Peripheral Circulating Tumor DNA Detection Predicts Poor Outcomes After Liver Resection for Metastatic Colorectal Cancer
Abstract
Background
Liver resection can be curative for well-selected metastatic colorectal cancer (CRC) patients. Circulating tumor DNA (ctDNA) has shown promise as a biomarker for tumor dynamics and recurrence following CRC resection. This prospective pilot study investigated the use of ctDNA to predict disease outcome in resected CRC patients.
Methods
Between November 2014 and November 2015, 60 patients with CRC were identified and prospectively enrolled. During liver resection, blood was drawn from peripheral (PERIPH), portal (PV), and hepatic (HV) veins, and 3–4 weeks postoperatively from a peripheral vein (POSTOP). Kappa statistics were used to compare mutated (mt) genes in tissue and ctDNA. Disease-specific and disease-free survival (DSS and DFS) were assessed from surgery with Kaplan–Meier and Cox methods.
Results
For the 59 eligible patients, the most commonly mutated genes were TP53 (mtTP53: 47.5%) and APC (mtAPC: 50.8%). Substantial to almost-perfect agreement was seen between ctDNA from PERIPH and PV (mtTP53: 89.8%, κ = 0.73, 95% confidence interval [CI] 0.53–0.93; mtAPC: 94.9%, κ = 0.83, 95% CI 0.64–1.00), as well as HV (mtTP53: 91.5%, κ = 0.78, 95% CI 0.60–0.96; mtAPC: 91.5%, κ = 0.73, 95% CI 0.51–0.95). Tumor mutations and PERIPH ctDNA had fair-to-moderate agreement (mtTP53: 72.9%, κ = 0.44, 95% CI 0.23–0.66; mtAPC: 61.0%, κ = 0.23, 95% CI 0.04–0.42). Detection of PERIPH mtTP53 was associated with worse 2-year DSS (mt+ 79% vs. mt− 90%, P = 0.024).
Conclusions
Peripheral blood reflects the perihepatic ctDNA signature. Disagreement between tissue and ctDNA mutations may reflect the true natural history of tumor genes or an assay limitation. Peripheral ctDNA detection before liver resection is associated with worse DSS.
Notes
Funding
This work was supported in part by the NIH/NCI P30 CA008748 Cancer Center Support Grant.
Disclosure
The authors declare that they have no conflict of interest.
References
- 1.Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177–93.CrossRefGoogle Scholar
- 2.van der Geest LG, Lam-Boer J, Koopman M, Verhoef C, Elferink MA, de Wilt JH. Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis. 2015;32(5):457–65.CrossRefGoogle Scholar
- 3.Riihimaki M, Hemminki A, Sundquist J, Hemminki K. Patterns of metastasis in colon and rectal cancer. Sci Rep. 2016;6:29765.CrossRefGoogle Scholar
- 4.Andres A, Mentha G, Adam R, et al. Surgical management of patients with colorectal cancer and simultaneous liver and lung metastases. Br J Surg. 2015;102(6):691–9.CrossRefGoogle Scholar
- 5.de Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg. 2009;250(3):440–8.Google Scholar
- 6.Litvak A, Cercek A, Segal N, et al. False-positive elevations of carcinoembryonic antigen in patients with a history of resected colorectal cancer. J Natl Compr Canc Netw. 2014;12(6):907–13.CrossRefGoogle Scholar
- 7.Loewenstein MS, Zamcheck N. Carcinoembryonic antigen (CEA) levels in benign gastrointestinal disease states. Cancer. 1978;42(3 Suppl):1412–8.CrossRefGoogle Scholar
- 8.Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66(8):3992–5.CrossRefGoogle Scholar
- 9.Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408–17.CrossRefGoogle Scholar
- 10.Yaeger R, Cercek A, Chou JF, et al. BRAF mutation predicts for poor outcomes after metastasectomy in patients with metastatic colorectal cancer. Cancer. 2014;120(15):2316–24.CrossRefGoogle Scholar
- 11.Gagniere J, Dupre A, Gholami SS, et al. Is hepatectomy justified for BRAF mutant colorectal liver metastases? A multi-institutional analysis of 1497 patients. Ann Surg. 2018. https://doi.org/10.1097/SLA.0000000000002968.
- 12.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.Google Scholar
- 13.Heitzer E, Auer M, Ulz P, Geigl JB, Speicher MR. Circulating tumor cells and DNA as liquid biopsies. Genome Med. 2013;5(8):73.CrossRefGoogle Scholar
- 14.Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985–90.CrossRefGoogle Scholar
- 15.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.CrossRefGoogle Scholar
- 16.Kidess E, Heirich K, Wiggin M, et al. Mutation profiling of tumor DNA from plasma and tumor tissue of colorectal cancer patients with a novel, high-sensitivity multiplexed mutation detection platform. Oncotarget. 2015;6(4):2549–61.CrossRefGoogle Scholar
- 17.Thierry AR, Mouliere F, El Messaoudi S, et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med. 2014;20(4):430–5.CrossRefGoogle Scholar
- 18.Spindler KL, Pallisgaard N, Andersen RF, Brandslund I, Jakobsen A. Circulating free DNA as biomarker and source for mutation detection in metastatic colorectal cancer. PLoS ONE. 2015;10(4):e0108247.CrossRefGoogle Scholar
- 19.Garlan F, Laurent-Puig P, Sefrioui D, et al. Early evaluation of circulating tumor DNA as marker of therapeutic efficacy in metastatic colorectal cancer patients (PLACOL Study). Clin Cancer Res. 2017;23(18):5416–25.CrossRefGoogle Scholar
- 20.Connor AA, McNamara K, Al-Sukhni E, et al. Central, but not peripheral, circulating tumor cells are prognostic in patients undergoing resection of colorectal cancer liver metastases. Ann Surg Oncol. 2016;23(7):2168–75.CrossRefGoogle Scholar
- 21.Jiao LR, Apostolopoulos C, Jacob J, et al. Unique localization of circulating tumor cells in patients with hepatic metastases. J Clin Oncol. 2009;27(36):6160–5.CrossRefGoogle Scholar
- 22.Cheng DT, Mitchell TN, Zehir A, et al. Memorial Sloan Kettering-integrated mutation profiling of actionable cancer targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015;17(3):251–64.CrossRefGoogle Scholar
- 23.Stadler ZK, Battaglin F, Middha S, et al. Reliable detection of mismatch repair deficiency in colorectal cancers using mutational load in next-generation sequencing panels. J Clin Oncol. 2016;34(18):2141–7.CrossRefGoogle Scholar
- 24.Thomas RK, Baker AC, Debiasi RM, et al. High-throughput oncogene mutation profiling in human cancer. Nat Genet. 2007;39(3):347–51.CrossRefGoogle Scholar
- 25.Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.CrossRefGoogle Scholar
- 26.Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1.CrossRefGoogle Scholar
- 27.Beije N, Helmijr JC, Weerts MJA, et al. Somatic mutation detection using various targeted detection assays in paired samples of circulating tumor DNA, primary tumor and metastases from patients undergoing resection of colorectal liver metastases. Mol Oncol. 2016;10(10):1575–84.CrossRefGoogle Scholar
- 28.Gai W, Ji L, Lam WKJ, et al. Liver- and colon-specific DNA methylation markers in plasma for investigation of colorectal cancers with or without liver metastases. Clin Chem. 2018;64(8):1239–49.CrossRefGoogle Scholar
- 29.Chang MT, Asthana S, Gao SP, et al. Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Nat Biotechnol. 2016;34(2):155–63.CrossRefGoogle Scholar
- 30.Chang MT, Bhattarai TS, Schram AM, et al. Accelerating discovery of functional mutant alleles in cancer. Cancer Discov. 2018;8(2):174–83.CrossRefGoogle Scholar
- 31.Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33(1):159–74.CrossRefGoogle Scholar
- 32.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):224ra224.CrossRefGoogle Scholar
- 33.Schmiegel W, Scott RJ, Dooley S, et al. Blood-based detection of RAS mutations to guide anti-EGFR therapy in colorectal cancer patients: concordance of results from circulating tumor DNA and tissue-based RAS testing. Mol Oncol. 2017;11(2):208–19.CrossRefGoogle Scholar
- 34.Sun Q, Liu Y, Liu B, Liu Y. Use of liquid biopsy in monitoring colorectal cancer progression shows strong clinical correlation. Am J Med Sci. 2018;355(3):220–7.CrossRefGoogle Scholar
- 35.Lecomte T, Berger A, Zinzindohoue F, et al. Detection of free-circulating tumor-associated DNA in plasma of colorectal cancer patients and its association with prognosis. Int J Cancer. 2002;100(5):542–8.CrossRefGoogle Scholar
- 36.Vietsch EE, Graham GT, McCutcheon JN, et al. Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer. Cancer Genet. 2017;218-219:39–50.CrossRefGoogle Scholar
- 37.Lin JK, Lin PC, Lin CH, et al. Clinical relevance of alterations in quantity and quality of plasma DNA in colorectal cancer patients: based on the mutation spectra detected in primary tumors. Ann Surg Oncol. 2014;21 Suppl 4:S680–6.CrossRefGoogle Scholar
- 38.Vakiani E, Janakiraman M, Shen R, et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol. 2012;30(24):2956–62.CrossRefGoogle Scholar
- 39.Chakravarty D, Gao J, Phillips SM, et al. OncoKB: a precision oncology knowledge base. JCO Precis Oncol. 2017;2017. https://doi.org/10.1200/PO.17.00011.
- 40.Spindler KG, Boysen AK, Pallisgard N, et al. Cell-free DNA in metastatic colorectal cancer: a systematic review and meta-analysis. Oncologist. 2017;22(9):1049–55.CrossRefGoogle Scholar
- 41.Jorissen RN, Christie M, Mouradov D, et al. Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer. Br J Cancer. 2015;113(6):979–88.CrossRefGoogle Scholar
- 42.Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87(2):159–70.CrossRefGoogle Scholar
- 43.Diehl F, Li M, Dressman D, et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci USA. 2005;102(45):16368–73.CrossRefGoogle Scholar
- 44.Lee SY, Haq F, Kim D, et al. Comparative genomic analysis of primary and synchronous metastatic colorectal cancers. PLoS ONE. 2014;9(3):e90459.CrossRefGoogle Scholar