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 PI3K/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. FUNDING This work was funding by the centre Georges Francois Leclerc.

中文翻译：

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转移性实体癌全外显子组测序的实施和使用。

背景技术基因组指导的临床试验是在具有遗传突变的不同肿瘤类型之间进行的，但是试验组织仍然很复杂。在这里，我们探讨了转移性癌症患者常规体细胞和体质外显子组分析的可行性和实用性。方法Exoma试验（NCT02840604）是一项多中心，前瞻性临床试验。符合条件的患者至少经过一系统治疗后出现转移性癌症。宪法遗传学测试需要遗传学家咨询。体细胞和种系外显子组分析仅限于317个基因。根据ESMO指南对变体进行分类，并由分子肿瘤委员会提出治疗建议。主要终点是通过接受治疗方案的患者比例评估该方法的可行性。结果在2016年5月至2018年10月之间，共纳入506例患者。接受肿瘤样品所需的中位时间为8天。从样品接收到结果的中位时间为52天。对456例患者进行了体细胞分析（90.1％）。对386例患者（76.3％）成功进行了体细胞和体质分析。总共有342名患者（75％）接受了治疗方案。在35（9％）位患者中发现了对癌症的遗传易感性。仅79例（23.1％）患者接受了NGS匹配疗法治疗，主要是PI3K / AKT / mTOR抑制剂22（27.8％），其次是PARP抑制剂19（24.1％），抗血管生成剂17（21.5％），MEK抑制剂7（8.9％） ）和免疫疗法5（6.3％）。由于疾病进展50（63％），治疗毒性18（23％），患者死亡4（5％），最终停止了匹配治疗。PFS2 / PFS1比为> 在采用NGS匹配疗法的患者中，有23.5％的患者为1.3，在采用标准疗法的患者中为23.7。解释研究表明，外显子组分析在癌症常规治疗中是可行的。该策略可改善对遗传易感性的检测，并增加获得靶疗法的机会。然而，在匹配疗法与标准疗法治疗的患者的PFS比率之间未观察到差异。资助这项工作由乔治·弗朗索瓦·勒克莱尔中心（Georges Francois Leclerc）资助。匹配疗法与标准疗法相比，患者的PFS比率没有差异。资助这项工作由乔治·弗朗索瓦·勒克莱尔中心（Georges Francois Leclerc）资助。匹配疗法与标准疗法相比，患者的PFS比率没有差异。资助这项工作是由乔治·弗朗索瓦·勒克莱尔中心资助的。