Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers.
During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance. 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.
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U54 CA224068 / CA / NCI NIH HHS / United States
R01CA208437 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
R01 CA208437 / CA / NCI NIH HHS / United States
K08 CA166510 / CA / NCI NIH HHS / United States
U54CA224068 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
P50CA127003 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
K08CA166510 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
P50 CA127003 / CA / NCI NIH HHS / United States
SU2C-AACR-DT22-17 / EIF | Stand Up To Cancer (SU2C)