Prognostic Significance of Post‐Surgery Circulating Tumor DNA in Non‐Metastatic Colorectal Cancer

Prognostic Significance of Post‐Surgery Circulating Tumor DNA in Non‐Metastatic Colorectal Cancer: Individual Patient Pooled Analysis of Three Cohort Studies:

ABSTRACT

Studies in multiple solid tumor types have demonstrated the prognostic significance of ctDNA analysis after curative intent surgery. A combined analysis of data across completed studies could further our understanding of circulating tumor DNA (ctDNA) as a prognostic marker and inform future trial design. We combined individual patient data from three independent cohort studies of non‐metastatic colorectal cancer (CRC). Plasma samples were collected 4‐10 weeks after surgery. Mutations in ctDNA were assayed using massively‐parallel‐sequencing with a technique called SafeSeqS. We analyzed 485 CRC patients (230 stage II colon, 96 stage III colon, 159 locally advanced rectal). ctDNA was detected after surgery in 59 (12%) patients overall (11.0%, 12.5% and 13.8% for samples taken at 4‐6, 6‐8 and 8‐10 weeks; P=0.740). ctDNA detection was associated with poorer 5‐year recurrence‐free (38.6% vs 85.5%; P<0.001) and overall survival (64.6% vs 89.4%; P<0.001). The predictive accuracy of post‐surgery ctDNA for recurrence was higher than that of individual clinico‐pathological risk features. Recurrence risk increased exponentially with increasing ctDNA mutant allele fraction (MAF) (hazard ratio, 1.2, 2.5 and 5.8 for MAF of 0.1, 0.5 and 1%). Post‐surgery ctDNA was detected in 3 of 20 (15%) patients with loco‐regional and 27 of 60 (45%) with distant recurrence (P=0.018). This analysis demonstrates a consistent long‐term impact of ctDNA as a prognostic marker across non‐metastatic CRC, where ctDNA outperforms other clinico‐pathological risk factors and MAF further stratifies recurrence risk. ctDNA is a better predictor of distant versus loco‐regional recurrence.

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