Cellular Network and Molecular Therapeutic Target Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
J Exp Clin Cancer Res. 2020 Dec 10;39(1):279. doi: 10.1186/s13046-020-01797-3.
HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines.
The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.
We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively).
Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.
HER2 靶向药物极大地改变了 HER2+晚期乳腺癌（ABC）的治疗格局。在很短的时间内，新疗法的快速引入导致了帕妥珠单抗联合曲妥珠单抗和紫杉烷在一线治疗中的批准，以及曲妥珠单抗-美坦新偶联物（T-DM1）在二线治疗中的批准。因此，曲妥珠单抗/帕妥珠单抗联合治疗后 T-DM1 疗效的证据有限，一些回顾性报告的数据表明其活性较低。本研究旨在探讨帕妥珠单抗预处理和未经帕妥珠单抗治疗的 HER2 阳性 ABC 患者中 T-DM1 的疗效。我们还旨在提供关于不同药物序列（包括帕妥珠单抗和 T-DM1）在 HER2 阳性细胞系中暴露的证据。
通过对耐药性 HER2+乳腺癌细胞系进行曲妥珠单抗、帕妥珠单抗及其联合序贯暴露，在体外研究 HER2 的生物学特性。体外实验与对 555 例接受 T-DM1 治疗的 HER2+ABC 患者的数据进行分析并行，评估了在二线接受 T-DM1 治疗的 371 例患者中的 T-DM1 疗效。生存估计以 Kaplan-Meier 曲线显示，通过对数秩检验进行比较，并在可能的情况下在多变量模型中进行确认。
我们在此证明，与曲妥珠单抗耐药细胞相比，两种对曲妥珠单抗+帕妥珠单抗耐药的 HER2+乳腺癌细胞系中 T-DM1 的活性较低。T-DM1 疗效较低与细胞膜上 HER2 表达的显著降低及其核转位有关。在 4 例曲妥珠单抗/帕妥珠单抗预处理患者的活检中证实了膜水平 HER2 下调。在接受二线 T-DM1 治疗的 371 例患者中，177 例患者在一线接受曲妥珠单抗/帕妥珠单抗治疗的患者中，从晚期疾病诊断开始的中位总生存期（mOS）和二线治疗的中位无进展生存期（mPFS2）分别为 52 个月和 6 个月，而 194 例未经帕妥珠单抗治疗的患者分别为 74 个月和 10 个月（OS 和 PFS2 的 p 值分别为 0.0006 和 0.03）。
我们的数据支持以下假设：帕妥珠单抗与曲妥珠单抗联合使用可减少可用的细胞膜 HER2 受体数量，从而限制 T-DM1 在癌细胞中的结合。这可能有助于解释与未经帕妥珠单抗治疗的患者相比，曲妥珠单抗/帕妥珠单抗预处理患者二线接受 T-DM1 治疗的结局较差。
