Abstract
There are limited data on circulating, cell-free, tumour (ct)DNA analysis in locally advanced rectal cancer (LARC). Digital droplet (dd)PCR was used to investigate KRAS/BRAF mutations in ctDNA from baseline blood samples of 97 LARC patients who were treated with CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in a randomised phase II trial. KRAS mutation in G12D, G12V or G13D was detected in the ctDNA of 43% and 35% of patients with tumours that were mutant and wild-type for these hotspot mutations, respectively, according to standard PCR-based analyses on tissue. The detection rate in the ctDNA of 10 patients with less common mutations was 50%. In 26 cases ctDNA analysis revealed KRAS mutations that were not previously found in tissue. Twenty-two of these (84.6%) were detected following repeat tissue testing by ddPCR. Overall, the ctDNA detection rate in the KRAS mutant population was 66%. Detection of KRAS mutation in ctDNA failed to predict prognosis or refine patient selection for cetuximab. While this study confirms the feasibility of ctDNA analysis in LARC and the high sensitivity of ddPCR, larger series are needed to better address the role of ctDNA as a prognostic or predictive tool in this setting.
Highlights
There are limited data on circulating, cell-free, tumourDNA analysis in locally advanced rectal cancer (LARC)
A reduction of DNA levels was observed after completion of chemoradiotherapy in all patients but neither baseline nor post-treatment DNA concentrations were predictive of pathological downstaging
In a larger study including 67 patients with cT3-4 and/or N+ tumours, Agostini et al showed that the circulating cell-free DNA integrity index was statistically significantly different between responding and non-responding patients only after completion of fluoropyrimidine-based chemoradiotherapy (p = 0.0009) but not at baseline[22]
Summary
There are limited data on circulating, cell-free, tumour (ct)DNA analysis in locally advanced rectal cancer (LARC). Over the last few years, detection and analysis of circulating, cell-free, tumour DNA (ctDNA) in the blood has emerged as an alternative analytic method with the potential to overcome the above limitations and provide a real-time, exhaustive characterisation of cancer genome[3]. Tissue-based, sampling procedures, blood sampling is quicker, less invasive and by far more convenient for both patients and clinicians/health providers All these advantages make liquid biopsy suitable for the dynamic assessment of tumour response to treatment or www.nature.com/scientificreports/. The clinical usefulness of ctDNA analysis is confirmed by the recent approval by the Food and Drug Administration of the cobas EGFR Mutation Test v2 as a blood-based diagnostic tool for the detection of epidermal growth factor receptor (EGFR) mutations and selection of non-small cell lung cancer patients who are candidates for erlotinib treatment[8]. Algorithms have been proposed for non-invasive diagnosis and discrimination of cancer type based on copy number variation in ctDNA9
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