Abstract LB-257: Liquid biopsy versus tissue biopsy to assess acquired resistance and tumor heterogeneity in gastrointestinal cancers
Authors: Parikh Aparna R. , Leshchiner Ignaty , Elagina Liudmila , Goyal Lipika , Levovitz Chaya , Siravegna Giulia , Livitz Dimitri , Rhrissorrakrai Kahn , Martin Liz , Seventer Emily E. Van , Hanna Megan , Slowik Kara , Utro Filippo , Pinto Christopher J. , Wong Alicia , Danysh Brian P. , Cruz Ferran Fece de la , Fetter Isobel J. , Nadres Brandon , Shahzade Heather A. , Allen Jill N. , Blaszkowsky Lawrence S. , Clark Jeffrey W. , Giantonio Bruce , Murphy Janet E. , Nipp Ryan D. , Roeland Eric , Ryan David P. , Weekes Colin D. , Kwak Eunice L. , Faris Jason E. , Aguet Francois , Guha Ipsita , Hazar-Rethinam Mehlika , Dias-Santagata Dora , Ting David T. , Zhu Andrew X. , Hong Theodore S. , Golub Todd R. , Iafrate A J. , Adalsteinsson Viktor , Bardelli Alberto , Parida Laxmi , Juric Dejan , Getz Gad , Corcoran Ryan B. 
Published: August 2019

Abstract
The inevitable emergence of acquired resistance is a major limitation to the clinical benefit of precision medicine strategies. Single-lesion tumor biopsies have long been the mainstay of understanding acquired resistance, but recent data suggest tumor biopsies may under-represent the molecular heterogeneity of acquired resistance. Alternatively, studies have suggested that liquid biopsy approaches analyzing cell-free DNA (cfDNA) may offer significant advantages, but extensive prospective comparisons of matched liquid vs. tumor biopsies obtained at the time of acquired resistance are lacking. Here, we assess systematic liquid biopsy upon acquired resistance to targeted therapy in 44 patients across seven molecularly defined subtypes of gastrointestinal cancers. Liquid biopsy at disease progression identified at least one functionally validated molecular mechanism of resistance in 75% of patients, wherein 52% exhibited &gt;1 resistance alteration (range 2-9, median 3 per patient). In 23 patients in whom a matched post-progression tumor biopsy could be obtained, tumor biopsy was less effective than liquid biopsy in identifying resistance mechanisms, with resistance alterations detected in only 48% of patients, and multiple resistance mechanisms detected in only 9% of cases. In matched cases, liquid biopsy detected at least one resistance alteration not detected in tumor biopsy in 78% of cases. Targeted analysis and whole-exome sequencing of serial cfDNA, multiple post-progression biopsies, and rapid autopsy specimens from select cases revealed key insights into the geographic and complex characteristics of heterogeneity captured by liquid biopsy in the setting of acquired resistance. These data illustrate that acquired resistance is characterized by frequent and profound tumor heterogeneity, and suggests that liquid biopsy may more effectively identify heterogeneous clinically relevant resistance alterations compared to standard tumor biopsy.
Citation Format: Aparna R. Parikh, Ignaty Leshchiner, Liudmila Elagina, Lipika Goyal, Chaya Levovitz, Giulia Siravegna, Dimitri Livitz, Kahn Rhrissorrakrai, Liz 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, Francois Aguet, Ipsita Guha, Mehlika Hazar-Rethinam, Dora Dias-Santagata, David T. Ting, Andrew X. Zhu, Theodore S. Hong, Todd R. Golub, A J. Iafrate, Viktor Adalsteinsson, Alberto Bardelli, Laxmi Parida, Dejan Juric, Gad Getz, Ryan B. Corcoran. Liquid biopsy versus tissue biopsy to assess acquired resistance and tumor heterogeneity in gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-257.