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Abstract：
The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome array-comparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores.
Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 \"candidate cancer\" genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a \"matched therapy\" and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES).
Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68-75%). Only 94/550 patients (17%, 95%CI 14-21) received an \"AGA-matched therapy\" on progression. The most frequent AGAs leading to \"matched therapy\" included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such \"matched therapy\" improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of \"matched therapy\" was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with \"matched therapy,\" and 6-month overall survival (OS) was 62% (95%CI 52-73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH.
Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a \"matched therapy\" in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results.
ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158 .
Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 \"candidate cancer\" genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a \"matched therapy\" and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES).
Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68-75%). Only 94/550 patients (17%, 95%CI 14-21) received an \"AGA-matched therapy\" on progression. The most frequent AGAs leading to \"matched therapy\" included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such \"matched therapy\" improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of \"matched therapy\" was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with \"matched therapy,\" and 6-month overall survival (OS) was 62% (95%CI 52-73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH.
Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a \"matched therapy\" in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results.
ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158 .
摘要：
基于相对有限的基因集和经常存档的样本的精准医学的益处仍未得到证实。PERMED-01(NCT02342158)是一项前瞻性单中心临床试验，在患有晚期实体癌的成年人中，基于迄今为止最大基因组的靶向NGS(t-NGS)和评估单基因改变和临床相关基因组评分的全基因组阵列-比较基因组杂交(aCGH),广泛分子谱分析应用于新活检肿瘤样本的可行性和影响.
符合条件的难治性癌症患者有一个肿瘤病灶可通过活检。通过t-NGS和aCGH剖析提取的肿瘤DNA。我们评估了802个“候选癌症”基因的改变和全球基因组评分，如同源重组缺陷(HRD)评分和肿瘤突变负担。主要终点是具有可操作遗传改变（AGA）的患者人数。本文报告的次要终点包括对接受“匹配疗法”的AGA患者及其临床结果的描述，以及使用t-NGS和aCGH与全外显子组测序（WES）进行AGA鉴定的比较。
在2014年11月至2019年9月之间，我们招募了550名严重预处理的患者。在441/550名患者（80％）中获得了可利用的完整分子谱。至少一个AGA,由我们的分子肿瘤委员会实时定义，在393/550名患者中发现(71%，双面90CI68-75%）。只有94/550名患者(17%，95CI14-21）在进展时接受了“AGA匹配治疗”。导致“匹配疗法”的最常见AGA包括PIK3CA突变，KRAS突变/扩增，PTEN缺失/突变,ERBB2扩增/突变，和BRCA1/2突变。在36％的病例中，与先前治疗（PFS1）的PFS相比，这种“匹配治疗”的无进展生存期（PFS2）至少提高了1.3倍，占登记患者的6%。在进展中接受AGA治疗的患者中，使用"匹配疗法"是与PFS2/PFS1比值改善相关的唯一变量.在接受“匹配疗法”治疗的19％的患者中观察到客观反应，6个月总生存率（OS）为62%（95CI52-73）。在112例转移性乳腺癌中，与t-NGS/aCGH相比，WES在AGA鉴定方面没有益处。
在大多数情况下，新活检的肿瘤样本的广泛分子谱分析鉴定为AGA，导致17%的筛查患者接受“匹配疗法”，其中36%获得临床益处。WES似乎没有改善这些结果。
ID-RCB标识符：2014-A00966-41；ClinicalTrials.gov标识符：NCT02342158。
符合条件的难治性癌症患者有一个肿瘤病灶可通过活检。通过t-NGS和aCGH剖析提取的肿瘤DNA。我们评估了802个“候选癌症”基因的改变和全球基因组评分，如同源重组缺陷(HRD)评分和肿瘤突变负担。主要终点是具有可操作遗传改变（AGA）的患者人数。本文报告的次要终点包括对接受“匹配疗法”的AGA患者及其临床结果的描述，以及使用t-NGS和aCGH与全外显子组测序（WES）进行AGA鉴定的比较。
在2014年11月至2019年9月之间，我们招募了550名严重预处理的患者。在441/550名患者（80％）中获得了可利用的完整分子谱。至少一个AGA,由我们的分子肿瘤委员会实时定义，在393/550名患者中发现(71%，双面90CI68-75%）。只有94/550名患者(17%，95CI14-21）在进展时接受了“AGA匹配治疗”。导致“匹配疗法”的最常见AGA包括PIK3CA突变，KRAS突变/扩增，PTEN缺失/突变,ERBB2扩增/突变，和BRCA1/2突变。在36％的病例中，与先前治疗（PFS1）的PFS相比，这种“匹配治疗”的无进展生存期（PFS2）至少提高了1.3倍，占登记患者的6%。在进展中接受AGA治疗的患者中，使用"匹配疗法"是与PFS2/PFS1比值改善相关的唯一变量.在接受“匹配疗法”治疗的19％的患者中观察到客观反应，6个月总生存率（OS）为62%（95CI52-73）。在112例转移性乳腺癌中，与t-NGS/aCGH相比，WES在AGA鉴定方面没有益处。
在大多数情况下，新活检的肿瘤样本的广泛分子谱分析鉴定为AGA，导致17%的筛查患者接受“匹配疗法”，其中36%获得临床益处。WES似乎没有改善这些结果。
ID-RCB标识符：2014-A00966-41；ClinicalTrials.gov标识符：NCT02342158。
