gnckКолопроктологияKoloproktologia2073-75562686-7303Russian Association of Coloproctology10.33878/2073-7556-2023-22-2-160-171gnck-1766Research ArticleОБЗОРЫ ЛИТЕРАТУРЫ И МЕТААНАЛИЗLITERATURE REVIEWS AND METAANALYSISКолоректальный рак: эпидемиология, канцерогенез, молекулярно-генетические и клеточные механизмы резистентности к терапии (аналитический обзор)Colorectal cancer: epidemiology, carcinogenesis, molecular subtypes and cellular mechanisms of therapy resistance (analytical review)https://orcid.org/0000-0001-5920-8664МаксимоваП. Е.MaksimovaP. E.

Максимова П.Е. — студентка шестого курса Первого медицинского факультета

бул. Ленина, д. 5/7, Республика Крым, г. Симферополь, 295051, Россия

Рolina E. Maksimova — sixth year student

Lenin blv, 5/7, Crimean Republic, Simferopol, 295051, Russia

pmaksq@mail.ruhttps://orcid.org/0000-0003-3917-924XГолубинскаяЕ. П.GolubinskayaE. P.

Голубинская Е.П. — д.м.н., ведущий научный сотрудник

бул. Ленина, д. 5/7, Республика Крым, г. Симферополь, 295051, Россия

Elena P. Golubinskaya — Dr.Med.Sci., Leading Researcher

Lenin blv, 5/7, Crimean Republic, Simferopol, 295051, Russia

https://orcid.org/0000-0003-0191-7665СеферовБ. Д.SeferovB. D.

Сеферов Б.Д. — к.м.н., ассистент кафедры онкологии

ул. Луговая, д. 16/2, Cимферопольский р-н, с.Мирное, 297503, Россия

Bekir D. Seferov — Cand.Med.Sci., Assistant of the Department of Oncology

Lenin blv, 5/7, Crimean Republic, Simferopol,295051, Russia

https://orcid.org/0000-0001-8216-4196ЗяблицкаяЕ. Ю.ZyablitskayaE. Yu.

Зяблицкая Е.Ю. — д.м.н., ведущий научный сотрудник

бул. Ленина, д. 5/7, Республика Крым, г. Симферополь, 295051, Россия

Evgenia Yu. Zyablitskaya — Dr.Med.Sci., Leading Researcher

Lenin blv, 5/7, Crimean Republic, Simferopol, 295051, Russia

Институт «Медицинская академия имени С.И. Георгиевского» ФГАОУ ВО «Крымский федеральный университет имени В.И. Вернадского»РоссияThe Institute «Medical Academy named after S.I. Georgievsky» V.I. Vernadsky Crimean Federal UniversityRussian FederationООО «Центр Клинической онкологии и гематологии»РоссияOOO«Center of Clinical Oncology and Hematology»Russian Federation202321062023222160171Copyright © Максимова П.Е., Голубинская Е.П., Сеферов Б.Д., Зяблицкая Е.Ю., 20232023Максимова П.Е., Голубинская Е.П., Сеферов Б.Д., Зяблицкая Е.Ю.Maksimova P.E., Golubinskaya E.P., Seferov B.D., Zyablitskaya E.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.ruproctology.com/jour/article/view/1766

В этой статье анализируются статистические данные о колоректальном раке в России и в мире, включая заболеваемость, смертность и выживаемость. Рассматриваются основные пути канцерогенеза колоректального рака, молекулярные подтипы и их влияние на различие при поражении проксимальных и дистальных отделов толстой кишки. В статье приводится обзор ведущих препаратов для химио- и таргетной терапии при колоректальном раке, а также основные причины развития терапевтической резистентности, в том числе изменение клеточного микроокружения опухоли.

This article analyzes the statistical data on colorectal cancer in Russia and in the world, including incidence, mortality and survival. The main pathways of colorectal cancer carcinogenesis, molecular subtypes and their influence on the difference in lesions of the proximal and distal large intestine are presented. The paper provides an overview of the leading chemotherapy agents and targeted therapy in colorectal cancer, as well as the main reasons for the development of therapeutic resistance, including changes in the cellular microenvironment of the tumor.

колоректальный ракраспространенностьканцерогенезтерапиялекарственная резистентностьcolorectal cancerprevalencecarcinogenesistherapydrug resistanceReferencesCho YA, Lee J, OhJ H, et al. Genetic Risk Score, Combined Lifestyle Factors and Risk of Colorectal Cancer. Cancer Res Treat. 2019;51(3):1033–1040. doi: 10.4143/crt.2018.447Cho YA, Lee J, OhJ H, et al. Genetic Risk Score, Combined Lifestyle Factors and Risk of Colorectal Cancer. Cancer Res Treat. 2019;51(3):1033–1040. doi: 10.4143/crt.2018.447Baidoun F, Elshiwy K, Elkeraie Y, et al. Colorectal Cancer Epidemiology: Recent Trends and Impact on Outcomes. Curr Drug Targets. 2021;22(9):9981009. doi: 10.2174/1389450121999201117115717Baidoun F, Elshiwy K, Elkeraie Y, et al. Colorectal Cancer Epidemiology: Recent Trends and Impact on Outcomes. Curr Drug Targets. 2021;22(9):9981009. doi: 10.2174/1389450121999201117115717Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020:GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–249. doi: 10.3322/caac.21660Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020:GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–249. doi: 10.3322/caac.21660Bray F. Transitions in human development and the global cancer burden. In: BW Stewart, CP Wild, eds. World Cancer Report 2014. WHO Press; 2014:42–55.Bray F. Transitions in human development and the global cancer burden. In: BW Stewart, CP Wild, eds. World Cancer Report 2014. WHO Press; 2014:42–55.Fidler MM, Soerjomataram I, Bray F. A global view on cancer incidence and national levels of the Human Development Index. Int J Cancer. 2016;139:2436–2446Fidler MM, Soerjomataram I, Bray F. A global view on cancer incidence and national levels of the Human Development Index. Int J Cancer. 2016;139:2436–2446Arnold M, Abnet CC, Neale RE, et al. Global burden of 5 major types of gastrointestinal cancer. Gastroenterology. 2020;159:335–349.e15.Arnold M, Abnet CC, Neale RE, et al. Global burden of 5 major types of gastrointestinal cancer. Gastroenterology. 2020;159:335–349.e15.Arnold M, Sierra MS, Laversanne M, et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66:683–691.Arnold M, Sierra MS, Laversanne M, et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66:683–691.Женщины и мужчины России. 2020: Стат.сб./ Росстат., М. 2020; 239 с.Zhenshhiny i muzhchiny Rossii. 2020: Stat.sb./ Rosstat. M., 2020: 239 p. (in Russ.).Каприн А.Д., Старинский В.В., Шахзадова А.О. Злокачественные новообразования в России в 2020 году (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена — филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2021.Kaprin A.D., Starinskij V.V., Shahzadova A.O. Zlokachestvennye novoobrazovanija v Rossii v 2020 godu (zabolevaemost’ i smertnost’). M.: MNIOI im. P.A. Gercena — filial FGBU «NMIC radiologii» Minzdrava Rossii, 2021. (in Russ.).Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145–164.Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145–164.Clinton SK, Giovannucci EL, Hursting SD. The World Cancer Research Fund/American Institute for Cancer Research Third Expert Report on Diet, Nutrition, Physical Activity, and Cancer: Impact and Future Directions. J Nutr. 2020 Apr 1;150(4):663–671. doi: 10.1093/jn/nxz268Clinton SK, Giovannucci EL, Hursting SD. The World Cancer Research Fund/American Institute for Cancer Research Third Expert Report on Diet, Nutrition, Physical Activity, and Cancer: Impact and Future Directions. J Nutr. 2020 Apr 1;150(4):663–671. doi: 10.1093/jn/nxz268Sullivan T, Sullivan R, Ginsburg OM. Screening for Cancer: Considerations for Low- and Middle-Income Countries. Cancer: Disease Control Priorities. 3rd ed. Volume 3. The International Bank for Reconstruction and Development/The World Bank. 2015: 211–222. doi: 10.1596/978-1-4648-0349-9_ch12Sullivan T, Sullivan R, Ginsburg OM. Screening for Cancer: Considerations for Low- and Middle-Income Countries. Cancer: Disease Control Priorities. 3rd ed. Volume 3. The International Bank for Reconstruction and Development/The World Bank. 2015: 211–222. doi: 10.1596/978-1-4648-0349-9_ch12Navarro M, Nicolas A, Ferrandez A, et al. Colorectal cancer population screening programs worldwide in 2016: an update. World J Gastroenterol. 2017;23:3632–3642.Navarro M, Nicolas A, Ferrandez A, et al. Colorectal cancer population screening programs worldwide in 2016: an update. World J Gastroenterol. 2017;23:3632–3642.Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 2010;116:544–573.Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 2010;116:544–573.Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018;68(4):250–281. doi: 10.3322/caac.21457Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018;68(4):250–281. doi: 10.3322/caac.21457Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019;16:713–732. doi: 10.1038/s41575-019-0189-8Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019;16:713–732. doi: 10.1038/s41575-019-0189-8Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177–193. doi: 10.3322/caac.21395Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177–193. doi: 10.3322/caac.21395Li J, Ma X, Chakravarti D, et al. Genetic and biological hallmarks of colorectal cancer. Genes Dev. 2021;35(11-12):787–820. doi: 10.1101/gad.348226.120Li J, Ma X, Chakravarti D, et al. Genetic and biological hallmarks of colorectal cancer. Genes Dev. 2021;35(11-12):787–820. doi: 10.1101/gad.348226.120Dekker E, Tanis PJ, Vleugels JLA, et al. Colorectal cancer. Lancet. 2019;394(10207):1467–1480. doi: 10.1016/S0140-6736(19)32319-0Dekker E, Tanis PJ, Vleugels JLA, et al. Colorectal cancer. Lancet. 2019;394(10207):1467–1480. doi: 10.1016/S0140-6736(19)32319-0Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–767. doi: 10.1016/0092-8674(90)90186-iFearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–767. doi: 10.1016/0092-8674(90)90186-iBoutin AT, Liao WT, Wang M, et al. Oncogenic Kras drives invasion and maintains metastases in colorectal cancer. Genes Dev. 2017;31(4):370–382. doi: 10.1101/gad.293449.116Boutin AT, Liao WT, Wang M, et al. Oncogenic Kras drives invasion and maintains metastases in colorectal cancer. Genes Dev. 2017;31(4):370–382. doi: 10.1101/gad.293449.116Liao W, Overman MJ, Boutin AT, et al. KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer. Cancer Cell. 2019;35(4):559–572.e7. doi: 10.1016/j.ccell.2019.02.008Liao W, Overman MJ, Boutin AT, et al. KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer. Cancer Cell. 2019;35(4):559–572.e7. doi: 10.1016/j.ccell.2019.02.008Rashtak S, Rego R, Sweetser SR, et al. Sessile Serrated Polyps and Colon Cancer Prevention. Cancer Prev Res (Phila). 2017;10(5):270–278. doi: 10.1158/1940-6207.CAPR-16-0264Rashtak S, Rego R, Sweetser SR, et al. Sessile Serrated Polyps and Colon Cancer Prevention. Cancer Prev Res (Phila). 2017;10(5):270–278. doi: 10.1158/1940-6207.CAPR-16-0264Dienstmann R, Vermeulen L, Guinney J, et al. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer. 2017;17(2):79–92. doi: 10.1038/nrc.2016.126Dienstmann R, Vermeulen L, Guinney J, et al. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer. 2017;17(2):79–92. doi: 10.1038/nrc.2016.126Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–1356. doi: 10.1038/nm.3967Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–1356. doi: 10.1038/nm.3967Müller MF, Ibrahim AE, Arends MJ. Molecular pathological classification of colorectal cancer. Virchows Arch. 2016;469(2):125–134. doi: 10.1007/s00428-016-1956-3Müller MF, Ibrahim AE, Arends MJ. Molecular pathological classification of colorectal cancer. Virchows Arch. 2016;469(2):125–134. doi: 10.1007/s00428-016-1956-3Zhong M, Wu B, Zhongguo Yi, et al. Recent Advances on the Differences between Left- and Right-sided. Colorectal Cancer. 2021;43(6):980–985. doi: 10.3881/j.issn.1000-503X.12867Zhong M, Wu B, Zhongguo Yi, et al. Recent Advances on the Differences between Left- and Right-sided. Colorectal Cancer. 2021;43(6):980–985. doi: 10.3881/j.issn.1000-503X.12867LaPointe LC, Dunne R, Brown GS, et al. Map of differential transcript expression in the normal human large intestine. Physiol Genomics. 2008;33(1):50–64. doi: 10.1152/physiolgenomics.00185.2006LaPointe LC, Dunne R, Brown GS, et al. Map of differential transcript expression in the normal human large intestine. Physiol Genomics. 2008;33(1):50–64. doi: 10.1152/physiolgenomics.00185.2006Hansen IO, Jess P. Possible better long-term survival in left versus right-sided colon cancer — a systematic review. Dan Med J. 2012;59(6):A4444.Hansen IO, Jess P. Possible better long-term survival in left versus right-sided colon cancer — a systematic review. Dan Med J. 2012;59(6):A4444.Augustus GJ, Ellis NA. Colorectal Cancer Disparity in African Americans: Risk Factors and Carcinogenic Mechanisms. Am J Pathol. 2018;188(2):291–303. doi: 10.1016/j.ajpath.2017.07.023Augustus GJ, Ellis NA. Colorectal Cancer Disparity in African Americans: Risk Factors and Carcinogenic Mechanisms. Am J Pathol. 2018;188(2):291–303. doi: 10.1016/j.ajpath.2017.07.023Dienstmann R, Mason MJ, Sinicrope FA, et al. Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study. Ann Oncol. 2017;28(5):1023–1031. doi: 10.1093/annonc/mdx052Dienstmann R, Mason MJ, Sinicrope FA, et al. Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study. Ann Oncol. 2017;28(5):1023–1031. doi: 10.1093/annonc/mdx052Aguiar Junior S, Oliveira MM, Silva DRME, et al. Survival of patients with colorectal cancer in a cancer center. Arq Gastroenterol. 2020;57(2):172–177. doi: 10.1590/S0004-2803.202000000-32Aguiar Junior S, Oliveira MM, Silva DRME, et al. Survival of patients with colorectal cancer in a cancer center. Arq Gastroenterol. 2020;57(2):172–177. doi: 10.1590/S0004-2803.202000000-32Lee MS, Menter DG, Kopetz S. Right Versus Left Colon Cancer Biology: Integrating the Consensus Molecular Subtypes. J Natl Compr Canc Netw. 2017;15(3):411–419. doi: 10.6004/jnccn.2017.0038Lee MS, Menter DG, Kopetz S. Right Versus Left Colon Cancer Biology: Integrating the Consensus Molecular Subtypes. J Natl Compr Canc Netw. 2017;15(3):411–419. doi: 10.6004/jnccn.2017.0038Loupakis F, Yang D, Yau L, et al. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst. 2015;107(3):dju427. doi: 10.1093/jnci/dju427Loupakis F, Yang D, Yau L, et al. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst. 2015;107(3):dju427. doi: 10.1093/jnci/dju427Lee GH, Malietzis G, Askari A, et al. Is right-sided colon cancer different to left-sided colorectal cancer? — a systematic review. Eur J Surg Oncol. 2015;41(3):300–8. doi: 10.1016/j.ejso.2014.11.001Lee GH, Malietzis G, Askari A, et al. Is right-sided colon cancer different to left-sided colorectal cancer? — a systematic review. Eur J Surg Oncol. 2015;41(3):300–8. doi: 10.1016/j.ejso.2014.11.001Baran B, Mert Ozupek N, Yerli Tetik N, et al. Difference Between Left-Sided and Right-Sided Colorectal Cancer: A Focused Review of Literature. Gastroenterology Res. 2018;11(4):264–273. doi: 10.14740/gr1062wBaran B, Mert Ozupek N, Yerli Tetik N, et al. Difference Between Left-Sided and Right-Sided Colorectal Cancer: A Focused Review of Literature. Gastroenterology Res. 2018;11(4):264–273. doi: 10.14740/gr1062wФедянин М.Ю., Ачкасов С.И., Болотина Л.В. и соавт. Практические рекомендации по лекарственному лечению рака ободочной кишки и ректосигмоидного соединения. Злокачественные опухоли. 2021;11(3s2–1):330–372. doi: 10.18027/2224-5057-Fedyanin M.Yu., Achkasov S.I., Bolotina L.V. et al. Practical recommendations for the drug treatment of colon cancer and rectosigmoid compound. Zlokachestvennye opuholi. 2021;11(3s2–1):330–372. (in Russ.). doi: 10.18027/2224-5057-2021-11-3s2-22-11-3s2-22Park SC, Sohn DK, Kim MJ, et al. Phase II Clinical Trial to Evaluate the Efficacy of Transanal Endoscopic Total Mesorectal Excision for Rectal Cancer. Dis Colon Rectum. 2018;61(5):554–560. doi: 10.1097/DCR.0000000000001058Park SC, Sohn DK, Kim MJ, et al. Phase II Clinical Trial to Evaluate the Efficacy of Transanal Endoscopic Total Mesorectal Excision for Rectal Cancer. Dis Colon Rectum. 2018;61(5):554–560. doi: 10.1097/DCR.0000000000001058Miller KD, Nogueira L, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019;69(5):363–385. doi: 10.3322/caac.21565Miller KD, Nogueira L, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019;69(5):363–385. doi: 10.3322/caac.21565Ogura A, Konishi T, Cunningham C, et al. Neoadjuvant (Chemo) radiotherapy With Total Mesorectal Excision Only Is Not Sufficient to Prevent Lateral Local Recurrence in Enlarged Nodes: Results of the Multicenter Lateral Node Study of Patients With Low cT3/4 Rectal Cancer. J Clin Oncol. 2019;37(1):33–43. doi: 10.1200/JCO.18.00032Ogura A, Konishi T, Cunningham C, et al. Neoadjuvant (Chemo) radiotherapy With Total Mesorectal Excision Only Is Not Sufficient to Prevent Lateral Local Recurrence in Enlarged Nodes: Results of the Multicenter Lateral Node Study of Patients With Low cT3/4 Rectal Cancer. J Clin Oncol. 2019;37(1):33–43. doi: 10.1200/JCO.18.00032Zacharakis M, Xynos ID, Lazaris A, et al. Predictors of survival in stage IV metastatic colorectal cancer. Anticancer Res. 2010;30(2):653–660Zacharakis M, Xynos ID, Lazaris A, et al. Predictors of survival in stage IV metastatic colorectal cancer. Anticancer Res. 2010;30(2):653–660Johdi NA, Sukor NF. Colorectal Cancer Immunotherapy: Options and Strategies. Front Immunol. 2020;11:1624. doi: 10.3389/fimmu.2020.01624Johdi NA, Sukor NF. Colorectal Cancer Immunotherapy: Options and Strategies. Front Immunol. 2020;11:1624. doi: 10.3389/fimmu.2020.01624Piawah S, Venook AP. Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer. Cancer. 2019;125(23):4139–4147. doi: 10.1002/cncr.32163Piawah S, Venook AP. Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer. Cancer. 2019;125(23):4139–4147. doi: 10.1002/cncr.32163Thirion P, Michiels S, Pignon JP, et al. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol. 1992;10:896–903 45. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29(6 Suppl 16):15–18. doi: 10.1053/sonc.2002.37263Thirion P, Michiels S, Pignon JP, et al. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol. 1992;10:896–903 45. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29(6 Suppl 16):15–18. doi: 10.1053/sonc.2002.37263Riechelmann R, Grothey A. Antiangiogenic therapy for refractory colorectal cancer: current options and future strategies. Ther Adv Med Oncol. 2017;9(2):106–126. doi: 10.1177/1758834016676703Riechelmann R, Grothey A. Antiangiogenic therapy for refractory colorectal cancer: current options and future strategies. Ther Adv Med Oncol. 2017;9(2):106–126. doi: 10.1177/1758834016676703Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42. doi: 10.1056/NEJMoa032691Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42. doi: 10.1056/NEJMoa032691Rosen LS, Jacobs IA, Burkes RL. Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars. Target Oncol. 2017;12(5):599–610. doi: 10.1007/s11523-017-0518-1Rosen LS, Jacobs IA, Burkes RL. Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars. Target Oncol. 2017;12(5):599–610. doi: 10.1007/s11523-017-0518-1Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–19. 97. doi: 10.1200/JCO.2007.14.9930Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–19. 97. doi: 10.1200/JCO.2007.14.9930Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an openlabel, randomised phase 3 trial. Lancet Oncol. 2013;14:1077–85. doi: 10.1016/S1470-2045(13)70154-2Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an openlabel, randomised phase 3 trial. Lancet Oncol. 2013;14:1077–85. doi: 10.1016/S1470-2045(13)70154-2Tang PA, Cohen SJ, Kollmannsberger C, et al. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res. 2012;18:6023–6031. doi: 10.1158/1078-0432.CCR-11-3252Tang PA, Cohen SJ, Kollmannsberger C, et al. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res. 2012;18:6023–6031. doi: 10.1158/1078-0432.CCR-11-3252Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:3499–3506. doi: 10.1200/JCO.2012.42.8201Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:3499–3506. doi: 10.1200/JCO.2012.42.8201Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16:499–508. doi: 10.1016/S1470-2045(15)70127-0Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16:499–508. doi: 10.1016/S1470-2045(15)70127-0Carter N. Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer. Drugs Aging. 2014;31:67–78. doi: 10.1007/s40266-013-0140-6Carter N. Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer. Drugs Aging. 2014;31:67–78. doi: 10.1007/s40266-013-0140-6Kasi PM, Kotani D, Cecchini M, et al. Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: a cohort study. BMC Cancer. 2016;16:467. doi: 10.1186/s12885-016-2491-yKasi PM, Kotani D, Cecchini M, et al. Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: a cohort study. BMC Cancer. 2016;16:467. doi: 10.1186/s12885-016-2491-yPfeiffer P, Yilmaz M, Möller S, et al. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(3):412–420. doi: 10.1016/S1470-2045(19)30827-7Pfeiffer P, Yilmaz M, Möller S, et al. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(3):412–420. doi: 10.1016/S1470-2045(19)30827-7Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015;51(5):587–594. doi: 10.1016/j.ejca.2015.01.054Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015;51(5):587–594. doi: 10.1016/j.ejca.2015.01.054Seshacharyulu P, Ponnusamy MP, Haridas D, et al. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16(1):15–31. doi: 10.1517/14728222.2011.648617Seshacharyulu P, Ponnusamy MP, Haridas D, et al. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16(1):15–31. doi: 10.1517/14728222.2011.648617Yarom N, Jonker DJ. The role of the epidermal growth factor receptor in the mechanism and treatment of colorectal cancer. Discov Med. 2011;11:95–105.Yarom N, Jonker DJ. The role of the epidermal growth factor receptor in the mechanism and treatment of colorectal cancer. Discov Med. 2011;11:95–105.Fakih M, Vincent M. Adverse events associated with antiEGFR therapies for the treatment of metastatic colorectal cancer. Curr Oncol. 2010;17 Suppl 1(Suppl 1):S18–S30. doi: 10.3747/co.v17is1.615Fakih M, Vincent M. Adverse events associated with antiEGFR therapies for the treatment of metastatic colorectal cancer. Curr Oncol. 2010;17 Suppl 1(Suppl 1):S18–S30. doi: 10.3747/co.v17is1.615Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012;30(23):2861–2868. doi: 10.1200/JCO.2011.40.9243Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012;30(23):2861–2868. doi: 10.1200/JCO.2011.40.9243Lenz HJ. Anti-EGFR mechanism of action: antitumor effect and underlying cause of adverse events. Oncology (Williston Park). 2006;20(5 Suppl 2):5–13.Lenz HJ. Anti-EGFR mechanism of action: antitumor effect and underlying cause of adverse events. Oncology (Williston Park). 2006;20(5 Suppl 2):5–13.Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on thePETACC-3, EORTC 40993, SAKK 60–00 trial. J Clin Oncol. 2010;28:466–74. doi: 10.1200/JCO.2009.23.3452Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on thePETACC-3, EORTC 40993, SAKK 60–00 trial. J Clin Oncol. 2010;28:466–74. doi: 10.1200/JCO.2009.23.3452Zhao B, Wang L, Qiu H, et al. Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. Oncotarget. 2017;8(3):3980–4000. doi: 10.18632/oncotarget.14012Zhao B, Wang L, Qiu H, et al. Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. Oncotarget. 2017;8(3):3980–4000. doi: 10.18632/oncotarget.14012Kopetz S, Guthrie KA, Morris VK, et al. Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAFMutant Metastatic Colorectal Cancer (SWOG S1406). J Clin Oncol. 2021;39(4):285–294. doi: 10.1200/JCO.20.01994Kopetz S, Guthrie KA, Morris VK, et al. Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAFMutant Metastatic Colorectal Cancer (SWOG S1406). J Clin Oncol. 2021;39(4):285–294. doi: 10.1200/JCO.20.01994Welsh SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol. 2015;7(2):122–136. doi: 10.1177/1758834014566428Welsh SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol. 2015;7(2):122–136. doi: 10.1177/1758834014566428Sinicrope FA, Sargent DJ. Clinical implications of microsatellite instability in sporadic colon cancers. Curr Opin Oncol. 2009;21(4):369–373. doi: 10.1097/CCO.0b013e32832c94bdSinicrope FA, Sargent DJ. Clinical implications of microsatellite instability in sporadic colon cancers. Curr Opin Oncol. 2009;21(4):369–373. doi: 10.1097/CCO.0b013e32832c94bdBenson AB, Venook AP, Cederquist L, et al. Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Colon Cancer. National Comprehensive Cancer. Network. 2018:1–132.Benson AB, Venook AP, Cederquist L, et al. Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Colon Cancer. National Comprehensive Cancer. Network. 2018:1–132.Kawakami H, Zaanan A, Sinicrope FA. Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options Oncol. 2015;16(7):30. doi: 10.1007/s11864-015-0348-22Kawakami H, Zaanan A, Sinicrope FA. Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options Oncol. 2015;16(7):30. doi: 10.1007/s11864-015-0348-22Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372(26):2509–2520. doi: 10.1056/NEJMoa1500596Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372(26):2509–2520. doi: 10.1056/NEJMoa1500596Ganesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 2019;16(6):361–375. doi: 10.1038/s41575-019-0126-xGanesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 2019;16(6):361–375. doi: 10.1038/s41575-019-0126-xJohnson DB, Chandra S, Sosman JA. Immune Checkpoint Inhibitor Toxicity in 2018. JAMA. 2018;320(16):1702–1703. doi: 10.1001/jama.2018.13995Johnson DB, Chandra S, Sosman JA. Immune Checkpoint Inhibitor Toxicity in 2018. JAMA. 2018;320(16):1702–1703. doi: 10.1001/jama.2018.13995Siena S, Sartore-Bianchi A, Marsoni S, et al. Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann Oncol. 2018;29(5):1108–1119. doi: 10.1093/annonc/mdy100Siena S, Sartore-Bianchi A, Marsoni S, et al. Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann Oncol. 2018;29(5):1108–1119. doi: 10.1093/annonc/mdy100Van der Jeught K, Xu HC, Li YJ, Lu XB, Ji G. Drug resistance and new therapies in colorectal cancer. World J Gastroenterol. 2018;24(34):3834–3848. doi: 10.3748/wjg.v24.i34.3834Van der Jeught K, Xu HC, Li YJ, Lu XB, Ji G. Drug resistance and new therapies in colorectal cancer. World J Gastroenterol. 2018;24(34):3834–3848. doi: 10.3748/wjg.v24.i34.3834Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as firstline treatment for metastatic colorectal cancer: a multicentre randomised trial [published correction appears in Lancet 2000 Apr 15;355(9212):1372]. Lancet. 2000;355(9209):1041–1047. doi: 10.1016/s0140-6736(00)02034-1Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as firstline treatment for metastatic colorectal cancer: a multicentre randomised trial [published correction appears in Lancet 2000 Apr 15;355(9212):1372]. Lancet. 2000;355(9209):1041–1047. doi: 10.1016/s0140-6736(00)02034-1Abdallah EA, Fanelli MF, Buim ME, et al. Thymidylate synthase expression in circulating tumor cells: a new tool to predict 5-fluorouracil resistance in metastatic colorectal cancer patients. Int J Cancer. 2015;137(6):1397–1405. doi: 10.1002/ijc.29495Abdallah EA, Fanelli MF, Buim ME, et al. Thymidylate synthase expression in circulating tumor cells: a new tool to predict 5-fluorouracil resistance in metastatic colorectal cancer patients. Int J Cancer. 2015;137(6):1397–1405. doi: 10.1002/ijc.29495Che J, Pan L, Yang X, et al. Thymidine phosphorylase expression and prognosis in colorectal cancer treated with 5-fluorouracil-based chemotherapy: A meta-analysis. Mol Clin Oncol. 2017;7(6):943–952. doi: 10.3892/mco.2017.1436Che J, Pan L, Yang X, et al. Thymidine phosphorylase expression and prognosis in colorectal cancer treated with 5-fluorouracil-based chemotherapy: A meta-analysis. Mol Clin Oncol. 2017;7(6):943–952. doi: 10.3892/mco.2017.1436Sakowicz-Burkiewicz M, Przybyla T, Wesserling M, et al. Suppression of TWIST1 enhances the sensitivity of colon cancer cells to 5-fluorouracil. Int J Biochem Cell Biol. 2016;78:268–278. doi: 10.1016/j.biocel.2016.07.024Sakowicz-Burkiewicz M, Przybyla T, Wesserling M, et al. Suppression of TWIST1 enhances the sensitivity of colon cancer cells to 5-fluorouracil. Int J Biochem Cell Biol. 2016;78:268–278. doi: 10.1016/j.biocel.2016.07.024Hicks LD, Hyatt JL, Stoddard S, et al. Improved, selective, human intestinal carboxylesterase inhibitors designed to modulate 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (Irinotecan; CPT-11) toxicity. J Med Chem. 2009;52(12):3742–3752. doi: 10.1021/jm9001296Hicks LD, Hyatt JL, Stoddard S, et al. Improved, selective, human intestinal carboxylesterase inhibitors designed to modulate 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (Irinotecan; CPT-11) toxicity. J Med Chem. 2009;52(12):3742–3752. doi: 10.1021/jm9001296Palshof JA, Høgdall EV, Poulsen TS, et al. Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer. BMC Cancer. 2017;17(1):48.. doi: 10.1186/s12885-016-3001-yPalshof JA, Høgdall EV, Poulsen TS, et al. Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer. BMC Cancer. 2017;17(1):48.. doi: 10.1186/s12885-016-3001-yNielsen DL, Palshof JA, Brünner N, et al. Implications of ABCG2 Expression on Irinotecan Treatment of Colorectal Cancer Patients: A Review. Int J Mol Sci. 2017;18(9):1926. doi: 10.3390/ijms18091926Nielsen DL, Palshof JA, Brünner N, et al. Implications of ABCG2 Expression on Irinotecan Treatment of Colorectal Cancer Patients: A Review. Int J Mol Sci. 2017;18(9):1926. doi: 10.3390/ijms18091926de Man FM, Goey AKL, van Schaik RHN, et al. Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics. Clin Pharmacokinet. 2018;57(10):1229–1254. doi: 10.1007/s40262-018-0644-7de Man FM, Goey AKL, van Schaik RHN, et al. Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics. Clin Pharmacokinet. 2018;57(10):1229–1254. doi: 10.1007/s40262-018-0644-7Meisenberg C, Ashour ME, El-Shafie L, et al. Epigenetic changes in histone acetylation underpin resistance to the topoisomerase I inhibitor irinotecan. Nucleic Acids Res. 2017;45(3):1159–1176. doi: 10.1093/nar/gkw1026Meisenberg C, Ashour ME, El-Shafie L, et al. Epigenetic changes in histone acetylation underpin resistance to the topoisomerase I inhibitor irinotecan. Nucleic Acids Res. 2017;45(3):1159–1176. doi: 10.1093/nar/gkw1026Gnoni A, Russo A, Silvestris N, et al. Pharmacokinetic and metabolism determinants of fluoropyrimidines and oxaliplatin activity in treatment of colorectal patients. Curr Drug Metab. 2011;12(10):918–931. doi: 10.2174/138920011798062300Gnoni A, Russo A, Silvestris N, et al. Pharmacokinetic and metabolism determinants of fluoropyrimidines and oxaliplatin activity in treatment of colorectal patients. Curr Drug Metab. 2011;12(10):918–931. doi: 10.2174/138920011798062300Yan D, Tu L, Yuan H, et al. WBSCR22 confers oxaliplatin resistance in human colorectal cancer. Sci Rep. 2017;7(1):15443. doi: 10.1038/s41598-017-15749-zYan D, Tu L, Yuan H, et al. WBSCR22 confers oxaliplatin resistance in human colorectal cancer. Sci Rep. 2017;7(1):15443. doi: 10.1038/s41598-017-15749-zMao L, Li Y, Zhao J, et al. Transforming growth factor-β1 contributes to oxaliplatin resistance in colorectal cancer via epithelial to mesenchymal transition. Oncol Lett. 2017;14(1):647–654. doi: 10.3892/ol.2017.6209Mao L, Li Y, Zhao J, et al. Transforming growth factor-β1 contributes to oxaliplatin resistance in colorectal cancer via epithelial to mesenchymal transition. Oncol Lett. 2017;14(1):647–654. doi: 10.3892/ol.2017.6209Hu J, Li J, Yue X, et al. Expression of the cancer stem cell markers ABCG2 and OCT-4 in right-sided colon cancer predicts recurrence and poor outcomes. Oncotarget. 2017;8(17):28463–28470. doi: 10.18632/oncotarget.15307Hu J, Li J, Yue X, et al. Expression of the cancer stem cell markers ABCG2 and OCT-4 in right-sided colon cancer predicts recurrence and poor outcomes. Oncotarget. 2017;8(17):28463–28470. doi: 10.18632/oncotarget.15307Zeuner A, Todaro M, Stassi G, et al. Colorectal cancer stem cells: from the crypt to the clinic. Cell Stem Cell. 2014;15(6):692–705. doi: 10.1016/j.stem.2014.11.012Zeuner A, Todaro M, Stassi G, et al. Colorectal cancer stem cells: from the crypt to the clinic. Cell Stem Cell. 2014;15(6):692–705. doi: 10.1016/j.stem.2014.11.012Paquet-Fifield S, Koh SL, Cheng L, et al. Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stemlike Cells. Cancer Res. 2018;78(11):2925–2938. doi: 10.1158/0008-5472.CAN-17-1869Paquet-Fifield S, Koh SL, Cheng L, et al. Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stemlike Cells. Cancer Res. 2018;78(11):2925–2938. doi: 10.1158/0008-5472.CAN-17-1869Hu J, Li J, Yue X, et al. Expression of the cancer stem cell markers ABCG2 and OCT-4 in right-sided colon cancer predicts recurrence and poor outcomes. Oncotarget. 2017;8(17):28463–28470. doi: 10.18632/oncotarget.15307Hu J, Li J, Yue X, et al. Expression of the cancer stem cell markers ABCG2 and OCT-4 in right-sided colon cancer predicts recurrence and poor outcomes. Oncotarget. 2017;8(17):28463–28470. doi: 10.18632/oncotarget.15307Hu J, Li J, Yue X, et al. Expression of the cancer stem cell markers ABCG2 and OCT-4 in right-sided colon cancer predicts recurrence and poor outcomes. Oncotarget. 2017;8(17):28463–28470. doi: 10.18632/oncotarget.15307

The authors declare that there are no conflicts of interest present.