【原】​二甲双胍对乳腺癌化疗患者的效果

　　临床前数据表明，降糖抗癌神药二甲双胍可能增强化疗对乳腺癌的效果。

　　2019年8月29日，欧洲乳腺癌专科医师学会《乳腺》在线发表加拿大多伦多大学、西奈山医院、玛格丽特公主癌症中心、圣迈克尔医院、安大略西部大学、美国佛蒙特大学的研究报告，比较了二甲双胍或安慰剂对晚期乳腺癌标准化疗患者无进展生存的影响。

　　该多中心双盲安慰剂随机对照二期临床研究于2011年8月～2016年7月入组非糖尿病晚期乳腺癌化疗患者40例，随机分组每天两次口服二甲双胍850毫克（22例）或安慰剂（18例）。主要结局为无进展生存，次要结局包括总生存、缓解率、毒性反应和生活质量。

　　结果，二甲双胍组与安慰剂组相比：

• 平均年龄：55岁比57岁

• 激素受体阳性乳腺癌：86.4%比83.3%

• 平均体重指数：27比27（kg/m2）

• 一线化疗：68.2%比66.7%

• 3～4级毒性反应：31.8%比58.8%

• 1～2级毒性反应：68.2%比35.3%

• 部分缓解：18.2%比25%

• 疾病稳定：36.4%比18.8%

• 疾病进展：45.4%比56.2%

• 平均无进展生存：5.4个月比6.3个月（风险比：1.2，95%置信区间：0.63～2.31，双侧P=0.58，单侧P=0.71）

• 平均总生存：20.2个月比24.2个月（风险比：1.68，95%置信区间：0.79～3.55，双侧P=0.18，单侧P=0.91）

• 整体健康状态评分：-0.6比+0.3（P=0.006）

　　因此，该研究结果表明，二甲双胍与安慰剂相比，对于非糖尿病晚期乳腺癌化疗患者的缓解率、无进展生存或总生存无显著影响，反而可能引起1～2级不良事件增加以及整体生活质量降低。

Breast. 2019 Aug 29;48:17-23.

A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy.

Isabel Pimentel, Ana Elisa Lohmann, Marguerite Ennis, Ryan J.O. Dowling, David Cescon, C. Elser, K.R. Potvin, R. Haq, C. Hamm, Martin C. Chang, Vuk Stambolic, Pamela J. Goodwin.

Mount Sinai Hospital, University of Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Ontario, Canada; Applied Statistician, Markham, Ontario, Canada; Western University, London, Ontario, Canada; St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada; University of Vermont Medical Center, Burlington, VT, USA.

HIGHLIGHTS

• The addition of metformin to standard chemotherapy in non-diabetic metastatic breast cancer patients showed no significant effect on response rate, PFS or OS, as compared to placebo.

• Metformin was associated with increased grade I and II adverse events and decreased global quality of life.

OBJECTIVES: Pre-clinical data suggest metformin might enhance the effect of chemotherapy in breast cancer (BC). We conducted a Phase II randomized trial of chemotherapy plus metformin versus placebo in metastatic breast cancer (MBC).

MATERIAL AND METHODS: In this double blind phase II trial we randomly assigned non-diabetic MBC patients on 1st to 4th line chemotherapy to receive metformin 850 mg po bid or placebo bid. Primary outcome was progression-free survival (PFS); secondary outcomes included overall survival (OS), response rate (RR), toxicity and quality of life (QOL). With 40 subjects and a type-one error of 0.2 (one-sided), a PFS hazard ratio (HR) of 0.58 could be detected with 80% power.

RESULTS: 40 patients were randomized (22 metformin, 18 placebo) with a mean age of 55 vs 57 years and ER/PR positive BC in 86.4% vs 83.3% off metformin vs placebo, respectively. Mean BMI was 27kg/m2 in both arms. The majority of patients were on 1st line chemotherapy. Grade 3-4 toxicity occurred in 31.8% (metformin) vs 58.8% (placebo). Best response: Partial response 18.2% metformin vs 25% placebo, stable disease 36.4% metformin vs 18.8% placebo, progressive disease 45.4% metformin vs 56.2% placebo. Mean PFS was 5.4 vs 6.3 months (metformin vs placebo), HR 1.2 (95% CI 0.63-2.31). Mean OS was 20.2 (metformin) vs 24.2 months (placebo), HR 1.68 (95% CI 0.79-3.55).

CONCLUSION: In this population metformin showed no significant effect on RR, PFS or OS. These results do not support the use of metformin with chemotherapy in non-diabetic MBC patients.

KEYWORDS: Metformin, Breast cancer, Trial registration: NCT01310231

DOI: 10.1016/j.breast.2019.08.003