Phenotyping of Small Bowel Adenocarcinoma
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 187
- 主要终点
- RFS in non-metastatic patients according to 46 genes and abnormal protein expression potentially implicated in carcinogenesis.
研究概览
简要总结
Despite the fact that small intestine makes up 75% of the length of the digestive tract and 90% of its mucosal surface area, small bowel adenocarcinoma (SBA) is rare. SBA is not equally dispatched along the small bowel, a predisposing disease is frequently associated. All these data suggest particular carcinogenesis pathway. SBA carries poor prognosis at all stages and no standard treatment have proved efficacy. So far, no data are available for targeted therapy. From the literature and a previous study of our group some biologic data showed that SBA carcinogenesis is closer to colorectal than gastric carcinogenesis. Nevertheless, some differences arise (ie: low Adenomatous Polyposis Coli mutation rate or frequent DNA mismatch repair deficiency). Even if some trends are founded the prognostic value of molecular alteration and phenotype variation according to small bowel segment, or predisposing disease could not been demonstrate due to small sample size.
BIONADEGE study is a planned biologic ancillary study of the NADEGE cohort that enrolled 366 patients with SBA from 2009 to 2012 in France. The tumour blocks and clinical data of 187 patients have been collected. The main objective is to assess the prognostic value for recurrence free survival (RFS) in non-metastatic patients and overall survival (OS) in metastatic patients of molecular alteration in a set of 46 genes and abnormal protein expression potentially implicated in carcinogenesis. The mains secondary objectives are: 1) to identify potential mutation targetable in small intestine tumours and protein expression, 2) to state the frequency of molecular alteration according to the tumour location, stage or predisposing disease and established clinico-biologic correlation. Tissue microarrays will be performed and several potential prognostic markers will be assessed. Sequencing on tumour DNA will investigate the presence of 740 hot spot somatic mutations in 46 genes involved.The abnormal protein expression or the genetic alterations with an expected frequency superior to 10% will be assessed as potential prognostic factor to RFS and OS.
These evaluations on a large cohort could allow comparison between pathways and will offer better knowledge of tumour molecular phenotype and prognosis will give rational for targeted therapy trials The predisposing diseases for SBA involved several different carcinogenesis pathways. Finally, a molecular classification of SBA will be attempt.
详细描述
The NADEGE cohort involves 75 centres and had enrolled 365 patients. Among them 232 patients had a resection of the primary tumour in 58 centres. This will is be the largest series in the world of SBA for biological study. The patients enrolled in the NADEGE cohort were aware of the biologic study and their authorisation to perform is already collected.
Baseline clinical data of patients enrolled in NADEGE cohort are already available and were presented in a poster discussion session at the European Society for Medical Oncology congress 2013. In all the cohort the primary location was duodenum in 51% of the patients, and a predisposing disease was reported in 18.8% of the patient mainly Crohn disease in 8% and Lynch syndrome in 6% of the patients. The follow-up is ongoing. The analyses of 3-years recurrence-free survival is planned in 2015 and the analysis of 5-years overall survival in 2017.
Today 187 tumour sample are collected and archived in the pathology department of Saint Antoine hospital (Paris). Among these 187 tumours the tumour stage are: stage 0: 4, stage I: 10, stage II: 34, stage III: 63, undetermined stage non-metastatic: 30 (thus 141 non-metastatic tumours) and stage IV: 48, and the primary are: duodenum: 128, jejunum: 31, ileon: 27, undetermined: 3. The chemotherapy performed was FOLFOX in 80% of the cases.
Work Package 1: Database (team 1) The clinical data of NADEGE cohort are collected with an e-crf. The initial descriptive data are already monitored by the GERCOR team. The results have been already presented. BIONADEGE is a planned ancillary study of the NADEGE cohort. The complementary queries for the purpose of BIONADEGE will be addressed by the team 1 to the NADEGE investigator. The follow-up data for progression (metastatic patients), recurrence (non-metastatic patient) and death (all patients) will be obtained every 6 months. Follow-up data will be collected until 2019 in order to obtain 5-years follow-up for all the patients.
Work Package 2: Anatomopathology (team 2) All the tumour samples are already bank in the pathology laboratory of Saint Antoine hospital. Slides from representative tumour area will be selected and send to Paris Descartes university to allow DNA extraction. Tissue microarrays (TMA) for immunohistochemistry validation studies will be performed. Several potential prognostic markers will be assessed as MismatchRepair (MMR) protein, P53, beta-catenin, c-myc protein. Other predictive markers for chemotherapy as hENT1, O6-methylguanine DNA methyltransferase (MGMT) and for targeted therapy as Proto-oncogene tyrosine-protein kinase (ROS1), hepatocyte growth factor receptor c-Met (HGFR), Alk, Human Epidermal Growth Factor Receptor-2 (HER-2) and Programmed cell death 1 (PD-1) will also be assessed. The cases overexpressing HER-2 and HGFR protein by immunohistochemistry will be tested by Fluorescent In Situ Hybridisation (FISH).
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Retrospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •patients included in NADEGE cohort
- •patients with available and exploitable biological samples from NADEGE cohort
排除标准
- 未提供
结局指标
主要结局
RFS in non-metastatic patients according to 46 genes and abnormal protein expression potentially implicated in carcinogenesis.
时间窗: 3 years
次要结局
- Rate of MMR status(3 years)
- OS in metastatic patients according to 46 genes and abnormal protein expression potentially implicated in carcinogenesis(3 years)