Circulating tumor DNA dynamics and clinical outcome in metastatic colorectal cancer patients undergoing front-line chemotherapy | Ghidini M, et al. | Clin Cancer Res. | Dec. 2024

Background

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.

Methods

Data was collected from electronic medical system at our center between 2019 and 2022. Patients who were diagnosed as mACC and treated with A+T regardless of prior therapy were included. Patients accepted A 12 mg once daily PO from day 1 to 14 and T 200mg IV on day 1 every 3 weeks. Baseline characteristics were recorded. Objective response rate(ORR) and disease control rate(DCR) were evaluated according to RECIST v1.1 and treatment related adverse events(TRAE) according to CTCAE v5.0. Progression free survival(PFS) and overall survival(OS) were analyzed using Kaplan Meier method.

Results

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.

Conclusions

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.