tumorsMalignant tumoursMalignant tumours2224-50572587-6813Rosoncoweb10.18027/2224-5057-2024-030tumors-1426Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL REPORTSБиомаркеры резистентности к анти-EGFR терапии у пациентов с левосторонним колоректальным раком: ретроспективный NGS анализBiomarkers of resistance to anti-EGFR therapy in patients with left-sided colorectal cancer: a retrospective NGS analysishttps://orcid.org/0000-0003-1920-5076ЛебедеваА. А.LebedevaA. A.

Александра Артёмовна Лебедева

119049 Москва, Ленинский проспект, 4с1А; 119991 Москва, ул. Трубецкая, 8, стр. 2

Aleksandra Artemovna Lebedeva

Build. 1A, 4 Leninskii Prospekt, Moscow 119049; Build. 2, 8 Trubetskaya St., Moscow 119991

lebedeva@oncoatlas.ruhttps://orcid.org/0000-0002-5296-0068БяховаМ. М.ByakhovaM. M.

Мария Михайловна Бяхова

117152 Москва, Загородное шоссе, 18А

Mariya Mikhailovna Byakhova

18A Zagorodnoe Shosse, Moscow 117152

https://orcid.org/0000-0001-9864-3837ПокатаевИ. А.PokataevI. A.

Илья Анатольевич Покатаев

117152 Москва, Загородное шоссе, 18А

Ilya Anatolevich Pokataev

18A Zagorodnoe Shosse, Moscow 117152

https://orcid.org/0009-0007-6646-7454АнтоноваТ. Г.AntonovaT. G.

Татьяна Галяутдиновна Антонова

117152 Москва, Загородное шоссе, 18А

Tatyana Galyautdinovna Antonova

18A Zagorodnoe Shosse, Moscow 117152

ИвановМ. В.IvanovM. V.

119049 Москва, Ленинский проспект, 4с1А; 119991 Москва, ул. Трубецкая, 8, стр. 2; 141701 Долгопрудный, Институтский переулок, 9

Build. 1A, 4 Leninskii Prospekt, Moscow 119049; Build. 2, 8 Trubetskaya St., Moscow 119991; 9 Institutskii Pereulok, Dolgoprudny 141701, Moscow Region

https://orcid.org/0000-0002-8433-0837СеменоваА. Б.SemenovaA. B.

Анна Борисовна Семенова

117152 Москва, Загородное шоссе, 18А

Anna Borisovna Semenova

18A Zagorodnoe Shosse, Moscow 117152

https://orcid.org/0000-0001-9732-4033МакиевГ. Г.MakievG. G.

Георгий Георгиевич Макиев

115478 Москва, Каширское шоссе, 23

Georgii Georgievich Makiev

23 Kashirskoe Shosse, Moscow 115478

https://orcid.org/0000-0002-8780-6159КравчукД. А.KravchukD. A.

Дарья Александровна Кравчук

108814 Москва, п. Коммунарка, ул. Сосенский стан, 8

Darya Aleksandrovna Kravchuk

8 Sosenskiy Stan St., Moscow 108814

https://orcid.org/0000-0002-0591-7921ЕвдокимовВ. И.EvdokimovV. I

Владимир Игоревич Евдокимов

108814 Москва, п. Коммунарка, ул. Сосенский стан, 8; 129281 Москва, Олонецкий пр-д, 4/2

Vladimir Igorevich Evdokimov

8 Sosenskiy Stan St., Moscow 108814; 4 / 2 Olonetskii proezd, Moscow 129281

https://orcid.org/0009-0000-0321-618XБольшаковаЕ. А.BolshakovaE. A

Елена Алексеевна Большакова

117152 Москва, Загородное шоссе, 18А

Elena Alekseevna Bolshakova

18A Zagorodnoe Shosse, Moscow 117152

https://orcid.org/0009-0002-1084-1551СтативкоО. А.StativkoO. A.

Олеся Алексеевна Стативко

117152 Москва, Загородное шоссе, 18А

Olesya Alekseevna Stativko

18A Zagorodnoe Shosse, Moscow 117152

https://orcid.org/0000-0002-0340-7119ФеоктистоваП. С.FeoktistovaP. S.

Полина Сергеевна Феоктистова

111123 Москва, Новогиреевская ул., 1, корп. 1

Polina Sergeevna Feoktistova

Build. 1, 1 Novogireevskaya St., Moscow 111123

ИгнатьеваМ. А.IgnatevaM. A.

111123 Москва, Новогиреевская ул., 1, корп. 1

Build. 1, 1 Novogireevskaya St., Moscow 111123

https://orcid.org/0000-0001-9054-1481ГригорьеваТ. В.GrigorevaT.  V.

Татьяна Викторовна Григорьева

119049 Москва, Ленинский проспект, 4с1А; 119991 Москва, ул. Трубецкая, 8, стр. 2

Tatyana Viktorovna Grigoreva

Build. 1A, 4 Leninskii Prospekt, Moscow 119049; Build. 2, 8 Trubetskaya St., Moscow 119991

https://orcid.org/0000-0003-3861-5281КавунА. И.KavunA. I.

Александра Ивановна Кавун

119049 Москва, Ленинский проспект, 4с1А

Aleksandra Ivanovna Kavun

Aleksandra Ivanovna KavunBuild. 1A, 4 Leninskii Prospekt, Moscow 119049

https://orcid.org/0000-0002-7701-8765БеловаЕ. В.BelovaE. V.

Екатерина Владимировна Белова

119049 Москва, Ленинский проспект, 4с1А; 119991 Москва, ул. Трубецкая, 8, стр. 2

Ekaterina Vladimirovna Belova

Build. 1A, 4 Leninskii Prospekt, Moscow 119049; Build. 2, 8 Trubetskaya St., Moscow 119991

https://orcid.org/0009-0009-3631-6537ВеселовскийЕ. М.VeselovskiiE. M.

Егор Михайлович Веселовский

119049 Москва, Ленинский проспект, 4с1А

Egor Mikhailovich Veselovskii

Build. 1A, 4 Leninskii Prospekt, Moscow 119049

https://orcid.org/0000-0002-0272-1747МилейкоВ. А.MileykoV. A.

Владислав Айкович Милейко

119049 Москва, Ленинский проспект, 4с1А; 119991 Москва, ул. Трубецкая, 8, стр. 2

Vladislav Aikovich Mileyko

Build. 1A, 4 Leninskii Prospekt, Moscow 119049; Build. 2, 8 Trubetskaya St., Moscow 119991

https://orcid.org/0000-0003-2245-214XТрякинА. А.TryakinA. A.

Алексей Александрович Трякин

115478 Москва, Каширское шоссе, 23

Aleksei Aleksandrovich Tryakin

23 Kashirskoe Shosse, Moscow 115478

https://orcid.org/0000-0001-5615-7806ФедянинМ. Ю.FedyaninM. Yu.

Михаил Юрьевич Федянин

115478 Москва, Каширское шоссе, 23; 108814 Москва, п. Коммунарка, ул. Сосенский стан, 8; 105203, Москва, ул. Нижняя Первомайская, 70

Mikhail Yurevich Fedyanin

23 Kashirskoe Shosse, Moscow 115478; 8 Sosenskiy Stan St., Moscow 108814; 70 Nizhnyaya Pervomaiskaya St., Moscow 105203

https://orcid.org/0000-0002-6619-6179ГалкинВ. Н.GalkinV.  N.

Всеволод Николаевич Галкин

117152 Москва, Загородное шоссе, 18А

Vsevolod Nikolaevich Galkin

18A Zagorodnoe Shosse, Moscow 117152

ООО «Онкоатлас»; ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет)РоссияOnсoatlas; I. M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University)Russian FederationОнкологический центр №1 «Городской клинической больницы имени С.С. Юдина Департамента здравоохранения города Москвы»РоссияOncology Center No. 1 of the City Clinical Hospital named after S. S. Yudin of the Moscow Department of HealthRussian FederationООО «Онкоатлас»; ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет); ФГАОУ ВО «Московский физико-технический институт (национальный исследовательский университет)»РоссияOnсoatlas; I. M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University); Moscow Institute of Physics and TechnologyRussian FederationФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава РоссииРоссияN. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaRussian FederationГБУЗ «Московский многопрофильный клинический центр «Коммунарка» Департамента здравоохранения г. Москвы»РоссияMoscow Multidisciplinary Clinical Center “Kommunarka”, Moscow Healthcare DepartmentRussian FederationГБУЗ «Московский многопрофильный клинический центр «Коммунарка» Департамента здравоохранения г. Москвы»; Хозяйственное партнерство «Независимые медицинские партнеры»РоссияMoscow Multidisciplinary Clinical Center “Kommunarka”, Moscow Healthcare Department; Independent Medical PartnersRussian FederationГБУЗ г. Москвы «Московский клинический научно-практический центр им. А.С. Логинова Департамента здравоохранения г. Москвы»РоссияA. S. Loginov Moscow Clinical Scientific Center, Moscow Healthcare DepartmentRussian FederationООО «Онкоатлас»РоссияOnсoatlasRussian FederationФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России; ГБУЗ «Московский многопрофильный клинический центр «Коммунарка» Департамента здравоохранения г. Москвы»; ФГБУ «Национальный медико-хирургический центр им. Н.И. Пирогова» Минздрава РоссииРоссияN. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; Moscow Multidisciplinary Clinical Center “Kommunarka”, Moscow Healthcare Department; National Medical and Surgical Center named after N. I. PirogovRussian Federation2024230120251445869Copyright © Лебедева А.А., Бяхова М.М., Покатаев И.А., Антонова Т.Г., Иванов М.В., Семенова А.Б., Макиев Г.Г., Кравчук Д.А., Евдокимов В.И., Большакова Е.А., Стативко О.А., Феоктистова П.С., Игнатьева М.А., Григорьева Т.В., Кавун А.И., Белова Е.В., Веселовский Е.М., Милейко В.А., Трякин А.А., Федянин М.Ю., Галкин В.Н., 20252025Лебедева А.А., Бяхова М.М., Покатаев И.А., Антонова Т.Г., Иванов М.В., Семенова А.Б., Макиев Г.Г., Кравчук Д.А., Евдокимов В.И., Большакова Е.А., Стативко О.А., Феоктистова П.С., Игнатьева М.А., Григорьева Т.В., Кавун А.И., Белова Е.В., Веселовский Е.М., Милейко В.А., Трякин А.А., Федянин М.Ю., Галкин В.Н.Lebedeva A.A., Byakhova M.M., Pokataev I.A., Antonova T.G., Ivanov M.V., Semenova A.B., Makiev G.G., Kravchuk D.A., Evdokimov V.I., Bolshakova E.A., Stativko O.A., Feoktistova P.S., Ignateva M.A., Grigoreva T.V., Kavun A.I., Belova E.V., Veselovskii E.M., Mileyko V.A., Tryakin A.A., Fedyanin M.Y., Galkin V.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.malignanttumors.org/jour/article/view/1426Введение

Введение: на сегодняшний день для определения кандидатов для получения анти-EGFR терапии моноклональными антителами при колоректальном раке (КРР) используется анализ мутаций в генах KRAS, NRAS, BRAF p. V600, а также микросателлитной нестабильности (MSI) и амплификации HER2 (ERBB2). Недавние результаты исследований PRESSING и PARADIGM демонстрируют, что негативная гиперселекция пациентов по результатам анализа широкого спектра генов позволяет лучше прогнозировать эффективность анти-EGFR терапии.

Цель исследования

Цель исследования: ретроспективная оценка встречаемости альтераций, ассоциированных с резистентностью, в образцах пациентов, получавших анти-EGFR терапию при левостороннем раке толстой кишки с диким типом генов RAS и BRAF.

Материалы и методы

Материалы и методы: в исследование были включены пациенты с морфологически подтвержденным левосторонним КРР, получившие анти-EGFR терапию в первой линии лечения в связи с отсутствием альтераций в генах KRAS/NRAS/BRAF V600 по результатам рутинной ПЦР диагностики, выполненной в различных лабораториях. FFPE образцы были проанализированы с использованием тест-системы Соло-тест Драйвер (38 генов + MSI) на основе секвенирования нового поколения (NGS). Для KRAS/NRAS/BRAF V600-положительных по результатам NGS образцов было выполнено повторное ПЦР-тестирование.

Результаты

Результаты: в рамках исследования было проанализировано 111 образцов с использованием NGS. Альтерации в покрываемых панелью генах были выявлены у 96 (86,5%) пациентов. Всего было выявлено 172 соматических альтераций в 17 генах. Диапазон частот альтернативного аллеля (ЧАА) среди обнаруженных вариантов составил 1,3–93,0%. По результатам NGS-анализа у 29 (26,1%) пациентов были выявлены онкогенные варианты в генах KRAS (n = 24), NRAS (n = 3) или вариант BRAF p. V600E (n = 4). Повторное ПЦР-тестирование было проведено для 16 (51,6%) RAS/BRAF p. V600E-положительных пациентов (100% конкордантность между ПЦР и NGS). Среди RAS/BRAF V600E-отрицательных образцов в 10 (12,3%) образцах были выявлены другие альтерации (ERBB2 амплификация, n = 3; PIK3CA, n = 2; MSI, n = 1; BRAF мутация II класса, n = 1; ERBB3, n = 1). Среди всех проанализированных образцов в 11 (10%) образцах было выявлено более 1 мутации потенциальной резистентности. Мутации BRAF II/III класса встретились в 4 образцах. Мутации PIK3CA были выявлены у 17 (15,3%) пациентов, среди них в 5 образцах были выявлены варианты в 21 экзоне.

Выводы

Выводы: описанные результаты демонстрируют высокую долю ложноотрицательных результатов по результатам рутинного ПЦР, что приводит к избыточному назначению таргетной терапии (~ 26% случаев). Расширение спектра

Background

Background: Routine analysis of KRAS, NRAS, BRAF V600 mutations, as well as MSI and HER2 guides treatment selection in colorectal cancer (CRC). Recent findings from the PRESSING and PARADIGM trials have demonstrated that the negative hyperselection of patients based on the results of comprehensive genomic profiling results in better treatment outcomes following anti-EGFR therapy. Study objective: The study aimed to retrospectively analyze the occurrence of alterations associated with potential resistance in samples from CRC patients treated with anti-EGFR therapy.

Materials and methods

Materials and methods: Patients with confirmed left-sided CRC treated with anti-EGFR therapy due to the lack of RAS / BRAFV600 mutations as per routine PCR were included in the study. FFPE samples were analyzed via NGS (Solo-test Atlas Pro, 38 genes, MSI). Samples determined as RAS / BRAFV600positive by NGS were validated with PCR.

Results

Results: A total of 111 samples were analyzed via NGS. A total of 172 alterations in 17 genes were found; alterations in any of the genes covered by the panel were found in 96 (86.5 %) samples. The variant allele frequency ranged 1.3–93.0 %. NGS identified 29 (26.1 %) samples with KRAS (n = 24), NRAS (n = 3) or BRAF p. V600E (n = 4) mutations. Confirmatory PCR testing of 16 RAS / BRAF p. V600E-positive samples resulted in 100 % agreement with NGS. Among RAS / BRAFV600negative samples, 10 (9 %) samples harbored other alterations (ERBB2 amplification, n = 3; PIK3CA, n = 2; MSI, n = 1; BRAF class II mutation, n = 1; ERBB3, n = 1). A total of 11 samples harbored more than 1 alterations associated with potential resistance. BRAF class II / III mutations were found in 4 samples, PIK3CA mutations — in 17 (15.3 %) samples (of those, 5 samples harbored mutations in exon 21).

Conclusions

Conclusions: The results of this retrospective analysis demonstrate that a high frequency of false-positive routine PCR results may lead to incorrect indication of anti-EGFR therapy in ~ 26 % cases. Analysis of alterations beyond RAS / BRAFV600 might identify an additional 9 % of patients whose tumors are potentially resistant to anti-EGFR therapy.

колоректальный раканти-EGFR терапиябиомаркеры резистентностиKRAScolorectal canceranti-EGFR therapyresistance biomarkersKRASИсследование выполнено при финансовой поддержке гранта Московского центра инноваций в здравоохранении (№2102–2/23).The study was carried out with financial support from the Moscow Center for Innovations in Healthcare (No. 2102–2 / 23).ReferencesЗлокачественные новообразования в России в 2021 году (заболеваемость и смертность). Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М.: МНИОИ им. П.А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2022.252 с.Malignant tumors in Russia in 2021 (morbidity and mortality). Eds.: А.D. Kaprin, V.V. Starinskiy, A.O. Shachzadova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2022.252 p (In Russ.)Bray F., Laversanne M., Sung H., et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–263. https://doi.org/10.3322/caac.21834 PMID: 38572751Bray F., Laversanne M., Sung H., et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–263. https://doi.org/10.3322/caac.21834 PMID: 38572751Казаченко Е.А., Шубин В.П., Отставнов С.С. и соавт. Статус генов RAS/BRAF у пациентов с колоректальным раком (обзор литературы). Колопроктология 2024;23(3):112–125. https://doi.org/10.33878/2073-7556-2024-23-3-112-125.Kazachenko E.A., Shubin V.P., Otstanov S.S., et al. The RAS/BRAF genes status in patients with colorectal cancer (review). Koloproktologia. 2024;23(3):112–125 (In Russ.). https://doi.org/10.33878/2073-7556-2024-23-3-112-125Davies H., Bignell G.R., Cox C., et al. Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949–954. https://doi.org/10.1038/nature00766 PMID: 12068308Davies H., Bignell G.R., Cox C., et al. Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949–954. https://doi.org/10.1038/nature00766 PMID: 12068308Barras D., Missiaglia E., Wirapati P., et al. BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression. Clin Cancer Res 2017;23(1):104–115. https://doi.org/10.1158/1078-0432.CCR-16-0140Barras D., Missiaglia E., Wirapati P., et al. BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression. Clin Cancer Res 2017;23(1):104–115. https://doi.org/10.1158/1078-0432.CCR-16-0140De Roock W., Claes B., Bernasconi D., et al. 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;11(8):753–762. https://doi.org/10.1016/S1470-2045(10)70130-3De Roock W., Claes B., Bernasconi D., et al. 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;11(8):753–762. https://doi.org/10.1016/S1470-2045(10)70130-3Cantwell-Dorris E.R., O’Leary J.J., Sheils O.M. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther 2011;10(3):385–394. https://doi.org/10.1158/1535-7163.MCT-10-0799Cantwell-Dorris E.R., O’Leary J.J., Sheils O.M. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther 2011;10(3):385–394. https://doi.org/10.1158/1535-7163.MCT-10-0799Arnold D., Lueza B., Douillard J.Y., et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol 2017;28(8):1713–1729. https://doi.org/10.1093/annonc/mdx175Arnold D., Lueza B., Douillard J.Y., et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol 2017;28(8):1713–1729. https://doi.org/10.1093/annonc/mdx175Cervantes A., Adam R., Roselló S., et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023;34(1):10–32. https://doi.org/10.1016/j.annonc.2022.10.003Cervantes A., Adam R., Roselló S., et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023;34(1):10–32. https://doi.org/10.1016/j.annonc.2022.10.003Sun H., Li Y., Su Y., et al. Efficacy and safety of anti-EGFR monoclonal antibodies combined with different chemotherapy regimens in patients with RAS wild-type metastatic colorectal cancer: A meta-analysis. J Evid Based Med 2019;12(4):300–312. https://doi.org/10.1111/jebm.12360Sun H., Li Y., Su Y., et al. Efficacy and safety of anti-EGFR monoclonal antibodies combined with different chemotherapy regimens in patients with RAS wild-type metastatic colorectal cancer: A meta-analysis. J Evid Based Med 2019;12(4):300–312. https://doi.org/10.1111/jebm.12360Douillard J.Y., Siena S., Cassidy J., et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28(31):4697–4705. https://doi.org/10.1200/JCO.2009.27.4860Douillard J.Y., Siena S., Cassidy J., et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28(31):4697–4705. https://doi.org/10.1200/JCO.2009.27.4860Peeters M., Price T.J., Cervantes A., et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010;28(31):4706–4713. https://doi.org/10.1200/JCO.2009.27.6055Peeters M., Price T.J., Cervantes A., et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010;28(31):4706–4713. https://doi.org/10.1200/JCO.2009.27.6055Van Cutsem E., Köhne C.H., Hitre E., et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360(14):1408–1417. https://doi.org/10.1056/NEJMoa0805019Van Cutsem E., Köhne C.H., Hitre E., et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360(14):1408–1417. https://doi.org/10.1056/NEJMoa0805019Amado R.G., Wolf M., Peeters M., et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26(10):1626–1634. https://doi.org/10.1200/JCO.2007.14.7116Amado R.G., Wolf M., Peeters M., et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26(10):1626–1634. https://doi.org/10.1200/JCO.2007.14.7116Misale S., Yaeger R., Hobor S., et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 2012;486(7404):532–536. https://doi.org/10.1038/nature11156Misale S., Yaeger R., Hobor S., et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 2012;486(7404):532–536. https://doi.org/10.1038/nature11156Venook A.P., Niedzwiecki D., Lenz H.J., et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA 2017;317(23):2392–2401. https://doi.org/10.1001/jama.2017.7105Venook A.P., Niedzwiecki D., Lenz H.J., et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA 2017;317(23):2392–2401. https://doi.org/10.1001/jama.2017.7105Cremolini C., Antoniotti C., Lonardi S., et al. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol 2018;4(4):529–536. https://doi.org/10.1001/jamaoncol.2017.5314Cremolini C., Antoniotti C., Lonardi S., et al. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol 2018;4(4):529–536. https://doi.org/10.1001/jamaoncol.2017.5314Bokemeyer C., Köhne C.H., Ciardiello F., et al. FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. Eur J Cancer 2015;51(10):1243–1252. https://doi.org/10.1016/j.ejca.2015.04.007Bokemeyer C., Köhne C.H., Ciardiello F., et al. FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. Eur J Cancer 2015;51(10):1243–1252. https://doi.org/10.1016/j.ejca.2015.04.007Kim T.W., Elme A., Kusic Z., et al. A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer 2016;115(10):1206–1214. https://doi.org/10.1038/bjc.2016.309 PMID: 27736842Kim T.W., Elme A., Kusic Z., et al. A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer 2016;115(10):1206–1214. https://doi.org/10.1038/bjc.2016.309 PMID: 27736842Douillard J.Y., Oliner K.S., Siena S., et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369(11):1023–1034. https://doi.org/10.1056/NEJMoa1305275Douillard J.Y., Oliner K.S., Siena S., et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369(11):1023–1034. https://doi.org/10.1056/NEJMoa1305275Benson A.B., Venook A.P., Adam M., et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Colon Cancer Version 3.2024 — May 24, 2024. Available on: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdfBenson A.B., Venook A.P., Adam M., et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Colon Cancer Version 3.2024 — May 24, 2024. Available on: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdfMorano F., Corallo S., Lonardi S., et al. Negative hyperselection of patients with RAS and BRAF wild-type metastatic colorectal cancer who received panitumumab-based maintenance therapy. J Clin Oncol 2019;37(33):3099–3110. https://doi.org/10.1200/JCO.19.01254Morano F., Corallo S., Lonardi S., et al. Negative hyperselection of patients with RAS and BRAF wild-type metastatic colorectal cancer who received panitumumab-based maintenance therapy. J Clin Oncol 2019;37(33):3099–3110. https://doi.org/10.1200/JCO.19.01254Watanabe J., Muro K., Shitara K., et al. Panitumumab vs bevacizumab added to standard first-line chemotherapy and overall survival among patients with RAS wild-type, left-sided metastatic colorectal cancer: a randomized clinical trial [published correction appears in JAMA. 2023 Jun 27;329(24):2196. JAMA 2023;329(15):1271–1282. https://doi.org/10.1001/jama.2023.4428Watanabe J., Muro K., Shitara K., et al. Panitumumab vs bevacizumab added to standard first-line chemotherapy and overall survival among patients with RAS wild-type, left-sided metastatic colorectal cancer: a randomized clinical trial [published correction appears in JAMA. 2023 Jun 27;329(24):2196. JAMA 2023;329(15):1271–1282. https://doi.org/10.1001/jama.2023.4428Vidal J., Bellosillo B., Santos Vivas C., et al. Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy. Ann Oncol 2019;30(3):439–446. https://doi.org/10.1093/annonc/mdz005Vidal J., Bellosillo B., Santos Vivas C., et al. Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy. Ann Oncol 2019;30(3):439–446. https://doi.org/10.1093/annonc/mdz005Ma W., Brodie S., Agersborg S., et al. Significant Improvement in Detecting BRAF, KRAS, and EGFR Mutations Using Next-Generation Sequencing as Compared with FDA-Cleared Kits. Mol Diagn Ther 2017;21(5):571–579. https://doi.org/10.1007/s40291-017-0290-zMa W., Brodie S., Agersborg S., et al. Significant Improvement in Detecting BRAF, KRAS, and EGFR Mutations Using Next-Generation Sequencing as Compared with FDA-Cleared Kits. Mol Diagn Ther 2017;21(5):571–579. https://doi.org/10.1007/s40291-017-0290-zWolf J., Seto T., Han J.Y., et al. Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. N Engl J Med 2020;383(10):944–957. https://doi.org/10.1056/NEJMoa2002787Wolf J., Seto T., Han J.Y., et al. Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. N Engl J Med 2020;383(10):944–957. https://doi.org/10.1056/NEJMoa2002787Chen J., Xu C., Wang Q., et al. Exploration on the first-line treatment of ERBB2-altered advanced non-small cell lung cancer: A multicenter retrospective study. Lung Cancer 2023;183:107315. https://doi.org/10.1016/j.lungcan.2023.107315Chen J., Xu C., Wang Q., et al. Exploration on the first-line treatment of ERBB2-altered advanced non-small cell lung cancer: A multicenter retrospective study. Lung Cancer 2023;183:107315. https://doi.org/10.1016/j.lungcan.2023.107315Song Z., Lv D., Chen S.Q., et al. Pyrotinib in patients with HER2-amplified advanced non-small cell lung cancer: a prospective, multicenter, single-arm trial. Clin Cancer Res 2022;28(3):461–467. https://doi.org/10.1158/1078-0432.CCR-21-2936Song Z., Lv D., Chen S.Q., et al. Pyrotinib in patients with HER2-amplified advanced non-small cell lung cancer: a prospective, multicenter, single-arm trial. Clin Cancer Res 2022;28(3):461–467. https://doi.org/10.1158/1078-0432.CCR-21-2936Camidge D.R., Otterson G.A., Clark J.W., et al. Crizotinib in patients with MET-amplified NSCLC. J Thorac Oncol 2021;16(6):1017–1029. https://doi.org/10.1016/j.jtho.2021.02.010Camidge D.R., Otterson G.A., Clark J.W., et al. Crizotinib in patients with MET-amplified NSCLC. J Thorac Oncol 2021;16(6):1017–1029. https://doi.org/10.1016/j.jtho.2021.02.010Rodón J., Damian S., Furqan M., et al. Pemigatinib in previously treated solid tumors with activating FGFR1-FGFR3 alterations: phase 2 FIGHT-207 basket trial. Nat Med 2024;30(6):1645–1654. https://doi.org/10.1038/s41591-024-02934-7. Erratum in: Nat Med. 2024 Aug;30(8):2377. https://doi.org/10.1038/s41591-024-03072-wRodón J., Damian S., Furqan M., et al. Pemigatinib in previously treated solid tumors with activating FGFR1-FGFR3 alterations: phase 2 FIGHT-207 basket trial. Nat Med 2024;30(6):1645–1654. https://doi.org/10.1038/s41591-024-02934-7. Erratum in: Nat Med. 2024 Aug;30(8):2377. https://doi.org/10.1038/s41591-024-03072-wRichards S., Aziz N., Bale S., et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405–424. https://doi.org/10.1038/gim.2015.30Richards S., Aziz N., Bale S., et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405–424. https://doi.org/10.1038/gim.2015.30Horak P., Griffith M., Danos A.M., et al. Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC) [published correction appears in Genet Med. 2022 Sep;24(9):1991. Genet Med 2022;24(5):986–998. https://doi.org/10.1016/j.gim.2022.01.001Horak P., Griffith M., Danos A.M., et al. Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC) [published correction appears in Genet Med. 2022 Sep;24(9):1991. Genet Med 2022;24(5):986–998. https://doi.org/10.1016/j.gim.2022.01.001Van Cutsem E., Lenz H.J., Köhne C.H., et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015;33(7):692–700. https://doi.org/10.1200/JCO.2014.59.4812Van Cutsem E., Lenz H.J., Köhne C.H., et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015;33(7):692–700. https://doi.org/10.1200/JCO.2014.59.4812Shitara K., Muro K., Watanabe J., et al. Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer. Nat Med 2024;30(3):730–739. https://doi.org/10.1038/s41591-023-02791-wShitara K., Muro K., Watanabe J., et al. Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer. Nat Med 2024;30(3):730–739. https://doi.org/10.1038/s41591-023-02791-wInnocenti F., Ou F.S., Qu X., et al. Mutational analysis of patients with colorectal cancer in CALGB/SWOG 80405 identifies new roles of microsatellite instability and tumor mutational burden for patient outcome. J Clin Oncol 2019;37(14):1217–1227. https://doi.org/10.1200/JCO.18.01798Innocenti F., Ou F.S., Qu X., et al. Mutational analysis of patients with colorectal cancer in CALGB/SWOG 80405 identifies new roles of microsatellite instability and tumor mutational burden for patient outcome. J Clin Oncol 2019;37(14):1217–1227. https://doi.org/10.1200/JCO.18.01798Доступно по: https://roszdravnadzor.gov.ru/Доступно по: https://roszdravnadzor.gov.ru/Nguyen B., Fong C., Luthra A., et al. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell 2022;185(3):563–575.e11. https://doi.org/10.1016/j.cell.2022.01.003Nguyen B., Fong C., Luthra A., et al. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell 2022;185(3):563–575.e11. https://doi.org/10.1016/j.cell.2022.01.003Pietrantonio F., Bergamo F., Rossini D., et al. Negative hyperselection of elderly patients with RAS and BRAF wild-type metastatic colorectal cancer receiving initial panitumumab plus FOLFOX or 5-FU/LV. Eur J Cancer 2023;195:113396. https://doi.org/10.1016/j.ejca.2023.113396Pietrantonio F., Bergamo F., Rossini D., et al. Negative hyperselection of elderly patients with RAS and BRAF wild-type metastatic colorectal cancer receiving initial panitumumab plus FOLFOX or 5-FU/LV. Eur J Cancer 2023;195:113396. https://doi.org/10.1016/j.ejca.2023.113396Su W.C., Tsai Y.C., Tsai H.L., et al. Comparison of next-generation sequencing and polymerase chain reaction for personalized treatment-related genomic status in patients with metastatic colorectal cancer. Curr Issues Mol Biol 2022;44(4):1552–1563. https://doi.org/10.3390/cimb44040106Su W.C., Tsai Y.C., Tsai H.L., et al. Comparison of next-generation sequencing and polymerase chain reaction for personalized treatment-related genomic status in patients with metastatic colorectal cancer. Curr Issues Mol Biol 2022;44(4):1552–1563. https://doi.org/10.3390/cimb44040106Kothari N., Schell M.J., Teer J.K., et al. Comparison of KRAS mutation analysis of colorectal cancer samples by standard testing and next-generation sequencing. J Clin Pathol 2014;67(9):764–767. https://doi.org/10.1136/jclinpath-2014-202405Kothari N., Schell M.J., Teer J.K., et al. Comparison of KRAS mutation analysis of colorectal cancer samples by standard testing and next-generation sequencing. J Clin Pathol 2014;67(9):764–767. https://doi.org/10.1136/jclinpath-2014-202405Darwanto A., Hein A.M., Strauss S., et al. Use of the QIAGEN GeneReader NGS system for detection of KRAS mutations, validated by the QIAGEN Therascreen PCR kit and alternative NGS platform. BMC Cancer 2017;17(1):358. https://doi.org/10.1186/s12885-017-3328-zDarwanto A., Hein A.M., Strauss S., et al. Use of the QIAGEN GeneReader NGS system for detection of KRAS mutations, validated by the QIAGEN Therascreen PCR kit and alternative NGS platform. BMC Cancer 2017;17(1):358. https://doi.org/10.1186/s12885-017-3328-zLaurent-Puig P., Pekin D., Normand C., et al. Clinical relevance of KRAS-mutated subclones detected with picodroplet digital PCR in advanced colorectal cancer treated with anti-EGFR therapy. Clin Cancer Res 2015;21(5):1087–1097. https://doi.org/10.1158/1078-0432.CCR-14-0983.Laurent-Puig P., Pekin D., Normand C., et al. Clinical relevance of KRAS-mutated subclones detected with picodroplet digital PCR in advanced colorectal cancer treated with anti-EGFR therapy. Clin Cancer Res 2015;21(5):1087–1097. https://doi.org/10.1158/1078-0432.CCR-14-0983.

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