Resistant colorectal cancer cells dynamically evolve in response to intermittent drug treatment.

  • Major finding: Resistant colorectal cancer cells dynamically evolve in response to intermittent drug treatment.

  • Concept: Analysis of circulating tumor DNA in blood can be used to monitor clonal evolution in colorectal cancer.

  • Impact: Liquid biopsies can identify patient-specific resistance mechanisms and inform treatment decisions.

Genomic profiling of single biopsies of primary tumors or metastases provides a spatially and temporally limited picture of the mutational landscape and may fail to capture tumor heterogeneity or therapy-induced molecular changes, emphasizing the need for repeated biopsies to monitor disease progression and drug resistance. Siravegna and colleagues evaluated whether analysis of circulating tumor DNA (ctDNA) in blood-based liquid biopsies could be used to track clonal evolution and therapeutic responses in patients with colorectal cancer. Indeed, the profiles of RAS pathway mutations in blood and tissue samples were highly concordant, and analysis of ctDNA highlighted mutations not detected in matched tumor tissue samples in eight patients. Furthermore, next-generation sequencing of ctDNA samples expanded the landscape of somatic genetic alterations associated with primary resistance to EGFR-targeted therapies by identifying ERBB2 amplification and MAP2K1 mutations, together with genomic changes previously implicated in acquired resistance to anti-EGFR antibodies, including KRAS mutations and MET amplification. Comparison of liquid biopsies taken at baseline and at relapse when anti-EGFR therapy was suspended revealed that the percentage of mutant KRAS alleles in ctDNA increased during treatment with EGFR-specific antibodies, but declined after treatment withdrawal. This decrease in mutant KRAS clones was also observed using in vitro preclinical models of acquired resistance and was associated with partial restoration of drug sensitivity. Consistent with this finding, rechallenge with EGFR-specific antibodies after additional lines of therapy was clinically effective in patients with colorectal cancer; longitudinal analysis of ctDNA from three patients receiving intermittent anti-EGFR treatment revealed a decline in mutant KRAS clones in the blood when the initial treatment was suspended, followed by an increase in the percentage of mutant KRAS alleles during rechallenge therapy. These findings indicate that the colorectal cancer genome dynamically adapts to pulsatile drug schedules and provide molecular support for the notion that rechallenge with EGFR-targeted therapies may be effective in colorectal cancer.

Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med 2015;21:795–801.

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