Circulating cell-free DNA as predictor of treatment failure after neo-adjuvant chemo-radiotherapy before surgery in patients with locally advanced rectal cancer

Abstract

Background

Treatment of patients with locally advanced rectal cancer (LARC) is based on a combination of chemo-radiotherapy (CRT) and surgery. The rate of distant recurrences remains over 25%. Circulating cell-free DNA (cfDNA) in plasma is a mixture of normal and cancer-specific DNA segments, and is a promising biomarker in patients with colorectal cancer. The aim of our study was to investigate plasma cfDNA as a prognostic marker for outcome in patients with LARC treated with neoadjuvant CRT and surgery.

Patients and Methods

123 patients with LARC were included in two biomarker studies. Patients were treated with neoadjuvant CRT before TME surgery. Fifty-two (42%) of the patients received induction chemotherapy (ICT) with capecitabine + oxaliplatin. Total cfDNA was measured by direct fluorescent assay in EDTA plasma samples obtained at baseline, after ICT, and after CRT. Serial samples 5 years after surgery were collected in 51 patients (41%).

Results

Median follow-up was 55 months. Distant or local recurrence were seen in 30.9% of the patients. Patients with baseline cfDNA levels above the 75th quartile had a higher risk of local or distant recurrence and shorter time to recurrence compared to patients with plasma cfDNA below the 75^th percentile (HR = 2.48, 95%CI:1.3–4.8, P = 0.007). The same applied to disease free survival (DFS) (HR = 2.43, 95%CI:1.27–4.7, P = 0.015). In multivariate analysis, a high cfDNA level was significantly associated with time to progression and DFS. During follow-up, the association remained significant regardless of time point for sample analysis.

Conclusion

We have demonstrated an association between a high baseline plasma level of cfDNA and increased risk of recurrence, shorter time to recurrence, and shorter DFS in patients with LARC. Consequently, cfDNA could potentially improve pre- and posttreatment risk assessment and facilitate individualized therapy for patients with LARC.