References

medalphabet

Медицинский алфавит

Medical alphabet

2078-56312949-2807

ООО «Альфмед»

medalphabet-362

Research Article

Статьи

Дорога длиною в 15 лет: место бевацизумаба в лечении метастатического рака толстой кишки

15-year route: place of bevacizumab in metastatic colon cancer treatment

Артамонова

Е. В.

Artamonova

E. V.

noemail@neicon.ru

ФГБУ «Национальный медицинский исследовательский центр онкологии имени Н. Н. Блохина» Минздрава РоссииРоссияNational Medical Research Centre of Oncology n.a. N. N. BlokhinRussian Federation

2017

12112017

335

Диагностика и онкотерапия

616

2017

Артамонова Е.В.

Artamonova E.V.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.med-alphabet.com/jour/article/view/362

Обзор посвящен 15-летним исследованиям бевацизумаба при метастатическом колоректальном раке. Показано, что препарат является универсальным химиотерапевтическим партнером и может назначаться в зависимости от клинической ситуации и целей лечения как с малоинтенсивными, так и со стандартными и высокоинтенсивными режимами ХТ, независимо от наличия или отсутствия мутаций в генах RAS и BRAF. Доказанная возможность использования бевацизумаба в поддерживающей терапии (предпочтительно в комбинации с фторпиримидином) позволяет проводить системное лечение больных с нерезектабельными метастазами в рамках современной стратегии деинтенсификации без снижения показателей выживаемости. Продолжение применения бевацизумаба после прогрессирования болезни со сменой режима ХТ увеличивает продолжительность жизни больных мКРР. Препарат может назначаться при опухолях как правосторонней, так и левосторонней локализации, а проводимые исследования по определению взаимосвязи молекулярных подтипов КРР и эффективности таргетной терапии помогут улучшить достигнутые на сегодняшний день результаты.

The review focuses on 15-year studies of bevacizumab in metastatic colorectal cancer. It is shown that the drug is a universal chemotherapeutic partner and can be prescribed depending on the clinical situation and the goals of treatment with both low-intensity and standard and high-intensity modes of chemotherapy, regardless of the presence or absence of mutations in the RAS and BRAF genes. The proven possibility of using bevacizumab in maintenance therapy (preferably in combination with fluoropyrimidine) allows systemic treatment of patients with unresectable metastases within the modern strategy of de-intensification without reducing survival rates. Continued use of bevacizumab after the progression of the disease with a change in the chemotherapy regime increases the life expectancy of mCRC patients. The drug can be prescribed for tumors of both right-sided and left-sided localization, and ongoing studies to determine the relationship of molecular CRR subtypes and the effectiveness of targeted therapy will help improve the results achieved to date.

метастатический колоректальный ракбевацизумабмутации RASподдерживающая терапиялокализация первичной опухоли

BRAFmetastatic colorectal cancerbevacizumabRAS mutationsBRAFmaintenance therapylocalization of primary tumor

References1

Weber SM, Jarnagin WR, DeMatteo RP et al. Survival after resection of multiple hepatic colorectalmetastases. Ann Surg Oncol2000; 7:643-650.

Choti MA, Sitzmann JV, Tiburi MF et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002; 235: 759-766.

Tomlinson JS, Jarnagin WR, DeMatteo RP et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007; 25: 4575-4580.

Adam R, Barroso C. Impact of the type and modalities of preoperative chemotherapy on the outcome of liver resection for colorectal metastases. J Clin Oncol 2011; 29: abstr 3519.

van Cutsem E., Cervantes A., Adam R., et al. ESMO Consensus Guidelines for management of patients with metastatic corectal cancer. Annals of Oncology 2016, Vol. 27, issue 8; p. 1386-1422.

Nordlinger B, Sorbye H, Glimelius B et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008; 371: 1007-1016.

Nordlinger B., Sorbye H., Glimelius B et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC40983): long-term results of a randomised, controlled; phase 3 trial. Lancet; published online October 11, 2013. http://dx.doi.org/10,1016/S 1470-2045(13)70447-9.

Primrose J. N., Falk S., Finch-Jones M. et al. A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer: The new EPOC study. Proc. ASCO 2013, abstr. 3504.

https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf.

Saltz 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. JCO 2008; 26: 2012-2019.

Cassidy J, Clarke S, Diaz-Rubio E et al. XELOX против FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011; 105 (1): 58-64.

Grothey A. A comparison of XELOX with FOLFOX-4 as first-line treatment for metastatic colorectal cancer. Nat Clin Pract Oncol. 2009; 6 (1): 10-1.

Tournigand C, Andre T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004; 22 (2): 229-37.

Jordan K, Kellner O, Kegel T et al. Phase II trial of capecitabine/irinotecan and capecitabine/oxaliplatin in advanced gastrointestinal cancers. Clin Colorectal Cancer. 2004; 4 (1): 46-50.

Kohne CH, De Greve J, Hartmann JT et al. Irinotecan combined with infusional 5-fiuorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol2008; 19: 920-926.

Fuchs CS, Marshall J, Mitchell E et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fiuoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 2007; 25: 4779-4786.

Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fiuorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004; 22: 23-30.

Falcone A, Ricci S, Brunetti I et al. Phase III trial of infusional fiuorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fiuorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007; 25 (13): 1670-6.

Kuramochi H, Hayashi K, Uchida K, et al. Vascular endothelial growth factor messenger RNA expression level is preserved in liver metastases compared with corresponding primary colorectal cancer. Clin Cancer Res. 2006; 12 (1): 29-33.

Tanigawa N, Amaya H, Matsumura M, et al. Tumor angiogenesis and mode of metastasis in patients with colorectal cancer. Cancer Res. 1997; 57 (6): 1043-1046.

Kang SM, Maeda K, Onoda N, et al. Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis. Int J Cancer. 1997;74 (5): 502-507.

Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995; 55 (18): 3964-3968.

Gordon MS, Margolin K, Talpaz M, Sledge GW, Jr, Holmgren E, Benjamin R, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001; 19 (3): 843-850,

Margolin K, Gordon MS, Holmgren E, et al. Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol. 2001; 19 (3): 851-856.

Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fiuorouracil (FU) / leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003; 21 (1): 60-65.

Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fiuorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335-42.

Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fiuorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200, J Clin Oncol. 2007; 25 (12): 1539-1544.

Gustason B, Carlsson G, Machover D, et al. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer. 2015; 14 (1): 1-10.

Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fiuoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007; 25 (30): 4779-4786.

Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008; 26 (21): 3523-3529.

Lenz HJ, Lee F, Yau L, et al. MAVERICC, a phase 2 study of mFOLFOX6-bev-acizumab (BV) против FOLFIRI-BV with biomarker stratification as first-line (1L) chemotherapy (CT) in patients (pts) with metastatic colorectal cancer (mCRC) J Clin Oncol. 2016; 34 (suppl 4S), abstr 493.

Saltz LB, Clarke S, Diaz-Rubio E at al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: efficacy results from XELOX-1/NO16966, a randomized phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC). 2007 GI Cancers Symposium, abstr. 238.

Adams RA, Meade AM, Seymour MT et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomized phase 3 MRC COIN trial. Lancet Oncol 2011; 12 (7): 642-53.

Maughan TS, Adams RA, Smith CG et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet, 2011; 377 (9783): 2103-14.

Tveit K., Guren T., Glimelius B. et al. (2011) Randomized phase III study of 5-flurouracil / folinate / oxaliplatin given continuously or intermittently with or without cetuximab, as first-line therapy of metastatic colorectal cancer: the NORDIC VII study (NCT0014314), by the Nordic Colorectal Cancer Biomodulation Group. J. Clin. Oncol., 29 (Suppl. 4): abstract 365.

Miles D, Harbeck N, Escudier JCO 2011, v29, N1.

Rosen O, Yi J, Hurwitz HI et al. Clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Ann Oncol 2008, 19 (Suppl 6): vi 19, abstr 0-035.

Hurwitz HI, Yi J, Ince W et al. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist 2009; 14 (1): 22-28.

Falcone A., Cremolini C., Masi G., et al. FOLFOXIRI / bevacizumab (bev) versus FOLFIRI / bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group. J Clin Oncol 31, 2013 (suppl); abstr 3505.

Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label; phase 3 TRIBE study. Lancet Oncol. 2015; 16 (13): 1306-1315. doi: 10,1016 / S 1470-2045(15)00122-9.

Tol J, Nagtegaal ID; punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med 2009; 361 (1): 98-9.

Souglakos J; philips J, Wang R, et al. Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer 2009; 101 (3): 465-72.

Van Cutsem E, Kohne CH, Larng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol2011; 29 (15): 2011-9.

Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 2011; 22 (7): 1535-46.

Ince WL, Jubb AM, Holden SN, et al. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst 2005; 97 (13): 981-9.

Richman SD, Seymour MT, Chambers P, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol2009; 27 (35): 5931-7.

Loupakis F., Schirripa M., Caparello C., et al. Histopathologic evaluation of livermetastases from colorectal cancer in patients treated with FOLFOXIRI plus bevacizumab. Bitish J Cancer 2013, 108: 2549-2556.

Gruenberger T, Bridgewater J, Chau I, Garcia Alfonso P, Rivoire M, Mudan S, Lasserre S, Hermann F, Waterkamp D, Adam R. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol. 2015; 26: 702-708.

Cunningham D., Lang I., Marcuello E., et al. Bevacizumab plus capecitabin verus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label randomized phase III trial. Lancet Oncol 2013, 14: 1077-85.

Saunders M. P., Lang I., Marcuello E., et al. Efficacy and safety according to age subgroups in AVEX, a randomized phase III trial of bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer. J Clin Oncol31,2013 (suppl); abstr3521/

Tournigand C, Cervantes A, Figer A et al. OPTIMOX1: A randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin stop-and-go fashion in advanced colorectal cancer - a GERCOR study. JCO 2006; 24: 394-400/

Chibaudel B, Maindrault-Goebel F, Lledo G et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. JCO 2009; 27: 5727-5733.

Grothey A, Hart LL, Rowland KM et al. Intermittent oxaliplatin (oxali) administration and time-to-treatment-failure (TTF) in metastatic colorectal cancer (mCRC): Final results of the phase III CONcePT trial. JCO 2008; 26 (15 suppl): 4010.

Tabernero J, Aranda E, Gomez A et al. Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus bevacizumab or singl-agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC): The MACRO Trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD]). JCO 2010; 28 (15 suppl): 3501.

Diaz-Rubio E, Gomaz-Espana A, Massuti B et al. First-Line XELOX Plus Bevacizumab Followed by XELOX Plus Bevacizumab or Single-Agent Bevacizumab as Maintenance Therapy in Patients with Metastatic Colorectal Cancer: The Phase III MACRO. Oncologist 2012, 17: 15-25.

Diaz-Rubio E, Gomez-Espana A, Massuti B et al. First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase IIIMACRO TTD study. Oncologist2012; 17: 15-25.

Tournigand C, Chibaudel B, Samson B et al. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label; phase trial. Lancet Oncol2015; 16: 1493-1505.

Koeberle D, Betticher DC, von Moos R et al. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK41/06). Ann Oncol2015; 26: 709-714.

Simkens LH, van Tinteren H, May A et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAI-RO3): a phase3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 2015; 385: 1843-1852.

Hegewisch-Becker S, Graeven U, Lerchenmuller CA et al. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, openlabel, phase 3 trial. Lancet Oncol2015; 16: 1355-1369.

Johnsson A, Hagman H, Frodin JE et al. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol 2013; 24: 2335-2341/

Stein A, Atanackovic D, Hildebrandt B et al. Upfront FOLFOXIRI + bevacizumab followed by fluoropyrimidin and bevacizumab maintenance in patients with molecularly unselected metastatic colorectal cancer. Br J Cancer 2015; 113: 872-877.

Grothey A, Sugrue MM; purdie DM et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: Results from a large observational cohort study (BRiTE). J Clin Oncol 2008; 26: 5326-5334.

Cohn AL, Bekaii-Saab T, Bendell JC et al. Clinical outcomes in bevacizumab (BV)-treated patients (pts) with metastatic colorectal cancer (mCRC): Results from ARIES observational cohort study (OCS) and confirmation of BRiTE data on BV beyond progression (BBP). J Clin Oncol 2010; 28 (15 suppl): 3596.

Arnold D, Andre T, Bennouna J et al. Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: results of randomized phase III intergroup study. J Clin Oncol 2012, 30 (15 S): abstr. CRA 3503.

Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, et al. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015; 26 (4): 724-730.

Hecht JR, et al. ClinColorectal Cancer. 2015; 14 (2): 72-80.

Shitara K, et al. 2016 ASCO #3567.

Bennouna J. et al. ESMO 2017 #477O.

Heinemann V., von Weikersthal L. F., Deker T., et al. Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). J Clin Oncol2013, 31 (suppl): abstr LBA3506.

Heinemann V., Stintzing S., Jung A., Rossius L, et al. Analysis of KRAS / NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. Eur J Cancer. 2013; 49 (Suppl 3): Abstract LBA 17.

Heinemann V, Stintzing S. FOLFIRI with cetuximab or bevacizumab: FIRE-3-authors’ reply. Lancet Oncol. 2014; 15 (13): 583-584.

Lenz H., Niedzwiecki D., InnocentiF., et al. CALGB / SWOG 80405: Phase III trial of irinotecan / 5-FU / leucovorin (FOLFIRI) or oxaliplatin / 5-FU / leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum (mCRC): expanded RAS analyses. Presented at ESMO 2014, abstr. 501O. Ann Oncol, 25 (suppl. 4) (2014) Abstract 501O.

Venook A. P., Niedzwiecki D., Lenz H.-J., et al. CALGB / SWOG 80405: Phase III trial of irinotecan / 5-FU / leucovorin (FOLFIRI) or oxaliplatin / 5-FU / leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). ASCO 2014, abstr. LBA3. J Clin Oncol, 32 (suppl) (2014); p. abstr LBA3.

Schwartzberg L. S., Rivera F., Karthaus M., et al. Analysis of KRAS / NRAS mutations in PEAK: A randomized phase II study of FOLFOX6 plus panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC). J Clin Oncol2013, 31 (suppl): abstr3631.

Missiaglia E, Jacobs B, D’Ario G, Di Narzo AF, Soneson C, Budinska E; popovici V, Vecchione L GersterS, Yan P, et al. Distal and proximal colon cancers differ in terms of molecular; pathological, and clinical features. Ann Oncol. 2014; 25: 1995-2001.

Petrelli F., Tomasello G., Borgonovo K. Prognostic survival associated with left-sided против right-sided colon cancer. JAMA Oncol2017, 3: 211-9.

Arnold D, Lueza B, Douillard JY, et al. Ann Oncol. 2017 Aug 1;28(8):1862-1868. doi: 10,1093 / annonc / mdx119. 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.

Boeckx N, Koukakis R, Op de Beeck K. Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: results from two randomized first-line panitumumab studies. Ann Oncol. 2017 Aug 1; 28 (8): 1862-1868. doi: 10,1093 / annonc / mdx119.

Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1o) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analy- sis of CALGB / SWOG 80405 (Alliance). J Clin Oncol. 2016; 34 (suppl; abstr 3504).

TejparS, Stintzing S, Ciardiello F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 2017; 3 (2): 194-201, doi: 10,1001 / jamaoncol.2016.3797.

Dienstmann R, Guinney J., Delorenzi M., et al. Colorectal Cancer Subtyping Consortium (CRCSC) identification of a consensus of molecular subtypes. Presented June 3,2014, ASCO 2014, Abstract3511, J Clin Oncol 2014, 32: 5s, (suppl; abstr 3511).

Guinney 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.3967.

Stintzing S, Wirapati P, Lenz H-J, et al. Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial. J Clin Oncol 35, 2017 (suppl; abstr 3510).

Lenz H., Ou F., Venook A. P., et al. Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB / SWOG 80405 (Alliance). J Clin Oncol2017, 35: 15s, 3511/

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