Genomic Profiling of HER2‐Positive Gastric Cancer: PI3K/Akt/mTOR Pathway as Predictor of Outcomes in HER2‐Positive Advanced Gastric Cancer Treated with Trastuzumab

• Published in: The oncologist (Dayton, Ohio) Vol. 23; no. 9; pp. 1092 - 1102
• Main Authors: Díaz‐Serrano, Asunción, Angulo, Barbara, Dominguez, Carolina, Pazo‐Cid, Roberto, Salud, Antonieta, Jiménez‐Fonseca, Paula, Leon, Ana, Galan, Maria Carmen, Alsina, Maria, Rivera, Fernando, Plaza, J. Carlos, Paz‐Ares, Luis, Lopez‐Rios, Fernando, Gómez‐Martín, Carlos
• Format: Journal Article
• Language: English
• Published: United States AlphaMed Press 01-09-2018
• Subjects: Gastric cancer; Gastrointestinal Cancer; HER2; Next‐generation sequencing; PI3K; Trastuzumab; Tyrosine kinase receptors; Tyrosine kinase receptors; PI3K; HER2; Next‐generation sequencing; Gastric cancer; Trastuzumab
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2017-0379

Background
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.
Patients and Methods
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.
Results
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.
Conclusion
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.
Implications for Practice
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.
摘要
背景。HER2阳性胃癌(GC)占所有胃癌的7%‐34% 。基于曲妥珠单抗的一线疗法已经成为HER2阳性晚期胃癌 (AGC)的标准治疗方法。然而,关于HER2靶向治疗耐药性,尚无经过临床验证的生物标志物。上调PI3K信号通路和酪氨酸激酶受体(TKR)改变已经被视为乳腺癌耐药性的分子机制。我们的研究旨在揭示HER2阳性AGC的分子特征,探索PI3K/Akt/mTOR信号通路激活和TKR基因拷贝数(GCN)增加作为预测性生物标志物在曲妥珠单抗经治HER2阳性AGC患者中的作用。
患者和方法。从接受基于曲妥珠单抗一线化疗方案治疗的患者中选取42份HER2阳性胃癌样本。DNA样本测序。实施PTEN和MET免疫组化。
结果。在97.1%的HER2阳性AGC样本中检测出并发的基因改变。我们在52.4%的患者中发现PI3K/Akt/mTOR信号通路激活,在38.1%的患者中发现TKR GCN增加。TKR GCN增加与总生存期(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化疗的有效性(在OS和PFS方面)产生不利影响。
结论。我们的结果首次提供了HER2阳性AGC并发基因改变的详细分子谱。PI3K信号通路激活可作为此类患者人群预后不良的预测性标志物。此外,此类亚组人群中其它TKR基因拷贝数的增加也可能影响曲妥珠单抗治疗的生存益处。
实践意义:本文首次报告了HER2阳性晚期胃癌(AGC)患者基因改变的详细分子谱。PI3K/Akt/mTOR信号通路激活看起来对接受基于曲妥珠单抗化疗方案治疗的AGC患者的总生存期和无进展生存期产生了不同的不利作用。不同靶向药物的联合应用可能是改善HER2阳性AGC预后的成功治疗策略。
This article describes genomic profiling of patients with HER2‐positive advanced gastric cancer who were treated with first‐line trastuzumab‐based chemotherapy, focusing on whether PI3K/Akt/mTOR pathway status could be relevant in selecting suitable patients for targeted therapies.