KRAS Muations in Plasma cfDNA as Predictor to Erolinib Response in Advanced Pancreatic Cancer

血浆 cfDNA 中的 KRAS 突变作为晚期胰腺癌埃罗尼布反应的预测因子

• 批准号: 9025173
• 负责人: Donghui Li
• 金额: $ 20.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9025173
• 关键词: Biological Markers; Blood specimen; Cancer Etiology; Cancer Patient; Cancer cell line; Cessation of life; Cetuximab; Clinical Trials; Collection; Colorectal Cancer; Confidence Intervals; DNA Sequence Alteration; Data; Data Set; Enrollment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Future; Genes; KRAS2 gene; Malignant neoplasm of pancreas; Measures; Methodology; Methods; Modeling; Mutate; Mutation; Mutation Detection; National Cancer Institute of Canada; Nature; Non-Small-Cell Lung Carcinoma; Outcome; Pancreas; Patient Selection; Patients; Phase; Phase III Clinical Trials; Pilot Projects; Placebos; Plasma; Plasma Cells; Predictive Value; Prognostic Marker; Progression-Free Survivals; Randomized; Receptor Inhibition; Risk; Sample Size; Sampling; Sensitivity and Specificity; Staging; Surrogate Markers; Technology; Testing; Tissues; Toxic effect; Work; arm; cancer cell; cancer diagnosis; cell free DNA; cost; digital; empowered; gemcitabine; hazard; improved; metastatic colorectal; mutant; mutational status; pancreatic cancer cells; pancreatic neoplasm; patient biomarkers; patient stratification; personalized cancer therapy; phase 3 study; pre-clinical; predictive marker; public health relevance; response; tumor

 DESCRIPTION (provided by applicant): More than 50% of the patients with pancreatic cancer are diagnosed at the metastatic stage, which is doomed with a poor outcome and limited treatment options. The demonstrated a survival advantage of two weeks, which subsequently led to FDA approval of this agent for the treatment of advanced pancreatic cancer. However, due to the small overall survival benefit, high cost, and increased risk of toxicity, the use of erlotinib in unselected pancreatic cancer is limited. Establishing predictive biomarkers that allow better selection of patients who will most likely benefit from the addition of erlotinib to the treatment of pancreatic cancer is in urgent need. KRAS mutation status represents a proven predictive biomarker for the benefit of anti-epidermal growth factor receptor (EGFR) therapy, such as erlotinib, in metastatic colorectal cancer and non-small cell lung cancer. KRAS mutation is seen in approximately 75% of pancreatic cancer patients. However, determination of the mutational status for pancreatic cancers is infrequent due to the difficulties in accessing the pancreas. The recently developed technology in mutation detection in circulating cell-free DNA (cfDNA) provides a quantitative measure of tumor mutational load and may serve as a surrogate predictive biomarker for tumor response. Preliminary data utilizing small pancreatic tumor datasets or cfDNA samples has suggested the predictive nature of KRAS for anti-EGFR therapy within pancreatic cancer patients, but the results are inconclusive due to the small sample size. In a pilot study, we have demonstrated the feasibility of using plasma cfDNA for KRAS mutation detection in patients with pancreatic cancer. Furthermore, we have gained access to the biospecimen collected by the only phase III study on erlotinib in pancreatic cancer with biospecimen collection. In the current project, we will examine the KRAS mutation status in plasma cfDNA of 378 patients enrolled in the PA.3 study using digital PCR method and demonstrate whether KRAS mutation status will represent a predictive biomarker for the anti-EGFR inhibitor erlotinib in metastatic pancreatic cancer. Findings of this study will demonstrate 1) the utility of using plasma cfDNA as a means to determine the KRAS mutational status of a patient with pancreatic cancer and 2) the predictive value of KRAS mutation status in patient response to anti-EGFR therapy in pancreatic cancer. Such information will enable and empower future molecularly directed patient selection for personalized cancer treatment.

 描述（由适用提供）：超过50％的胰腺癌患者在转移阶段被诊断出，这注定要失败，结果不佳和有限的治疗选择。该表现出了两周的生存优势，随后导致了该药物治疗晚期胰腺癌的批准。但是，由于总体生存益处，高成本和毒性风险增加，在未选择的胰腺癌中使用erlotinib是有限的。建立允许的预测生物标志物 迫切需要更好地选择从添加厄洛替尼来治疗胰腺癌的患者。 KRAS突变状态代表了抗皮肤生长因子受体（EGFR）疗法的益处，例如Erlotinib，在转移性癌症和非小细胞肺癌中的益处。在大约75％的胰腺癌患者中可以看到KRAS突变。但是，由于难以进入胰腺，因此很少有胰腺癌突变状态的确定。最近开发的在循环无细胞DNA（CFDNA）中突变检测的技术提供了对肿瘤突变负荷的定量测量，并且可以作为肿瘤反应的替代预测生物标志物。利用小胰腺肿瘤数据集或CFDNA样品的初步数据提出了KRAS在胰腺癌患者内对抗EGFR治疗的预测性质，但由于样本量较小，结果尚无定论。在一项初步研究中，我们证明了在胰腺癌患者中使用血浆CFDNA进行KRAS突变检测的可行性。此外，我们已经获得了唯一的III期埃洛替尼在胰腺癌中收集的生物测量，并收集了生物测量。在当前的项目中，我们将检查使用数字PCR研究参加PA的378名患者的血浆CFDNA中的KRAS突变状态，并证明KRAS突变状态是否代表转移性胰腺癌中抗EGFR抑制剂Erlotinib的预测性生物标志物。这项研究的结果将证明1）使用血浆CFDNA作为确定胰腺癌患者KRAS突变状态的一种手段； 2）KRAS突变状态在患者对胰腺癌抗EGFR治疗的反应中的预测值。这些信息将使未来的分子定向患者选择进行个性化癌症治疗。