Implementation and use of whole exome sequencing for metastatic solid cancer
Implementation and use of whole exome sequencing for metastatic solid cancer
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DOI：
10.1016/j.ebiom.2019.102624
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发表时间：
2020-01-01
期刊：
影响因子：
11.1
通讯作者：
Ghiringhelli, Francois
中科院分区：
文献类型：
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作者：
Reda, Manon;Richard, Corentin;Ghiringhelli, Francois
背景资料：基因组指导的临床试验在共享基因突变的不同肿瘤类型中进行，但试验组织仍然很复杂。在这里，我们解决的可行性和实用性的常规体细胞和宪法exome分析在transmitted cancer patients.Methods：Exoma试验（NCT 02840604）是一个多中心，前瞻性的临床试验。符合条件的患者在至少一线全身治疗后出现转移性癌症进展。体质遗传学测试需要遗传学家咨询。体细胞和生殖系外显子组分析仅限于317个基因。对变异进行分类，分子肿瘤委员会根据ESMO指南提出治疗建议。主要终点是该方法的可行性，通过接受治疗proposal.Findings的患者比例进行评估：2016年5月至2018年10月，纳入了506例患者。肿瘤样本接收所需的中位时间为8天。从样品接收到结果的中位时间为52天。对456例患者（90.1%）进行了体细胞分析。对386例患者（76.3%）成功进行了躯体和体质分析。总共有342名患者（75%）接受了治疗建议。在35名（9%）患者中发现了癌症的遗传易感性。仅79例（23.1%）患者接受了NGS匹配治疗，主要是Pl 3 K/ AKT/mTOR抑制剂22例（27.8%），其次是PARP抑制剂19例（24.1%），抗血管生成药物17例（21.5%），MEK抑制剂7例（8.9%）和免疫治疗5例（6.3%）。最终因疾病进展50例（63%），治疗毒性18例（23%），患者死亡4例（5%）而停止匹配治疗。对于用NGS匹配疗法治疗的23.5%的患者和用标准疗法治疗的23.7%的患者，PFS 2/PFS 1比率> 1.3。这一策略改善了遗传易感性的检测，并提高了靶向治疗的可及性。然而，接受匹配治疗与标准治疗的患者的PFS比值之间未观察到差异。(C)2019作者由爱思唯尔公司出版
Background: Genomically-guided clinical trials are performed across different tumor types sharing genetic mutations, but trial organization remains complex. Here we address the feasibility and utility of routine somatic and constitutional exome analysis in metastatic cancer patients.Methods: Exoma trial (NCT02840604) is a multicenter, prospective clinical trial. Eligible patients presented a metastatic cancer progressing after at least one line of systemic therapy. Constitutional genetics testing required geneticist consultation. Somatic and germline exome analysis was restricted to 317 genes. Variants were classified and molecular tumor board made therapeutic recommendations based on ESMO guidelines. Primary endpoint was the feasibility of the approach evaluated by the proportion of patient that received a therapeutic proposal.Findings: Between May 2016 and October 2018, 506 patients were included. Median time required for tumor sample reception was 8 days. Median time from sample reception to results was 52 days. Somatic analysis was performed for 456 patients (90.1%). Both somatic and constitutional analyses were successfully performed for 386 patients (76.3%). In total, 342 patients (75%) received a therapeutic proposal. Genetic susceptibility to cancer was found in 35 (9%) patients. Only, 79 patients (23.1%) were treated with NGS matched therapy mainly Pl3K/ AKT/mTOR inhibitors 22 (27.8%), followed by PARP inhibitors 19 (24.1%), antiangiogenics 17 (21.5%), MEK inhibitors 7 (8.9%) and immunotherapy 5 (6.3%). Matched treatment was finally stopped because of disease progression 50 (63%), treatment toxicity 18 (23%), patients' death 4 (5%). PFS2/PFS1 ratio was > 1,3 for 23,5% of patients treated with the NGS matched therapy and 23,7% of patients treated with standard therapy.Interpretation: Study shows that exome analysis is feasible in cancer routine care. This strategy improves detection of genetic predispositions and enhances access to target therapies. However, no differences were observed between PFS ratios of patients treated with matched therapy versus standard therapy. (C) 2019 The Authors. Published by Elsevier B.V.