Understanding the resistance mechanisms of tumor is crucial for advancing cancer therapies. The prospective MATCH-R trial (NCT02517892), led by Gustave Roussy, aimed to characterize resistance mechanisms to cancer treatments through molecular analysis of fresh tumor biopsies. This report presents the genomic data analysis of the MATCH-R study conducted from 2015 to 2022 and focuses on targeted therapies. The study included resistant metastatic patients (pts) who accepted an image-guided tumor biopsy. After evaluation of tumor content (TC) in frozen tissue biopsies, targeted NGS (10 < TC < 30%) or Whole Exome Sequencing and RNA sequencing (TC > 30%) were performed before and/or after the anticancer therapy. Patient-derived xenografts (PDX) were established by implanting tumor fragments into NOD scid gamma mice and amplified up to five passages. A total of 1,120 biopsies were collected from 857 pts with the most frequent tumor types being lung (38.8%), digestive (16.3%) and prostate (14.1%) cancer. Molecular targetable driver were identified in 30.9% (n = 265/857) of the patients, with EGFR (41.5%), FGFR2/3 (15.5%), ALK (11.7%), BRAF (6.8%), and KRAS (5.7%) being the most common altered genes. Furthermore, 66.0% (n = 175/265) had a biopsy at progression on targeted therapy. Among resistant cases, 41.1% (n = 72/175) had no identified molecular mechanism, 32.0% (n = 56/175) showed on-target resistance, and 25.1% (n = 44/175) exhibited a by-pass resistance mechanism. Molecular profiling of the 44 patients with by-pass resistance identified 51 variants, with KRAS (13.7%), PIK3CA (11.8%), PTEN (11.8%), NF2 (7.8%), AKT1 (5.9%), and NF1 (5.9%) being the most altered genes. Treatment was tailored for 45% of the patients with a resistance mechanism identified leading to an 11 months median extension of clinical benefit. A total of 341 biopsies were implanted in mice, successfully establishing 136 PDX models achieving a 39.9% success rate. PDX models are available for EGFR (n = 31), FGFR2/3 (n = 26), KRAS (n = 18), ALK (n = 16), BRAF (n = 6) and NTRK (n = 2) driven cancers. These models closely recapitulate the biology of the original tumors in term of molecular alterations and pharmacological status, and served as valuable models to validate overcoming treatment strategies. The MATCH-R study highlights the feasibility of on purpose image guided tumor biopsies and PDX establishment to characterize resistance mechanisms and guide personalized therapies to improve outcomes in pre-treated metastatic patients.

中文翻译：

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破译癌症的耐药机制：MATCH-R 研究的最终报告，重点关注分子驱动因素和 PDX 开发


了解肿瘤的耐药机制对于推进癌症治疗至关重要。由 Gustave Roussy 领导的前瞻性 MATCH-R 试验 （NCT02517892） 旨在通过对新鲜肿瘤活检的分子分析来表征对癌症治疗的耐药机制。本报告介绍了 2015 年至 2022 年进行的 MATCH-R 研究的基因组数据分析，重点关注靶向治疗。该研究包括接受图像引导肿瘤活检的耐药转移性患者 （pts）。在评估冷冻组织活检中的肿瘤含量 （TC） 后，在抗癌治疗之前和/或之后进行靶向 NGS （10 < TC < 30%） 或全外显子组测序和 RNA 测序 （TC > 30%）。通过将肿瘤片段植入 NOD scid γ 小鼠中来建立患者来源的异种移植物 （PDX），并扩增多达 5 代。共从 857 个点中收集了 1,120 份活检，最常见的肿瘤类型是肺癌 （38.8%） 、消化道癌 （16.3%） 和前列腺癌 （14.1%）。在 30.9% （n = 265/857） 的患者中确定了分子靶向驱动因素，其中 EGFR （41.5%） 、FGFR2/3 （15.5%） 、ALK （11.7%） 、BRAF （6.8%） 和 KRAS （5.7%） 是最常见的改变基因。此外，66.0% （n = 175/265） 在靶向治疗进展时进行了活检。在耐药病例中，41.1% （n = 72/175） 没有确定的分子机制，32.0% （n = 56/175） 表现出靶向耐药，25.1% （n = 44/175） 表现出旁路耐药机制。对 44 名旁路耐药患者的分子分析确定了 51 个变异，其中 KRAS （13.7%） 、PIK3CA （11.8%）、PTEN （11.8%）、NF2 （7.8%）、AKT1 （5.9%） 和 NF1 （5.9%） 是改变最大的基因。 为 45% 的患者量身定制了治疗，确定了耐药机制，导致临床获益中位延长 11 个月。共在小鼠体内植入 341 次活检，成功建立 136 个 PDX 模型，成功率为 39.9%。PDX 模型可用于 EGFR （n = 31）、FGFR2/3 （n = 26）、KRAS （n = 18）、ALK （n = 16）、BRAF （n = 6） 和 NTRK （n = 2） 驱动的癌症。这些模型在分子改变和药理状态方面紧密概括了原始肿瘤的生物学特性，并作为验证克服治疗策略的有价值的模型。MATCH-R 研究强调了有目的地图像引导肿瘤活检和 PDX 建立的可行性，以表征耐药机制并指导个性化治疗以改善预先治疗的转移性患者的预后。