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% and biomarkers to detect treatment failure are urgently needed. Circulating cell-free DNA (cfDNA) in plasma is a mixture of normal and cancer specific DNA segments, and a promising biomarker in patients with colorectal cancer. Only few studies have examined the potential utility of cfDNA in LARC but suggest a correlation between cfDNA and the response to neoadjuvant CRT. The aim of our study was to investigate plasma cfDNA in patients with LARC treated with induction chemotherapy (ICT), CRT and surgery.
A total of 124 patients with LARC were prospectivily included at Herlev Hospital, Denmark, from 2010-14. Patients were treated with neoadjuvant CRT and 52 also received 1-3 cycles of ICT with CAPEOX. Total cfDNA levels were measured by direct fluorescent assay in plasma samples obtained at baseline, after ICT and after CRT. Mann-Whitney test, Kaplan-Meier plots and Cox regression analysis were used for statistical analyses. Disease free survival (DFS) was measured from start until distant recurrence or death from any cause.
Median baseline level of cfDNA was 0.96 ng/µL (range 0.46-2.28). Baseline cfDNA did not differ between stage II & III disease (p = 0.15). Median follow-up was 54 months and 27.4% of the patients had distant recurrence during follow-up. When dividing patients in groups of cfDNA quartiles, increasing cfDNA levels were associated with impaired outcome. Patients with baseline cfDNA levels above the 75th quartile, had a higher risk of distant recurrence and shorter median RFS compared to those below, (HR 2.63; CI95%: 1.34-5.15; p = 0.008). The same applied to DFS (HR 1.97, CI95%: 1.09-1.97, p = 0.003). High cfDNA level after CRT was associated with an increased risk of distant recurrence (p = 0.052).
Our results demonstrate a strong correlation between high baseline level of cfDNA and increased risk of distant recurrence in patients with LARC treated with neo-adjuvant CRT. Consequently, cfDNA could hold potential for better pre-treatment risk assessment and as tool for individualized therapy in this setting.
Clinical trial identification
Legal entity responsible for the study
Jakob Vasehus Schou
All authors have declared no conflicts of interest.