Circulating tumor DNA to predict the risk of venous thromboembolism in locally advanced rectal cancer

Venous thromboembolism (VTE) is a common complication in cancer patients and negatively affects prognosis. Colorectal cancer (CRC) has the second highest incidence of VTE among the four most common cancers. In locally advanced rectal cancer (LARC), circulating tumor DNA (ctDNA) has emerged as a biomarker of residual disease and tumor burden, but its association with thrombotic risk remains unclear. We aimed to explore the association between baseline ctDNA levels and VTE occurrence in LARC.

We conducted a prospective study of patients with LARC treated with chemoradiation at IEO. Plasma ctDNA was analyzed by droplet digital PCR for tumor-specific mutations identified in tissue samples, including KRAS, NRAS, BRAF, and PIK3CA. Baseline ctDNA, defined as variant allele frequency (VAF), was correlated with VTE occurrence using univariable and exploratory adjusted analyses.

Sixty-one patients underwent ctDNA assessment and were classified as VAF-low (n = 33) or VAF-high (n = 28) according to the median baseline value. Twenty-three patients (38%) were VAF-negative. After a median follow-up of 58 months, 9 VTE events (15%) were observed. Higher VTE cumulative incidence was observed in VAF-high versus VAF-low patients [HR 2.42, 95% CI 0.61-9.59; p = 0.21] and in ctDNA-positive versus ctDNA-negative patients [HR 5.70, 95% CI 0.70-46.1; p = 0.10]. In the KRAS-mutant subgroup, all VTE events occurred in patients with high baseline VAF (p = 0.001).

Higher baseline ctDNA levels may be associated with increased VTE occurrence in KRAS-mutant LARC. These exploratory findings require validation in larger prospective studies.