Phosphoinositide-3-Kinase Catalytic Alpha and KRAS Mutations are Important Predictors of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Advanced Non-small Cell Lung Cancer
Phosphoinositide-3-Kinase Catalytic Alpha and KRAS Mutations are Important Predictors of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Advanced Non-small Cell Lung Cancer
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DOI：
10.1097/jto.0b013e31820a3a6b
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发表时间：
2011-04-01
影响因子：
20.4
通讯作者：
Crino, Lucio
中科院分区：
文献类型：
--
作者：
Ludovini, Vienna;Bianconi, Fortunato;Crino, Lucio
背景：表皮生长因子受体（EGFR）基因的特定突变可预测对酪氨酸激酶抑制剂（TKIs）的良好反应，并与良好预后相关。相反， Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变已被证明可预测对此类治疗反应不佳。然而，最初对EGFR - TKIs有反应的肿瘤几乎不可避免地会在后期产生耐药性。对EGFR抑制剂耐药的其他机制可能涉及其他主要EGFR效应通路的激活突变，即磷酸肌醇 - 3 - 激酶/第10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）/α丝氨酸/苏氨酸蛋白激酶（AKT）通路。本研究的目的是探讨磷酸肌醇 - 3 - 激酶催化亚基α（PIK3CA）、EGFR和KRAS基因突变在预测接受EGFR - TKIs治疗的非小细胞肺癌（NSCLC）患者的反应和生存方面的作用。
患者和方法：共纳入166例接受EGFR - TKI治疗且有可用存档组织标本的晚期NSCLC患者。使用基于聚合酶链反应的测序方法分析PIK3CA、EGFR和KRAS突变。
结果：在25.3%的患者中检测到EGFR突变，在4.1%的患者中检测到PIK3CA突变，在6.7%的患者中检测到KRAS突变。PIK3CA突变与较短的中位无进展时间（TTP）相关（p = 0.01），且与较差的总生存期（OS）相关（p < 0.001）。EGFR突变（p < 0.0001）与对TKIs治疗的良好反应以及较长的TTP相关（p < 0.0001）。KRAS突变与疾病进展相关（p = 0.05），且与较短的中位TTP相关（p = 0.003），但与OS无关。包括组织学和体能状态的Cox多变量分析表明，PIK3CA突变是预测较差OS（p = 0.0001）和较短TTP（p = 0.03）的独立因素，而KRAS突变可预测较短的TTP（p = 0.01）。
结论：PIK3CA和KRAS突变似乎是非小细胞肺癌患者接受EGFR - TKIs治疗耐药和生存期差的指标。
Background: Specific mutations of the epidermal growth factor receptor (EGFR) gene are predictive for favorable response to tyrosine kinase inhibitors (TKIs) and are associated with a good prognosis. In contrast, Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation has been shown to predict poor response to such therapy. Nevertheless, tumor that initially responds to EGFR-TKIs almost inevitably becomes resistant later. Other mechanisms of resistance to EGFR inhibitors could involve activating mutations of the other main EGFR effector pathway, i.e., the phosphoinositide-3-kinase/phosphate and tensin homologue deleted from chromosome 10 (PTEN)/alpha serine/threonine protein kinase (AKT) pathway. The aim of this study was to investigate the role of phosphoinositide-3-kinase catalytic alpha (PIK3CA), EGFR, and KRAS gene mutations in predicting response and survival in patients with non-small cell lung cancer (NSCLC) treated with EGFR-TKIs.Patients and Methods: A total of 166 patients with advanced NSCLC treated with EGFR-TKI with available archival tissue specimens were included. PIK3CA, EGFR, and KRAS mutations were analyzed using polymerase chain reaction-based sequencing.Results: EGFR mutation was detected in 25.3% of patients, PIK3CA mutation in 4.1%, and KRAS mutation in 6.7%. PIK3CA mutation correlated with shorter median time to progression (TTP) (p = 0.01) and worse overall survival (OS) (p < 0.001). EGFR mutation (p < 0.0001) correlated with favorable response to TKIs treatment and longer TTP (p < 0.0001). KRAS mutation correlated with progressive disease (p = 0.05) and shorter median TTP (p = 0.003) but not with OS. Cox multivariate analysis including histology and performance status showed that PIK3CA mutation was an independent factor to predict worse OS (p = 0.0001) and shorter TTP (p = 0.03), while KRAS mutation to predict shorter TTP (p = 0.01).Conclusion: PIK3CA and KRAS mutations seem to be indicators of resistance and poor survival in patients with NSCLC treated with EGFR-TKIs.