Serial circulating tumour DNA analysis for locally advanced rectal cancer treated with preoperative therapy: prediction of pathological response and postoperative recurrence

Satoshi Murahashi,Masashi Ueno,Yosuke Fukunaga,Tetsuo Noda,Takeshi Sano,Takashi Akiyoshi,Hitoshi Zembutsu

doi:10.1038/s41416-020-0941-4

Satoshi Murahashi, Masashi Ueno + Show 5 more

Open Access

https://doi.org/10.1038/s41416-020-0941-4

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Abstract

BackgroundThe “watch-and-wait” approach is a common treatment option amongst patients with locally advanced rectal cancer (LARC). However, the diagnostic sensitivity of clinical modalities, such as colonoscopy and magnetic resonance imaging to determine pathological response, is not high. We analysed the clinical utility of circulating tumour DNA (ctDNA) of patients with LARC to predict response to preoperative therapy and postoperative recurrence.MethodsA serial ctDNA analysis of 222 plasma samples from 85 patients with LARC was performed using amplicon-based deep sequencing on a cell-free DNA panel covering 14 genes with over 240 hotspots.ResultsctDNA was detected in 57.6% and 22.3% of samples at baseline and after preoperative treatment, respectively, which was significantly different (P = 0.0003). Change in ctDNA was an independent predictor of complete response to preoperative therapy (P = 0.0276). In addition, postoperative ctDNA and carcinoembryonic antigen (CEA) were independent prognostic markers for risk of recurrence after surgery (ctDNA, P = 0.0127 and CEA, P = 0.0105), with a combined analysis having cumulative effects on recurrence-free survival (P = 1.0 × 10–16).ConclusionsSerial ctDNA analysis may offer clinically useful predictive and prognostic markers for response to preoperative therapy and postoperative recurrence in patients with LARC.

Highlights

The “watch-and-wait” approach is a common treatment option amongst patients with locally advanced rectal cancer (LARC)
Studies have shown that chemoradiation therapy (CRT) before surgery can reduce tumour volume and invoke pathological complete response in 15–20% of patients.[4,5,6]
We examined mutant allele fractions of 14 genes that are frequently mutated in colorectal cancer using targeted nextgeneration sequencing (NGS)

Summary

Introduction

The “watch-and-wait” approach is a common treatment option amongst patients with locally advanced rectal cancer (LARC). The diagnostic sensitivity of clinical modalities, such as colonoscopy and magnetic resonance imaging to determine pathological response, is not high. Radiation therapy can improve local recurrence rates in patients with locally advanced rectal cancer (LARC),[1,2,3] with preoperative chemoradiation therapy (CRT) considered the standard of care for these patients. Studies have shown that CRT before surgery can reduce tumour volume and invoke pathological complete response (pCR, ypT0N0M0) in 15–20% of patients.[4,5,6] The achievement of pCR is associated with improved local and distant control, disease-free survival and overall survival; some patients who achieve pCR may not even require surgery.[7]. Despite the range of options available to detect pCR, including digital rectal examinations, endoscopic assessments of mucosal integrity and magnetic resonance imaging (MRI) for changes in primary lesions, the accuracy of these modalities is questionable.[12,13,14]

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