Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
Clin Cancer Res. 2021 Jun 15;27(12):3443-3455. doi: 10.1158/1078-0432.CCR-20-4928. Epub 2021 Mar 30.
The mTOR complex C1 (mTORC1) inhibitor everolimus in combination with the aromatase inhibitor exemestane is an effective treatment for patients with hormone receptor-positive (HR), HER2-negative (HER2), advanced breast cancer (HR/HER2 aBC). However, everolimus can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/protein kinase B (AKT)/mTORC1 pathway and induce tumor resistance to everolimus.
We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and on-treatment (i.e., during first 3 months of therapy) blood glucose levels on progression-free survival (PFS) in patients with HR/HER2 aBC treated with everolimus-exemestane.
We evaluated 809 patients with HR/HER2 aBC treated with everolimus-exemestane as any line of therapy for advanced disease. When evaluated as dichotomous variables, baseline and on-treatment glycemia were not significantly associated with PFS. However, when blood glucose concentration was evaluated as a continuous variable, a multivariable model accounting for clinically relevant patient- and tumor-related variables revealed that both baseline and on-treatment glycemia are associated with PFS, and this association is largely attributable to their interaction. In particular, patients who are normoglycemic at baseline and experience on-treatment diabetes have lower PFS compared with patients who are already hyperglycemic at baseline and experience diabetes during everolimus-exemestane therapy (median PFS, 6.34 vs. 10.32 months; HR, 1.76; 95% confidence interval, 1.15-2.69; = 0.008).
The impact of on-treatment glycemia on the efficacy of everolimus-exemestane therapy in patients with HR/HER2 aBC depends on baseline glycemia. This study lays the foundations for investigating novel therapeutic approaches to target the glucose/insulin axis in combination with PI3K/AKT/mTORC1 inhibitors in patients with HR/HER2 aBC.
mTOR 复合物 C1（mTORC1）抑制剂依维莫司联合芳香酶抑制剂依西美坦是治疗激素受体阳性（HR）、HER2 阴性（HER2）、晚期乳腺癌（HR/HER2 aBC）患者的有效方法。然而，依维莫司会导致高血糖和高胰岛素血症，这可能会重新激活 PI3K/蛋白激酶 B（AKT）/mTORC1 通路并诱导肿瘤对依维莫司产生耐药性。
我们进行了一项多中心、回顾性、意大利研究，旨在调查 HR/HER2 aBC 患者接受依维莫司-依西美坦治疗时，基线和治疗期间（即治疗的前 3 个月内）的血糖水平对无进展生存期（PFS）的影响。
我们评估了 809 例接受依维莫司-依西美坦治疗的 HR/HER2 aBC 患者，这些患者接受的是晚期疾病的任何一线治疗。当作为二分类变量评估时，基线和治疗中的血糖与 PFS 无显著相关性。然而，当以连续变量评估血糖浓度时，一个考虑到患者和肿瘤相关的临床相关变量的多变量模型显示，基线和治疗中的血糖均与 PFS 相关，这种相关性主要归因于它们之间的相互作用。具体来说，基线时血糖正常但在依维莫司-依西美坦治疗期间发生糖尿病的患者与基线时血糖升高且在依维莫司-依西美坦治疗期间发生糖尿病的患者相比，PFS 较低（中位 PFS，6.34 个月与 10.32 个月；HR，1.76；95%置信区间，1.15-2.69；P=0.008）。
在 HR/HER2 aBC 患者中，治疗期间血糖对依维莫司-依西美坦治疗疗效的影响取决于基线血糖。这项研究为研究针对 HR/HER2 aBC 患者的葡萄糖/胰岛素轴与 PI3K/AKT/mTORC1 抑制剂联合的新治疗方法奠定了基础。
