Abstract
We tested whether circulating tumor DNA (ctDNA) changes may be used to assess early response and clinical outcomes in patients with metastatic colorectal cancer (mCRC) undergoing first-line systemic anticancer therapy (SACT).
Eight hundred sixty-two plasma samples were collected 4-weekly from baseline (BL) until disease progression in patients with mCRC receiving first-line SACT. ctDNA was tested using tissue-agnostic next-generation sequencing panels. ctDNA normalization was defined as ≥99% clearance after 1 month of therapy (Mo1) in the three variants with the highest allele frequency in BL ctDNA.
Eighty-three paired samples from 75 patients were available for analysis. Twelve pairs (14.4%) showed no variants in either BL or Mo1. In the remaining 71 comparisons (65 patients), 37 (52.1%) showed ctDNA normalization at Mo1. Patients who cleared ctDNA had significantly longer overall (45.6 months) and progression-free survival (13.9 months) compared with nonnormalized patients [overall survival = 22.6 months (log-rank P = 0.01) and progression-free survival = 10.7 months (log-rank P = 0.036), respectively]. In addition, a higher response rate was observed in patients with ctDNA clearance (72.9%) compared with nonnormalized cases (38.2%). Longitudinal sequencing of at least four time points in patients with a progression-free survival of >10 months showed emerging variants in 47.8% of cases; in all these patients, the trajectory of these new “outlier” variants seemed in stark contrast with the clinical–radiological course of disease and the trend in other mutations.
ctDNA clearance represents an early indicator of benefit from SACT in patients with mCRC; serial tracking of multiple variants is warranted to improve specificity and avoid misleading information due to the emergence of mutations of unknown clinical significance.
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