Biol Neoplasia 1998;3:49.
[19]Wagner JD, Kaplan JR, Burkman RT. Reproductive hormones and cardiovascular disease mechanism of acrion and clinical implications[J]. Obstet Gynecol Clin North Am 2002:29:475.
[20]Bernard Fisher, Joseph P. Costantino, D. Lawrence Wickerham, et al. Tamoxifen for the Prevention of Breast Cancer:Current Status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study[J]. Journal of the National Cancer Institute,2005,12; (97): 22:1652-1662.
[21]Day R, Ganz PA, Costantino JP, et al. Health-realted quality of life and tamoxifen in breast cancer prevention:a report from the National Surgical Adjuvant Breast and Bowel project P-1 Study[J]. J Clin Oncol 1999:17:2659-2669.
[22]Cuzick J, Forbes J, Edwards R, et al. First results from the international Breast Cancer Intervention Study:a randomized prevention trial [J]. Lancet,2002,360:817-823. [23] Vogel VG, Costantino JP, Wickerham DL, et al. The study of tamoxifen and raloxifene:preliminary enrollment data from a randomized breast cancer risk reduction trial[J]. Clin Breast Cancer 2002;3:153.
[24]林毅,唐汉均.现代中医乳房病学[M].人民卫生出版社2003年第1版：122-123.
[25]司徒红林,陈前军.消癖1-6号口服液干预治疗乳腺癌癌前病变的研究[J].肿瘤防治杂志,2002,9(2)：176-179.
[26]司徒红林,周劬志,卓睿,等.消癖口服液治疗乳腺良性病变不典型增生的临床研究[J].甘肃中医,2001；2：53-57.
[27]陈前军,徐飚,司徒红林,等.“消癖颗粒”阻断SD大鼠乳腺癌癌变及其对EGFR-STAT3通路影响研究[J].辽宁中医药大学学报,2012；14(8)：19-21.
[28]Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer. Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study[J]. J Natl Cancer Inst 1998:90:1371.
[29]Tekmal RR, Liu YG, Nair HB, et al. Estrogen receptor alpha is required for mammary development and the induction of mammary hyperplasia and epigenetic alterations in the aromatase transgenic mice [J]. JSteroid Biochem Mol Biol,2005,95(1-5):9-15.
[30]Leung G, Tsao SW, W ong YC. Sex hormone-induced mammary carcinogenesis in female Noble rats:detection of differentially expressed genes [J]. Breast Cancer Res Treat, 2003,77(1):49-63.
[31]Liu W L, Guo X, Guo ZG. Estrogen prevents bovine aortic endothelial cells from TNF-alpha—induced apoptosis via opposing effects on P38 and P44/42 CCDPK[J]. Acta Pharmacol Sin,2002,23:213-225.
[32]Plotkin LI, Aguirre JI, Kousteni S, et al. Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal--regulated kinase activation[J]. J Biol Chem,2005,'280:7317-7324.
[33]HAURA EB, TURKSON J, JOVE R. Mechanisms of disease:Insights into the emerging role of signal transducers and activators of transcription in cancer[J]. Nat Clin Pract Oncol, 2005,2(6):315-324.
[34]Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer [J]. BiochemBiophys ges Common,2005,335 (2):292-299.
[35]Haura EB, Turkson J, Jove R. Mechanisms of disease:Insights into the emerging role of signal transducers and activators of transcription in cancer [J]. Nat Clin Pratt Oncol, 2005,2(6):315-324.
[36]Sordella R, Bell DW, Haber DA, et al. Geftinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways[J]. Science,2004; 305(5687):1163-1167.
[37]Ford A C, Grandis J R. Targeting epidermal growth factor receptor in head and neck cancer[J]. Head Neck,2003,25(1); 67-73.
[38]Folkman J.What is the evidence that tumours are angiogenesis dependent [J]. J Natl Cancer Inst 1990;82:4-6.
[39]Ottinetti A, Sapino A. Morphometric evaluation of microvessels surrounding hyperplastic and nroplastic mammary lesions [J]. Breast Cancer Res Treat 1988; 11:241-248.
[40]Fregene TA, Kellog C, Pienta KJ. Microvessel quantitation as a measure of angiogenic activity in benign breast tissues lesions:a marker for precancerous disease [J]. Int J Oncol 1994:4:1199-1202.
[41]Guidi A,Fischer L, Harris J, et al. Microvessel density and distribution in ductal carcinoman in situ of the breast[J]. J Natl Cancer Inst 1994:86:614-619.
[42]Engels K,Fox SB. Whitehouse RM, et al. Up-regulation of thymidine phosphorylase expression is associated with high-grade in situ ductal carcinomas of the breast[J]. J Pathol 1997:181:207-212.
[43]Aberg UW, Saarinen N, Abrahamsson A, et al. Tamoxifen and flaxseed alter angiogenesis regulators in normal human breast tissue in vivo. PLOS One.2011;6(9):e25720. doi:10.1371/journal. pone.0025720,2011.9.30.
[44]Allred DC,Medina D. Introduction:models of premalignant breast disease[J].J Mary Gland Biol Neoplasia,2000,5(4):339-340.
[45]Henry J. Thompson, Meenakshi Singh. Rat models of premalignant breast disease[J].J Mammary Gland Biol Neoplasia.2000,5(4):409-420.
[46]李静蔚,宋爱莉,张敬涛等.DMBA诱导大鼠乳腺癌癌前病变的组织病理学研究[J].中华中医药学刊,2008,(3)：505-508.
[47]王峰,马忠兵,方允治等.乳腺癌癌前病变大鼠模型的建立.中国现代普通外科进展[J],2009,5：12(5)：38-41.
[48]宋爱莉,叶林,李静蔚等.乳复汤对乳腺非典型增生病证结合造模大鼠微循环的影响[J].山东中医杂志,2003,10；22(10)：622-626.
[49]Dawson PJ, Wolman SR, Tait L, et al.A models for the evolution of cancer from proliferative breast disease [J]. AM J Path.1996,148:313-319.
[50]PJ Dawson, SR Wolman, L.Tait, et al. MCF10AT:a model for the evolution of cancer from proliferative breast disease[J]. Am J Pathol.1996 January; 148(1):313-319.
[51]孙敬方.动物实验方法学[M].北京：人民卫生出版社,2001：424—-426.
[52]Russo J, Irma H. Atlas and histologie classifcation of tumors of the rat mammary gland [J]. J Mammary Gland Biol Neoplasia,2000,5(2):187-200.
[53]Weidner N. Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors[J]. Breast Cancer Res Treat,1995,36:169.
[54]Tanaka K, lwamoto S, Con G, et al. Expression of surviving and its relationship to loss of apotosis in breast carcinomas[J]. Clin Cancer Res,2000,6(1),127-134.
[55]Kanda N, Seno H, Konda Y, et al. STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells [J]. Oncogene, 2004,23(28):4921-4929.
[56]陈婷婷,王岳君,杨苗苗等.pSTAT3和SOCS3在人乳腺癌组织中的表达及意义[J].中国组织化学与细胞化学杂志.2012,6；(21)3：295-299.
[57]国外期刊摘译[J].现代泌尿外科杂志.2010,5;15(3)：52.
[58]Yon Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvantchemotherapy and Bevacizumab for HER2—negative breast cancer [J]. N Engl J Med,2012,366(4):299-309.
[59]Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer[J]. N Engl J Med,2012,366(4):310-320.
[60]师永红.乳腺癌与癌前期病变[J].内蒙古医学杂志,2007；39(7)：769-770.
[61]Tavassoli FA, Devilee P WHO classification of tumours. Pathology and genetics. Tumours of the breast and female genital organs. Lyon:IARC Press,2003:63-67.
[62]沈镇宙.乳腺肿瘤学[M].上海：世纪出版集团上海科学技术出版社.2005：22.
[63]Well ings SR, Jensen HM. On the origin and progression of ductal carcinoma in the human breast[J]. J Natl Cancer Inst 1973;50:1111-1118.
[64]Wellings SR, Jensen HM, Marcum RG. An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions[J].J Natl Cancer Inst 1975:55:231-243.
[65]龚西瑜.WHO乳腺肿瘤组织学分类(2003)简介[J].临床与实验病理学杂志.2004,2；20(1)：5-10.
[66]Dupont WD, Page DL. Rsik factors for breast cancer in women with proliferative breast disease[J].N Engl J Med 1985:312:146-151.
[67]Dupont WD, Parl FF, Hartmann WH, et al. Breast cancer risk associated with proliferative breast disease an atypical hyperplasia[J]. Cancer 1993:71:1258-1265.
[68]Dupont WD, Page DL. Relative risk of breast cancer varies with time since diagnosis of atypical hyperplasia[J]. Hum Pathol 1989:20:723-725.
[69]Dupont WD, Parl FF, Hartmann WH, et al. Breast cancer risk associated with proliferative breast disease an atypical hyperplasia[J]. Cancer 1993:71:1258-1265.
[70]王峰,马忠兵,方允治,等.乳腺癌癌前病变大鼠模型的建立[J].中国现代普通外科进展.2009,5；12(5)：387-390.
[71]杨世杰,杨宝峰,颜光美,等.药理学[M].北京：人民卫生出版社,2010：7-9.
[72]韦史利,赵学军.逍遥丸对高架十字迷宫小鼠行为影响的实验研究[J].辽宁中医药大学学报,2010,12(6)：265-266.
[73]侯素春,刘晓明,林熙然,等.不同剂量凉血活血复方对小鼠上皮细胞增殖、表皮细胞分化、血浆内皮素1及血清可溶性E-选择素的影响[J].中国中西医结合皮肤性病医学杂志,2003,2(2)：76-79.
[74]唐迅.病例-对照研究：实施转化医学研究的承前启后[J].北京大学学报(医学版).2010,12；42(6)：687-689.
[75]Lean ME, Mann JI, Hoek JA, et al. Translational research [J]. BMJ,2008,337(7672):a863.
[76]周业勤.论慢病管理的对象及方法[J].中国卫生事业管理-2011(10).788-790.
[77]葛卫红,谢菡.慢病管理现状[J].药学与临床研究-2012.20(6).479-484.
[78]江泽飞,于世英,孙燕.CSCO乳腺癌骨转移临床诊疗专家共识(200版)[J].丹东医药-2007(4)：45-49.
[79]Powles T, Eeles R, Ashley S, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomized chemoprevention trial [J]. Lancet 1998:352:98-101.
[80]Powles TJ. The Royal Marsden Hospital(RMH) trial:key points and remaining questions[J]. Ann N Y Acad sci 2001:949:109-112.
[81]Veronesi U, Maisonneuve P, Costa A, et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomized trial among hysterectomised women[J]. Lancet 1998:352:93-97.
[82]Veronesi U, Maisonneuve P, Rotmensz N, et al. Italian randomized trial among women with hysterectomy:tamoxifen and hormone-dependent breast cancer in high-risk women[J]. J Natl Cancer Inst 2003:95:160-165.
[83]Vogel VG. Raloxifene:a second-generationg selective estrogen receptor modulator for reducing the risk of invasive breast cancer in postmenopausal women [J]. Women's Health 2007; 3:139-153.
[84]Land SR, Wickerham DL, Costantino JP, et al. Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention:The NSABP study of Tamoxifen and Raloxifene (STAR) P-2 Trial [J]. JAMA 2006:295:2742-2751.
[85]Baum M, Buzdar A, Cuzik M, et al. Anastrozole alone or in combination with tamoxifen versus alone for adjuvant treatment of postmenopausal women with early stage breast cancer:result of the ATAC(arimides, tamoxifen alone or in combination) trail efficacy and safety up date analyses[J]. Cancer 2003:98:1802-1810.
[86]Howell A, et al. Results of the ATAC(arimides, tamoxifen alone or in combination) trail after completion of 5 year's adjuvant treatment for breast cancer[J]. Lancet 2005:365:60-62.
[87]The Arimidex, Tamoxifen, Alone or in Combination(ATAC) Trialist's Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer:100-month analysis of the ATAC trial [J]. Lancet Oncol 2008:9:45-53.
[88]Ingle JN. Endocrine therapy trials of aromatase inhibitors for breast cancer in the adjuvant and prevention settings[J]. Clin Cancer Res 2005;11:900s-905s.
[89]杜凤香,王淑斌.中药周期疗法治疗乳腺增生病830例[J].中国中医药科技.2006,5；13(3)：195-196.
[90]贾香坡.中医药周期疗法治疗乳腺增生病216例[J].河南中医.2006,9；26(9)：44-45.
[91]刘凤琳.乳腺增生病中药周期疗法的临床观察[J].四川中医.2007；25(10)：80.
[92]洪宋贞,蔡芳英,朱华宇.消癖口服液系列治疗乳腺增生病的疗效[J].实用医学杂志.2007；23(20)：3276-3277.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |