Sonnenblick Amir, Agbor-Tarh Dominique, Bradbury Ian, Di Cosimo Serena, Azim Hatem A, Fumagalli Debora, Sarp Severine, Wolff Antonio C, Andersson Michael, Kroep Judith, Cufer Tanja, Simon Sergio D, Salman Pamela, Toi Masakazu, Harris Lyndsay, Gralow Julie, Keane Maccon, Moreno-Aspitia Alvaro, Piccart-Gebhart Martine, de Azambuja Evandro
Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
J Clin Oncol. 2017 May 1;35(13):1421-1429. doi: 10.1200/JCO.2016.69.7722. Epub 2017 Mar 13.
Purpose Previous studies have suggested an association between metformin use and improved outcome in patients with diabetes and breast cancer. In the current study, we aimed to explore this association in human epidermal growth factor receptor 2 (HER2 ) -positive primary breast cancer in the context of a large, phase III adjuvant trial. Patients and Methods The ALTTO trial randomly assigned patients with HER2-positive breast cancer to receive 1 year of either trastuzumab alone, lapatinib alone, their sequence, or their combination. In this substudy, we evaluated whether patients with diabetes at study entry-with or without metformin treatment-were associated with different disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) compared with patients without diabetes. Results A total of 8,381 patients were included in the current analysis: 7,935 patients (94.7%) had no history of diabetes at diagnosis, 186 patients (2.2%) had diabetes with no metformin treatment, and 260 patients (3.1%) were diabetic and had been treated with metformin. Median follow-up was 4.5 years (0.16 to 6.31 years), at which 1,205 (14.38%), 929 (11.08%), and 528 (6.3%) patients experienced DFS, DDFS, and OS events, respectively. Patients with diabetes who had not been treated with metformin experienced worse DFS (multivariable hazard ratio [HR], 1.40; 95% CI, 1.01 to 1.94; P = .043), DDFS (multivariable HR, 1.56; 95% CI, 1.10 to 2.22; P = .013), and OS (multivariable HR, 1.87; 95% CI, 1.23 to 2.85; P = .004). This effect was limited to hormone receptor-positive patients. Whereas insulin treatment was associated with a detrimental effect, metformin had a salutary effect in patients with diabetes who had HER2-positive and hormone receptor-positive breast cancer. Conclusion Metformin may improve the worse prognosis that is associated with diabetes and insulin treatment, mainly in patients with primary HER2-positive and hormone receptor-positive breast cancer.
目的 既往研究提示，糖尿病患者使用二甲双胍与乳腺癌患者预后改善之间存在关联。在本研究中，我们旨在一项大型Ⅲ期辅助试验背景下，探讨人表皮生长因子受体2（HER2）阳性原发性乳腺癌中的这种关联。
患者与方法 ALTTO试验将HER2阳性乳腺癌患者随机分配接受1年曲妥珠单抗单药治疗、拉帕替尼单药治疗、二者序贯治疗或联合治疗。在这项亚研究中，我们评估了研究入组时患有糖尿病的患者（无论是否接受二甲双胍治疗）与无糖尿病患者相比，无病生存期（DFS）、远处无病生存期（DDFS）和总生存期（OS）是否存在差异。
结果 本分析共纳入8381例患者：7935例患者（94.7%）诊断时无糖尿病病史，186例患者（2.2%）患有糖尿病且未接受二甲双胍治疗，260例患者（3.1%）患有糖尿病且接受过二甲双胍治疗。中位随访时间为4.5年（0.16至6.31年），此时分别有1205例（14.38%）、929例（11.08%）和528例（6.3%）患者经历DFS、DDFS和OS事件。未接受二甲双胍治疗的糖尿病患者DFS较差（多变量风险比[HR]，1.40；95%CI，1.01至1.94；P = 0.043），DDFS较差（多变量HR，1.56；95%CI，1.10至2.22；P = 0.013），OS较差（多变量HR，1.87；95%CI，1.23至2.85；P = 0.004）。这种影响仅限于激素受体阳性患者。胰岛素治疗有不良影响，而二甲双胍对患有HER2阳性和激素受体阳性乳腺癌的糖尿病患者有有益作用。
结论 二甲双胍可能改善与糖尿病和胰岛素治疗相关的较差预后，主要是在原发性HER2阳性和激素受体阳性乳腺癌患者中。
