解密癌症的抗药性机制:MATCH-R 研究的最终报告,重点关注分子驱动因素和 PDX 开发。

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cancer Pub Date : 2024-10-04 DOI:10.1186/s12943-024-02134-4
Damien Vasseur, Ludovic Bigot, Kristi Beshiri, Juan Flórez-Arango, Francesco Facchinetti, Antoine Hollebecque, Lambros Tselikas, Mihaela Aldea, Felix Blanc-Durand, Anas Gazzah, David Planchard, Ludovic Lacroix, Noémie Pata-Merci, Catline Nobre, Alice Da Silva, Claudio Nicotra, Maud Ngo-Camus, Floriane Braye, Sergey I Nikolaev, Stefan Michiels, Gérôme Jules-Clement, Ken André Olaussen, Fabrice André, Jean-Yves Scoazec, Fabrice Barlesi, Santiago Ponce, Jean-Charles Soria, Benjamin Besse, Yohann Loriot, Luc Friboulet
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引用次数: 0

摘要

背景:了解肿瘤的抗药性机制对于推进癌症治疗至关重要。由古斯塔夫-鲁西(Gustave Roussy)领导的前瞻性MATCH-R试验(NCT02517892)旨在通过对新鲜肿瘤活检组织的分子分析来确定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,重点关注靶向疗法:研究对象包括接受影像引导下肿瘤活检的耐药转移性患者(pts)。在对冷冻组织活检中的肿瘤内容(TC)进行评估后,在抗癌治疗前和/或治疗后进行了靶向 NGS(10 30%)。通过将肿瘤片段植入 NOD scid gamma 小鼠体内建立了患者衍生异种移植(PDX),并扩增至五次传代:共收集了 857 名患者的 1120 份活检样本,最常见的肿瘤类型为肺癌(38.8%)、消化道癌(16.3%)和前列腺癌(14.1%)。30.9%的患者(n = 265/857)发现了分子靶向驱动基因,其中最常见的改变基因是表皮生长因子受体(EGFR)(41.5%)、表皮生长因子受体2/3(FGFR2/3)(15.5%)、ALK(11.7%)、BRAF(6.8%)和KRAS(5.7%)。此外,66.0%(n = 175/265)的患者在接受靶向治疗时进行了活检。在耐药病例中,41.1%(n = 72/175)未发现分子机制,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名旁路耐药患者进行的分子图谱分析发现了51个变异基因,其中KRAS(13.7%)、PIK3CA(11.8%)、PTEN(11.8%)、NF2(7.8%)、AKT1(5.9%)和NF1(5.9%)是改变最多的基因。为45%的患者量身定制了治疗方案,并确定了耐药机制,从而将临床获益的中位时间延长了11个月。共将 341 例活检组织植入小鼠体内,成功建立了 136 个 PDX 模型,成功率为 39.9%。PDX模型可用于表皮生长因子受体(EGFR)(n = 31)、表皮生长因子受体2/3(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密切再现了原始肿瘤的生物学特性,是验证克服治疗策略的宝贵模型:MATCH-R研究强调了在图像引导下进行肿瘤活检和建立PDX以确定耐药机制和指导个性化疗法的可行性,从而改善预处理转移性患者的预后。
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Deciphering resistance mechanisms in cancer: final report of MATCH-R study with a focus on molecular drivers and PDX development.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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