Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain.
Oncologist. 2018 Sep;23(9):1092-1102. doi: 10.1634/theoncologist.2017-0379. Epub 2018 Apr 26.
HER2-positive gastric cancer (GC) affects 7%-34% of patients with GC. Trastuzumab-based first-line treatment has become the standard of care for HER2-positive advanced gastric cancer (AGC). However, there are no clinically validated biomarkers for resistance to HER2-targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2-positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2-positive AGC treated with trastuzumab.
Forty-two HER2-positive GC samples from patients treated with trastuzumab-based first-line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed.
Concurrent genetic alterations were detected in 97.1% of HER2-positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression-free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab-based chemotherapy in terms of OS and PFS.
Our results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2-positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab.
This article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2-positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression-free survival in AGC treated with trastuzumab-based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2-positive AGC.
HER2 阳性胃癌（GC）影响 7%-34%的 GC 患者。曲妥珠单抗为基础的一线治疗已成为 HER2 阳性晚期胃癌（AGC）的标准治疗方法。然而，目前还没有针对 HER2 靶向治疗耐药的临床验证生物标志物。PI3K 通路和酪氨酸激酶受体（TKR）改变的上调已被认为是乳腺癌耐药的分子机制。我们的研究旨在对 HER2 阳性 AGC 进行分子特征分析，并研究 PI3K/Akt/mTOR 信号通路激活和 TKR 基因拷贝数（GCN）增益作为接受曲妥珠单抗治疗的 HER2 阳性 AGC 的预测生物标志物的作用。
选择 42 例接受曲妥珠单抗为基础的一线化疗治疗的 HER2 阳性 GC 患者的肿瘤组织样本。对 DNA 样本进行测序。还进行了 PTEN 和 MET 免疫组化检测。
97.1%的 HER2 阳性 AGC 患者存在同时性遗传改变。我们发现 52.4%的患者存在 PI3K/Akt/mTOR 通路激活，38.1%的患者存在 TKR GCN 增益。TKR GCN 增益与总生存期（OS）或无进展生存期（PFS）无关。多变量 Cox 模型显示，PI3K/Akt/mTOR 激活对基于曲妥珠单抗的化疗治疗的有效性产生负面影响，表现为 OS 和 PFS。
我们的研究结果首次提供了 HER2 阳性 AGC 同时性遗传改变的详细分子谱。PI3K 通路激活可作为该患者群体预后不良的预测标志物。此外，该亚组中其他 TKR 基因的拷贝数增益也可能影响曲妥珠单抗带来的生存获益。
本文首次报道了 HER2 阳性晚期胃癌（AGC）患者基因组改变的详细分子谱。PI3K/Akt/mTOR 信号通路激活似乎对接受曲妥珠单抗为基础的化疗治疗的 AGC 的总生存期和无进展生存期有不同的负面影响。联合使用不同的靶向药物可能是改善 HER2 阳性 AGC 预后的一种成功的治疗策略。
