Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00050348.xml
Download PDF
CC BY 4.0 · Indian J Med Paediatr Oncol
DOI: 10.1055/s-0045-1812018
DOI: 10.1055/s-0045-1812018
Review Article
Molecular Targets in Metastatic Colorectal Cancer: A Review
Authors
Abstract
In recent years, the molecular and genetic features of colorectal cancer (CRC) have been used to categorize the disease, which has made it possible to develop therapeutic approaches based on predictive biomarkers. Valuable drivers for individualized treatment plans are biomarkers including NTRK fusions, RAS and BRAF mutations, HER2 amplification, and microsatellite instability (MSI). Furthermore, the regular use of molecular predictive diagnostics, including liquid biopsies and the reintroduction of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, presents new opportunities for the therapeutic management of patients with CRC. With an emphasis on recent developments in EGFR blockade and novel biomarkers (MSI, HER2, and NTRK), we have provided an overview of the state of targeted therapy for patients with metastatic CRC in this review.
Patient Consent
Patient consent is not required.
Publication History
Article published online:
25 September 2025
© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
-
References
- 1 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
- 2 Chibaudel B, Tournigand C, Bonnetain F. et al. Therapeutic strategy in unresectable metastatic colorectal cancer: an updated review. Ther Adv Med Oncol 2015; 7 (03) 153-169
- 3 Lièvre A, Bachet J-B, Le Corre D. et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006; 66 (08) 3992-3995
- 4 Cercek A, Braghiroli MI, Chou JF. et al. Clinical features and outcomes of patients with colorectal cancers harboring NRAS mutations. Clin Cancer Res 2017; 23 (16) 4753-4760
- 5 Allegra CJ, Rumble RB, Hamilton SR. et al. Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology Provisional Clinical Opinion update 2015. J Clin Oncol 2016; 34 (02) 179-185
- 6 Van Cutsem E, Cervantes A, Adam R. et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016; 27 (08) 1386-1422
- 7 Parseghian CM, Napolitano S, Loree JM, Kopetz S. Mechanisms of innate and acquired resistance to anti-EGFR therapy: a review of current knowledge with a focus on rechallenge therapies. Clin Cancer Res 2019; 25 (23) 6899-6908
- 8 Pietrantonio F, Vernieri C, Siravegna G. et al. Heterogeneity of acquired resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. Clin Cancer Res 2017; 23 (10) 2414-2422
- 9 Karapetis CS, Jonker D, Daneshmand M. et al; NCIC Clinical Trials Group and the Australasian Gastro-Intestinal Trials Group. PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer–results from NCIC CTG/AGITG CO.17. Clin Cancer Res 2014; 20 (03) 744-753
- 10 Jhawer M, Goel S, Wilson AJ. et al. PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 2008; 68 (06) 1953-1961
- 11 Cremolini C, Morano F, Moretto R. et al. Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclonal antibodies: the PRESSING case-control study. Ann Oncol 2017; 28 (12) 3009-3014
- 12 Laurent-Puig P, Grisoni M-L, Heinemann V. et al. Validation of miR-31–3p expression to predict cetuximab efficacy when used as first-line treatment in RAS wild-type metastatic colorectal cancer. Clin Cancer Res 2019; 25 (01) 134-141
- 13 Anandappa G, Lampis A, Cunningham D. et al. miR- 31–3p expression and benefit from anti-EGFR inhibitors in metastatic colorectal cancer patients enrolled in the prospective phase II PROSPECT-C trial. Clin Cancer Res 2019; 25 (13) 3830-3838
- 14 Pugh S, Thiébaut R, Bridgewater J. et al. Association between miR-31-3p expression and cetuximab efficacy in patients with KRAS wild-type metastatic colorectal cancer: a post-hoc analysis of the New EPOC trial. Oncotarget 2017; 8 (55) 93856-93866
- 15 Taieb J, Tabernero J, Mini E. et al; PETACC-8 Study Investigators. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15 (08) 862-873
- 16 Bridgewater JA, Pugh SA, Maishman T. et al; New EPOC investigators. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 2020; 21 (03) 398-411
- 17 Gholami S, Grothey A. EGFR antibodies in resectable metastatic colorectal liver metastasis: more harm than benefit?. Lancet Oncol 2020; 21 (03) 324-326
- 18 Modest DP, Martens UM, Riera-Knorrenschild J. et al. FOLFOXIRI plus panitumumab as first-line treatment of RAS wild-type metastatic colorectal cancer: the randomized, open-label, phase II VOLFI study (AIO KRK0109). J Clin Oncol 2019; 37 (35) 3401-3411
- 19 Douillard J-Y, Oliner KS, Siena S. et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013; 369 (11) 1023-1034
- 20 Van 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
- 21 Bokemeyer C, Bondarenko I, Makhson A. et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009; 27 (05) 663-671
- 22 Moosmann N, von Weikersthal LF, Vehling-Kaiser U. et al. Cetuximab plus capecitabine and irinotecan compared with cetuximab plus capecitabine and oxaliplatin as first-line treatment for patients with metastatic colorectal cancer: AIO KRK-0104–a randomized trial of the German AIO CRC study group. J Clin Oncol 2011; 29 (08) 1050-1058
- 23 Bokemeyer C, Van Cutsem E, Rougier P. et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 2012; 48 (10) 1466-1475
- 24 André T, Blons H, Mabro M. et al; GERCOR. Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study. Ann Oncol 2013; 24 (02) 412-419
- 25 Seymour MT, Brown SR, Middleton G. et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol 2013; 14 (08) 749-759
- 26 Cunningham D, Humblet Y, Siena S. et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351 (04) 337-345
- 27 Carrato A, Abad A, Massuti B. et al; Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD). First-line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases: a randomised, phase II trial (PLANET-TTD). Eur J Cancer 2017; 81: 191-202
- 28 Jonker DJ, O'Callaghan CJ, Karapetis CS. et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007; 357 (20) 2040-2048
- 29 Sobrero AF, Maurel J, Fehrenbacher L. et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26 (14) 2311-2319
- 30 Qin S, Li J, Wang L. et al. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol 2018; 36 (30) 3031-3039
- 31 Tveit KM, Guren T, Glimelius B. et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol 2012; 30 (15) 1755-1762
- 32 Maughan TS, Adams RA, Smith CG. et al; MRC COIN Trial Investigators. 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) 2103-2114
- 33 Price TJ, Peeters M, Kim TW. et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 2014; 15 (06) 569-579
- 34 Tejpar S, 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 2016
- 35 Arnold 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 (08) 1713-1729
- 36 Yin J, Cohen R, Jin Z. et al. Prognostic and predictive impact of primary tumor sidedness in first-line trials for advanced colorectal cancer: an analysis of 7,828 patients in the ARCAD database. J Clin Oncol 2020; 38: 188
- 37 Benson AB, Venook AP, Al-Hawary MM. et al. NCCN guidelines insights: colon cancer, version 2.2018. J Natl Compr Canc Netw 2018; 16 (04) 359-369
- 38 Mauri G, Pizzutilo EG, Amatu A. et al. Retreatment with anti-EGFR monoclonal antibodies in metastatic colorectal cancer: systematic review of different strategies. Cancer Treat Rev 2019; 73: 41-53
- 39 Tonini G, Imperatori M, Vincenzi B, Frezza AM, Santini D. Rechallenge therapy and treatment holiday: different strategies in management of metastatic colorectal cancer. J Exp Clin Cancer Res 2013; 32 (01) 92
- 40 Siravegna G, Mussolin B, Buscarino M. et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med 2015; 21 (07) 827
- 41 Martinelli E, Ciardiello D, Martini G. et al. Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives. Ann Oncol 2020; 31 (01) 30-40
- 42 Cremolini C, Rossini D, Dell'Aquila E. et al. Rechallenge for patients with RAS and BRAF wild-type metastatic colorectal cancer with acquired resistance to first-line cetuximab and irinotecan: a phase 2 single-arm clinical trial. JAMA Oncol 2019; 5 (03) 343-350
- 43 Venderbosch S, Nagtegaal ID, Maughan TS. et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res 2014; 20 (20) 5322-5330
- 44 Jones JC, Renfro LA, Al-Shamsi HO. et al. Non- V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J Clin Oncol 2017; 35 (23) 2624-2630
- 45 Yaeger R, Kotani D, Mondaca S. et al. Response to anti-EGFR therapy in patients with BRAF non-V600-mutant metastatic colorectal cancer. Clin Cancer Res 2019; 25 (23) 7089-7097
- 46 Johnson B, Loree JM, Morris VK. et al. Activity of EGFR inhibition in atypical (non-V600E) BRAF-mutated metastatic colorectal cancer. J Clin Oncol 2019; 37: 596
- 47 Pagani F, Randon G, Guarini V. et al. The landscape of actionable gene fusions in colorectal cancer. Int J Mol Sci 2019; 20 (21) 5319
- 48 Cocco E, Benhamida J, Middha S. et al. Colorectal carcinomas containing hypermethylated MLH1 promoter and wild-type BRAF/KRAS are enriched for targetable kinase fusions. Cancer Res 2019; 79 (06) 1047-1053
- 49 Tran B, Kopetz S, Tie J. et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer 2011; 117 (20) 4623-4632
- 50 Overman MJ, Lonardi S, Wong KYM. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair- deficient/microsatellite instability-high metastatic colorectal. J Clin Oncol 2018; 36 (08) 773-779
- 51 Morris V, Overman MJ, Jiang Z-Q. et al. Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. Clin Colorectal Cancer 2014; 13 (03) 164-171
- 52 Seligmann JF, Fisher D, Smith CG. et al. Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials. Ann Oncol 2017; 28 (03) 562-568
- 53 de la Fouchardière C, Cohen R, Malka D. et al. Characteristics of BRAF V600E mutant, deficient mismatch repair/proficient mismatch repair, metastatic colorectal cancer: a multicenter series of 287 patients. Oncologist 2019; 24 (12) e1331-e1340
- 54 Loupakis F, Cremolini C, Antoniotti C. et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as initial treatment for metastatic colorectal cancer (TRIBE study): updated survival results and final molecular subgroups analyses. J Clin Oncol 2015; 33: 3510
- 55 Cremolini C, Antoniotti C, Lonardi S. et al. Updated results of TRIBE2, a phase III, randomized strategy study by GONO in the 1st- and 2nd- line treatment of unresectable mCRC. Ann Oncol 2019; 37: 3058
- 56 Hurwitz H, Fehrenbacher L, Novotny W. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350 (23) 2335-2342
- 57 Price TJ, Hardingham JE, Lee CK. et al. Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J Clin Oncol 2011; 29 (19) 2675-2682
- 58 Wirapati P, Pomella V, VandenBosch B. et al. LBA-005VELOUR trial biomarkers update: impact of RAS, BRAF, and sidedness on aflibercept activity. Ann Oncol 2017; 28: iii151-iii152
- 59 Yoshino T, Portnoy DC, Obermannová R. et al. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study. Ann Oncol 2019; 30 (01) 124-131
- 60 Gelsomino F, Casadei-Gardini A, Rossini D. et al. The role of anti-angiogenics in pre-treated metastatic BRAF-mutant colorectal cancer: a pooled analysis. Cancers (Basel) 2020; 12 (04) 1022
- 61 Pietrantonio F, Petrelli F, Coinu A. et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer 2015; 51 (05) 587-594
- 62 Rowland A, Dias MM, Wiese MD. et al. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J Cancer 2015; 112 (12) 1888-1894
- 63 Stintzing S, Miller-Phillips L, Modest DP. et al; FIRE-3 Investigators. Impact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: analysis of the FIRE-3 (AIO KRK-0306) study. Eur J Cancer 2017; 79: 50-60
- 64 Kopetz S, Grothey A, Yaeger R. et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E–mutated colorectal cancer. N Engl J Med 2019; 381 (17) 1632-1643
- 65 Corcoran RB, Ebi H, Turke AB. et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2012; 2 (03) 227-235
- 66 Yaeger R, Cercek A, O'Reilly EM. et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res 2015; 21 (06) 1313-1320
- 67 Hong DS, Morris VK, El Osta B. et al. Phase 1B study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with BRAF V600E mutation. Cancer Discov 2016; 6 (12) 1352-1365
- 68 van Geel RMJM, Tabernero J, Elez E. et al. A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer. Cancer Discov 2017; 7 (06) 610-619
- 69 Kopetz S, McDonough SL, Morris VK. et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). J Clin Oncol 2017; 35: 520
- 70 Corcoran RB, André T, Atreya CE. et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAF V600E- mutant colorectal cancer. Cancer Discov 2018; 8 (04) 428-443
- 71 Kopetz S, Grothey A, Van Cutsem E. et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J Clin Oncol 2020; 38: 4001
- 72 Kopetz S, Yoshino T, Van Cutsem E. et al. BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer. Oral abstract session ASCO GI 2025 San Francisco
- 73 Beyzarov E, Zhang X, Ferrier G, Zhang X, Tabernero J. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med 2025; 1: 234-245
- 74 Battaglin F, Puccini A, Intini R. et al. The role of tumor angiogenesis as a therapeutic target in colorectal cancer. Expert Rev Anticancer Ther 2018; 18 (03) 251-266
- 75 Wirapati P, Pomella V, Kerr P. et al. Velour trial biomarkers update: impact of RAS, BRAF, and sidedness on aflibercept activity. J Clin Oncol 2017; 35: 3538
- 76 Nagasaka M, Li Y, Sukari A, Ou SI, Al-Hallak MN, Azmi AS. KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne?. Cancer Treat Rev 2020; 84: 101974
- 77 Fakih M, Desai J, Kuboki Y. et al. CodeBreak 100: activity of AMG 510, a novel small molecule inhibitor of KRASG12C, in patients with advanced colorectal cancer. J Clin Oncol 2020; 38: 4018
- 78 Colle R, Cohen R, Cochereau D. et al. Immunotherapy and patients treated for cancer with microsatellite instability. Bull Cancer 2017; 104 (01) 42-51
- 79 André T, de Gramont A, Vernerey D. et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the mosaic study. J Clin Oncol 2015; 33 (35) 4176-4187
- 80 Sargent DJ, Marsoni S, Monges G. et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010; 28 (20) 3219-3226
- 81 Zaanan A, Shi Q, Taieb J. et al. Role of deficient DNA mismatch repair status in patients with stage III colon cancer treated with FOLFOX adjuvant chemotherapy: a pooled analysis from 2 randomized clinical trials. JAMA Oncol 2018; 4 (03) 379-383
- 82 Innocenti 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
- 83 Tougeron D, Sueur B, Zaanan A. et al; Association des Gastro-entérologues Oncologues (AGEO). Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: an AGEO retrospective multicenter study. Int J Cancer 2020; 147 (01) 285-296
- 84 Taieb J, Shi Q, Pederson L. et al. Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies. Ann Oncol 2019; 30 (09) 1466-1471
- 85 Stadler ZK, Battaglin F, Middha S. et al. Reliable detection of mismatch repair deficiency in colorectal cancers using mutational load in next-generation sequencing panels. J Clin Oncol 2016; 34 (18) 2141-2147
- 86 Muzny DM, Bainbridge MN, Chang K. et al; Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487 (7407): 330-337
- 87 Maby P, Tougeron D, Hamieh M. et al. Correlation between density of CD8+ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: a rationale for personalized immunotherapy. Cancer Res 2015; 75 (17) 3446-3455
- 88 Marisa L, Svrcek M, Collura A. et al. The balance between cytotoxic T-cell lymphocytes and immune checkpoint expression in the prognosis of colon tumors. J Natl Cancer Inst 2018; 110 (01) 110
- 89 Llosa NJ, Cruise M, Tam A. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 2015; 5 (01) 43-51
- 90 Le DT, Kim TW, Van Cutsem E. et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability– high/mismatch repair–deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol 2020; 38 (01) 11-19
- 91 Le DT, Durham JN, Smith KN. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357 (6349): 409-413
- 92 André T, Berton D, de Braud F. et al. Safety and efficacy of anti-PD-1 antibody dostarlimab in patients (pts) with mismatch repair deficient (dMMR) GI cancers. J Clin Oncol 2020; 38: 218
- 93 Kim JH, Kim SY, Baek JY. et al. A phase II study of avelumab monotherapy in patients with mismatch repair-deficient/microsatellite instability-high or POLE-mutated metastatic or unresectable colorectal cancer. Cancer Res Treat 2020; 52 (04) 1135-1144
- 94 Segal NH, Wainberg ZA, Overman MJ. et al. Safety and clinical activity of durvalumab monotherapy in patients with microsatellite instability–high (MSI-H) tumors. J Clin Oncol 2019; 37: 670
- 95 Le DT, Uram JN, Wang H. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372 (26) 2509-2520
- 96 Lenz H-JJ, Van Cutsem E, Limon ML. et al. LBA18_PRDurable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Ann Oncol 2018; •••: 29
- 97 Andre T, Shiu K-K, Kim TW. et al. Pembrolizumab versus chemotherapy for microsatellite instability- high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 Study. J Clin Oncol 2020; 38: LBA4
- 98 Chalabi M, Fanchi LF, Dijkstra KK. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020; 26 (04) 566-576
- 99 Loupakis F, Depetris I, Biason P. et al. Prediction of benefit from checkpoint inhibitors in mismatch repair deficient metastatic colorectal cancer: role of tumor infiltrating lymphocytes. Oncologist 2020; 25 (06) 481-487
- 100 Cohen R, Hain E, Buhard O. et al. Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status. JAMA Oncol 2018
- 101 Middha S, Yaeger R, Shia J. et al. Majority of B2M-mutant and -deficient colorectal carcinomas achieve clinical benefit from immune checkpoint inhibitor therapy and are microsatellite instability-high. JCO Precis Oncol 2019; 3: 3
- 102 Shin DS, Zaretsky JM, Escuin-Ordinas H. et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov 2017; 7 (02) 188-201
- 103 Schrock AB, Ouyang C, Sandhu J. et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol 2019; 30 (07) 1096-1103
- 104 Mandal R, Samstein RM, Lee K-W. et al. Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science 2019; 364 (6439): 485-491
- 105 Richman SD, Southward K, Chambers P. et al. HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials. J Pathol 2016; 238 (04) 562-570
- 106 Shimada Y, Yagi R, Kameyama H. et al. Utility of comprehensive genomic sequencing for detecting HER2-positive colorectal cancer. Hum Pathol 2017; 66: 1-9
- 107 Nam SK, Yun S, Koh J. et al. BRAF, PIK3CA, and HER2 oncogenic alterations according to KRAS mutation status in advanced colorectal cancers with distant metastasis. PLoS One 2016; 11 (03) e0151865
- 108 Ross JS, Fakih M, Ali SM. et al. Targeting HER2 in colorectal cancer: the landscape of amplification and short variant mutations in ERBB2 and ERBB3. Cancer 2018; 124 (07) 1358-1373
- 109 Missiaglia E, Jacobs B, D'Ario G. et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol 2014; 25 (10) 1995-2001
- 110 Sartore-Bianchi A, Trusolino L, Martino C. et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 2016; 17 (06) 738-746
- 111 Siena S, Sartore-Bianchi A, Marsoni S. et al. Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann Oncol 2018; 29 (05) 1108-1119
- 112 Wang G, He Y, Sun Y. et al. Prevalence, prognosis and predictive status of HER2 amplification in anti-EGFR-resistant metastatic colorectal cancer. Clin Transl Oncol 2020; 22 (06) 813-822
- 113 Valtorta E, Martino C, Sartore-Bianchi A. et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol 2015; 28 (11) 1481-1491
- 114 Meric-Bernstam F, Hurwitz H, Raghav KPS. et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 2019; 20 (04) 518-530
- 115 Strickler JH, Zemla T, Ou F-S. et al. Trastuzumab and tucatinib for the treatment of HER2 amplified metastatic colorectal cancer (mCRC): initial results from the MOUNTAINEER trial. Ann Oncol 2019; 30: v200
- 116 Sartore-Bianchi A, Martino C, Lonardi S. et al. Phase II study of pertuzumab and trastuzumab-emtansine (T-DM1) in patients with HER2- positive metastatic colorectal cancer: the HERACLES-B (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification, cohort B) trial. Ann Oncol 2019; 30: v869-v870
- 117 Drilon A, Laetsch TW, Kummar S. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018; 378 (08) 731-739
- 118 Drilon A, Siena S, Ou SI. et al. Safety and antitumor activity of the multitargeted Pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372–001 and STARTRK-1). Cancer Discov 2017; 7 (04) 400-409
- 119 Solomon JP, Benayed R, Hechtman JF, Ladanyi M. Identifying patients with NTRK fusion cancer. Ann. Oncol 2019; 30 (Suppl. 08) viii16-viii22
- 120 Yoshino T, Pentheroudakis G, Mishima S. et al. JSCO-ESMO-ASCO-JSMO-TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions. Ann Oncol 2020; 31 (07) 861-872
- 121 Lasota J, Chłopek M, Lamoureux J. et al. Colonic adenocarcinomas harboring NTRK fusion genes: a clinicopathologic and molecular genetic study of 16 cases and review of the literature. Am J Surg Pathol 2020; 44 (02) 162-173
- 122 Pietrantonio F, Di Nicolantonio F, Schrock AB. et al. ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer. J Natl Cancer Inst 2017; 109 (12) 109
- 123 Okamura R, Boichard A, Kato S, Sicklick JK, Bazhenova L, Kurzrock R. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis Oncol 2018; 2018: PO.18.00183
- 124 Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15 (12) 731-747
- 125 Chou A, Fraser T, Ahadi M. et al. NTRK gene rearrangements are highly enriched in MLH1/PMS2 deficient, BRAF wild-type colorectal carcinomas—a study of 4569 cases. Mod Pathol 2020; 33 (05) 924-932