Fig. 4. Tumour dynamics of patients receiving biomarker-selected targeted therapies.

Patients with RAS/RAF-wild-type, HER2-negative colorectal cancer receiving anti-EGFR antibodies demonstrate growth of clones of resistant cells over time, as reflected by increases in the variant allele frequency (VAF) of the resistance mutations present in these clones in circulating tumour DNA (ctDNA) (part a). Of note, the emergence of such aberrations in ctDNA typically predates radiographic or clinical disease progression. Such patients can be managed in several ways, including a ‘holiday’ from the targeted agent during the next line of therapy followed by the subsequent re-introduction of the original targeted agent based on a reduction in the VAF of resistance mutations on ctDNA-based monitoring (part b); by introducing a different biomarker-selected targeted therapy or an agent targeting treatment-emergent mechanisms of resistance, as determined by ctDNA findings (part c); or the introduction of one or more agents with activity against other downstream targets (part d).