Circulating Tumor DNA as a Biomarker for Outcomes Prediction in Colorectal Cancer Patients

Angelica       Petrillo; Massimiliano       Salati; Dario       Trapani; Michele       Ghidini
Abstract

Circulating tumour DNA (ctDNA) is a novel tool that has been investigated in several types of tumours, including colorectal cancer (CRC). In fact, the techniques based on liquid biopsies are proposed as appealing non-invasive alternatives to tissue biopsy, adding more insights into tumour molecular profile, heterogeneity and for cancer detection and monitoring. Additionally, some analysis showed that in CRC patients, ctDNA seems to act as a biomarker able to predict the outcome (prognostic role) and the response to treatments (predictive role). In particular, in the early stage CRC (stage I-III), it could represent a time marker of adjuvant therapy as well as a marker of minimal residual disease and recurrence risk in addition to the already recognized risk factors. In metastatic CRC, the analysis of molecular tumour profile by ctDNA has shown to have high concordance with the tissue biopsy at diagnosis. Additionally, some studies demonstrated that ctDNA level during the treatment was linked with the early response to treatment and prognosis. Finally, the quantitative analysis of ctDNA and copy number alterations may be useful in order to detect resistance to therapy at the time of progression of disease and to help in finding new therapeutic targets.
Keywords: Molecular profile, RAS, heterogeneity, ctDNA, metastatic, minimal residual disease, stage II, EGFR.
Graphical Abstract

[1] 
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin  2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593] 
[2] 
Howlader N, Noone AM, Krapcho M, et al. SSEER Cancer Statistics Review, 1975–2016 Bethesda, MD: National Cancer Institute https://seer.cancer.gov/csr/1975_2016 [April, 19th, 2020.]2020. Available at:
[3] 
Van Cutsem E, Cervantes A, Nordlinger B, Arnold D. ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol  2014; 25(Suppl. 3): iii1-9.
[http://dx.doi.org/10.1093/annonc/mdu260] [PMID: 25190710] 
[4] 
Zare-Bandamiri M, Fararouei M, Zohourinia S, Daneshi N, Dianatinasab M. Risk factors predicting colorectal cancer recurrence following initial treatment: a 5-year Cohort Study. Asian Pac J Cancer Prev  2017; 18(9): 2465-70.
[PMID: 28952277] 
[5] 
Palmirotta R, Lovero D, Cafforio P, et al. Liquid biopsy of cancer: a multimodal diagnostic tool in clinical oncology. Ther Adv Med Oncol  2018; 10: 1758835918794630.
[http://dx.doi.org/10.1177/1758835918794630] [PMID: 30181785] 
[6] 
Perakis S, Speicher MR. Emerging concepts in liquid biopsies. BMC Med  2017; 15(1): 75.
[http://dx.doi.org/10.1186/s12916-017-0840-6] [PMID: 28381299] 
[7] 
Jahr S, Hentze H, Englisch S, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res  2001; 61(4): 1659-65.
[PMID: 11245480] 
[8] 
Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med  2014; 6(224): 224ra24.
[http://dx.doi.org/10.1126/scitranslmed.3007094] [PMID: 24553385] 
[9] 
Benesova L, Belsanova B, Suchanek S, et al. Mutation-based detection and monitoring of cell-free tumor DNA in peripheral blood of cancer patients. Anal Biochem  2013; 433(2): 227-34.
[http://dx.doi.org/10.1016/j.ab.2012.06.018] [PMID: 22750103] 
[10] 
Wood-Bouwens CM, Ji HP. Single color multiplexed ddpcr copy number measurements and single nucleotide variant genotyping. Methods Mol Biol  2018; 1768: 323-33.
[http://dx.doi.org/10.1007/978-1-4939-7778-9_18] [PMID: 29717451] 
[11] 
Li M, Diehl F, Dressman D, Vogelstein B, Kinzler KW. BEAMing up for detection and quantification of rare sequence variants. Nat Methods  2006; 3(2): 95-7.
[http://dx.doi.org/10.1038/nmeth850] [PMID: 16432518] 
[12] 
Logan J, Edwards K, Saunders N, Eds. Real-Time PCR: Current Technology and Applications. Caister Academic Press 2009.978-1-904455-39-4.
[13] 
Hendrix MM, Foster SL, Cordovado SK. Newborn screening quality assurance program for cftr mutation detection and gene sequencing to identify cystic fibrosis. J Inborn Errors Metab Screen  2016; 4
[http://dx.doi.org/10.1177/2326409816661358] [PMID: 28261631] 
[14] 
Little S. Amplification-refractory mutation system (ARMS) analysis of point mutations. Curr Protoc Hum Genet 2001 May;  Chapter 9:Unit 9.8.
[15] 
Song N, Zhong X, Li Q. Real-time bidirectional pyrophosphorolysis-activated polymerization for quantitative detection of somatic mutations. PLoS One  2014; 9(4): e96420.
[http://dx.doi.org/10.1371/journal.pone.0096420] [PMID: 24769870] 
[16] 
Guha M, Castellanos-Rizaldos E, Liu P, Mamon H, Makrigiorgos GM. Differential strand separation at critical temperature: a minimally disruptive enrichment method for low-abundance unknown DNA mutations. Nucleic Acids Res  2013; 41(3): e50.
[http://dx.doi.org/10.1093/nar/gks1250] [PMID: 23258702] 
[17] 
Ku JL, Jeon YK, Park JG. Methylation-specific PCR. Methods Mol Biol  2011; 791: 23-32.
[http://dx.doi.org/10.1007/978-1-61779-316-5_3] [PMID: 21913069] 
[18] 
Chiu RW, Chan KC, Gao Y, et al. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc Natl Acad Sci USA  2008; 105(51): 20458-63.
[http://dx.doi.org/10.1073/pnas.0810641105] [PMID: 19073917] 
[19] 
Behjati S, Tarpey PS. What is next generation sequencing? Arch Dis Child Educ Pract Ed  2013; 98(6): 236-8.
[http://dx.doi.org/10.1136/archdischild-2013-304340] [PMID: 23986538] 
[20] 
Gale D, Lawson ARJ, Howarth K, et al. Development of a highly sensitive liquid biopsy platform to detect clinically-relevant cancer mutations at low allele fractions in cell-free DNA. PLoS One  2018; 13(3): e0194630.
[http://dx.doi.org/10.1371/journal.pone.0194630] [PMID: 29547634] 
[21] 
Kivioja T, Vähärautio A, Karlsson K, et al. Counting absolute numbers of molecules using unique molecular identifiers. Nat Methods  2011; 9(1): 72-4.
[http://dx.doi.org/10.1038/nmeth.1778] [PMID: 22101854] 
[22] 
Labianca R, Nordlinger B, Beretta GD, et al. ESMO Guidelines Working Group. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol  2013; 24(Suppl. 6): vi64-72.
[http://dx.doi.org/10.1093/annonc/mdt354] [PMID: 24078664] 
[23] 
Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med  2008; 14(9): 985-90.
[http://dx.doi.org/10.1038/nm.1789] [PMID: 18670422] 
[24] 
Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med  2016; 8(346): 346ra92.
[http://dx.doi.org/10.1126/scitranslmed.aaf6219] [PMID: 27384348] 
[25] 
Tie J, Cohen JD, Wang Y, et al. Circulating tumor dna analyses as markers of recurrence risk and benefit of adjuvant therapy for stage iii colon cancer. JAMA Oncol  2019 Dec; 5(12): 1811.
[26] 
Reinert T, Henriksen TV, Christensen E, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol  2019; 5: 1124.
[http://dx.doi.org/10.1001/jamaoncol.2019.0528] [PMID: 31070691] 
[27] 
Wang Y, Li L, Cohen JD, et al. Prognostic potential of circulating tumor DNA measurement in postoperative surveillance of nonmetastatic colorectal cancer. JAMA Oncol  2019; 5: 1118.
[http://dx.doi.org/10.1001/jamaoncol.2019.0512] [PMID: 31070668] 
[28] 
Tie J, Cohen JD, Wang Y, et al. Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study. Gut  2019; 68(4): 663-71.
[http://dx.doi.org/10.1136/gutjnl-2017-315852] [PMID: 29420226] 
[29] 
Khakoo S, Carter PD, Brown G, et al. MRI tumor regression grade and circulating tumor dna as complementary tools to assess response and guide therapy adaptation in rectal cancer. Clin Cancer Res  2020; 26(1): 183-92.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-1996] [PMID: 31852830] 
[30] 
Boysen AK, Schou JV, Spindler KG. Cell-free DNA and preoperative chemoradiotherapy for rectal cancer: a systematic review. Clin Transl Oncol  2019; 21(7): 874-80.
[http://dx.doi.org/10.1007/s12094-018-1997-y] [PMID: 30506526] 
[31] 
Parikh A, Van Seventer E, Boland GM, et al. A plasma-only integrated genomic and epigenomic circulating tumor DNA (ctDNA) assay to inform recurrence risk in colorectal cancer (CRC). J Clinical Oncol  2019; 37(15_suppl): 3602-2.
[32] 
Arnold D, Lueza B, Douillard JY, et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol  2017; 28(8): 1713-29.
[http://dx.doi.org/10.1093/annonc/mdx175] [PMID: 28407110] 
[33] 
Fanelli GN, Dal Pozzo CA, Depetris I, et al. The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer. Cancer Cell Int  2020; 2920(30): eCollection.
[http://dx.doi.org/10.1186/s12935-020-1117-2] 
[34] 
Garcia-Carbonero N, Martinez-Useros J, Li W, et al. KRAS and BRAF mutations as prognostic and predictive biomarkers for standard chemotherapy response in metastatic colorectal cancer: a single institutional study. Cells  2020; 9(1): E219.
[http://dx.doi.org/10.3390/cells9010219] [PMID: 31952366] 
[35] 
Grasselli J, Elez E, Caratù G, et al. Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer. Ann Oncol  2017; 28(6): 1294-301.
[http://dx.doi.org/10.1093/annonc/mdx112] [PMID: 28368441] 
[36] 
Normanno N, Cervantes A, Ciardiello F, De Luca A, Pinto C. The liquid biopsy in the management of colorectal cancer patients: Current applications and future scenarios. Cancer Treat Rev  2018; 70: 1-8.
[http://dx.doi.org/10.1016/j.ctrv.2018.07.007] [PMID: 30053724] 
[37] 
Vidal J, Muinelo L, Dalmases A, et al. Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients. Ann Oncol  2017; 28(6): 1325-32.
[http://dx.doi.org/10.1093/annonc/mdx125] [PMID: 28419195] 
[38] 
Martinelli E, Cardone C, Troiani T, et al. Clinical activity and tolerability of FOLFIRI and cetuximab in elderly patients with metastatic colorectal cancer in the CAPRI-GOIM first-line trial. ESMO Open  2017; 1(6): e000086.
[http://dx.doi.org/10.1136/esmoopen-2016-000086] [PMID: 28848656] 
[39] 
Normanno N, Esposito Abate R, Lambiase M, et al. CAPRI-GOIM Investigators. RAS testing of liquid biopsy correlates with the outcome of metastatic colorectal cancer patients treated with first-line FOLFIRI plus cetuximab in the CAPRI-GOIM trial. Ann Oncol  2018; 29(1): 112-8.
[http://dx.doi.org/10.1093/annonc/mdx417] [PMID: 28950295] 
[40] 
El Messaoudi S, Mouliere F, Du Manoir S, et al. Circulating DNA as a strong multimarker prognostic tool for metastatic colorectal cancer patient management care. Clin Cancer Res  2016; 22(12): 3067-77.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0297] [PMID: 26847055] 
[41] 
Cohen SJ, Punt CJ, Iannotti N, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol  2008; 26(19): 3213-21.
[http://dx.doi.org/10.1200/JCO.2007.15.8923] [PMID: 18591556] 
[42] 
Elez E, Chianese C, Sanz-García E, et al. Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer. Mol Oncol  2019; 13(9): 1827-35.
[http://dx.doi.org/10.1002/1878-0261.12547] [PMID: 31322322] 
[43] 
Groot Koerkamp B, Rahbari NN, Büchler MW, Koch M, Weitz J. Circulating tumor cells and prognosis of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer: a meta-analysis. Ann Surg Oncol  2013; 20(7): 2156-65.
[http://dx.doi.org/10.1245/s10434-013-2907-8] [PMID: 23456317] 
[44] 
Huang X, Gao P, Song Y, et al. Meta-analysis of the prognostic value of circulating tumor cells detected with the cell search system in colorectal cancer. BMC Cancer  2015; 15: 202.
[http://dx.doi.org/10.1186/s12885-015-1218-9] [PMID: 25880692] 
[45] 
Fan G, Zhang K, Yang X, Ding J, Wang Z, Li J. Prognostic value of circulating tumor DNA in patients with colon cancer: Systematic review. PLoS One  2017; 12(2): e0171991.
[http://dx.doi.org/10.1371/journal.pone.0171991] [PMID: 28187169] 
[46] 
Chibaudel B. Extended ras mutational status analysis in circulating tumor dna from patients with advanced colorectal cancer in daily clinical practice. The Franco-British Institute Experience and Recommendations Biomed J Sci Tech Res  2018; 6.
[47] 
Normanno N, Barone C, Maiello E, et al. Analysis of liquid biopsies from metastatic colorectal carcinoma (mCRC) patients (pts) enrolled in the ERMES clinical trial. J Clin Oncol  2018; 36: e15507.
[http://dx.doi.org/10.1200/JCO.2018.36.15_suppl.e15507] 
[48] 
Maurel J, Alonso V, Escudero P, et al. Clinical impact of circulating tumor ras and braf mutation dynamics in patients with metastatic colorectal cancer treated with first-line chemotherapy plus anti–epidermal growth factor receptor therapy. JCO Precis Oncol  2019; 1-16.
[49] 
Vitiello PP, De Falco V, Giunta EF, et al. Clinical practice use of liquid biopsy to identify ras/braf mutations in patients with metastatic colorectal cancer (mCRC): A Single Institution Experience. Cancers (Basel)  2019; 11(10): E1504.
[http://dx.doi.org/10.3390/cancers11101504] [PMID: 31597339] 
[50] 
Vivancos A, Aranda E, Benavides M, et al. Comparison of the clinical sensitivity of the idylla platform and the oncobeam ras crc assay for kras mutation detection in liquid biopsy samples. Sci Rep  2019; 9(1): 8976.
[http://dx.doi.org/10.1038/s41598-019-45616-y] [PMID: 31222012] 
[51] 
Siravegna G, Mussolin B, Buscarino M, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med  2015; 21(7): 795-801.
[http://dx.doi.org/10.1038/nm.3870] [PMID: 26030179] 
[52] 
Tie J, Kinde I, Wang Y, et al. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol  2015; 26(8): 1715-22.
[http://dx.doi.org/10.1093/annonc/mdv177] [PMID: 25851626] 
[53] 
Russo M, Siravegna G, Blaszkowsky LS, et al. Tumor heterogeneity and lesionspecific response to targeted therapy in colorectal cancer. Cancer Discov  2016; 6(2): 147-53.
[http://dx.doi.org/10.1158/2159-8290.CD-15-1283] [PMID: 26644315] 
[54] 
Corcoran RB, Chabner BA. Application of cell-free dna analysis to cancer treatment. N Engl J Med  2018; 379(18): 1754-65.
[http://dx.doi.org/10.1056/NEJMra1706174] [PMID: 30380390] 
[55] 
Garraway LA, Jänne PA. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov  2012; 2(3): 214-26.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0012] [PMID: 22585993] 
[56] 
Bach S, Sluiter NR, Beagan J, et al. Circulating tumor DNA analysis: clinical implications for colorectal cancer patients. A systematic review JNCI Cancer Spectrum  2019; 3(3): pkz042.
[57] 
Yamauchi M, Urabe Y, Ono A, Miki D, Ochi H, Chayama K. Serial profiling of circulating tumor DNA for optimization of anti-VEGF chemotherapy in metastatic colorectal cancer patients. Int J Cancer  2018; 142(7): 1418-26.
[http://dx.doi.org/10.1002/ijc.31154] [PMID: 29134647] 
[58] 
Yamada T, Hirai S, Katayama Y, et al. Retrospective efficacy analysis of immune checkpoint inhibitors in patients with EGFR-mutated non-small cell lung cancer. Cancer Med  2019; 8(4): 1521-9.
[http://dx.doi.org/10.1002/cam4.2037] [PMID: 30790471] 
[59] 
Kim ST, Lee WS, Lanman RB, et al. Prospective blinded study of somatic mutation detection in cell-free DNA utilizing a targeted 54-gene next generation sequencing panel in metastatic solid tumor patients. Oncotarget  2015; 6(37): 40360-9.
[http://dx.doi.org/10.18632/oncotarget.5465] [PMID: 26452027] 
[60] 
Khan KH, Cunningham D, Werner B, et al. Longitudinal liquid biopsy and mathematical modeling of clonal evolution forecast time to treatment failure in the prospect-c phase ii colorectal cancer clinical trial. Cancer Discov  2018; 8(10): 1270-85.
[http://dx.doi.org/10.1158/2159-8290.CD-17-0891] [PMID: 30166348] 
[61] 
Cao H, Liu X, Chen Y, et al. Circulating Tumor DNA Is Capable of Monitoring the Therapeutic Response and Resistance in Advanced Colorectal Cancer Patients Undergoing Combined Target and Chemotherapy. Front Oncol  2020; 10: 466.
[http://dx.doi.org/10.3389/fonc.2020.00466] [PMID: 32318348] 
[62] 
Strickler JH, Loree JM, Ahronian LG, et al. Genomic landscape of cell-free DNA in patients with colorectal cancer. Cancer Discov  2018; 8(2): 164-73.
[http://dx.doi.org/10.1158/2159-8290.CD-17-1009] [PMID: 29196463] 
[63] 
Thierry AR, Pastor B, Jiang ZQ, et al. Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer. Clin Cancer Res  2017; 23(16): 4578-91.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-0232] [PMID: 28400427] 
[64] 
Fernandes MS, Carneiro F, Oliveira C, Seruca R. Colorectal cancer and RASSF family--a special emphasis on RASSF1A. Int J Cancer  2013; 132(2): 251-8.
[http://dx.doi.org/10.1002/ijc.27696] [PMID: 22733432] 
[65] 
van Engeland M, Roemen GM, Brink M, et al. K-ras mutations and RASSF1A promoter methylation in colorectal cancer. Oncogene  2002; 21(23): 3792-5.
[http://dx.doi.org/10.1038/sj.onc.1205466] [PMID: 12032847] 
[66] 
Parseghian CM, Napolitano S, Loree JM, Kopetz S. Mechanisms of innate and acquired resistance to anti-egfr therapy: a review of current knowledge with a focus on rechallenge therapies. Clin Cancer Res  2019; 25(23): 6899-908.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-0823] [PMID: 31263029] 
[67] 
Choi IS, Kato S, Fanta PT, et al. Genomic profiling of blood-derived circulating tumor dna from patients with colorectal cancer: implications for response and resistance to targeted therapeutics. Mol Cancer Ther  2019; 18(10): 1852-62.
[http://dx.doi.org/10.1158/1535-7163.MCT-18-0965] [PMID: 31320401] 
[68] 
Liao HW, Hsu JM, Xia W, et al. PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response. J Clin Invest  2015; 125(12): 4529-43.
[http://dx.doi.org/10.1172/JCI82826] [PMID: 26571401] 
[69] 
Garrido-Laguna I, Hong DS, Janku F, et al. KRASness and PIK3CAness in patients with advanced colorectal cancer: outcome after treatment with early-phase trials with targeted pathway inhibitors. PLoS One  2012; 7(5): e38033.
[http://dx.doi.org/10.1371/journal.pone.0038033] [PMID: 22675430] 
[70] 
Montagut C, Argilés G, Ciardiello F, et al. Efficacy of sym004 in patients with metastatic colorectal cancer with acquired resistance to anti-egfr therapy and molecularly selected by circulating tumor dna analyses: a phase 2 randomized clinical trial. JAMA Oncol  2018; 4(4): e175245.
[http://dx.doi.org/10.1001/jamaoncol.2017.5245] [PMID: 29423521] 
[71] 
Peeters M, Price TJ, Cervantes A, et al. Final results from a randomized phase 3 study of FOLFIRI +/- panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol  2014; 25(1): 107-16.
[http://dx.doi.org/10.1093/annonc/mdt523] [PMID: 24356622] 
[72] 
Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol  2014; 15(6): 569-79.
[http://dx.doi.org/10.1016/S1470-2045(14)70118-4] [PMID: 24739896] 
[73] 
Kim TW, Peeters M, Thomas A, et al. Impact of emergent circulating tumor dna ras mutation in panitumumab-treated chemoresistant metastatic colorectal cancer. Clin Cancer Res  2018; 24(22): 5602-9.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-3377] [PMID: 29898991] 
[74] 
Cremolini C, Rossini D, Dell’Aquila E, et al. Rechallenge for patients with ras and braf wild-type metastatic colorectal cancer with acquired resistance to first-line cetuximab and irinotecan: a phase 2 single-arm clinical trial. JAMA Oncol  2019; 5(3): 343-50.
[http://dx.doi.org/10.1001/jamaoncol.2018.5080] [PMID: 30476968] 
[75] 
Kilgour E, Rothwell DG, Brady G, Dive C. Liquid biopsy-based biomarkers of treatment response and resistance. Cancer Cell  2020; 37(4): 485-95.
[http://dx.doi.org/10.1016/j.ccell.2020.03.012] [PMID: 32289272] 
Cite As
Current Drug Targets

Circulating Tumor DNA as a Biomarker for Outcomes Prediction in Colorectal Cancer Patients

Abstract

Graphical Abstract
