Laboratory of Predictive Oncology, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 232 Boulevard Sainte-Marguerite, 13009, Marseille, France.
Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.
Genome Med. 2021 May 18;13(1):87. doi: 10.1186/s13073-021-00897-9.
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 .
基于相对有限的基因集和常用存档样本的精准医学的益处尚未得到证实。PERMED-01（NCT02342158）是一项前瞻性单中心临床试验，评估了新活检肿瘤样本的广泛分子分析在治疗晚期实体瘤成人患者中的可行性和影响，该分析基于靶向 NGS（t-NGS），其中包含迄今为止最大的基因面板和全基因组阵列比较基因组杂交（aCGH），同时评估了单基因改变和临床相关基因组评分。
有难治性癌症的合格患者有一个可进行活检的肿瘤病灶。提取的肿瘤 DNA 通过 t-NGS 和 aCGH 进行分析。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。主要终点是有可治疗遗传改变（AGA）的患者数量。本文报道的次要终点包括描述接受“匹配治疗”的 AGA 患者及其临床结局，以及比较 t-NGS 和 aCGH 与全外显子组测序（WES）对 AGA 的识别。
2014 年 11 月至 2019 年 9 月，我们共招募了 550 名接受过多线治疗的患者。在 550 名患者中，441 名（80%）获得了可利用的完整分子谱。在 550 名患者中，至少有一名 AGA（根据我们的分子肿瘤委员会实时定义），393 名（71%，双侧 90%CI 68-75%）。仅 94 名（17%，95%CI 14-21）名患者在进展时接受了“AGA 匹配治疗”。导致“匹配治疗”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。在接受匹配治疗的 36%（6%的入组患者）的情况下，与先前治疗的无进展生存期（PFS1）相比，至少提高了 1.3 倍的 PFS2（匹配治疗的无进展生存期）。在进展时接受“匹配治疗”的 AGA 患者中，仅使用“匹配治疗”是与改善 PFS2/PFS1 比值相关的唯一变量。接受“匹配治疗”的患者中有 19%观察到客观缓解，6 个月总生存率（OS）为 62%（95%CI 52-73）。在 112 例转移性乳腺癌亚组中，与 t-NGS/aCGH 相比，WES 在 AGA 识别方面没有提供益处。
对新活检肿瘤样本进行广泛的分子分析可以识别出大多数病例的 AGA，从而使 17%的筛选患者接受“匹配治疗”，其中 36%的患者从中获得临床获益。WES 似乎没有改善这些结果。
ID-RCB 标识符：2014-A00966-41；临床试验.gov 标识符：NCT02342158。
