Colorectal cancer (CRC) remains a serious health problem worldwide. Approximately half of patients will develop distant metastasis after CRC resection, usually with very poor prognosis afterwards. Because patient performance after distant metastasis surgery remains very heterogeneous, ranging from death within 2 years to a long-term cure, there is a clinical need for a precise risk stratification of patients to aid pre- and post-operative decisions. Furthermore, around 20% of identified CRC cases are at IV stage disease, known as a metastatic CRC (mCRC). In this review, we overview possible molecular and clinicopathological biomarkers that may provide prognostic and predictive information for patients with distant metastasis. These may comprise sidedness of the tumor, molecular profile and epigenetic characteristics of the primary tumor and arising metastatic CRC, and early markers reflecting cancer cell resistance in mCRC and biomarkers identified from transcriptome. This review discusses current stage in employment of these biomarkers in clinical practice as well as summarizes current experience in identifying predictive biomarkers in mCRC treatment.

Biomedical Centre Faculty of Medicine in Pilsen Charles University Alej Svobody 1655 32300 Pilsen Czech Republic

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Videnska 1083 14220 Prague Czech Republic

Department of Oncology and Radiotherapy Charles University Faculty of Medicine in Hradec Kralove Šimkova 870 50001 Hradec Králové Czech Republic

Department of Surgery University Hospital in Hradec Kralove Sokolská 581 50005 Hradec Králové Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Albertov 4 12800 Prague Czech Republic

The Fingerland Department of Pathology University Hospital in Hradec Kralove Sokolská 581 50005 Hradec Králové Czech Republic

Zobrazit více v PubMed

Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2019. CA Cancer J. Clin. 2019;69:7–34. doi: 10.3322/caac.21551. PubMed DOI

Siegel R.L., Miller K.D., Goding Sauer A., Fedewa S.A., Butterly L.F., Anderson J.C., Cercek A., Smith R.A., Jemal A. Colorectal cancer statistics, 2020. CA A Cancer J. Clin. 2020;70:145–164. doi: 10.3322/caac.21601. PubMed DOI

Oki E., Ando K., Nakanishi R., Sugiyama M., Nakashima Y., Kubo N., Kudou K., Saeki H., Nozoe T., Emi Y., et al. Recent advances in treatment for colorectal liver metastasis. Ann. Gastroenterol. Surg. 2018;2:167–175. doi: 10.1002/ags3.12071. PubMed DOI PMC

Kim H.J., Choi G. Clinical Implications of Lymph Node Metastasis in Colorectal Cancer: Current Status and Future Perspectives. Ann. Coloproctol. 2019;35:109–117. doi: 10.3393/ac.2019.06.12. PubMed DOI PMC

Fessler E., Dijkgraaf F.E., De Sousa E., Melo F., Medema J.P. Cancer stem cell dynamics in tumor progression and metastasis: Is the microenvironment to blame? Cancer Lett. 2013;341:97–104. doi: 10.1016/j.canlet.2012.10.015. PubMed DOI

Zarour L.R., Anand S., Billingsley K.G., Bisson W.H., Cercek A., Clarke M.F., Coussens L.M., Gast C.E., Geltzeiler C.B., Hansen L., et al. Colorectal Cancer Liver Metastasis: Evolving Paradigms and Future Directions. Cell Mol. Gastroenterol. Hepatol. 2017;3:163–173. doi: 10.1016/j.jcmgh.2017.01.006. PubMed DOI PMC

Bozzetti F., Doci R., Bignami P., Morabito A., Gennari L. Patterns of Failure Following Surgical Resection of Colorectal Cancer Liver Metastases: Rationale for a Multimodal Approach. Ann. Surg. 1987;205:264–270. doi: 10.1097/00000658-198703000-00008. PubMed DOI PMC

Misiakos E.P., Karidis N.P., Kouraklis G. Current treatment for colorectal liver metastases. World J. Gastroenterol. 2011;17:4067–4075. doi: 10.3748/wjg.v17.i36.4067. PubMed DOI PMC

Jones R.P., Jackson R., Dunne D.F.J., Malik H.Z., Fenwick S.W., Poston G.J., Ghaneh P. Systematic review and meta-analysis of follow-up after hepatectomy for colorectal liver metastases. Br. J. Surg. 2012;99:477–486. doi: 10.1002/bjs.8667. PubMed DOI

Yamazaki K., Nagase M., Tamagawa H., Ueda S., Tamura T., Murata K., Eguchi Nakajima T., Baba E., Tsuda M., Moriwaki T., et al. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G) Ann. Oncol. 2016;27:1539–1546. doi: 10.1093/annonc/mdw206. PubMed DOI

Pastorino U., Buyse M., Friedel G., Ginsberg R.J., Girard P., Goldstraw P., Johnston M., McCormack P., Pass H., Putnam J.B. Long-term results of lung metastasectomy: Prognostic analyses based on 5206 cases. J. Thorac. Cardiovasc. Surg. 1997;113:37–49. doi: 10.1016/S0022-5223(97)70397-0. PubMed DOI

Abdalla E.K., Hicks M.E., Vauthey J.N. Portal vein embolization: Rationale, technique and future prospects. Br. J. Surg. 2001;88:165–175. doi: 10.1046/j.1365-2168.2001.01658.x. PubMed DOI

Okita A., Takahashi S., Ouchi K., Inoue M., Watanabe M., Endo M., Honda H., Yamada Y., Ishioka C. Consensus molecular subtypes classification of colorectal cancer as a predictive factor for chemotherapeutic efficacy against metastatic colorectal cancer. Oncotarget. 2018;9:18698–18711. doi: 10.18632/oncotarget.24617. PubMed DOI PMC

Ciombor K.K., Bekaii-Saab T. Emerging treatments in recurrent and metastatic colorectal cancer. J. Natl. Compr. Cancer Netw. 2013;11(Suppl. S4):S18–S27. doi: 10.6004/jnccn.2013.0217. PubMed DOI PMC

Van Cutsem E., Cervantes A., Adam R., Sobrero A., Van Krieken J.H., Aderka D., Aranda Aguilar E., Bardelli A., Benson A., Bodoky G., et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol. 2016;27:1386–1422. doi: 10.1093/annonc/mdw235. PubMed DOI

Turan N., Benekli M., Koca D., Ustaalioglu B.O., Dane F., Ozdemir N., Ulas A., Oztop I., Gumus M., Ozturk M.A., et al. Adjuvant systemic chemotherapy with or without bevacizumab in patients with resected liver metastases from colorectal cancer. Oncology. 2013;84:14–21. doi: 10.1159/000342429. PubMed DOI

Nappi A., Berretta M., Romano C., Tafuto S., Cassata A., Casaretti R., Silvestro L., Divitiis C.D., Alessandrini L., Fiorica F., et al. Metastatic Colorectal Cancer: Role of Target Therapies and Future Perspectives. Curr. Cancer Drug Targets. 2018;18:421–429. doi: 10.2174/1568009617666170209095143. PubMed DOI

Tsilimigras D.I., Ntanasis-Stathopoulos I., Bagante F., Moris D., Cloyd J., Spartalis E., Pawlik T.M. Clinical significance and prognostic relevance of KRAS, BRAF, PI3K and TP53 genetic mutation analysis for resectable and unresectable colorectal liver metastases: A systematic review of the current evidence. Surg. Oncol. 2018;27:280–288. doi: 10.1016/j.suronc.2018.05.012. PubMed DOI

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;230:309–318, discussion 318–321. doi: 10.1097/00000658-199909000-00004. PubMed DOI PMC

Iwatsuki S., Dvorchik I., Madariaga J.R., Marsh J.W., Dodson F., Bonham A.C., Geller D.A., Gayowski T.J., Fung J.J., Starzl T.E. Hepatic resection for metastatic colorectal adenocarcinoma: A proposal of a prognostic scoring system. J. Am. Coll. Surg. 1999;189:291–299. doi: 10.1016/S1072-7515(99)00089-7. PubMed DOI PMC

Rees M., Tekkis P.P., Welsh F.K.S., O’Rourke T., John T.G. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: A multifactorial model of 929 patients. Ann. Surg. 2008;247:125–135. doi: 10.1097/SLA.0b013e31815aa2c2. PubMed DOI

Zakaria S., Donohue J.H., Que F.G., Farnell M.B., Schleck C.D., Ilstrup D.M., Nagorney D.M. Hepatic resection for colorectal metastases: Value for risk scoring systems? Ann. Surg. 2007;246:183–191. doi: 10.1097/SLA.0b013e3180603039. PubMed DOI PMC

Nathan H., de Jong M.C., Pulitano C., Ribero D., Strub J., Mentha G., Gigot J.-F., Schulick R.D., Choti M.A., Aldrighetti L., et al. Conditional Survival after Surgical Resection of Colorectal Liver Metastasis: An International Multi-Institutional Analysis of 949 Patients. J. Am. Coll. Surg. 2010;210:755–764. doi: 10.1016/j.jamcollsurg.2009.12.041. PubMed DOI

Roberts K.J., White A., Cockbain A., Hodson J., Hidalgo E., Toogood G.J., Lodge J.P.A. Performance of prognostic scores in predicting long-term outcome following resection of colorectal liver metastases. Br. J. Surg. 2014;101:856–866. doi: 10.1002/bjs.9471. PubMed DOI

Kattan M.W., Gönen M., Jarnagin W.R., DeMatteo R., D’Angelica M., Weiser M., Blumgart L.H., Fong Y. A nomogram for predicting disease-specific survival after hepatic resection for metastatic colorectal cancer. Ann. Surg. 2008;247:282–287. doi: 10.1097/SLA.0b013e31815ed67b. PubMed DOI

Balachandran V.P., Arora A., Gönen M., Ito H., Turcotte S., Shia J., Viale A., Snoeren N., van Hooff S.R., Rinkes I.H.M.B., et al. A Validated Prognostic Multigene Expression Assay for Overall Survival in Resected Colorectal Cancer Liver Metastases. Clin. Cancer Res. 2016;22:2575–2582. doi: 10.1158/1078-0432.CCR-15-1071. PubMed DOI PMC

Barbon C., Margonis G.A., Andreatos N., Rezaee N., Sasaki K., Buettner S., Damaskos C., Pawlik T.M., He J., Wolfgang C.L., et al. Colorectal Liver Metastases: Does the Future of Precision Medicine Lie in Genetic Testing? J. Gastrointest. Surg. 2018;22:1286–1296. doi: 10.1007/s11605-018-3766-1. PubMed DOI

Tie J., Lipton L., Desai J., Gibbs P., Jorissen R.N., Christie M., Drummond K.J., Thomson B.N.J., Usatoff V., Evans P.M., et al. KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin. Cancer Res. 2011;17:1122–1130. doi: 10.1158/1078-0432.CCR-10-1720. PubMed DOI

Sideris M., Papagrigoriadis S. Molecular biomarkers and classification models in the evaluation of the prognosis of colorectal cancer. Anticancer Res. 2014;34:2061–2068. PubMed

Sagaert X. Prognostic biomarkers in colorectal cancer: Where do we stand? Virchows Arch. 2014;464:379–391. doi: 10.1007/s00428-013-1532-z. PubMed DOI

Adam R. Developing strategies for liver metastases from colorectal cancer. Semin. Oncol. 2007;34:S7–S11. doi: 10.1053/j.seminoncol.2007.01.003. PubMed DOI

Molinari C., Marisi G., Passardi A., Matteucci L., De Maio G., Ulivi P. Heterogeneity in Colorectal Cancer: A Challenge for Personalized Medicine? Int. J. Mol. Sci. 2018;19:3733. doi: 10.3390/ijms19123733. PubMed DOI PMC

Blank A., Roberts D.E., Dawson H., Zlobec I., Lugli A. Tumor Heterogeneity in Primary Colorectal Cancer and Corresponding Metastases. Does the Apple Fall Far From the Tree? Front. Med. (Lausanne) 2018;5:234. doi: 10.3389/fmed.2018.00234. PubMed DOI PMC

Ulintz P.J., Greenson J.K., Wu R., Fearon E.R., Hardiman K.M. Lymph Node Metastases in Colon Cancer Are Polyclonal. Clin. Cancer Res. 2018;24:2214–2224. doi: 10.1158/1078-0432.CCR-17-1425. PubMed DOI PMC

Lee S.Y., Haq F., Kim D., Jun C., Jo H.-J., Ahn S.-M., Lee W.-S. Comparative genomic analysis of primary and synchronous metastatic colorectal cancers. PLoS ONE. 2014;9:e90459. doi: 10.1371/journal.pone.0090459. PubMed DOI PMC

Hunter K.W., Amin R., Deasy S., Ha N.-H., Wakefield L. Genetic insights into the morass of metastatic heterogeneity. Nat. Rev. Cancer. 2018;18:211–223. doi: 10.1038/nrc.2017.126. PubMed DOI PMC

Mogensen M.B., Rossing M., Østrup O., Larsen P.N., Heiberg Engel P.J., Jørgensen L.N., Hogdall E.V., Eriksen J., Ibsen P., Jess P., et al. Genomic alterations accompanying tumour evolution in colorectal cancer: Tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing. BMC Cancer. 2018;18:752. doi: 10.1186/s12885-018-4639-4. PubMed DOI PMC

Carethers J.M., Jung B.H. Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer. Gastroenterology. 2015;149:1177–1190.e3. doi: 10.1053/j.gastro.2015.06.047. PubMed DOI PMC

Zellmer V.R., Zhang S. Evolving concepts of tumor heterogeneity. Cell Biosci. 2014;4:69. doi: 10.1186/2045-3701-4-69. PubMed DOI PMC

Nowell P. The clonal evolution of tumor cell populations. Science. 1976;194:23–28. doi: 10.1126/science.959840. PubMed DOI

Jamal-Hanjani M., Quezada S.A., Larkin J., Swanton C. Translational Implications of Tumor Heterogeneity. Clin. Cancer Res. 2015;21:1258–1266. doi: 10.1158/1078-0432.CCR-14-1429. PubMed DOI PMC

The Cancer Genome Atlas Network Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337. doi: 10.1038/nature11252. PubMed DOI PMC

Kim R., Schell M.J., Teer J.K., Greenawalt D.M., Yang M., Yeatman T.J. Co-Evolution of Somatic Variation in Primary and Metastatic Colorectal Cancer May Expand Biopsy Indications in the Molecular Era. PLoS ONE. 2015;10:e0126670. doi: 10.1371/journal.pone.0126670. PubMed DOI PMC

Brannon A.R., Vakiani E., Sylvester B.E., Scott S.N., McDermott G., Shah R.H., Kania K., Viale A., Oschwald D.M., Vacic V., et al. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions. Genome Biol. 2014;15:454. doi: 10.1186/s13059-014-0454-7. PubMed DOI PMC

Vignot S., Lefebvre C., Frampton G.M., Meurice G., Yelensky R., Palmer G., Capron F., Lazar V., Hannoun L., Miller V.A., et al. Comparative analysis of primary tumour and matched metastases in colorectal cancer patients: Evaluation of concordance between genomic and transcriptional profiles. Eur. J. Cancer. 2015;51:791–799. doi: 10.1016/j.ejca.2015.02.012. PubMed DOI

Sleeman J.P., Cady B., Pantel K. The connectivity of lymphogenous and hematogenous tumor cell dissemination: Biological insights and clinical implications. Clin. Exp. Metastasis. 2012;29:737–746. doi: 10.1007/s10585-012-9489-x. PubMed DOI

Cady B. Lymph Node Metastases: Indicators, but Not Governors of Survival. Arch. Surg. 1984;119:1067. doi: 10.1001/archsurg.1984.01390210063014. PubMed DOI

Naxerova K., Reiter J.G., Brachtel E., Lennerz J.K., van de Wetering M., Rowan A., Cai T., Clevers H., Swanton C., Nowak M.A., et al. Origins of lymphatic and distant metastases in human colorectal cancer. Science. 2017;357:55–60. doi: 10.1126/science.aai8515. PubMed DOI PMC

Koehler A., Bataille F., Schmid C., Ruemmele P., Waldeck A., Blaszyk H., Hartmann A., Hofstaedter F., Dietmaier W. Gene expression profiling of colorectal cancer and metastases divides tumours according to their clinicopathological stage. J. Pathol. 2004;204:65–74. doi: 10.1002/path.1606. PubMed DOI

Lee J.-R., Kwon C.H., Choi Y., Park H.J., Kim H.S., Jo H.-J., Oh N., Park D.Y. Transcriptome analysis of paired primary colorectal carcinoma and liver metastases reveals fusion transcripts and similar gene expression profiles in primary carcinoma and liver metastases. BMC Cancer. 2016;16:539. doi: 10.1186/s12885-016-2596-3. PubMed DOI PMC

Vermaat J.S., Nijman I.J., Koudijs M.J., Gerritse F.L., Scherer S.J., Mokry M., Roessingh W.M., Lansu N., de Bruijn E., van Hillegersberg R., et al. Primary Colorectal Cancers and Their Subsequent Hepatic Metastases Are Genetically Different: Implications for Selection of Patients for Targeted Treatment. Clin. Cancer Res. 2012;18:688–699. doi: 10.1158/1078-0432.CCR-11-1965. PubMed DOI

Cervena K., Vodicka P., Vymetalkova V. Diagnostic and prognostic impact of cell-free DNA in human cancers: Systematic review. Mutat. Res./Rev. Mutat. Res. 2019;781:100–129. doi: 10.1016/j.mrrev.2019.05.002. PubMed DOI

Vymetalkova V., Cervena K., Bartu L., Vodicka P. Circulating Cell-Free DNA and Colorectal Cancer: A Systematic Review. IJMS. 2018;19:3356. doi: 10.3390/ijms19113356. PubMed DOI PMC

Marcuello M., Vymetalkova V., Neves R.P.L., Duran-Sanchon S., Vedeld H.M., Tham E., van Dalum G., Flügen G., Garcia-Barberan V., Fijneman R.J., et al. Circulating biomarkers for early detection and clinical management of colorectal cancer. Mol. Asp. Med. 2019;69:107–122. doi: 10.1016/j.mam.2019.06.002. PubMed DOI

Tejpar S., Stintzing S., Ciardiello F., Tabernero J., Van Cutsem E., Beier F., Esser R., Lenz H.-J., Heinemann V. Prognostic and Predictive Relevance of Primary Tumor Location in Patients with RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials. JAMA Oncol. 2017;3:194. doi: 10.1001/jamaoncol.2016.3797. PubMed DOI PMC

Engstrand J., Nilsson H., Strömberg C., Jonas E., Freedman J. Colorectal cancer liver metastases-a population-based study on incidence, management and survival. BMC Cancer. 2018;18:78. doi: 10.1186/s12885-017-3925-x. PubMed DOI PMC

Shen H., Yang J., Huang Q., Jiang M.-J., Tan Y.-N., Fu J.-F., Zhu L.-Z., Fang X.-F., Yuan Y. Different treatment strategies and molecular features between right-sided and left-sided colon cancers. World J. Gastroenterol. 2015;21:6470–6478. doi: 10.3748/wjg.v21.i21.6470. PubMed DOI PMC

Vauthey J.-N., Zimmitti G., Kopetz S.E., Shindoh J., Chen S.S., Andreou A., Curley S.A., Aloia T.A., Maru D.M. RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases. Ann. Surg. 2013;258:619–626, discussion 626–627.:619–626, discussion 626–627. doi: 10.1097/SLA.0b013e3182a5025a. PubMed DOI PMC

Brudvik K.W., Kopetz S.E., Li L., Conrad C., Aloia T.A., Vauthey J.-N. Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases: KRAS status and survival after resection of colorectal liver metastases. Br. J. Surg. 2015;102:1175–1183. doi: 10.1002/bjs.9870. PubMed DOI

Alison M.R., Islam S., Wright N.A. Stem cells in cancer: Instigators and propagators? J. Cell Sci. 2010;123:2357–2368. doi: 10.1242/jcs.054296. PubMed DOI

Ailles L.E., Weissman I.L. Cancer stem cells in solid tumors. Curr. Opin. Biotechnol. 2007;18:460–466. doi: 10.1016/j.copbio.2007.10.007. PubMed DOI

Kalluri R., Weinberg R.A. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 2009;119:1420–1428. doi: 10.1172/JCI39104. PubMed DOI PMC

Thiery J.P. Epithelial–mesenchymal transitions in development and pathologies. Curr. Opin. Cell Biol. 2003;15:740–746. doi: 10.1016/j.ceb.2003.10.006. PubMed DOI

Mani S.A., Guo W., Liao M.-J., Eaton E.N., Ayyanan A., Zhou A.Y., Brooks M., Reinhard F., Zhang C.C., Shipitsin M., et al. The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells. Cell. 2008;133:704–715. doi: 10.1016/j.cell.2008.03.027. PubMed DOI PMC

Chaffer C.L., Brueckmann I., Scheel C., Kaestli A.J., Wiggins P.A., Rodrigues L.O., Brooks M., Reinhardt F., Su Y., Polyak K., et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc. Natl. Acad. Sci. USA. 2011;108:7950–7955. doi: 10.1073/pnas.1102454108. PubMed DOI PMC

Pang R., Law W.L., Chu A.C.Y., Poon J.T., Lam C.S.C., Chow A.K.M., Ng L., Cheung L.W.H., Lan X.R., Lan H.Y., et al. A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer. Cell Stem Cell. 2010;6:603–615. doi: 10.1016/j.stem.2010.04.001. PubMed DOI

Mulholland D.J., Kobayashi N., Ruscetti M., Zhi A., Tran L.M., Huang J., Gleave M., Wu H. Pten Loss and RAS/MAPK Activation Cooperate to Promote EMT and Metastasis Initiated from Prostate Cancer Stem/Progenitor Cells. Cancer Res. 2012;72:1878–1889. doi: 10.1158/0008-5472.CAN-11-3132. PubMed DOI PMC

Fabregat I., Malfettone A., Soukupova J. New Insights into the Crossroads between EMT and Stemness in the Context of Cancer. JCM. 2016;5:37. doi: 10.3390/jcm5030037. PubMed DOI PMC

Tanabe S., Quader S., Cabral H., Ono R. Interplay of EMT and CSC in Cancer and the Potential Therapeutic Strategies. Front. Pharmacol. 2020;11:904. doi: 10.3389/fphar.2020.00904. PubMed DOI PMC

Mansoori M., Madjd Z., Janani L., Rasti A. Circulating cancer stem cell markers in breast carcinomas: A systematic review protocol. Syst. Rev. 2017;6:262. doi: 10.1186/s13643-017-0660-y. PubMed DOI PMC

Settleman J. Bet on drug resistance. Nature. 2016;529:289–290. doi: 10.1038/nature16863. PubMed DOI

Vodenkova S., Buchler T., Cervena K., Veskrnova V., Vodicka P., Vymetalkova V. 5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future. Pharmacol. Ther. 2020;206:107447. doi: 10.1016/j.pharmthera.2019.107447. PubMed DOI

Ricci-Vitiani L., Lombardi D.G., Pilozzi E., Biffoni M., Todaro M., Peschle C., De Maria R. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445:111–115. doi: 10.1038/nature05384. PubMed DOI

Catalano V., Di Franco S., Iovino F., Dieli F., Stassi G., Todaro M. CD133 as a target for colon cancer. Expert Opin. Ther. Targets. 2012;16:259–267. doi: 10.1517/14728222.2012.667404. PubMed DOI

Dalerba P., Dylla S.J., Park I.-K., Liu R., Wang X., Cho R.W., Hoey T., Gurney A., Huang E.H., Simeone D.M., et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl. Acad. Sci. USA. 2007;104:10158–10163. doi: 10.1073/pnas.0703478104. PubMed DOI PMC

Ying X., Wu J., Meng X., Zuo Y., Xia Q., Chen J., Feng Y., Liu R., Li L., Huang W. AC133 expression associated with poor prognosis in stage II colorectal cancer. Med. Oncol. 2013;30:356. doi: 10.1007/s12032-012-0356-z. PubMed DOI

Muraro M.G., Mele V., Däster S., Han J., Heberer M., Cesare Spagnoli G., Iezzi G. CD133+, CD166+CD44+, and CD24+CD44+ phenotypes fail to reliably identify cell populations with cancer stem cell functional features in established human colorectal cancer cell lines. Stem Cells Transl. Med. 2012;1:592–603. doi: 10.5966/sctm.2012-0003. PubMed DOI PMC

Rocco A., Liguori E., Pirozzi G., Tirino V., Compare D., Franco R., Tatangelo F., Palaia R., D’Armiento F.P., Pollastrone G., et al. CD133 and CD44 cell surface markers do not identify cancer stem cells in primary human gastric tumors. J. Cell. Physiol. 2012;227:2686–2693. doi: 10.1002/jcp.23013. PubMed DOI

Zhao Y., Peng J., Zhang E., Jiang N., Li J., Zhang Q., Zhang X., Niu Y. CD133 expression may be useful as a prognostic indicator in colorectal cancer, a tool for optimizing therapy and supportive evidence for the cancer stem cell hypothesis: A meta-analysis. Oncotarget. 2016;7:10023–10036. doi: 10.18632/oncotarget.7054. PubMed DOI PMC

Huang X., Sheng Y., Guan M. Co-expression of stem cell genes CD133 and CD44 in colorectal cancers with early liver metastasis. Surg. Oncol. 2012;21:103–107. doi: 10.1016/j.suronc.2011.06.001. PubMed DOI

Chen K., Pan F., Jiang H., Chen J., Pei L., Xie F., Liang H. Highly enriched CD133(+)CD44(+) stem-like cells with CD133(+)CD44(high) metastatic subset in HCT116 colon cancer cells. Clin. Exp. Metastasis. 2011;28:751–763. doi: 10.1007/s10585-011-9407-7. PubMed DOI

Dylla S.J., Beviglia L., Park I.-K., Chartier C., Raval J., Ngan L., Pickell K., Aguilar J., Lazetic S., Smith-Berdan S., et al. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS ONE. 2008;3:e2428. doi: 10.1371/annotation/2aa6a20a-e63c-49b6-aeea-aae62435617f. PubMed DOI PMC

Park Y.Y., An C.H., Oh S.T., Chang E.D., Lee J. Expression of CD133 is associated with poor prognosis in stage II colorectal carcinoma. Medicine (Baltimore) 2019;98:e16709. doi: 10.1097/MD.0000000000016709. PubMed DOI PMC

Khelwatty S.A., Essapen S., Bagwan I., Green M., Seddon A.M., Modjtahedi H. Co-expression and prognostic significance of putative CSC markers CD44, CD133, wild-type EGFR and EGFRvIII in metastatic colorectal cancer. Oncotarget. 2019;10:1704–1715. doi: 10.18632/oncotarget.26722. PubMed DOI PMC

Abbasian M., Mousavi E., Arab-Bafrani Z., Sahebkar A. The most reliable surface marker for the identification of colorectal cancer stem-like cells: A systematic review and meta-analysis. J. Cell. Physiol. 2019;234:8192–8202. doi: 10.1002/jcp.27619. PubMed DOI

Akbari M., Shomali N., Faraji A., Shanehbandi D., Asadi M., Mokhtarzadeh A., Shabani A., Baradaran B. CD133: An emerging prognostic factor and therapeutic target in colorectal cancer. Cell Biol. Int. 2020;44:368–380. doi: 10.1002/cbin.11243. PubMed DOI

Jesinghaus M., Wolf T., Pfarr N., Muckenhuber A., Ahadova A., Warth A., Goeppert B., Sers C., Kloor M., Endris V., et al. Distinctive Spatiotemporal Stability of Somatic Mutations in Metastasized Microsatellite-stable Colorectal Cancer. Am. J. Surg. Pathol. 2015;39:1140–1147. doi: 10.1097/PAS.0000000000000423. PubMed DOI

Lang H., Baumgart J., Heinrich S., Tripke V., Passalaqua M., Maderer A., Galle P.R., Roth W., Kloth M., Moehler M. Extended Molecular Profiling Improves Stratification and Prediction of Survival After Resection of Colorectal Liver Metastases. Ann. Surg. 2019;270:799–805. doi: 10.1097/SLA.0000000000003527. PubMed DOI

Testa U., Pelosi E., Castelli G. Colorectal cancer: Genetic abnormalities, tumor progression, tumor heterogeneity, clonal evolution and tumor-initiating cells. Med. Sci. 2018;6:31. doi: 10.3390/medsci6020031. PubMed DOI PMC

Jeantet M., Tougeron D., Tachon G., Cortes U., Archambaut C., Fromont G., Karayan-Tapon L. High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer. Int. J. Mol. Sci. 2016;17:15. doi: 10.3390/ijms17122015. PubMed DOI PMC

Korenkova V., Slyskova J., Novosadova V., Pizzamiglio S., Langerova L., Bjorkman J., Vycital O., Liska V., Levy M., Veskrna K., et al. The focus on sample quality: Influence of colon tissue collection on reliability of qPCR data. Sci. Rep. 2016;6:29023. doi: 10.1038/srep29023. PubMed DOI PMC

Pagès F., Berger A., Camus M., Sanchez-Cabo F., Costes A., Molidor R., Mlecnik B., Kirilovsky A., Nilsson M., Damotte D., et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 2005;353:2654–2666. doi: 10.1056/NEJMoa051424. PubMed DOI

Kawakami H., Zaanan A., Sinicrope F.A. Microsatellite instability testing and its role in the management of colorectal cancer. Curr. Treat Options Oncol. 2015;16:30. doi: 10.1007/s11864-015-0348-2. PubMed DOI PMC

Evrard C., Tachon G., Randrian V., Karayan-Tapon L., Tougeron D. Microsatellite Instability: Diagnosis, Heterogeneity, Discordance, and Clinical Impact in Colorectal Cancer. Cancers. 2019;11:1567. doi: 10.3390/cancers11101567. PubMed DOI PMC

Le D.T., Uram J.N., Wang H., Bartlett B.R., Kemberling H., Eyring A.D., Skora A.D., Luber B.S., Azad N.S., Laheru D., et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 2015;372:2509–2520. doi: 10.1056/NEJMoa1500596. PubMed DOI PMC

Le D.T., Durham J.N., Smith K.N., Wang H., Bartlett B.R., Aulakh L.K., Lu S., Kemberling H., Wilt C., Luber B.S., et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–413. doi: 10.1126/science.aan6733. PubMed DOI PMC

Venderbosch S., Nagtegaal I.D., Maughan T.S., Smith C.G., Cheadle J.P., Fisher D., Kaplan R., Quirke P., Seymour M.T., Richman S.D., et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: A pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin. Cancer Res. 2014;20:5322–5330. doi: 10.1158/1078-0432.CCR-14-0332. PubMed DOI PMC

Tougeron D., Sueur B., Zaanan A., de la Fouchardiére C., Sefrioui D., Lecomte T., Aparicio T., Des Guetz G., Artru P., Hautefeuille V., et al. Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: An AGEO retrospective multicenter study. Int. J. Cancer. 2020;147:285–296. doi: 10.1002/ijc.32879. PubMed DOI

Overman M.J., Lonardi S., Wong K.Y.M., Lenz H.-J., Gelsomino F., Aglietta M., Morse M.A., Van Cutsem E., McDermott R., Hill A., et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J. Clin. Oncol. 2018;36:773–779. doi: 10.1200/JCO.2017.76.9901. PubMed DOI

Xie Y.-H., Chen Y.-X., Fang J.-Y. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct. Target. Ther. 2020;5:22. doi: 10.1038/s41392-020-0116-z. PubMed DOI PMC

Vaughn C.P., ZoBell S.D., Furtado L.V., Baker C.L., Samowitz W.S. Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosom. Cancer. 2011;50:307–312. doi: 10.1002/gcc.20854. PubMed DOI

Lièvre A., Bachet J.-B., Boige V., Cayre A., Le Corre D., Buc E., Ychou M., Bouché O., Landi B., Louvet C., et al. KRAS Mutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab. JCO. 2008;26:374–379. doi: 10.1200/JCO.2007.12.5906. PubMed DOI

Karapetis C.S., Khambata-Ford S., Jonker D.J., O’Callaghan C.J., Tu D., Tebbutt N.C., Simes R.J., Chalchal H., Shapiro J.D., Robitaille S., et al. K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer. N. Engl. J. Med. 2008;359:1757–1765. doi: 10.1056/NEJMoa0804385. PubMed DOI

Amado R.G., Wolf M., Peeters M., Van Cutsem E., Siena S., Freeman D.J., Juan T., Sikorski R., Suggs S., Radinsky R., et al. Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer. JCO. 2008;26:1626–1634. doi: 10.1200/JCO.2007.14.7116. PubMed DOI

Douillard J.-Y., Oliner K.S., Siena S., Tabernero J., Burkes R., Barugel M., Humblet Y., Bodoky G., Cunningham D., Jassem J., et al. Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer. N. Engl. J. Med. 2013;369:1023–1034. doi: 10.1056/NEJMoa1305275. PubMed DOI

Bokemeyer C., Kohne C.-H., Ciardiello F., Lenz H.-J., Heinemann V., Klinkhardt U., Beier F., Duecker K., Tejpar S. Treatment outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/without cetuximab. JCO. 2014;32:3505. doi: 10.1200/jco.2014.32.15_suppl.3505. DOI

Sorich M.J., Wiese M.D., Rowland A., Kichenadasse G., McKinnon R.A., Karapetis C.S. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: A meta-analysis of randomized, controlled trials. Ann. Oncol. 2015;26:13–21. doi: 10.1093/annonc/mdu378. PubMed DOI

Rowland A., Dias M.M., Wiese M.D., Kichenadasse G., McKinnon R.A., Karapetis C.S., Sorich M.J. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br. J. Cancer. 2015;112:1888–1894. doi: 10.1038/bjc.2015.173. PubMed DOI PMC

Kopetz S., Grothey A., Yaeger R., Van Cutsem E., Desai J., Yoshino T., Wasan H., Ciardiello F., Loupakis F., Hong Y.S., et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. N. Engl. J. Med. 2019;381:1632–1643. doi: 10.1056/NEJMoa1908075. PubMed DOI

Latchman J., Guastella A., Tofthagen C. 5-Fluorouracil Toxicity and Dihydropyrimidine Dehydrogenase Enzyme: Implications for Practice. Clin. J. Oncol. Nurs. 2014;18:581–585. doi: 10.1188/14.CJON.581-585. PubMed DOI PMC

Zhang L., Xing X., Meng F., Wang Y., Zhong D. Oral fluoropyrimidine versus intravenous 5-fluorouracil for the treatment of advanced gastric and colorectal cancer: Meta-analysis: Oral fluoropyrimidines for gastrointestinal cancer. J. Gastroenterol. Hepatol. 2018;33:209–225. doi: 10.1111/jgh.13845. PubMed DOI

Cordier P.-Y., Nau A., Ciccolini J., Oliver M., Mercier C., Lacarelle B., Peytel E. 5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: A report of two cases. Cancer Chemother. Pharmacol. 2011;68:823–826. doi: 10.1007/s00280-011-1666-0. PubMed DOI

Braun M.S., Seymour M.T. Balancing the efficacy and toxicity of chemotherapy in colorectal cancer. Ther. Adv. Med. Oncol. 2011;3:43–52. doi: 10.1177/1758834010388342. PubMed DOI PMC

Grothey A. Clinical Management of Oxaliplatin-Associated Neurotoxicity. Clin. Colorectal Cancer. 2005;5:S38–S46. doi: 10.3816/CCC.2005.s.006. PubMed DOI

Boige V., Mendiboure J., Pignon J.-P., Loriot M.-A., Castaing M., Barrois M., Malka D., Trégouët D.-A., Bouché O., Le Corre D., et al. Pharmacogenetic Assessment of Toxicity and Outcome in Patients With Metastatic Colorectal Cancer Treated With LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05. JCO. 2010;28:2556–2564. doi: 10.1200/JCO.2009.25.2106. PubMed DOI

Tournigand C., André T., Bonnetain F., Chibaudel B., Lledo G., Hickish T., Tabernero J., Boni C., Bachet J.-B., Teixeira L., et al. Adjuvant Therapy With Fluorouracil and Oxaliplatin in Stage II and Elderly Patients (between ages 70 and 75 years) With Colon Cancer: Subgroup Analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer Trial. JCO. 2012;30:3353–3360. doi: 10.1200/JCO.2012.42.5645. PubMed DOI

Gustavsson B., Carlsson G., Machover D., Petrelli N., Roth A., Schmoll H.-J., Tveit K.-M., Gibson F. A Review of the Evolution of Systemic Chemotherapy in the Management of Colorectal Cancer. Clin. Colorectal Cancer. 2015;14:1–10. doi: 10.1016/j.clcc.2014.11.002. PubMed DOI

Bardelli A., Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J. Clin. Oncol. 2010;28:1254–1261. doi: 10.1200/JCO.2009.24.6116. PubMed DOI

Hammond W.A., Swaika A., Mody K. Pharmacologic resistance in colorectal cancer: A review. Ther. Adv. Med. Oncol. 2016;8:57–84. doi: 10.1177/1758834015614530. PubMed DOI PMC

Mashouri L., Yousefi H., Aref A.R., Ahadi A.M., Molaei F., Alahari S.K. Exosomes: Composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol. Cancer. 2019;18:75. doi: 10.1186/s12943-019-0991-5. PubMed DOI PMC

Kim H.-S., Do S.-I., Noh B.-J., Jeong Y.I., Park S.J., Kim Y.W. Expression of phosphorylated extracellular signal-regulated kinase at the invasive front of hepatic colorectal metastasis. Oncol. Lett. 2015;9:1261–1265. doi: 10.3892/ol.2015.2874. PubMed DOI PMC

Sottoriva A., Kang H., Ma Z., Graham T.A., Salomon M.P., Zhao J., Marjoram P., Siegmund K., Press M.F., Shibata D., et al. A Big Bang model of human colorectal tumor growth. Nat. Genet. 2015;47:209–216. doi: 10.1038/ng.3214. PubMed DOI PMC

Chakedis J., Squires M.H., Beal E.W., Hughes T., Lewis H., Paredes A., Al-Mansour M., Sun S., Cloyd J.M., Pawlik T.M. Update on current problems in colorectal liver metastasis. Curr. Probl. Surg. 2017;54:554–602. doi: 10.1067/j.cpsurg.2017.10.002. PubMed DOI

Huo T., Canepa R., Sura A., Modave F., Gong Y. Colorectal cancer stages transcriptome analysis. PLoS ONE. 2017;12:e0188697. doi: 10.1371/journal.pone.0188697. PubMed DOI PMC

Ma S., Ogino S., Parsana P., Nishihara R., Qian Z., Shen J., Mima K., Masugi Y., Cao Y., Nowak J.A., et al. Continuity of transcriptomes among colorectal cancer subtypes based on meta-analysis. Genome Biol. 2018;19:142. doi: 10.1186/s13059-018-1511-4. PubMed DOI PMC

Pira G., Uva P., Scanu A.M., Rocca P.C., Murgia L., Uleri E., Piu C., Porcu A., Carru C., Manca A., et al. Landscape of transcriptome variations uncovering known and novel driver events in colorectal carcinoma. Sci. Rep. 2020;10:432. doi: 10.1038/s41598-019-57311-z. PubMed DOI PMC

Fehlker M., Huska M.R., Jöns T., Andrade-Navarro M.A., Kemmner W. Concerted down-regulation of immune-system related genes predicts metastasis in colorectal carcinoma. BMC Cancer. 2014;14:64. doi: 10.1186/1471-2407-14-64. PubMed DOI PMC

Johnston P.G. Identification of clinically relevant molecular subtypes in colorectal cancer: The dawning of a new era. Oncologist. 2014;19:568–573. doi: 10.1634/theoncologist.2014-038. PubMed DOI PMC

Li Z., Chen Y., Ren W.U., Hu S., Tan Z., Wang Y., Chen Y., Zhang J., Wu J., Li T., et al. Transcriptome Alterations in Liver Metastases of Colorectal Cancer After Acquired Resistance to Cetuximab. Cancer Genom. Proteom. 2019;16:207–219. doi: 10.21873/cgp.20126. PubMed DOI PMC

Zhang Y., Song J., Zhao Z., Yang M., Chen M., Liu C., Ji J., Zhu D. Single-cell transcriptome analysis reveals tumor immune microenvironment heterogenicity and granulocytes enrichment in colorectal cancer liver metastases. Cancer Lett. 2020;470:84–94. doi: 10.1016/j.canlet.2019.10.016. PubMed DOI

Lin A.Y., Chua M.-S., Choi Y.-L., Yeh W., Kim Y.H., Azzi R., Adams G.A., Sainani K., van de Rijn M., So S.K., et al. Comparative profiling of primary colorectal carcinomas and liver metastases identifies LEF1 as a prognostic biomarker. PLoS ONE. 2011;6:e16636. doi: 10.1371/journal.pone.0016636. PubMed DOI PMC

Lopez G., Boggio F., Ferrero S., Fusco N., Del Gobbo A. Molecular and Immunohistochemical Markers with Prognostic and Predictive Significance in Liver Metastases from Colorectal Carcinoma. Int. J. Mol. Sci. 2018;19:14. doi: 10.3390/ijms19103014. PubMed DOI PMC

Paschos K.A., Majeed A.W., Bird N.C. Natural history of hepatic metastases from colorectal cancer--pathobiological pathways with clinical significance. World J. Gastroenterol. 2014;20:3719–3737. doi: 10.3748/wjg.v20.i14.3719. PubMed DOI PMC

Yang P.-S., Hsu H.-H., Hsu T.-C., Chen M.-J., Wang C.-D., Yu S.-L., Hsu Y.-C., Li K.-C. Genome-Wide Scan for Copy Number Alteration Association with Relapse-Free Survival in Colorectal Cancer with Liver Metastasis Patients. J. Clin. Med. 2018;7:446. doi: 10.3390/jcm7110446. PubMed DOI PMC

Koncina E., Haan S., Rauh S., Letellier E. Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges. Cancers. 2020;12:319. doi: 10.3390/cancers12020319. PubMed DOI PMC

Lee M.K.C., Loree J.M. Current and emerging biomarkers in metastatic colorectal cancer. Curr. Oncol. 2019;26:S7–S15. doi: 10.3747/co.26.5719. PubMed DOI PMC

Baran B., Mert Ozupek N., Yerli Tetik N., Acar E., Bekcioglu O., Baskin Y. Difference Between Left-Sided and Right-Sided Colorectal Cancer: A Focused Review of Literature. Gastroenterol. Res. 2018;11:264–273. doi: 10.14740/gr1062w. PubMed DOI PMC

Loupakis F., Yang D., Yau L., Feng S., Cremolini C., Zhang W., Maus M.K.H., Antoniotti C., Langer C., Scherer S.J., et al. Primary Tumor Location as a Prognostic Factor in Metastatic Colorectal Cancer. JNCI J. Natl. Cancer Inst. 2015;107 doi: 10.1093/jnci/dju427. PubMed DOI PMC

Petrelli F., Tomasello G., Borgonovo K., Ghidini M., Turati L., Dallera P., Passalacqua R., Sgroi G., Barni S. Prognostic Survival Associated With Left-Sided vs. Right-Sided Colon Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2017;3:211. doi: 10.1001/jamaoncol.2016.4227. PubMed DOI

Mas L., Bachet J.-B., Taly V., Bouché O., Taieb J., Cohen R., Meurisse A., Normand C., Gornet J.-M., Artru P., et al. BRAF Mutation Status in Circulating Tumor DNA from Patients with Metastatic Colorectal Cancer: Extended Mutation Analysis from the AGEO RASANC Study. Cancers. 2019;11:998. doi: 10.3390/cancers11070998. PubMed DOI PMC

Bergheim J., Semaan A., Gevensleben H., Groening S., Knoblich A., Dietrich J., Weber J., Kalff J.C., Bootz F., Kristiansen G., et al. Potential of quantitative SEPT9 and SHOX2 methylation in plasmatic circulating cell-free DNA as auxiliary staging parameter in colorectal cancer: A prospective observational cohort study. Br. J. Cancer. 2018;118:1217–1228. doi: 10.1038/s41416-018-0035-8. PubMed DOI PMC

Siravegna G., Marsoni S., Siena S., Bardelli A. Integrating liquid biopsies into the management of cancer. Nat. Rev. Clin. Oncol. 2017;14:531–548. doi: 10.1038/nrclinonc.2017.14. PubMed DOI

Frenel J.S., Carreira S., Goodall J., Roda D., Perez-Lopez R., Tunariu N., Riisnaes R., Miranda S., Figueiredo I., Nava-Rodrigues D., et al. Serial Next-Generation Sequencing of Circulating Cell-Free DNA Evaluating Tumor Clone Response To Molecularly Targeted Drug Administration. Clin. Cancer Res. 2015;21:4586–4596. doi: 10.1158/1078-0432.CCR-15-0584. PubMed DOI PMC

Couraud S., Vaca-Paniagua F., Villar S., Oliver J., Schuster T., Blanche H., Girard N., Tredaniel J., Guilleminault L., Gervais R., et al. Noninvasive Diagnosis of Actionable Mutations by Deep Sequencing of Circulating Free DNA in Lung Cancer from Never-Smokers: A Proof-of-Concept Study from BioCAST/IFCT-1002. Clin. Cancer Res. 2014;20:4613–4624. doi: 10.1158/1078-0432.CCR-13-3063. PubMed DOI

Rothé F., Laes J.-F., Lambrechts D., Smeets D., Vincent D., Maetens M., Fumagalli D., Michiels S., Drisis S., Moerman C., et al. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer. Ann. Oncol. 2014;25:1959–1965. doi: 10.1093/annonc/mdu288. PubMed DOI

Bettegowda C., Sausen M., Leary R.J., Kinde I., Wang Y., Agrawal N., Bartlett B.R., Wang H., Luber B., Alani R.M., et al. Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies. Sci. Transl. Med. 2014;6:224ra24. doi: 10.1126/scitranslmed.3007094. PubMed DOI PMC

Demuth C., Spindler K.-L.G., Johansen J.S., Pallisgaard N., Nielsen D., Hogdall E., Vittrup B., Sorensen B.S. Measuring KRAS Mutations in Circulating Tumor DNA by Droplet Digital PCR and Next-Generation Sequencing. Transl. Oncol. 2018;11:1220–1224. doi: 10.1016/j.tranon.2018.07.013. PubMed DOI PMC

Newman A.M., Bratman S.V., To J., Wynne J.F., Eclov N.C.W., Modlin L.A., Liu C.L., Neal J.W., Wakelee H.A., Merritt R.E., et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat. Med. 2014;20:548–554. doi: 10.1038/nm.3519. PubMed DOI PMC

Strickler J.H., Loree J.M., Ahronian L.G., Parikh A.R., Niedzwiecki D., Pereira A.A.L., McKinney M., Korn W.M., Atreya C.E., Banks K.C., et al. Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer. Cancer Discov. 2018;8:164–173. doi: 10.1158/2159-8290.CD-17-1009. PubMed DOI PMC

Diaz Jr L.A., Williams R.T., Wu J., Kinde I., Hecht J.R., Berlin J., Allen B., Bozic I., Reiter J.G., Nowak M.A., et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486:537–540. doi: 10.1038/nature11219. PubMed DOI PMC

Mohan S., Heitzer E., Ulz P., Lafer I., Lax S., Auer M., Pichler M., Gerger A., Eisner F., Hoefler G., et al. Changes in Colorectal Carcinoma Genomes under Anti-EGFR Therapy Identified by Whole-Genome Plasma DNA Sequencing. PLoS Genet. 2014;10:e1004271. doi: 10.1371/journal.pgen.1004271. PubMed DOI PMC

Montagut C., Argilés G., Ciardiello F., Poulsen T.T., Dienstmann R., Kragh M., Kopetz S., Lindsted T., Ding C., Vidal J., 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:e175245. doi: 10.1001/jamaoncol.2017.5245. PubMed DOI PMC

Ng S.B., Chua C., Ng M., Gan A., Poon P.S., Teo M., Fu C., Leow W.Q., Lim K.H., Chung A., et al. Individualised multiplexed circulating tumour DNA assays for monitoring of tumour presence in patients after colorectal cancer surgery. Sci. Rep. 2017;7:40737. doi: 10.1038/srep40737. PubMed DOI PMC

Kidess E., Heirich K., Wiggin M., Vysotskaia V., Visser B.C., Marziali A., Wiedenmann B., Norton J.A., Lee M., Jeffrey S.S., 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;6:2549–2561. doi: 10.18632/oncotarget.3041. PubMed DOI PMC

Schrock A.B., Ouyang C., Sandhu J., Sokol E., Jin D., Ross J.S., Miller V.A., Lim D., Amanam I., Chao J., et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann. Oncol. 2019;30:1096–1103. doi: 10.1093/annonc/mdz134. PubMed DOI

Domingo E., Camps C., Kaisaki P.J., Parsons M.J., Mouradov D., Pentony M.M., Makino S., Palmieri M., Ward R.L., Hawkins N.J., et al. Mutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: Results from the QUASAR 2 clinical trial and an Australian community-based series. Lancet Gastroenterol. Hepatol. 2018;3:635–643. doi: 10.1016/S2468-1253(18)30117-1. PubMed DOI PMC

Fenizia F., Esposito Abate R., Pasquale R., Roma C., Lambiase M., Chicchinelli N., Graziano P., Botti G., Tatangelo F., Scognamiglio G., et al. Tumour mutation burden and microsatellite instability in colorectal cancer. Ann. Oncol. 2019;30:v39. doi: 10.1093/annonc/mdz239.036. DOI

Sartore-Bianchi A., Ardini E., Bosotti R., Amatu A., Valtorta E., Somaschini A., Raddrizzani L., Palmeri L., Banfi P., Bonazzina E., et al. Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer. JNCI J. Natl. Cancer Inst. 2016;108 doi: 10.1093/jnci/djv306. PubMed DOI PMC

Amatu A., Somaschini A., Cerea G., Bosotti R., Valtorta E., Buonandi P., Marrapese G., Veronese S., Luo D., Hornby Z., et al. Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer. Br. J. Cancer. 2015;113:1730–1734. doi: 10.1038/bjc.2015.401. PubMed DOI PMC

Cesi G., Philippidou D., Kozar I., Kim Y.J., Bernardin F., Van Niel G., Wienecke-Baldacchino A., Felten P., Letellier E., Dengler S., et al. A new ALK isoform transported by extracellular vesicles confers drug resistance to melanoma cells. Mol. Cancer. 2018;17:145. doi: 10.1186/s12943-018-0886-x. PubMed DOI PMC

Yonesaka K., Zejnullahu K., Okamoto I., Satoh T., Cappuzzo F., Souglakos J., Ercan D., Rogers A., Roncalli M., Takeda M., et al. Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab. Sci. Transl. Med. 2011;3:99ra86. doi: 10.1126/scitranslmed.3002442. PubMed DOI PMC

Martin V., Landi L., Molinari F., Fountzilas G., Geva R., Riva A., Saletti P., De Dosso S., Spitale A., Tejpar S., et al. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients. Br. J. Cancer. 2013;108:668–675. doi: 10.1038/bjc.2013.4. PubMed DOI PMC

Bertotti A., Migliardi G., Galimi F., Sassi F., Torti D., Isella C., Cora D., Di Nicolantonio F., Buscarino M., Petti C., et al. A Molecularly Annotated Platform of Patient-Derived Xenografts (“Xenopatients”) Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer. Cancer Discov. 2011;1:508–523. doi: 10.1158/2159-8290.CD-11-0109. PubMed DOI

Raghav K., Loree J.M., Morris J.S., Overman M.J., Yu R., Meric-Bernstam F., Menter D., Korphaisarn K., Kee B., Muranyi A., et al. Validation of HER2 Amplification as a Predictive Biomarker for Anti–Epidermal Growth Factor Receptor Antibody Therapy in Metastatic Colorectal Cancer. JCO Precis. Oncol. 2019:1–13. doi: 10.1200/PO.18.00226. PubMed DOI

Guinney J., Dienstmann R., Wang X., de Reyniès A., Schlicker A., Soneson C., Marisa L., Roepman P., Nyamundanda G., Angelino P., et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 2015;21:1350–1356. doi: 10.1038/nm.3967. PubMed DOI PMC

Lenz H.-J., Ou F.-S., Venook A.P., Hochster H.S., Niedzwiecki D., Goldberg R.M., Mayer R.J., Bertagnolli M.M., Blanke C.D., Zemla T., et al. Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance) JCO. 2019;37:1876–1885. doi: 10.1200/JCO.18.02258. PubMed DOI PMC

Isella C., Brundu F., Bellomo S.E., Galimi F., Zanella E., Porporato R., Petti C., Fiori A., Orzan F., Senetta R., et al. Selective analysis of cancer-cell intrinsic transcriptional traits defines novel clinically relevant subtypes of colorectal cancer. Nat. Commun. 2017;8:15107. doi: 10.1038/ncomms15107. PubMed DOI PMC

Sveen A., Bruun J., Eide P.W., Eilertsen I.A., Ramirez L., Murumägi A., Arjama M., Danielsen S.A., Kryeziu K., Elez E., et al. Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies. Clin. Cancer Res. 2018;24:794–806. doi: 10.1158/1078-0432.CCR-17-1234. PubMed DOI

Berg K.C.G., Eide P.W., Eilertsen I.A., Johannessen B., Bruun J., Danielsen S.A., Bjørnslett M., Meza-Zepeda L.A., Eknæs M., Lind G.E., et al. Multi-omics of 34 colorectal cancer cell lines-a resource for biomedical studies. Mol. Cancer. 2017;16:116. doi: 10.1186/s12943-017-0691-y. PubMed DOI PMC

Galon J. Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome. Science. 2006;313:1960–1964. doi: 10.1126/science.1129139. PubMed DOI

Becht E., de Reyniès A., Giraldo N.A., Pilati C., Buttard B., Lacroix L., Selves J., Sautès-Fridman C., Laurent-Puig P., Fridman W.H. Immune and Stromal Classification of Colorectal Cancer Is Associated with Molecular Subtypes and Relevant for Precision Immunotherapy. Clin. Cancer Res. 2016;22:4057–4066. doi: 10.1158/1078-0432.CCR-15-2879. PubMed DOI

Galon J., Pagès F., Marincola F.M., Angell H.K., Thurin M., Lugli A., Zlobec I., Berger A., Bifulco C., Botti G., et al. Cancer classification using the Immunoscore: A worldwide task force. J. Transl. Med. 2012;10:205. doi: 10.1186/1479-5876-10-205. PubMed DOI PMC

Pagès F., Mlecnik B., Marliot F., Bindea G., Ou F.-S., Bifulco C., Lugli A., Zlobec I., Rau T.T., Berger M.D., et al. International validation of the consensus Immunoscore for the classification of colon cancer: A prognostic and accuracy study. Lancet. 2018;391:2128–2139. doi: 10.1016/S0140-6736(18)30789-X. PubMed DOI

Mlecnik B., Bindea G., Angell H.K., Maby P., Angelova M., Tougeron D., Church S.E., Lafontaine L., Fischer M., Fredriksen T., et al. Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability. Immunity. 2016;44:698–711. doi: 10.1016/j.immuni.2016.02.025. PubMed DOI

Pietrantonio F., Di Nicolantonio F., Schrock A.B., Lee J., Tejpar S., Sartore-Bianchi A., Hechtman J.F., Christiansen J., Novara L., Tebbutt N., et al. ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer. J. Natl. Cancer Inst. 2017;109 doi: 10.1093/jnci/djx089. PubMed DOI

Kheder E.S., Hong D.S. Emerging Targeted Therapy for Tumors with NTRK Fusion Proteins. Clin. Cancer Res. 2018;24:5807–5814. doi: 10.1158/1078-0432.CCR-18-1156. PubMed DOI

Ardini E., Bosotti R., Borgia A.L., De Ponti C., Somaschini A., Cammarota R., Amboldi N., Raddrizzani L., Milani A., Magnaghi P., et al. The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition. Mol. Oncol. 2014;8:1495–1507. doi: 10.1016/j.molonc.2014.06.001. PubMed DOI PMC

Cremolini C., Pietrantonio F. How the Lab is Changing Our View of Colorectal Cancer. Tumori J. 2016;102:541–547. doi: 10.5301/tj.5000551. PubMed DOI

Ross J.S., Fakih M., Ali S.M., Elvin J.A., Schrock A.B., Suh J., Vergilio J.-A., Ramkissoon S., Severson E., Daniel S., et al. Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3: ERBB2 and ERBB3 in CRC. Cancer. 2018;124:1358–1373. doi: 10.1002/cncr.31125. PubMed DOI PMC

Angell H., Galon J. From the immune contexture to the Immunoscore: The role of prognostic and predictive immune markers in cancer. Curr. Opin. Immunol. 2013;25:261–267. doi: 10.1016/j.coi.2013.03.004. PubMed DOI

Berghoff A.S., Fuchs E., Ricken G., Mlecnik B., Bindea G., Spanberger T., Hackl M., Widhalm G., Dieckmann K., Prayer D., et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. OncoImmunology. 2016;5:e1057388. doi: 10.1080/2162402X.2015.1057388. PubMed DOI PMC

Galon J., Mlecnik B., Bindea G., Angell H.K., Berger A., Lagorce C., Lugli A., Zlobec I., Hartmann A., Bifulco C., et al. Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours: Immunoscore classification of malignant tumours. J. Pathol. 2014;232:199–209. doi: 10.1002/path.4287. PubMed DOI PMC

Galon J., Pagès F., Marincola F.M., Thurin M., Trinchieri G., Fox B.A., Gajewski T.F., Ascierto P.A. The immune score as a new possible approach for the classification of cancer. J. Transl. Med. 2012;10:1. doi: 10.1186/1479-5876-10-1. PubMed DOI PMC

Mlecnik B., Bindea G., Angell H.K., Sasso M.S., Obenauf A.C., Fredriksen T., Lafontaine L., Bilocq A.M., Kirilovsky A., Tosolini M., et al. Functional Network Pipeline Reveals Genetic Determinants Associated with in Situ Lymphocyte Proliferation and Survival of Cancer Patients. Sci. Transl. Med. 2014;6:228ra37. doi: 10.1126/scitranslmed.3007240. PubMed DOI

Pagès F., Kirilovsky A., Mlecnik B., Asslaber M., Tosolini M., Bindea G., Lagorce C., Wind P., Marliot F., Bruneval P., et al. In Situ Cytotoxic and Memory T Cells Predict Outcome in Patients with Early-Stage Colorectal Cancer. JCO. 2009;27:5944–5951. doi: 10.1200/JCO.2008.19.6147. PubMed DOI

Manceau G., Imbeaud S., Thiebaut R., Liebaert F., Fontaine K., Rousseau F., Genin B., Corre D.L., Didelot A., Vincent M., et al. Hsa-miR-31-3p Expression Is Linked to Progression-free Survival in Patients with KRAS Wild-type Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy. Clin. Cancer Res. 2014;20:3338–3347. doi: 10.1158/1078-0432.CCR-13-2750. PubMed DOI

Mosakhani N., Lahti L., Borze I., Karjalainen-Lindsberg M.-L., Sundström J., Ristamäki R., Österlund P., Knuutila S., Sarhadi V.K. MicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF. Cancer Genet. 2012;205:545–551. doi: 10.1016/j.cancergen.2012.08.003. PubMed DOI

Mlcochova J., Faltejskova-Vychytilova P., Ferracin M., Zagatti B., Radova L., Svoboda M., Nemecek R., John S., Kiss I., Vyzula R., et al. MicroRNA expression profiling identifies miR-31-5p/3p as associated with time to progression in wild-type RAS metastatic colorectal cancer treated with cetuximab. Oncotarget. 2015;6:38695–38704. doi: 10.18632/oncotarget.5735. PubMed DOI PMC

Laurent-Puig P., Grisoni M.-L., Heinemann V., Liebaert F., Neureiter D., Jung A., Montestruc F., Gaston-Mathe Y., Thiébaut R., Stintzing S. Validation of miR-31-3p Expression to Predict Cetuximab Efficacy When Used as First-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer. Clin. Cancer Res. 2019;25:134–141. doi: 10.1158/1078-0432.CCR-18-1324. PubMed DOI

Pugh S., Thiébaut R., Bridgewater J., Grisoni M.-L., Moutasim K., Rousseau F., Thomas G.J., Griffiths G., Liebaert F., Primrose J., et al. Association between miR-31-3p expression and cetuximab efficacy in patients with KRAS wild-type metastatic colorectal cancer: A post-hoc analysis of the New EPOC trial. Oncotarget. 2017;8:93856–93866. doi: 10.18632/oncotarget.21291. PubMed DOI PMC

Van Rijnsoever M., Elsaleh H., Joseph D., McCaul K., Iacopetta B. CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer. Clin. Cancer Res. 2003;9:2898–2903. PubMed

Ahn J.B., Chung W.B., Maeda O., Shin S.J., Kim H.S., Chung H.C., Kim N.K., Issa J.-P.J. DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer. 2011;117:1847–1854. doi: 10.1002/cncr.25737. PubMed DOI PMC

Shiovitz S., Bertagnolli M.M., Renfro L.A., Nam E., Foster N.R., Dzieciatkowski S., Luo Y., Lao V.V., Monnat R.J., Emond M.J., et al. CpG Island Methylator Phenotype Is Associated With Response to Adjuvant Irinotecan-Based Therapy for Stage III Colon Cancer. Gastroenterology. 2014;147:637–645. doi: 10.1053/j.gastro.2014.05.009. PubMed DOI PMC

Cervena K., Siskova A., Buchler T., Vodicka P., Vymetalkova V. Methylation-Based Therapies for Colorectal Cancer. Cells. 2020;9:1540. doi: 10.3390/cells9061540. PubMed DOI PMC

Valastyan S., Weinberg R.A. Tumor metastasis: Molecular insights and evolving paradigms. Cell. 2011;147:275–292. doi: 10.1016/j.cell.2011.09.024. PubMed DOI PMC

Arnold D., Lueza B., Douillard J.-Y., Peeters M., Lenz H.-J., Venook A., Heinemann V., Van Cutsem E., Pignon J.-P., Tabernero J., 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;28:1713–1729. doi: 10.1093/annonc/mdx175. PubMed DOI PMC

Li X., Wang M., Liu G.-Y., Ma J.-L. Dual VEGF/EGFR inhibition versus single targeted agent treatment in patients with metastatic colorectal cancer: A meta-analysis of randomized trials. Int. J. Colorectal Dis. 2016;31:1655–1656. doi: 10.1007/s00384-016-2593-7. PubMed DOI

Fromme J.E., Schildhaus H.-U. [FGFR3 overexpression is a relevant alteration in colorectal cancer] Pathologe. 2018;39:189–192. doi: 10.1007/s00292-018-0504-0. PubMed DOI

Greally M., Kelly C.M., Cercek A. HER2: An emerging target in colorectal cancer. Curr. Probl. Cancer. 2018;42:560–571. doi: 10.1016/j.currproblcancer.2018.07.001. PubMed DOI

Guler I., Askan G., Klostergaard J., Sahin I.H. Precision medicine for metastatic colorectal cancer: An evolving era. Expert Rev. Gastroenterol. Hepatol. 2019;13:919–931. doi: 10.1080/17474124.2019.1663174. PubMed DOI

Svrcek M., Lascols O., Cohen R., Collura A., Jonchère V., Fléjou J.-F., Buhard O., Duval A. MSI/MMR-deficient tumor diagnosis: Which standard for screening and for diagnosis? Diagnostic modalities for the colon and other sites: Differences between tumors. Bull. Cancer. 2019;106:119–128. doi: 10.1016/j.bulcan.2018.12.008. PubMed DOI

Grasso C.S., Giannakis M., Wells D.K., Hamada T., Mu X.J., Quist M., Nowak J.A., Nishihara R., Qian Z.R., Inamura K., et al. Genetic Mechanisms of Immune Evasion in Colorectal Cancer. Cancer Discov. 2018;8:730–749. doi: 10.1158/2159-8290.CD-17-1327. PubMed DOI PMC

Singh A., Patel P., Patel V.K., Jain D.K., Veerasamy R., Sharma P.C., Rajak H. Histone Deacetylase Inhibitors for the Treatment of Colorectal Cancer: Recent Progress and Future Prospects. Curr. Cancer Drug Targets. 2017;17:456–466. doi: 10.2174/1568009617666170109150134. PubMed DOI

He Y., Ma X., Chen K., Liu F., Cai S., Han-Zhang H., Hou T., Xiang J., Peng J. Perioperative Circulating Tumor DNA in Colorectal Liver Metastases: Concordance with Metastatic Tissue and Predictive Value for Tumor Burden and Prognosis. Cancer Manag. Res. 2020;12:1621–1630. doi: 10.2147/CMAR.S240869. PubMed DOI PMC

Differences in genome, transcriptome, miRNAome, and methylome in synchronous and metachronous liver metastasis of colorectal cancer

Analysis of MicroRNA Expression Changes During the Course of Therapy In Rectal Cancer Patients