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Circulating tumour DNA as a biomarker in resectable and irresectable stage IV colorectal cancer; a systematic review and meta-analysis

Published:January 07, 2021DOI:https://doi.org/10.1016/j.ejca.2020.11.025

      Highlights

      • ctDNA is detectable in 80–90% of patients with mCRC.
      • Levels of ctDNA are strongly predictive of survival in mCRC.
      • Dynamic assessment of ctDNA offers an early marker of treatment efficacy.
      • ctDNA may offer a route to stratified treatments for mCRC.

      Abstract

      Background

      For patients with metastatic colorectal cancer, stratification for treatment (surgery or chemotherapy) is often based on crude clinicopathological characteristics like tumour size and number of lesions. Circulating tumour DNA (ctDNA) acts as a potential biomarker of disease trajectory and biology, allowing better stratification.
      This study aims to systematically review ctDNA in stage IV colorectal cancer to assess its potential role as a prospective biomarker to guide management decisions.

      Methods

      A literature search was performed to identify studies where the measurement of ctDNA in stage IV colorectal cancer was correlated with a clinical outcome (radiological response, secondary resection rate, PFS, DFS or OS).

      Results

      Twenty-eight studies were included, reporting on 2823 patients. Circulating tumour DNA was detectable in between 80% and 90% of patients prior to treatment. Meta-analysis identified a strong correlation between detectable ctDNA after treatment (surgery or chemotherapy) and overall survival (HR 2.2, 95% CI 1.79–2.69, p < 0.00001), as well as progression-free survival (HR 3.15, 95% CI 2.10–4.73, p < 0.00001). ctDNA consistently offered an early marker of long-term prognosis in irresectable disease, with changes after one cycle of systemic therapy demonstrating prognostic value. In resectable disease treated with curative intent, detection of ctDNA offered a lead time over radiological recurrence of 10 months.

      Conclusion

      Circulating tumour DNA is detectable in the majority of resectable and irresectable patients. The presence of ctDNA is clearly associated with shorter overall survival, with changes in ctDNA an early biomarker of adverse disease behaviour. Prospective trials are essential to test its clinical efficacy.

      Keywords

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      References

        • Jones R.P.
        • et al.
        Systematic review and meta-analysis of follow-up after hepatectomy for colorectal liver metastases.
        Br J Surg. 2012; 99: 477-486
        • Nordlinger B.
        • et al.
        Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial.
        Lancet. 2008; 371: 1007-1016
        • Nordlinger B.
        • et al.
        Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial.
        Lancet Oncol. 2013; 14: 1208-1215
        • Sorbye H.
        • et al.
        Predictive factors for the benefit of perioperative FOLFOX for resectable liver metastasis in colorectal cancer patients (EORTC Intergroup Trial 40983).
        Ann Surg. 2012; 255: 534-539
        • Fong Y.
        • Fortner J.
        • Sun R.L.
        • Brennan M.F.
        • Blumgart L.H.
        Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases.
        Ann Surg. 1999; 230 (discussion 318-21): 309-318
        • Ayez N.
        • et al.
        The use of neo-adjuvant chemotherapy in patients with resectable colorectal liver metastases: clinical risk score as possible discriminator.
        Eur J Surg Oncol. 2015; 41: 859-867
        • Primrose J.
        • et al.
        Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial.
        Lancet Oncol. 2014; 15: 601-611
        • Bridgewater J.A.
        • et al.
        Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.
        Lancet Oncol. 2020; https://doi.org/10.1016/S1470-2045(19)30798-3
        • Mitry E.
        • et al.
        Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials.
        J Clin Oncol. 2008; 26: 4906-4911
        • Ychou M.
        • et al.
        A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer.
        Ann Oncol. 2009; 20: 1964-1970
        • Kanemitsu Y.
        • et al.
        A randomized phase II/III trial comparing hepatectomy followed by mFOLFOX6 with hepatectomy alone for liver metastasis from colorectal cancer: JCOG0603 study.
        J Clin Oncol. 2020; 38: 4005
        • Bhangu J.
        • et al.
        Circulating free methylated tumor DNA markers for sensitive assessment of tumor burden and early response monitoring in patients receiving systemic chemotherapy for colorectal cancer liver metastasis.
        Ann Surg. 2018; 268: 894-902
        • Narayan R.R.
        • et al.
        Peripheral circulating tumor DNA detection predicts poor outcomes after liver resection for metastatic colorectal cancer.
        Ann Surg Oncol. 2019; 26: 1824-1832
        • Schøler L.V.
        • et al.
        Clinical implications of monitoring circulating tumor DNA in patients with colorectal cancer.
        Clin Canc Res. 2017; 23: 5437-5445
        • Reinert T.
        • et al.
        Analysis of circulating tumour DNA to monitor disease burden following colorectal cancer surgery.
        Gut. 2016; 65: 625-634
        • Bedin C.
        • et al.
        Diagnostic and prognostic role of cell-free DNA testing for colorectal cancer patients.
        Int J Canc. 2017; 140: 1888-1898
        • Lefebure B.
        • et al.
        Prognostic value of circulating mutant DNA in unresectable metastatic colorectal cancer.
        Ann Surg. 2010; 251: 275-280
        • Barault L.
        • et al.
        Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer.
        Gut. 2018; 67: 1995-2005
        • Herbst A.
        • et al.
        Methylated free-circulating HPP1 DNA is an early response marker in patients with metastatic colorectal cancer.
        Int J Canc. 2017; 140: 2134-2144
        • Philipp A.B.
        • et al.
        Prognostic role of methylated free circulating DNA in colorectal cancer.
        Int J Canc. 2012; 131: 2308-2319
        • Garrigou S.
        • et al.
        A study of hypermethylated circulating tumor DNA as a universal colorectal cancer biomarker.
        Clin Chem. 2016; 62: 1129-1139
        • Garlan F.
        • et al.
        Early evaluation of circulating tumor DNA as marker of therapeutic efficacy in metastatic colorectal cancer patients (PLACOL study).
        Clin Canc Res. 2017; 23: 5416-5425
        • Jia N.
        • et al.
        Serial monitoring of circulating tumor DNA in patients with metastatic colorectal cancer to predict the therapeutic response.
        Front Genet. 2019; 10
        • Kato S.
        • et al.
        Genomic assessment of blood-derived circulating tumor DNA in patients with colorectal cancers: correlation with tissue sequencing, therapeutic response, and survival.
        JCO Precis Oncol. 2019; 3
        • Lyskjær I.
        • et al.
        Correlation between early dynamics in circulating tumour DNA and outcome from FOLFIRI treatment in metastatic colorectal cancer.
        Sci Rep. 2019; 9: 1-10
        • Messaoudi S.E.
        • et al.
        Circulating DNA as a strong multimarker prognostic tool for metastatic colorectal cancer patient management care.
        Clin Canc Res. 2016; 22: 3067-3077
        • Vandeputte C.
        • et al.
        Circulating tumor DNA in early response assessment and monitoring of advanced colorectal cancer treated with a multi-kinase inhibitor.
        Oncotarget. 2018; 9: 17756-17769
        • Peeters M.
        • et al.
        Evaluation of emergent mutations in circulating cell-free DNA and clinical outcomes in patients with metastatic colorectal cancer treated with panitumumab in the ASPECCT study.
        Clin Canc Res. 2019; 25: 1216-1225
        • Kim T.W.
        • et al.
        Impact of emergent circulating tumor DNA RAS mutation in panitumumab-treated chemoresistant metastatic colorectal cancer.
        Clin Canc Res. 2018; 24: 5602-5609
        • Hsu H.-C.
        • et al.
        Targeted sequencing of circulating tumor DNA to monitor genetic variants and therapeutic response in metastatic colorectal cancer.
        Mol Canc Therapeut. 2018; 17: 2238-2247
        • Tie J.
        • et al.
        Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study.
        Gut. 2018; https://doi.org/10.1136/gutjnl-2017-315852
        • Thomsen C.B.
        • et al.
        Monitoring the effect of first line treatment in RAS/RAF mutated metastatic colorectal cancer by serial analysis of tumor specific DNA in plasma.
        J Exp Clin Canc Res. 2018; 37
        • Bidard F.-C.
        • et al.
        Circulating tumor cells and circulating tumor DNA detection in potentially resectable metastatic colorectal cancer: a prospective ancillary study to the unicancer prodige-14 trial.
        Cells. 2019; 8
        • Elez E.
        • et al.
        Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer.
        Mol Oncol. 2019; 13: 1827-1835
        • Khan K.
        • et al.
        Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study.
        Gut. 2018; 67: 1484-1492
        • Yamauchi M.
        • et al.
        Serial profiling of circulating tumor DNA for optimization of anti-VEGF chemotherapy in metastatic colorectal cancer patients.
        Int J Canc. 2018; 142: 1418-1426
        • Dasari A.
        • et al.
        ctDNA applications and integration in colorectal cancer: an NCI Colon and Rectal–Anal Task Forces whitepaper.
        Nat Rev Clin Oncol. 2020; https://doi.org/10.1038/s41571-020-0392-0
        • Tie J.
        • et al.
        Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III Colon cancer.
        JAMA Oncol. 2019; 5: 1710
        • Brudvik K.W.
        • et al.
        RAS mutation clinical risk score to predict survival after resection of colorectal liver metastases.
        Ann Surg. 2017; https://doi.org/10.1097/SLA.0000000000002319
        • Koncina Haan
        • Rauh
        • Letellier
        Prognostic and predictive molecular biomarkers for colorectal cancer: updates and challenges.
        Cancers. 2020; 12: 319
        • Vidal J.
        • et al.
        Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients.
        Ann Oncol. 2017; 28: 1325-1332
        • Jadad A.R.
        • et al.
        Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
        Contr Clin Trials. 1996; 17: 1-12