Objective For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC.
Design We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4–10 weeks after surgery. Somatic mutations in individual patient’s tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results.
Results We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77%, 8.3% and 12% of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33% for the postoperative ctDNA-positive patients and 87% for the postoperative ctDNA-negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001).
Conclusion Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy.
- tumour markers
- colorectal cancer
- clinical decision making
- molecular oncology
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BV and PG contributed equally.
JT and JDC contributed equally.
Contributors JT, BV and PG designed the study; BV, JDC, YW, MJS, JP, LD, NS, IK, KK and NP performed MPS and bioinformatic analyses; CT and LL were responsible for developing the algorithm for classifying ctDNA status; MC performed pathology assessment of the tumour tissue; HE, RW, SK, DY, ML, BT, DR, MB, DG, MS, IS, IF, CB, AH, ITJ, CSK and TP contributed to patient recruitment; JT, JDC, YW, CT, LL, KS, LD, BV and PG analysed and interpreted the data; all authors contributed to the writing and review of the manuscript.
Funding Australian National Health and Medical Research Council (GNT1026230), the National Institute of Health (CA62924, GM07309, and P30-CA006973), Virginia and D K Ludwig Fund for Cancer Research, The John Templeton Foundation, The Conrad R Hilton Foundation, The Sol Goldman Sequencing Facility at Johns Hopkins.
Competing interests KK, NP, LD and BV are founders of PapGene and Personal Genome Diagnostics and members of the Scientific Advisory Boards of Morphotek and Sysmex-Inostics. IK is an employee of PapGene. These companies and others have licensed patent applications on genetic technologies from Johns Hopkins, some of which result in royalty payments to KK, NP, LD, BV, and IK. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies.
Ethics approval Melbourne Health.
Provenance and peer review Not commissioned; externally peer reviewed.
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