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

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 ShahzadeJill 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, François 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

Research output: Contribution to journalArticlepeer-review


During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1-3. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4-8. 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.

Original languageEnglish
Pages (from-to)1415-1421
Number of pages7
JournalNature Medicine
Issue number9
Publication statusPublished - Sep 2019


  • Autopsy
  • Cell-Free Nucleic Acids/blood
  • Cohort Studies
  • DNA, Neoplasm/blood
  • Drug Resistance, Neoplasm/genetics
  • Female
  • Gastrointestinal Neoplasms/blood
  • Genetic Heterogeneity
  • Humans
  • Liquid Biopsy
  • Male
  • Middle Aged
  • Mutation
  • Proto-Oncogene Proteins B-raf/genetics
  • Whole Exome Sequencing


Dive into the research topics of 'Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers'. Together they form a unique fingerprint.

Cite this