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降胆固醇药物可以改善乳腺癌患者辅助治疗临床结局

  既往研究发现,降胆固醇药物可以预防乳腺癌复发,其作用机制可能为降低27-羟胆固醇(雌激素胆固醇代谢物)水平,从而减弱雌激素受体信号传导。内分泌治疗对胆固醇水平和高胆固醇血症的影响,可能抵消芳香酶抑制剂的预期效果。

  2017年2月13日,美国临床肿瘤学会官方期刊《临床肿瘤学杂志》在线发表美国达纳法伯癌症研究所、哈佛大学医学院、国际乳腺癌研究组织、哈佛大学陈曾熙公共卫生学院、前沿科学技术研究基金会、瑞典隆德大学、佛蒙特大学、意大利米兰欧洲肿瘤研究所、匈牙利国家肿瘤学研究所、法国伯格尼研究所、丹麦乳腺癌协作组、丹麦哥本哈根大学医院、瑞士格劳宾登医院、瑞士临床癌症研究组织、瑞士伯尔尼大学小岛医院、瑞士圣加仑医院、英国伦敦皇家马斯登医院、澳大利亚悉尼大学公共卫生学院的国际乳腺癌组织(BIG)的研究报告,发现降胆固醇药物可以降低乳腺癌复发风险。

  该随机Ⅲ期双盲研究(BIG1-98)于1998~2003年入组8010绝经后激素受体阳性早期浸润性乳腺癌女性,在研究开始时和开始后5.5年内每6个月测量全身总胆固醇水平并记录降胆固醇用药(他汀类或非他汀类)

  结果发现,他莫昔芬治疗期间胆固醇水平降低。在内分泌治疗期间开始降胆固醇用药的789例患者中,使用来曲唑单药、他莫昔芬→来曲唑、来曲唑→他莫昔芬、他莫昔芬单药治疗者分别为318、189、176、106例。

  重要的是,在内分泌治疗期间开始降胆固醇用药的患者,任何恶性疾病或任何原因死亡风险、乳腺癌复发风险、乳腺癌远处复发风险分别降低21%、24%、26%(无疾病生存、无乳腺癌间期、无远处复发间期的风险比分别为:0.79、0.76、0.74,95%置信区间:0.66~0.95、0.60~0.97、0.56~0.97,P=0.01、0.02、0.03)。

  因此,激素受体阳性早期乳腺癌术后辅助内分泌治疗期间,降胆固醇药物可能有防止复发的作用,作者建议进行前瞻随机研究证实这些观察结果。

J Clin Oncol. 2017 Feb 13. [Epub ahead of print]

Cholesterol, Cholesterol-Lowering Medication Use, and Breast Cancer Outcome in the BIG 1-98 Study.

Signe Borgquist, Anita Giobbie-Hurder, Thomas P. Ahern, Judy E. Garber, Marco Colleoni, István Láng, Marc Debled, Bent Ejlertsen, Roger von Moos, Ian Smith, Alan S. Coates, Aron Goldhirsch, Manuela Rabaglio, Karen N. Price, Richard D. Gelber, Meredith M. Regan, Beat Thürlimann.

Dana-Farber Cancer Institute, Harvard Medical School; International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, Frontier Science and Technology Research Foundation; IBCSG Statistical Center and Frontier Science and Technology Research Foundation; IBCSG Statistical Center, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA; Lund University, Lund, Sweden; University of Vermont, Burlington, VT; IBCSG and European Institute of Oncology, Milan, Italy; IBCSG and National Institute of Oncology, Budapest, Hungary; Institut Bergonié, Bordeaux, France; Danish Breast Cancer Cooperative Group, Rigshospitalet, Copenhagen, Denmark; Cantonal Hospital Graubuenden, Chur; Swiss Group for Clinical Cancer Research and IBCSG; IBCSG Coordinating Center and Inselspital, Bern; Breast Center St. Gallen, Kantonsspital, St. Gallen; Swiss Group for Clinical Cancer Research and IBCSG, Bern, Switzerland; The Royal Marsden Hospital, London, United Kingdom; IBCSG and University of Sydney School of Public Health, Sydney, Australia.

PURPOSE: Cholesterol-lowering medication (CLM) has been reported to have a role in preventing breast cancer recurrence. CLM may attenuate signaling through the estrogen receptor by reducing levels of the estrogenic cholesterol metabolite 27-hydroxycholesterol. The impact of endocrine treatment on cholesterol levels and hypercholesterolemia per se may counteract the intended effect of aromatase inhibitors.

PATIENTS AND METHODS: The Breast International Group (BIG) conducted a randomized, phase III, double-blind trial, BIG 1-98, which enrolled 8,010 postmenopausal women with early-stage, hormone receptor-positive invasive breast cancer from 1998 to 2003. Systemic levels of total cholesterol and use of CLM were measured at study entry and every 6 months up to 5.5 years. Cumulative incidence functions were used to describe the initiation of CLM in the presence of competing risks. Marginal structural Cox proportional hazards modeling investigated the relationships between initiation of CLM during endocrine therapy and outcome. Three time-to-event end points were considered: disease-free-survival, breast cancer-free interval, and distant recurrence-free interval.

RESULTS: Cholesterol levels were reduced during tamoxifen therapy. Of 789 patients who initiated CLM during endocrine therapy, the majority came from the letrozole monotherapy arm (n = 318), followed by sequential tamoxifen-letrozole (n = 189), letrozole-tamoxifen (n = 176), and tamoxifen monotherapy (n = 106). Initiation of CLM during endocrine therapy was related to improved disease-free-survival (hazard ratio [HR], 0.79; 95% CI, 0.66 to 0.95; P = .01), breast cancer-free interval (HR, 0.76; 95% CI, 0.60 to 0.97; P = .02), and distant recurrence-free interval (HR, 0.74; 95% CI, 0.56 to 0.97; P = .03).

CONCLUSION: Cholesterol-lowering medication during adjuvant endocrine therapy may have a role in preventing breast cancer recurrence in hormone receptor-positive early-stage breast cancer. We recommend that these observational results be addressed in prospective randomized trials.

DOI: 10.1200/JCO.2016.70.3116

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