Ferroni Patrizia, Riondino Silvia, Laudisi Anastasia, Portarena Ilaria, Formica Vincenzo, Alessandroni Jhessica, D'Alessandro Roberta, Orlandi Augusto, Costarelli Leopoldo, Cavaliere Francesco, Guadagni Fiorella, Roselli Mario
San Raffaele Roma Open University, Rome, Italy
Interinstitutional Multidisciplinary Biobank, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy Department of Systems Medicine, Medical Oncology, Tor Vergata Clinical Center, Tor Vergata University of Rome, Rome, Italy.
Oncologist. 2016 Sep;21(9):1041-9. doi: 10.1634/theoncologist.2015-0462. Epub 2016 Jul 7.
Based on the hypothesis that impaired glucose metabolism might be associated with survival outcomes independently of overt diabetes, we sought to investigate the prognostic value of routinely used glycemic parameters in a prospective study of breast cancer (BC) patients.
Fasting blood glucose, insulin and HbA1c levels, and insulin resistance (assessed by the Homeostasis Model Assessment [HOMA] index) at diagnosis were evaluated in 286 nondiabetic BC patients (249 with primary cancer, 37 with metastatic) with respect to those parameters' possible associations with clinicopathological features and survival outcomes. As a control group, 143 healthy women matched in a 2:1 ratio for age, blood lipid levels, and body mass index were also investigated.
Fasting blood glucose level (mean ± SD: 99 ± 26 vs. 85 ± 15 mg/dL), insulin level (median: 10.0 vs. 6.8 μIU/mL), and HOMA index (median: 2.2 vs. 1.4), but not HbA1c level, were significantly elevated in BC patients compared with control subjects. Receiver operating characteristics analysis showed comparable areas for blood glucose and insulin levels, and HOMA index (ranging from 0.668 to 0.671). Using a cutoff level of 13 μIU/mL, insulin had the best specificity (92%) and sensitivity (41%), was significantly associated with disease stage, and acted as a negative prognostic marker of progression-free survival (hazard ratio: 2.17; 95% confidence interval: 1.13-4.20) independently of menopausal status, disease stage, hormone receptor status, and human epidermal growth factor receptor 2 and Ki67 expression.
These results suggest that insulin determination might provide prognostic information in BC and support the hypothesis that lifestyle and/or pharmacological interventions targeting glucose metabolism could be considered to improve survival outcome of selected BC patients.
Pretreatment insulin levels may represent a biomarker of adverse prognosis in nondiabetic women with breast cancer, independently of other well-established prognostic factors (i.e., stage, hormone receptors, HER2/neu, and Ki67). This finding has important implications, because it provides the rationale for lifestyle or insulin-targeting pharmacologic interventions as a means of improving breast cancer outcomes not only in early stages, but also in advanced-stage breast cancer patients with aggressive tumor phenotypes (HER2-negative hormone-resistant, or triple-negative breast cancer), in which treatments are still challenging. The possibility of using insulin as a biomarker to guide insulin-targeted interventions also should be taken into account.
基于葡萄糖代谢受损可能与生存结局相关，而与显性糖尿病无关这一假设，我们试图在一项乳腺癌（BC）患者的前瞻性研究中，探究常规使用的血糖参数的预后价值。
对286例非糖尿病BC患者（249例原发性癌症患者，37例转移性癌症患者）诊断时的空腹血糖、胰岛素和糖化血红蛋白（HbA1c）水平以及胰岛素抵抗（通过稳态模型评估[HOMA]指数评估）进行了评估，以研究这些参数与临床病理特征和生存结局之间的可能关联。作为对照组，还对143名年龄、血脂水平和体重指数按2:1比例匹配的健康女性进行了调查。
与对照组相比，BC患者的空腹血糖水平（均值±标准差：99±26 vs. 85±15 mg/dL）、胰岛素水平（中位数：10.0 vs. 6.8 μIU/mL）和HOMA指数（中位数：2.2 vs. 1.4）显著升高，但HbA1c水平无显著变化。受试者工作特征分析显示，血糖、胰岛素水平和HOMA指数的曲线下面积相当（范围为0.668至0.671）。胰岛素水平以13 μIU/mL为临界值时，具有最佳特异性（92%）和敏感性（41%），与疾病分期显著相关，并且独立于绝经状态、疾病分期、激素受体状态、人表皮生长因子受体2和Ki67表达，是无进展生存的负性预后标志物（风险比：2.17；95%置信区间：1.13 - 4.20）。
这些结果表明，检测胰岛素可能为BC患者提供预后信息，并支持这样一种假设，即针对葡萄糖代谢的生活方式和/或药物干预可考虑用于改善特定BC患者的生存结局。
治疗前胰岛素水平可能是非糖尿病乳腺癌女性不良预后的生物标志物，独立于其他已确立的预后因素（即分期、激素受体、HER2/neu和Ki67）。这一发现具有重要意义，因为它为生活方式或胰岛素靶向药物干预提供了理论依据，不仅可以改善早期乳腺癌患者的预后，还可以改善具有侵袭性肿瘤表型（HER2阴性激素抵抗型或三阴性乳腺癌）的晚期乳腺癌患者的预后，而这些患者的治疗仍然具有挑战性。还应考虑将胰岛素用作生物标志物以指导胰岛素靶向干预的可能性。
