美国哈佛医学院Ryan B. Corcoran和Gad Getz课题组合作，研究出用于检测胃肠癌中获得性抗性和肿瘤异质性的液体与组织活检的方法。这一研究成果发表于2019年9月出版的国际学术期刊《自然—医学》上。

在这个前瞻性队列研究中，有42名患有分子定义的胃肠癌和获得性靶向治疗的患者，后进展cfDNA（无细胞DNA）与肿瘤活检的直接比较显示，cfDNA更明确地确定了临床相关的耐药性突变和多种耐药机制。检测出在匹配有肿瘤活检的78％的病例中，未发现的耐药性突变。肿瘤活检和快速解剖标本的连续cfDNA全外显子组测序，阐明了病变存在着显着的地理和进化差异。他们的数据表明，获得性耐药通常以严重的肿瘤异质性为特征，并且个体患者中多个耐药性突变的出现可能代表“常规”而非“例外”。这些发现具有深远的治疗意义，并突出了cfDNA在获得性耐药群体中，组织活检存在潜在优势。

在癌症治疗期间，肿瘤异质性可以驱动多个肿瘤亚克隆的进化，这些亚克隆在个体患者中具有独特的抗性机制。以前的病例报告和小病例系列表明液体活检（特别是cfDNA）可以更好地捕获获得性耐药的异质性。然而，cfDNA与标准单病变肿瘤活组织检查的有效性，尚未在靶向治疗进展后的大规模前瞻性队列中进行直接比较

附：英文原文

Title: Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers

Author: Aparna R. Parikh, Ignaty Leshchiner, Liudmila Elagina, Lipika Goyal, Chaya Levovitz, Giulia Siravegna, Dimitri Livitz, Kahn Rhrissorrakrai, Elizabeth E. Martin, Emily E. Van Seventer, Megan Hanna, Kara Slowik, Filippo Utro, Christopher J. Pinto, Alicia Wong, Brian P. Danysh, Ferran Fece de la Cruz, Isobel J. Fetter, Brandon Nadres, Heather A. Shahzade, Jill N. Allen, Lawrence S. Blaszkowsky, Jeffrey W. Clark, Bruce Giantonio, Janet E. Murphy, Ryan D. Nipp, Eric Roeland, David P. Ryan, Colin D. Weekes, Eunice L. Kwak, Jason E. Faris, Jennifer Y. Wo, Franois Aguet, Ipsita Dey-Guha, Mehlika Hazar-Rethinam, Dora Dias-Santagata, David T. Ting, Andrew X. Zhu, Theodore S. Hong, Todd R. Golub, A. John Iafrate, Viktor A. Adalsteinsson, Alberto Bardelli, Laxmi Parida, Dejan Juric, Gad Getz, Ryan B. Corcoran

Issue&Volume:Volume 25 Issue 9

Abstract: During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient13. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance48. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the rule rather than the exception. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance. Direct prospective comparison of circulating tumor DNA and tissue biopsy sequencing shows the superiority of liquid biopsies for capturing clinically relevant alterations mediating resistance to targeted therapies in cancer patients.

DOI: 10.1038/s41591-019-0561-9

Source:https://www.nature.com/articles/s41591-019-0561-9