Comparison of cfDNA and Tissue Biopsy Shows Heterogeneity in Resistance

Acquired resistance to antitumor targeted therapy is mediated by outgrowth of tumor subclones with resistance-associated genomic alterations. Such alterations within metastatic lesions are currently identified by genomic analysis of single-lesion tumor biopsies, but this analysis might underestimate tumor heterogeneity and not account for development of multiple resistant subclones arising concurrently in an individual patient. Liquid biopsy identifies circulating cell-free DNA (cfDNA) shed from tumor cells and thus would presumably better identify multiple resistance mechanisms than a single tumor tissue biopsy, but the two approaches have not yet been compared in a prospective manner. Parikh, Leshchiner, Elagina, and colleagues directly compared liquid biopsies with tissue biopsies in a prospective cohort of 42 patients with gastrointestinal cancers that progressed following targeted therapy. Genomic analysis of cfDNA identified at least one validated resistance alteration in 76% of patients; among them, 53% exhibited more than one resistance alteration. Overall, 78 different resistance alterations were found. Matched postprogression tumor biopsies, analyzed in 23 patients, identified resistance alterations in 11 of 23 (48%) patients, whereas cfDNA analysis identified at least one resistance alteration in 20 of 23 (87%) patients. Only one of the 23 patients harbored a resistance alteration that was detected in tumor biopsy but not liquid biopsy. In 5 cases in which multiple biopsies or rapid autopsies were available, the presence of multiple resistance alterations across distinct metastatic lesions was confirmed. Although the number of patients analyzed was limited, these results demonstrate that acquired resistance to targeted therapy in gastrointestinal cancer is highly heterogeneous and that cfDNA from liquid biopsy can simultaneously identify multiple resistance alterations originating from different metastatic lesions in the same patient that a single tissue biopsy might not. These findings provide further evidence that incorporating liquid biopsy may be clinically valuable to detect acquired resistance mechanisms in patients whose cancers progress after targeted therapy.

Parikh AR, Leshchiner I, Elagina L, Goyal L, Levovitz C, Siravegna G, et al. Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers. Nat Med 2019;25:1415–21.

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