oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2016-15-1-59-66oncotomsk-311Research ArticleОБЗОРЫREVIEWSМОЛЕКУЛЯРНЫЕ МАРКЕРЫ ЧУВСТВИТЕЛЬНОСТИ И РЕЗИСТЕНТНОСТИ КАРЦИНОМ ТОЛСТОЙ КИШКИ К ТЕРАПИИ АНТАГОНИСТАМИ EGFRMOLECULAR MARKERS OF SENSITIVITY AND RESISTANCE OF COLORECTAL CANCER TO ANTI-EGFR TИванцовА. О.IvantsovA. O.

кандидат медицинских наук, младший научный сотрудник научной лаборатории морфологии опухолей, 

197758, г. Санкт-Петербург, п. Песочный, ул. Ленинградская, д. 68

MD, PhD, Researcher, Laboratory of Tumor Morphology,

68, Leningradskaya Str., Pesochny, 197758-Saint-Petersburg

ЯнусГ. А.YanusG. A.

197758, г. Санкт-Петербург, п. Песочный, ул. Ленинградская, д. 68

68, Leningradskaya Str., Pesochny, 197758-Saint-Petersburg

octavedoctor@yandex.ruСуспицынЕ. Н.SuspitsinE. N.

кандидат медицинских наук, старший научный сотрудник лаборатории молекулярной онкологии,

197758, г. Санкт-Петербург, п. Песочный, ул. Ленинградская, д. 68

MD, PhD, Senior Researcher, Laboratory of Molecular Oncology, 

68, Leningradskaya Str., Pesochny, 197758-Saint-Petersburg

evgeny.suspitsin@gmail.comАнисимоваЕ. И.AnisimovaE. I.

г. Санкт-Петербург

St-Petersburg State Pediatric Medical University,

N.N. Petrov Institute of Oncology,

Saint-Petersburg

ИмянитовЕ. Н.ImyanitovE. N.

доктор медицинских наук, профессор, руководитель отдела биологии опухолевого роста, 

197758, г. Санкт-Петербург, п. Песочный, ул. Ленинградская, д. 68

MD, Professor, Head of Department of Biology of Tumor Growth,

68, Leningradskaya Str., Pesochny, 197758-Saint-Petersburg

evgeny@imyanitov.spb.ruНИИ онкологии им. Н.Н. Петрова, г. Санкт-Петербург; Санкт-Петербургский государственный педиатрический медицинский университет, г. Санкт-ПетербургРоссияSt-Petersburg Pediatric Medical University; N.N. Petrov Institute of OncologyRussian FederationСанкт-Петербургский государственный педиатрический медицинский университетРоссияN.N. Petrov Institute of OncologyRussian FederationНИИ онкологии им. Н.Н. Петрова, г. Санкт-Петербург; Санкт-Петербургский государственный педиатрический медицинский университет, г. Санкт-Петербург; Северо-Западный государственный медицинский университет им. И.И. Мечникова, г. Санкт-ПетербургРоссияSt-Petersburg Pediatric Medical University; N.N. Petrov Institute of Oncology; I.I. Mechnikov North-Western Medical UniversityRussian Federation2016240420161515966Copyright © Иванцов А.О., Янус Г.А., Суспицын Е.Н., Анисимова Е.И., Имянитов Е.Н., 20162016Иванцов А.О., Янус Г.А., Суспицын Е.Н., Анисимова Е.И., Имянитов Е.Н.Ivantsov A.O., Yanus G.A., Suspitsin E.N., Anisimova E.I., Imyanitov E.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/311

Таргетная терапия метастатического рака толстой кишки отличается отсутствием молекулярных маркеров, позволяющих предсказать наличие выраженной чувствительности к специфическому лечению. Вместе с тем для анти-EGFR антител известны надежные маркеры резистентности к терапии. Их определение стало обязательной процедурой, предшествующей назначению соответствующих лекарственных препаратов. «Золотым стандартом» сегодняшнего дня, обозначенным в различных клинических рекомендациях, является анализ всей кодирующей последовательности генов KRAS и NRAS в опухолевой ткани. Мутации в KRAS и NRAS встречаются в 45–65 % карцином толстой кишки. Тем не менее исключение пациентов, в чьих опухолях были обнаружены мутации KRAS и NRAS, не решает полностью проблему отбора больных. Это стимулирует поиск новых предиктивных маркеров. К настоящему моменту практически доказана предиктивная роль мутаций V600E в гене BRAF. Интенсивно изучается роль мутаций и/или нарушений экспрессии генов PIK3CA, PTEN, EREG, AREG, IGF2, а также амплификаций HER2/neu и MET. Ожидается, что работы в данном направлении позволят существенно повысить клиническую и экономическую эффективность лечения рака толстой кишки.

Targeted therapy of metastatic colorectal cancer lacks predictive markers with positive predictive value, i.e. the selection of potentially responsive patients remains highly complicated. In contrast, there are very reliable markers indicating resistance to the therapy by anti-EGFR antibodies. Assessment of such markers is mandatory when EGFR targeting is considered. An analysis of tumor DNA for mutations in coding regions of KRAS and NRAS genes has become a standard procedure; the occurrence of these mutations is within 45-65%. Nevertheless, exclusion of KRAS/NRAS-mutated cases remains insufficient for the reliable selection of potential responders. There is a continuing search for novel predictive biomarkers. Multiple evidences support the role of BRAF V600E mutation in determining non-response to anti-EGFR therapy. Some data suggest an impact of PIK3CA, PTEN, EREG, AREG, IGF2 mutations and/or expression changes, as well as the significance of MET and HER2/neu gene amplifications. Further progress in this field is expected to improve clinical and economic efficacy of colorectal cancer treatment.

аденокарциномарак толстой кишкианти-EGFR антителапредиктивные маркерыKRASNRASBRAFadenocarcinomacolorectal canceranti-EGFR antibodiespredictive markersKRASNRASBRAFРНФReferencesÅlgars A., Lintunen M., Carpén O., Ristamäki R., Sundström J. EGFR gene copy number assessment from areas with highest EGFR expression predicts response to anti-EGFR therapy in colorectal cancer // Br. J. Cancer. 2011. Vol. 105 (2). P. 255–262. doi: 10.1038/bjc.2011.223.Ålgars A., Lintunen M., Carpén O., Ristamäki R., Sundström J. EGFR gene copy number assessment from areas with highest EGFR expression predicts response to anti-EGFR therapy in colorectal cancer // Br. J. Cancer. 2011. Vol. 105 (2). P. 255–262. doi: 10.1038/bjc.2011.223.Ahronian L.G., Sennott E.M., Van Allen E.M., Wagle N., Kwak E.L., Faris J.E., Godfrey J.T., Nishimura K., Lynch K.D., Mermel C.H., Lockerman E.L., Kalsy A., Gurski J.M. Jr., Bahl S., Anderka K., Green L.M., Lennon N.J., Huynh T.G., Mino-Kenudson M., Getz G., Dias-Santagata D., Iafrate A.J., Engelman J.A., Garraway L.A., Corcoran R.B. Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations // Cancer Discov. 2015. Vol. 5 (4). P. 358–367. doi: 10.1158/2159-8290.CD-14-1518.Ahronian L.G., Sennott E.M., Van Allen E.M., Wagle N., Kwak E.L., Faris J.E., Godfrey J.T., Nishimura K., Lynch K.D., Mermel C.H., Lockerman E.L., Kalsy A., Gurski J.M. Jr., Bahl S., Anderka K., Green L.M., Lennon N.J., Huynh T.G., Mino-Kenudson M., Getz G., Dias-Santagata D., Iafrate A.J., Engelman J.A., Garraway L.A., Corcoran R.B. Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations // Cancer Discov. 2015. Vol. 5 (4). P. 358–367. doi: 10.1158/2159-8290.CD-14-1518.Amado R.G., Wolf M., Peeters M., Van Cutsem E., Siena S., Freeman D.J., Juan T., Sikorski R., Suggs S., Radinsky R., Patterson S.D., Chang D.D. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer // J. Clin. Oncol. 2008. Vol. 26 (10). P. 1626–1634. doi: 10.1200/JCO.2007.14.7116.Amado R.G., Wolf M., Peeters M., Van Cutsem E., Siena S., Freeman D.J., Juan T., Sikorski R., Suggs S., Radinsky R., Patterson S.D., Chang D.D. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer // J. Clin. Oncol. 2008. Vol. 26 (10). P. 1626–1634. doi: 10.1200/JCO.2007.14.7116.Arena S., Bellosillo B., Siravegna G., Martínez A., Cañadas I., Lazzari L., Ferruz N., Russo M., Misale S., González I., Iglesias M., Gavilan E., Corti G., Hobor S., Crisafulli G., Salido M., Sánchez J., Dalmases A., Bellmunt J., De Fabritiis G., Rovira A., Di Nicolantonio F., Albanell J., Bardelli A., Montagut C. Emergence of Multiple EGFR Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer // Clin. Cancer Res. 2015. Vol. 21 (9). P. 2157–2166. doi: 10.1158/1078-0432.CCR-14-2821.Arena S., Bellosillo B., Siravegna G., Martínez A., Cañadas I., Lazzari L., Ferruz N., Russo M., Misale S., González I., Iglesias M., Gavilan E., Corti G., Hobor S., CrisafulliG., Salido M., Sánchez J., Dalmases A., Bellmunt J., De Fabritiis G., Rovira A., Di Nicolantonio F., Albanell J., Bardelli A., Montagut C. Emergence of Multiple EGFR Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer // Clin. Cancer Res. 2015. Vol. 21 (9). P. 2157–2166. doi: 10.1158/1078-0432.CCR-14-2821.Barber T.D., Vogelstein B., Kinzler K.W., Velculescu V.E. Somatic mutations of EGFR in colorectal cancers and glioblastomas // N. Engl. J. Med. 2004. Vol. 351 (27). P. 2883.Barber T.D., Vogelstein B., Kinzler K.W., Velculescu V.E. Somatic mutations of EGFR in colorectal cancers and glioblastomas // N. Engl. J. Med. 2004. Vol. 351 (27). P. 2883.Bardelli A., Corso S., Bertotti A., Hobor S., Valtorta E., Siravegna G., Sartore-Bianchi A., Scala E., Cassingena A., Zecchin D., Apicella M., Migliardi G., Galimi F., Lauricella C., Zanon C., Perera T., Veronese S., Corti G., Amatu A., Gambacorta M., Diaz L.A. Jr., Sausen M., Velculescu V.E., Comoglio P., Trusolino L., Di Nicolantonio F., Giordano S., Siena S. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer // Cancer Discov. 2013. Vol. 3 (6). P. 658–673. doi: 10.1158/2159-8290.Bardelli A., Corso S., Bertotti A., Hobor S., Valtorta E., Siravegna G., Sartore-Bianchi A., Scala E., Cassingena A., Zecchin D., Apicella M., Migliardi G., Galimi F., Lauricella C., Zanon C., Perera T., Veronese S., Corti G., Amatu A., Gambacorta M., Diaz L.A. Jr., Sausen M., Velculescu V.E., Comoglio P., Trusolino L., Di Nicolantonio F., Giordano S., Siena S. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer // Cancer Discov. 2013. Vol. 3 (6). P. 658–673. doi: 10.1158/2159-8290.Benvenuti S., Sartore-Bianchi A., Di Nicolantonio F., Zanon C., Moroni M., Veronese S., Siena S., Bardelli A. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies // Cancer Res. 2007. Vol. 67 (6). P. 2643–2648.Benvenuti S., Sartore-Bianchi A., Di Nicolantonio F., Zanon C., Moroni M., Veronese S., Siena S., Bardelli A. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies // Cancer Res. 2007. Vol. 67 (6). P. 2643–2648.Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer // Nature. 2012. Vol. 487 (7407). P. 330–337. doi: 10.1038/nature11252.Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer // Nature. 2012. Vol. 487 (7407). P. 330–337. doi: 10.1038/nature11252.Chung K.Y., Shia J., Kemeny N.E., Shah M., Schwartz G.K., Tse A., Hamilton A., Pan D., Schrag D., Schwartz L., Klimstra D.S., Fridman D., Kelsen D.P., Saltz L.B. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry // J. Clin. Oncol. 2005. Vol. 23 (9). P. 1803–1810.Chung K.Y., Shia J., Kemeny N.E., Shah M., Schwartz G.K., Tse A., Hamilton A., Pan D., Schrag D., Schwartz L., Klimstra D.S., Fridman D., Kelsen D.P., Saltz L.B. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry // J. Clin. Oncol. 2005. Vol. 23 (9). P. 1803–1810.Cremolini C., DiBartolomeoM., Amatu A., Antoniotti C., Moretto R., Berenato R., Perrone F., Tamborini E., Aprile G., Lonardi S., SartoreBianchi A., Fontanini G., Milione M., Lauricella C., Siena S., Falcone A., de Braud F., Loupakis F., Pietrantonio F. BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis // Ann. Oncol. 2015. Vol. 26 (10). P. 2092–2097. doi: 10.1093/annonc/mdv290.Cremolini C., DiBartolomeoM., Amatu A., Antoniotti C., Moretto R., Berenato R., Perrone F., Tamborini E., Aprile G., Lonardi S., SartoreBianchi A., Fontanini G., Milione M., Lauricella C., Siena S., Falcone A., de Braud F., Loupakis F., Pietrantonio F. BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis // Ann. Oncol. 2015. Vol. 26 (10). P. 2092–2097. doi: 10.1093/annonc/mdv290.De Roock W., Claes B., Bernasconi D., De Schutter J., Biesmans B., Fountzilas G., Kalogeras K.T., Kotoula V., Papamichael D., LaurentPuig P., Penault-Llorca F., Rougier P., Vincenzi B., Santini D., Tonini G., Cappuzzo F., Frattini M., Molinari F., Saletti P., De Dosso S., Martini M., Bardelli A., Siena S., Sartore-Bianchi A., Tabernero J., Macarulla T., Di Fiore F., Gangloff A.O., Ciardiello F., Pfeiffer P., Qvortrup C., Hansen T.P., Van Cutsem E., Piessevaux H., Lambrechts D., Delorenzi M., Tejpar S. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis // Lancet Oncol. 2010. Vol. 11 (8). P. 753–762. doi: 10.1016/S1470-2045(10)70130-3.De Roock W., Claes B., Bernasconi D., De Schutter J., Biesmans B., Fountzilas G., Kalogeras K.T., Kotoula V., Papamichael D., LaurentPuig P., Penault-Llorca F., Rougier P., Vincenzi B., Santini D., Tonini G., Cappuzzo F., Frattini M., Molinari F., Saletti P., De Dosso S., Martini M., Bardelli A., Siena S., Sartore-Bianchi A., Tabernero J., Macarulla T., Di Fiore F., Gangloff A.O., Ciardiello F., Pfeiffer P., Qvortrup C., Hansen T.P., Van Cutsem E., Piessevaux H., Lambrechts D., Delorenzi M., Tejpar S. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis // Lancet Oncol. 2010. Vol. 11 (8). P. 753–762. doi: 10.1016/S1470-2045(10)70130-3.Disel U., Germain A., Yilmazel B., Abali H., Bolat F.A., Yelensky R., Elvin J.A., Lipson D., Chmielecki J., Wang K., Stephens P.J., Ross J.S., Miller V.A., Ali S.M., George T.J. Jr. Durable clinical benefit to trastuzumab and chemotherapy in a patient with metastatic colon adenocarcinoma harboring ERBB2 amplification // Oncoscience. 2015. Vol. 2 (6). P. 581–584.Disel U., Germain A., Yilmazel B., Abali H., Bolat F.A., Yelensky R., Elvin J.A., Lipson D., Chmielecki J., Wang K., Stephens P.J., Ross J.S., Miller V.A., Ali S.M., George T.J. Jr. Durable clinical benefit to trastuzumab and chemotherapy in a patient with metastatic colon adenocarcinoma harboring ERBB2 amplification // Oncoscience. 2015. Vol. 2 (6). P. 581–584.Fakih M.G. Metastatic colorectal cancer: current state and future directions // J. Clin Oncol. 2015. Vol. 33 (16). P. 1809–1824. doi: 10.1200/JCO.2014.59.7633.Fakih M.G. Metastatic colorectal cancer: current state and future directions // J. Clin Oncol. 2015. Vol. 33 (16). P. 1809–1824. doi: 10.1200/JCO.2014.59.7633.Flanagan J.U., Shepherd P.R. Structure, function and inhibition of the phosphoinositide 3-kinase p110α enzyme // Biochem. Soc. Trans. 2014. Vol. 42 (1). P. 120–124. doi: 10.1042/BST20130255.Flanagan J.U., Shepherd P.R. Structure, function and inhibition of the phosphoinositide 3-kinase p110α enzyme // Biochem. Soc. Trans. 2014. Vol. 42 (1). P. 120–124. doi: 10.1042/BST20130255.Forbes S.A., Beare D., Gunasekaran P., Leung K., Bindal N., Boutselakis H., Ding M., Bamford S., Cole C., Ward S., Kok C.Y., Jia M., De T., Teague J.W., Stratton M.R., McDermott U., Campbell P.J. COSMIC: exploring the world’s knowledge of somatic mutations in human cancer // Nucleic Acids Res. 2015. Vol. 43 (Database issue). P. D805-811. doi: 10.1093/nar/gku1075.Forbes S.A., Beare D., Gunasekaran P., Leung K., Bindal N., Boutselakis H., Ding M., Bamford S., Cole C., Ward S., Kok C.Y., Jia M., De T., Teague J.W., Stratton M.R., McDermott U., Campbell P.J. COSMIC: exploring the world’s knowledge of somatic mutations in human cancer // Nucleic Acids Res. 2015. Vol. 43 (Database issue). P. D805-811. doi:10.1093/nar/gku1075.Frattini M., Saletti P., Romagnani E., Martin V., Molinari F., Ghisletta M., Camponovo A., Etienne L.L., Cavalli F., Mazzucchelli L. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients // Br. J. Cancer. 2007. Vol. 97 (8). P. 1139–1145.Frattini M., Saletti P., Romagnani E., Martin V., Molinari F., Ghisletta M., Camponovo A., Etienne L.L., Cavalli F., Mazzucchelli L. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients // Br. J. Cancer. 2007. Vol. 97 (8). P. 1139–1145.Haley L., Tseng L.H., Zheng G., Dudley J., Anderson D.A., Azad N.S., Gocke C.D., Eshleman J.R., Lin M.T. Performance characteristics of next-generation sequencing in clinical mutation detection of colorectal cancers // Mod. Pathol. 2015. Vol. 28 (10). P. 1390–1399. doi: 10.1038/modpathol.2015.86.Haley L., Tseng L.H., Zheng G., Dudley J., Anderson D.A., Azad N.S., Gocke C.D., Eshleman J.R., Lin M.T. Performance characteristics of next-generation sequencing in clinical mutation detection of colorectal cancers // Mod. Pathol. 2015. Vol. 28 (10). P. 1390–1399. doi: 10.1038/modpathol.2015.86.Hecht J.R., Douillard J.Y., Schwartzberg L., Grothey A., Kopetz S., Rong A., Oliner K.S., Sidhu R. Extended RAS analysis for anti-epidermal growth factor therapy in patients with metastatic colorectal cancer // Cancer Treat. Rev. 2015. Vol. 41 (8). P. 653–659. doi: 10.1016/j.ctrv.2015.05.008.Hecht J.R., Douillard J.Y., Schwartzberg L., Grothey A., Kopetz S., Rong A., Oliner K.S., Sidhu R. Extended RAS analysis for anti-epidermal growth factor therapy in patients with metastatic colorectal cancer // Cancer Treat. Rev. 2015. Vol. 41 (8). P. 653–659. doi: 10.1016/j.ctrv.2015.05.008.Hobor S., Van Emburgh B.O., Crowley E., Misale S., Di Nicolantonio F., Bardelli A. TGFα and amphiregulin paracrine network promotes resistance to EGFR blockade in colorectal cancer cells // Clin. Cancer Res. 2014. Vol. 20 (24). P. 6429–6438. doi: 10.1158/1078-0432. CCR-14-0774.Hobor S., Van Emburgh B.O., Crowley E., Misale S., Di Nicolantonio F., Bardelli A. TGFα and amphiregulin paracrine network promotes resistance to EGFR blockade in colorectal cancer cells // Clin. Cancer Res. 2014. Vol. 20 (24). P. 6429–6438. doi: 10.1158/1078-0432.CCR-14-0774.Huang L., Liu Z., Deng D., Tan A., Liao M., Mo Z., Yang X. Antiepidermal growth factor receptor monoclonal antibody-based therapy for metastatic colorectal cancer: a meta- analysis of the effect of PIK3CA mutations in KRAS wild-type patients // Arch. Med. Sci. 2014. Vol. 10 (1). P. 1–9. doi: 10.5114/aoms.2014.40728.Huang L., Liu Z., Deng D., Tan A., Liao M., Mo Z., Yang X. Antiepidermal growth factor receptor monoclonal antibody-based therapy for metastatic colorectal cancer: a meta-analysis of the effect of PIK3CA mutations in KRAS wild-type patients // Arch. Med. Sci. 2014. Vol. 10 (1). P. 1–9. doi: 10.5114/aoms.2014.40728.Hutchinson R.A., Adams R.A., McArt D.G., Salto-Tellez M., Jasani B., Hamilton P.W. Epidermal growth factor receptor immunohistochemistry: new opportunities in metastatic colorectal cancer // J. Transl. Med. 2015. Vol. 13. P. 217. doi: 10.1186/s12967-015-0531-z.Hutchinson R.A., Adams R.A., McArt D.G., Salto-Tellez M., Jasani B., Hamilton P.W. Epidermal growth factor receptor immunohistochemistry: new opportunities in metastatic colorectal cancer // J. Transl. Med. 2015. Vol. 13. P. 217. doi: 10.1186/s12967-015-0531-z.Italiano A., Follana P., Caroli F.X., Badetti J.L., Benchimol D., Garnier G., Gugenheim J., Haudebourg J., Keslair F., Lesbats G., Lledo G., Roussel J.F., Pedeutour F., François E. Cetuximab shows activity in colorectal cancer patients with tumors for which FISH analysis does not detect an increase in EGFR gene copy number // Ann. Surg. Oncol. 2008. Vol. 15 (2). P. 649–654.Italiano A., Follana P., Caroli F.X., Badetti J.L., Benchimol D., Garnier G., Gugenheim J., Haudebourg J., Keslair F., Lesbats G., Lledo G., Roussel J.F., Pedeutour F., François E. Cetuximab shows activity in colorectal cancer patients with tumors for which FISH analysis does not detect an increase in EGFR gene copy number // Ann. Surg. Oncol. 2008. Vol. 15 (2). P. 649–654.Jiang Z., Li C., Li F., Wang X. EGFR gene copy number as a prognostic marker in colorectal cancer patients treated with cetuximab or panitumumab: a systematic review and meta analysis // PLoS One. 2013. Vol. 8, № 2. P. e56205. doi: 10.1371/journal.pone.0056205.Jiang Z., Li C., Li F., Wang X. EGFR gene copy number as a prognostic marker in colorectal cancer patients treated with cetuximab or panitumumab: a systematic review and meta analysis // PLoS One. 2013. Vol. 8, № 2. P. e56205. doi: 10.1371/journal.pone.0056205.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., Price T.J., Shepherd L., Au H.J., Langer C., Moore M.J., Zalcberg J.R. K-ras mutations and benefit from cetuximab in advanced colorectal cancer // N. Engl. J. Med. 2008. Vol. 359 (17). P. 1757–1765. doi: 10.1056/NEJMoa0804385.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., Price T.J., Shepherd L., Au H.J., Langer C., Moore M.J., Zalcberg J.R. K-ras mutations and benefit from cetuximab in advanced colorectal cancer // N. Engl. J. Med. 2008. Vol. 359 (17). P. 1757–1765. doi: 10.1056/NEJMoa0804385.Kavuri S.M., Jain N., Galimi F., Cottino F., Leto S.M., Migliardi G., Searleman A.C., Shen W., Monsey J., Trusolino L., Jacobs S.A., Bertotti A., Bose R. HER2 Activating Mutations Are Targets for Colorectal Cancer Treatment // Cancer Discov. 2015. Vol. 5 (8). P. 832–841. doi: 10.1158/2159-8290.CD-14-1211.Kavuri S.M., Jain N., Galimi F., Cottino F., Leto S.M., Migliardi G., Searleman A.C., Shen W., Monsey J., Trusolino L., Jacobs S.A., Bertotti A., Bose R. HER2 Activating Mutations Are Targets for Colorectal Cancer Treatment // Cancer Discov. 2015. Vol. 5 (8). P. 832–841. doi: 10.1158/2159-8290.CD-14-1211.Khambata-Ford S., Garrett C.R., Meropol N.J., Basik M., Harbison C.T., Wu S., Wong T.W., Huang X., Takimoto C.H., Godwin A.K., Tan B.R., Krishnamurthi S.S., Burris H.A. 3rd, Poplin E.A., Hidalgo M., Baselga J., Clark E.A., Mauro D.J. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab // J. Clin Oncol. 2007. Vol. 25 (22). P. 3230–3237.Khambata-Ford S., Garrett C.R., Meropol N.J., Basik M., Harbison C.T., Wu S., Wong T.W., Huang X., Takimoto C.H., Godwin A.K., Tan B.R., Krishnamurthi S.S., Burris H.A. 3rd, Poplin E.A., Hidalgo M., Baselga J., Clark E.A., Mauro D.J. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab // J. Clin Oncol. 2007. Vol. 25 (22). P. 3230–3237.Kidess E., Heirich K., Wiggin M., Vysotskaia V., Visser B.C., Marziali A., Wiedenmann B., Norton J.A., Lee M., Jeffrey S.S., Poultsides G.A. 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. Vol. 6 (4). P. 2549–2561.Kidess E., Heirich K., Wiggin M., Vysotskaia V., Visser B.C., Marziali A., Wiedenmann B., Norton J.A., Lee M., Jeffrey S.S., Poultsides G.A. 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. Vol. 6 (4). P. 2549–2561.Kloth M., Ruesseler V., Engel C., Koenig K., Peifer M., Mariotti E., Kuenstlinger H., Florin A., Rommerscheidt-Fuss U., Koitzsch U., Wodtke C., Ueckeroth F., Holzapfel S., Aretz S., Propping P., Loeffler M., Merkelbach-Bruse S., Odenthal M., Friedrichs N., Heukamp L.C., Zander T., Buettner R. Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer // Gut. 2015. pii: gutjnl-2014-309026. doi: 10.1136/gutjnl-2014-309026.Kloth M., Ruesseler V., Engel C., Koenig K., Peifer M., Mariotti E., Kuenstlinger H., Florin A., Rommerscheidt-Fuss U., Koitzsch U., Wodtke C., Ueckeroth F., Holzapfel S., Aretz S., Propping P., Loeffler M., Merkelbach-Bruse S., Odenthal M., Friedrichs N., Heukamp L.C., Zander T., Buettner R. Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer // Gut. 2015. pii: gutjnl-2014-309026. doi: 10.1136/gutjnl-2014-309026.Laurent-Puig P., Pekin D., Normand C., Kotsopoulos S.K., Nizard P., Perez-Toralla K., Rowell R., Olson J., Srinivasan P., Le Corre D., Hor T., El Harrak Z., Li X., Link D.R., Bouché O., Emile J.F., Landi B., Boige V., Hutchison J.B., Taly V. Clinical relevance of KRAS-mutated subclones detected with picodroplet digital PCR in advanced colorectal cancer treated with anti-EGFR therapy // Clin. Cancer Res. 2015. Vol. 21 (5). P. 1087–1097. doi: 10.1158/1078-0432.CCR-14-0983.Laurent-Puig P., Pekin D., Normand C., Kotsopoulos S.K., Nizard P., Perez-Toralla K., Rowell R., Olson J., Srinivasan P., Le Corre D., Hor T., El Harrak Z., Li X., Link D.R., Bouché O., Emile J.F., Landi B., Boige V., Hutchison J.B., Taly V. Clinical relevance of KRAS-mutated subclones detected with picodroplet digital PCR in advanced colorectal cancer treated with anti-EGFR therapy // Clin. Cancer Res. 2015. Vol. 21 (5). P. 1087–1097. doi: 10.1158/1078-0432.CCR-14-0983.Lièvre A., Bachet J.B., Le Corre D., Boige V., Landi B., Emile J.F., Côté J.F., Tomasic G., Penna C., Ducreux M., Rougier P., Penault-Llorca F., Laurent-Puig P. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer // Cancer Res. 2006. Vol. 66 (8). P. 3992–3995.Lièvre A., Bachet J.B., Le Corre D., Boige V., Landi B., Emile J.F., Côté J.F., Tomasic G., Penna C., Ducreux M., Rougier P., Penault-Llorca F., Laurent-Puig P. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer // Cancer Res. 2006. Vol. 66 (8). P. 3992–3995.Llosa N.J., Cruise M., Tam A., Wicks E.C., Hechenbleikner E.M., Taube J.M., Blosser R.L., Fan H., Wang H., Luber B.S., Zhang M., Papadopoulos N., Kinzler K.W., Vogelstein B., Sears C.L., Anders R.A., Pardoll D.M., Housseau F. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counterinhibitory checkpoints // Cancer Discov. 2015. Vol. 5 (1). P. 43–51. doi: 10.1158/2159-8290.CD-14-0863.Llosa N.J., Cruise M., Tam A., Wicks E.C., Hechenbleikner E.M., Taube J.M., Blosser R.L., Fan H., Wang H., Luber B.S., Zhang M., Papadopoulos N., Kinzler K.W., Vogelstein B., Sears C.L., Anders R.A., Pardoll D.M., Housseau F. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counterinhibitory checkpoints // Cancer Discov. 2015. Vol. 5 (1). P. 43–51. doi: 10.1158/2159-8290.CD-14-0863.Llovet P., Sastre J., Ortega J.S., Bando I., Ferrer M., García-Alfonso P., Donnay O., Carrato A., Jiménez A., Aranda E., León A., Grávalos C., Cámara J.C., Feliú J., Sanchíz B., Caldés T., Díaz-Rubio E. Prognostic Value of BRAF, PI3K, PTEN, EGFR Copy Number, Amphiregulin and Epiregulin Status in Patients with KRAS Codon 12 Wild-Type Metastatic Colorectal Cancer Receiving First-Line Chemotherapy with Anti-EGFR Therapy // Mol. Diagn. Ther. 2015. Vol. 19 (6). P. 397–408. doi: 10.1007/s40291-015-0165-0.Llovet P., Sastre J., Ortega J.S., Bando I., Ferrer M., GarcíaAlfonso P., Donnay O., Carrato A., Jiménez A., Aranda E., León A., Grávalos C., Cámara J.C., Feliú J., Sanchíz B., Caldés T., Díaz-Rubio E. Prognostic Value of BRAF, PI3K, PTEN, EGFR Copy Number, Amphiregulin and Epiregulin Status in Patients with KRAS Codon 12 Wild-Type Metastatic Colorectal Cancer Receiving First-Line Chemotherapy with Anti-EGFR Therapy // Mol. Diagn. Ther. 2015. Vol. 19 (6). P. 397–408. doi: 10.1007/s40291-015-0165-0.Loupakis F., Ruzzo A., Cremolini C., Vincenzi B., Salvatore L., Santini D., Masi G., Stasi I., Canestrari E., Rulli E., Floriani I., Bencardino K., Galluccio N., Catalano V., Tonini G., Magnani M., Fontanini G., Basolo F., Falcone A., Graziano F. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer // Br. J. Cancer. 2009. Vol. 101 (4). P. 715–721. doi: 10.1038/sj.bjc.6605177.Loupakis F., Ruzzo A., Cremolini C., Vincenzi B., Salvatore L., Santini D., Masi G., Stasi I., Canestrari E., Rulli E., Floriani I., Bencardino K., Galluccio N., Catalano V., Tonini G., Magnani M., Fontanini G., Basolo F., Falcone A., Graziano F. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer // Br. J. Cancer. 2009. Vol. 101 (4). P. 715–721. doi: 10.1038/sj.bjc.6605177.Montagut C., Dalmases A., Bellosillo B., Crespo M., Pairet S., Iglesias M., Salido M., Gallen M., Marsters S., Tsai S.P., Minoche A., Seshagiri S., Serrano S., Himmelbauer H., Bellmunt J., Rovira A., Settleman J., Bosch F., Albanell J. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer // Nat. Med. 2012. Vol. 18 (2). P. 221–223. doi: 10.1038/nm.2609.Montagut C., Dalmases A., Bellosillo B., Crespo M., Pairet S., Iglesias M., Salido M., Gallen M., Marsters S., Tsai S.P., Minoche A., Seshagiri S., Serrano S., Himmelbauer H., Bellmunt J., Rovira A., Settleman J., Bosch F., Albanell J. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer // Nat. Med. 2012. Vol. 18 (2). P. 221–223. doi: 10.1038/nm.2609.Morelli M.P., Overman M.J., Dasari A., Kazmi S.M., Mazard T., Vilar E., Morris V.K., Lee M.S., Herron D., Eng C., Morris J., Kee B.K., Janku F., Deaton F.L., Garrett C., Maru D., Diehl F., Angenendt P., Kopetz S. Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment // Ann. Oncol. 2015. Vol. 26 (4). P. 731–736. doi: 10.1093/annonc/mdv005.Morelli M.P., Overman M.J., Dasari A., Kazmi S.M., Mazard T., Vilar E., Morris V.K., Lee M.S., Herron D., Eng C., Morris J., Kee B.K., Janku F., Deaton F.L., Garrett C., Maru D., Diehl F., Angenendt P., Kopetz S. Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment // Ann. Oncol. 2015. Vol. 26 (4). P. 731–736. doi: 10.1093/annonc/mdv005.Moroni M., Veronese S., Benvenuti S., Marrapese G., SartoreBianchi A., Di Nicolantonio F., Gambacorta M., Siena S., Bardelli A. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study // Lancet Oncol. 2005. Vol. 6 (5). P. 279–286.Moroni M., Veronese S., Benvenuti S., Marrapese G., SartoreBianchi A., Di Nicolantonio F., Gambacorta M., Siena S., Bardelli A. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study // Lancet Oncol. 2005. Vol. 6 (5). P. 279–286.Ooi A., Takehana T., Li X., Suzuki S., Kunitomo K., Iino H., Fujii H., Takeda Y., Dobashi Y. Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: an immunohistochemical and fluorescent in situ hybridization study // Mod. Pathol. 2004. Vol. 17 (8). P. 895–904.Ooi A., Takehana T., Li X., Suzuki S., Kunitomo K., Iino H., Fujii H., Takeda Y., Dobashi Y. Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: an immunohistochemical and fluorescent in situ hybridization study // Mod. Pathol. 2004. Vol. 17 (8). P. 895–904.Peeters M., Douillard J.Y., Van Cutsem E., Siena S., Zhang K., Williams R., Wiezorek J. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab // J. Clin. Oncol. 2013. Vol. 31 (6). P. 759–765. doi: 10.1200/JCO.2012.45.1492.Peeters M., Douillard J.Y., Van Cutsem E., Siena S., Zhang K., Williams R., Wiezorek J. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab // J. Clin. Oncol. 2013. Vol. 31 (6). P. 759–765. doi: 10.1200/JCO.2012.45.1492.Pietrantonio F., Petrelli F., Coinu A., Di Bartolomeo M., Borgonovo K., Maggi C., Cabiddu M., Iacovelli R., Bossi I., Lonati V., Ghilardi M., de Braud F., Barni S. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a metaanalysis // Eur. J. Cancer. 2015. Vol. 51 (5). P. 587–594. doi: 10.1016/j.ejca.2015.01.054.Pietrantonio F., Petrelli F., Coinu A., Di Bartolomeo M., Borgonovo K., Maggi C., Cabiddu M., Iacovelli R., Bossi I., Lonati V., Ghilardi M., de Braud F., Barni S. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a metaanalysis // Eur. J. Cancer. 2015. Vol. 51 (5). P. 587–594. doi: 10.1016/j.ejca.2015.01.054.Piton N., Lonchamp E., Nowak F., Sabourin J.C.; KRAS group. Real-Life Distribution of KRAS and NRAS Mutations in Metastatic Colorectal Carcinoma from French Routine Genotyping // Cancer Epidemiol. Biomarkers Prev. 2015. Vol. 24 (9). P. 1416–1418. doi: 10.1158/1055-9965.EPI-15-0059.Piton N., Lonchamp E., Nowak F., Sabourin J.C.; KRAS group. Real-Life Distribution of KRAS and NRAS Mutations in Metastatic Colorectal Carcinoma from French Routine Genotyping // Cancer Epidemiol. Biomarkers Prev. 2015. Vol. 24 (9). P. 1416–1418. doi: 10.1158/1055-9965.EPI-15-0059.Razis E., Pentheroudakis G., Rigakos G., Bobos M., Kouvatseas G., Tzaida O., Makatsoris T., Papakostas P., Bai M., Goussia A., Samantas E., Papamichael D., Romanidou O., Efstratiou I., Tsolaki E., Psyrri A., De Roock W., Bafaloukos D., Klouvas G., Tejpar S., Kalogeras K.T., Pectasides D., Fountzilas G. EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetuximab // J. Cancer Res. Clin. Oncol. 2014. Vol. 140 (5). P. 737–748. doi: 10.1007/s00432-014-1626-2.Razis E., Pentheroudakis G., Rigakos G., Bobos M., Kouvatseas G., Tzaida O., Makatsoris T., Papakostas P., Bai M., Goussia A., Samantas E., Papamichael D., Romanidou O., Efstratiou I., Tsolaki E., Psyrri A., De Roock W., Bafaloukos D., Klouvas G., Tejpar S., Kalogeras K.T., Pectasides D., Fountzilas G. EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetuximab // J. Cancer Res. Clin. Oncol. 2014. Vol. 140 (5). P. 737–748. doi: 10.1007/s00432-014-1626-2.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. Vol. 112 (12). P. 1888–1894. doi: 10.1038/bjc.2015.173.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. Vol. 112 (12). P. 1888–1894. doi: 10.1038/bjc.2015.173.Saltz L.B., Meropol N.J., Loehrer P.J. Sr., Needle M.N., Kopit J., Mayer R.J. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor // J. Clin. Oncol. 2004. Vol. 22 (7). P. 1201–1208.Saltz L.B., Meropol N.J., Loehrer P.J. Sr., Needle M.N., Kopit J., Mayer R.J. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor // J. Clin. Oncol. 2004. Vol. 22 (7). P. 1201–1208.Sartore-Bianchi A., Fieuws S., Veronese S., Moroni M., Personeni N., Frattini M., Torri V., Cappuzzo F., Vander Borght S., Martin V., Skokan M., Santoro A., Gambacorta M., Tejpar S., Varella-Garcia M., Siena S. Standardisation of EGFR FISH in colorectal cancer: results of an international interlaboratory reproducibility ring study // J. Clin. Pathol. 2012. Vol. 65 (3). P. 218–223. doi: 10.1136/jclinpath-2011-200353.Sartore-Bianchi A., Fieuws S., Veronese S., Moroni M., Personeni N., Frattini M., Torri V., Cappuzzo F., Vander Borght S., Martin V., Skokan M., Santoro A., Gambacorta M., Tejpar S., Varella-Garcia M., Siena S. Standardisation of EGFR FISH in colorectal cancer: results of an international interlaboratory reproducibility ring study // J. Clin. Pathol. 2012. Vol. 65 (3). P. 218–223. doi: 10.1136/jclinpath-2011-200353.Seo Y., Ishii Y., Ochiai H., Fukuda K., Akimoto S., Hayashida T., Okabayashi K., Tsuruta M., Hasegawa H., Kitagawa Y. Cetuximabmediated ADCC activity is correlated with the cell surface expression level of EGFR but not with the KRAS/BRAF mutational status in colorectal cancer // Oncol. Rep. 2014. Vol. 31 (5). P. 2115–2122. doi: 10.3892/or.2014.3077.Seo Y., Ishii Y., Ochiai H., Fukuda K., Akimoto S., Hayashida T., Okabayashi K., Tsuruta M., Hasegawa H., Kitagawa Y. Cetuximabmediated ADCC activity is correlated with the cell surface expression level of EGFR but not with the KRAS/BRAF mutational status in colorectal cancer // Oncol. Rep. 2014. Vol. 31 (5). P. 2115–2122. doi: 10.3892/or.2014.3077.Seppälä T.T., Böhm J.P., Friman M., Lahtinen L., Väyrynen V.M., Liipo T.K., Ristimäki A.P., Kairaluoma M.V., Kellokumpu I.H., Kuopio T.H., Mecklin J.P. Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer // Br. J. Cancer. 2015. Vol. 112 (12). P. 1966–1975. doi: 10.1038/bjc.2015.160.Seppälä T.T., Böhm J.P., Friman M., Lahtinen L., Väyrynen V.M., Liipo T.K., Ristimäki A.P., Kairaluoma M.V., Kellokumpu I.H., Kuopio T.H., Mecklin J.P. Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer // Br. J. Cancer. 2015. Vol. 112 (12). P. 1966–1975. doi: 10.1038/bjc.2015.160.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. Vol. 26 (1). P. 13–21. doi: 10.1093/annonc/mdu378.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. Vol. 26 (1). P. 13–21. doi: 10.1093/annonc/mdu378.Valtorta E., Misale S., Sartore-Bianchi A., Nagtegaal I.D., Paraf F., Lauricella C., Dimartino V., Hobor S., Jacobs B., Ercolani C., Lamba S., Scala E., Veronese S., Laurent-Puig P., Siena S., Tejpar S., Mottolese M., Punt C.J., Gambacorta M., Bardelli A., Di Nicolantonio F. KRAS gene amplification in colorectal cancer and impact on response to EGFRtargeted therapy // Int. J. Cancer. 2013. Vol. 133 (5). P. 1259–1265. doi: 10.1002/ijc.28106.Valtorta E., Misale S., Sartore-Bianchi A., Nagtegaal I.D., Paraf F., Lauricella C., Dimartino V., Hobor S., Jacobs B., Ercolani C., Lamba S., Scala E., Veronese S., Laurent-Puig P., Siena S., Tejpar S., Mottolese M., Punt C.J., Gambacorta M., Bardelli A., Di Nicolantonio F. KRAS gene amplification in colorectal cancer and impact on response to EGFRtargeted therapy // Int. J. Cancer. 2013. Vol. 133 (5). P. 1259–1265. doi: 10.1002/ijc.28106.Westwood M., van Asselt T., Ramaekers B., Whiting P., Joore M., Armstrong N., Noake C., Ross J., Severens J., Kleijnen J. KRAS mutation testing of tumours in adults with metastatic colorectal cancer: a systematic review and cost-effectiveness analysis // Health Technol. Assess. 2014. Vol. 18 (62). P. 1–132. doi: 10.3310/hta18620.Westwood M., van Asselt T., Ramaekers B., Whiting P., Joore M., Armstrong N., Noake C., Ross J., Severens J., Kleijnen J. KRAS mutation testing of tumours in adults with metastatic colorectal cancer: a systematic review and cost-effectiveness analysis // Health Technol. Assess. 2014. Vol. 18 (62). P. 1–132. doi: 10.3310/hta18620.Yang Z.Y., Shen W.X., Hu X.F., Zheng D.Y., Wu X.Y., Huang Y.F., Chen J.Z., Mao C., Tang J.L. EGFR gene copy number as a predictive biomarker for the treatment of metastatic colorectal cancer with antiEGFR monoclonal antibodies: a meta-analysis // J. Hematol. Oncol. 2012. Vol. 5. P. 52.Yang Z.Y., Shen W.X., Hu X.F., Zheng D.Y., Wu X.Y., Huang Y.F., Chen J.Z., Mao C., Tang J.L. EGFR gene copy number as a predictive biomarker for the treatment of metastatic colorectal cancer with antiEGFR monoclonal antibodies: a meta-analysis // J. Hematol. Oncol. 2012. Vol. 5. P. 52.Yang Z.Y., Wu X.Y., Huang Y.F., Di M.Y., Zheng D.Y., Chen J.Z., Ding H., Mao C., Tang J.L. Promising biomarkers for predicting the outcomes of patients with KRAS wild-type metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a systematic review with meta-analysis // Int. J. Cancer. 2013. Vol. 133 (8). P. 1914–1925. doi: 10.1002/ijc.28153.Yang Z.Y., Wu X.Y., Huang Y.F., Di M.Y., Zheng D.Y., Chen J.Z., Ding H., Mao C., Tang J.L. Promising biomarkers for predicting the outcomes of patients with KRAS wild-type metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a systematic review with meta-analysis // Int. J. Cancer. 2013. Vol. 133 (8). P. 1914–1925. doi: 10.1002/ijc.28153.Yanus G.A., Belyaeva A.V., Ivantsov A.O., Kuligina E.Sh., Suspitsin E.N., Mitiushkina N.V., Aleksakhina S.N., Iyevleva A.G., Zaitseva O.A., Yatsuk O.S., Gorodnova T.V., Strelkova T.N., Efremova S.A., Lepenchuk A.Y., Ochir-Garyaev A.N., Paneyah M.B., Matsko D.E., Togo A.V., Imyanitov E.N. Pattern of clinically relevant mutations in consecutive series of Russian colorectal cancer patients // Med. Oncol. 2013. Vol. 30 (3). P. 686. doi: 10.1007/s12032-013-0686-5.Yanus G.A., Belyaeva A.V., Ivantsov A.O., Kuligina E.Sh., Suspitsin E.N., Mitiushkina N.V., Aleksakhina S.N., Iyevleva A.G., Zaitseva O.A., Yatsuk O.S., Gorodnova T.V., Strelkova T.N., Efremova S.A., Lepenchuk A.Y., Ochir-GaryaevA.N., Paneyah M.B., Matsko D.E., Togo A.V., Imyanitov E.N. Pattern of clinically relevant mutations in consecutive series of Russian colorectal cancer patients // Med. Oncol. 2013. Vol. 30 (3). P. 686. doi: 10.1007/s12032-013-0686-5.Yonesaka K., Zejnullahu K., Okamoto I., Satoh T., Cappuzzo F., Souglakos J., Ercan D., Rogers A., Roncalli M., Takeda M., Fujisaka Y., Philips J., Shimizu T., Maenishi O., Cho Y., Sun J., Destro A., Taira K., Takeda K., Okabe T., Swanson J., Itoh H., Takada M., Lifshits E., Okuno K., Engelman J.A., Shivdasani R.A., Nishio K., Fukuoka M., Varella-Garcia M., Nakagawa K., Jänne P.A. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab // Sci. Transl. Med. 2011. Vol. 3 (99). P. 99ra86. doi: 10.1126/scitranslmed.3002442.Yonesaka K., Zejnullahu K., Okamoto I., Satoh T., Cappuzzo F., Souglakos J., Ercan D., Rogers A., Roncalli M., Takeda M., Fujisaka Y., Philips J., Shimizu T., Maenishi O., Cho Y., Sun J., Destro A., Taira K., Takeda K., Okabe T., Swanson J., Itoh H., Takada M., Lifshits E., Okuno K., Engelman J.A., Shivdasani R.A., Nishio K., Fukuoka M., Varella-Garcia M., Nakagawa K., Jänne P.A. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab // Sci. Transl. Med. 2011. Vol. 3 (99). P. 99ra86. doi: 10.1126/scitranslmed.3002442.Zanella E.R., Galimi F., Sassi F., Migliardi G., Cottino F., Leto S.M., Lupo B., Erriquez J., Isella C., Comoglio P.M., Medico E., Tejpar S., Budinská E., Trusolino L., Bertotti A. IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies // Sci. Transl. Med. 2015. Vol. 7 (272). P. 272ra12. doi: 10.1126/scitranslmed.3010445.Zanella E.R., Galimi F., Sassi F., Migliardi G., Cottino F., Leto S.M., Lupo B., Erriquez J., Isella C., Comoglio P.M., Medico E., Tejpar S., Budinská E., Trusolino L., Bertotti A. IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies // Sci. Transl. Med. 2015. Vol. 7 (272). P. 272ra12. doi: 10.1126/scitranslmed.3010445.

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