Table Info

Table 2.

Main clinical trials that explored predictive biomarkers in CRC

Biomarker	Clinical trial	Results
*RAS*	PRIME [15]	The combination of panitumumab and FOLFOX4 significantly improved PFS in patients with KRAS wild-type tumors.
	CRYSTAL [20]	Molecular testing of tumors for all activating RAS mutations is essential before considering anti-epidermal growth factor receptor therapy, thereby allowing the further tailoring of cetuximab administration to maximize patient benefit.
	OPUS [16]	The addition of cetuximab to FOLFOX-4 significantly improved PFS and response in patients with KRAS wild-type tumors.
	MRC COIN [17]	This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced CRC.
	FIRE-3 [23]	In this study a significantly higher OS was demonstrated for FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup.
	NCT03600883 [35]	Early results suggest antitumor activity of single-agent AMG 510 in KRAS^G12C mutant solid tumors.
	NCT03785249 [33]	The trial is ongoing and responses to treatment with MRTX849 have been observed in both lung and CRC KRASG12C mutant patients.
*BRAF*	SWOG 1406 [62]	The addition of vemurafenib to the combination of cetuximab and irinotecan in BRAFV600 mutated tumors resulted in a prolongation of PFS and a higher disease control rate.
*BRAF*	BEACON CRC [63]	A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer OS and a higher response rate than standard therapy in patients with mCRC with the BRAF V600E mutation.
MSI	NCT01876511 [71]	This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab.
MSI	CheckMate 142 [73]	Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H mCRC.
HER-2	HERACLES [81]	The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive tumors.
HER-2	MyPathway [86]	Durable responses were seen in patients with refractory colorectal cancers with HER2 activation/overexpression when the approved targeted therapy regimen administered without chemotherapy.
CMSs	CALGB/SWOG 80405 [131]	The CMSs are highly prognostic and predictive for OS and PFS.
CMSs	Fire-3(AIO KRK-0306) [132]	Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS2 and CMS4.

OS: overall survival

Declarations

Author contributions

AMR and NN contributed conception and design of the review; AMR wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108. [DOI] [PubMed]

Wolpin BM, Mayer RJ. Systemic treatment of colorectal cancer. Gastroenterology. 2008;134:1296–310. [DOI] [PubMed] [PMC]

Boeckx N, Janssens K, Van Camp G, Rasschaert M, Papadimitriou K, Peeters M, et al. The predictive value of primary tumor location in patients with metastatic colorectal cancer: a systematic review. Crit Rev Oncol Hematol. 2018;121:1–10. [DOI] [PubMed]

Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386–422. [DOI] [PubMed]

Normanno N, Tejpar S, Morgillo F, De Luca A, Van Cutsem E, Ciardiello F. Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol. 2009;6:519–27. [DOI] [PubMed]

The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;48:330–7. [DOI]

Goodsell DS. The molecular perspective: the ras oncogene. Oncologist. 1999;4:263–4. [DOI] [PubMed]

Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13:828–51. [DOI] [PubMed] [PMC]

Piton N, Lonchamp E, Nowak F, Sabourin JC; KRAS group. Real-life distribution of KRAS and NRAS mutations in metastatic colorectal carcinoma from French routine genotyping. Cancer Epidemiol Biomarkers Prev. 2015;24:1416–8. [DOI] [PubMed]

10.

Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–34. [DOI] [PubMed]

11.

Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65. [DOI] [PubMed]

12.

Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71. [DOI] [PubMed]

13.

Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17. [DOI] [PubMed]

14.

Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, 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;28:4706–13. [DOI] [PubMed]

15.

Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, 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;28:4697–705. [DOI] [PubMed]

16.

Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, 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;22:1535–46. [DOI] [PubMed]

17.

Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, 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;377:2103–14. [DOI] [PubMed] [PMC]

18.

Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015;26:13–21. [DOI] [PubMed]

19.

Bokemeyer C, Kohne CH, Ciardiello F, Lenz HJ, Heinemann V, Klinkhardt U, et al. FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. Eur J Cancer. 2015;51:1243–52. [DOI] [PubMed]

20.

Van Cutsem E, Lenz HJ, Kohne CH, Heinemann V, Tejpar S, Melezínek I, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33:692–700. [DOI] [PubMed]

21.

Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34. [DOI] [PubMed]

22.

Peeters M, Oliner KS, Price TJ, Cervantes A, Sobrero AF, Ducreux M, et al. Analysis of KRAS/NRAS mutations in a phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clin Cancer Res. 2015;21:5469–79. [DOI] [PubMed]

23.

Stintzing S, Modest DP, Rossius L, Lerch MM, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016;17:1426–34. [DOI] [PubMed]

24.

Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, et al. Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Mol Diagn. 2017;19:187–225. [DOI] [PubMed] [PMC]

25.

McGranahan N, Favero F, de Bruin EC, Birkbak NJ, Szallasi Z, Swanton C. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci Transl Med. 2015;7:283ra54. [DOI]

26.

Normanno N, Rachiglio AM, Lambiase M, Martinelli E, Fenizia F, Esposito C, et al. Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial. Ann Oncol. 2015;26:1710–4. [DOI] [PubMed]

27.

Normanno N, Esposito Abate R, Lambiase M, Forgione L, Cardone C, Iannaccone A, et al. RAS testing of liquid biopsy correlates with the outcome of metastatic colorectal cancer patients treated with first-line FOLFIRI plus cetuximab in the CAPRI-GOIM trial. Ann Oncol. 2018;29:112–8. [DOI] [PubMed]

28.

Khan KH, Cunningham D, Werner B, Vlachogiannis G, Spiteri I, Heide T, et al. Longitudinal liquid biopsy and mathematical modeling of clonal evolution forecast time to treatment failure in the PROSPECT-C phase II colorectal cancer clinical trial. Cancer Discov. 2018;8:1270–85. [DOI] [PubMed] [PMC]

29.

Vidal J, Bellosillo B, Santos Vivas C, García-Alfonso P, Carrato A, Cano MT, et al. Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy. Ann Oncol. 2019;30:439–46. [DOI] [PubMed]

30.

Santos C, Azuara D, Viéitez JM, Páez D, Falcó E, Élez E, et al. Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial. Ann Oncol. 2019;30:796–803. [DOI] [PubMed]

31.

O’Bryan JP. Pharmacological targeting of RAS: recent success with direct inhibitors. Pharmacol Res. 2019;139:503–11. [DOI] [PubMed] [PMC]

32.

Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. The KRASG12C inhibitor, MRTX849, provides insight toward therapeutic susceptibility of KRAS mutant cancers in mouse models and patients. Cancer Discov. 2020;10:54–71. [DOI] [PubMed] [PMC]

33.

Papadopoulos KP, Ou SI, Johnson ML, Christensen J, Velastegui K, Potvin D, et al. A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation. J Clin Oncol. 2019;37:15_suppl TPS3161. [DOI]

34.

Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575:217–23. [DOI] [PubMed]

35.

Govindan R, Fakih MG, Price TJ, Falchook GS, Desai J, Kuo JC, et al. Phase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours. Annn Oncol. 2019;30 suppl_5:v163–4. [DOI]

36.

Yuan ZX, Wang XY, Qin QY, Chen DF, Zhong QH, Wang L, et al. The prognostic role of BRAF mutation in metastatic colorectal cancer receiving anti-EGFR monoclonal antibodies: a meta-analysis. PLoS One. 2013;8:e65995. [DOI] [PubMed] [PMC]

37.

Forbes SA, Bhamra G, Bamford S, Dawson E, Kok C, Clements J, et al. The catalogue of somatic mutations in cancer (COSMIC). Curr Protoc Hum Genet. 2008;57.

38.

Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855–67. [DOI] [PubMed]

39.

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54. [DOI] [PubMed]

40.

Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007;50:113–30. [DOI] [PubMed]

41.

Schirripa M, Lenz HJ. Biomarker in colorectal cancer. Cancer J. 2016;22:156–64. [DOI] [PubMed] [PMC]

42.

Lai E, Pretta A, Impera V, Mariani S, Giampieri R, Casula L, et al. BRAF-mutant colorectal cancer, a different breed evolving. Expert Rev Mol Diagn. 2018;18:499–512. [DOI] [PubMed]

43.

Roma C, Rachiglio AM, Pasquale R, Fenizia F, Iannaccone A, Tatangelo F, et al. BRAF V600E mutation in metastatic colorectal cancer: Methods of detection and correlation with clinical and pathologic features. Cancer Biol Ther. 2016;17:840–8. [DOI] [PubMed] [PMC]

44.

Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117:4623–32. [DOI] [PubMed] [PMC]

45.

Fariña-Sarasqueta A, van Lijnschoten G, Moerland E, Creemers GJ, Lemmens VE, Rutten HJ, et al. The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol. 2010;21:2396–402. [DOI] [PubMed]

46.

Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361:98–9.

47.

Sinicrope FA, Shi Q, Allegra CJ, Smyrk TC, Thibodeau SN, Goldberg RM, et al. Association of DNA mismatch repair and mutations in BRAF and KRAS with survival after recurrence in stage III colon cancers: a secondary analysis of 2 randomized clinical trials. JAMA Oncol. 2017;3:472–80. [DOI] [PubMed] [PMC]

48.

Teng HW, Huang YC, Lin JK, Chen WS, Lin TC, Jiang JK, et al. BRAF mutation is a prognostic biomarker for colorectal liver metastasectomy. J Surg Oncol. 2012;106:123–9. [DOI] [PubMed]

49.

Karagkounis G, Torbenson MS, Daniel HD, Azad NS, Diaz LA Jr, Donehower RC, et al. Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer. 2013;119:4137–44. [DOI] [PubMed] [PMC]

50.

Schirripa M, Bergamo F, Cremolini C, Casagrande M, Lonardi S, Aprile G, et al. BRAF and RAS mutations as prognostic factors in metastatic colorectal cancer patients undergoing liver resection. Br J Cancer. 2015;112:1921–8. [DOI] [PubMed] [PMC]

51.

Seligmann JF, Fisher D, Smith CG, Richman SD, Elliott F, Brown S, et al. Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials. Ann Oncol. 2017;28:562–8. [DOI] [PubMed]

52.

Yao Z, Torres NM, Tao A, Gao Y, Luo L, Li Q, et al. BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell. 2015;28:370–83. [DOI] [PubMed] [PMC]

53.

Yao Z, Yaeger R, Rodrik-Outmezguine VS, Tao A, Torres NM, Chang MT, et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature. 2017;548:234–8. [DOI] [PubMed] [PMC]

54.

Jones JC, Renfro LA, Al-Shamsi HO, Schrock AB, Rankin A, Zhang BY, et al. Non-V600BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J Clin Oncol. 2017;35:2624–30. [DOI] [PubMed] [PMC]

55.

Cremolini C, Di Bartolomeo M, Amatu A, Antoniotti C, Moretto R, Berenato R, et al. BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis. Ann Oncol. 2015;26:2092–7. [DOI] [PubMed]

56.

Schirripa M, Biason P, Lonardi S, Pella N, Pino MS, Urbano F, et al. Class 1, 2, and 3 BRAF-mutated metastatic colorectal cancer: a detailed clinical, pathologic, and molecular characterization. Clin Cancer Res. 2019;25:3954–61. [DOI] [PubMed]

57.

Pietrantonio F, Petrelli F, Coinu A, Di Bartolomeo M, Borgonovo K, Maggi C, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015;51:587–94. [DOI] [PubMed]

58.

Rowland A, Dias MM, Wiese MD, Kichenadasse G, McKinnon RA, Karapetis CS, 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;112:1888–94. [DOI] [PubMed] [PMC]

59.

Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF (V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100–3. [DOI] [PubMed]

60.

Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol. 2015;33:4023–31. [DOI] [PubMed] [PMC]

61.

Corcoran RB, André T, Atreya CE, Schellens JHM, Yoshino T, Bendell JC, et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAFV600E-mutant colorectal cancer. Cancer Discov. 2018;8:428–43. [DOI] [PubMed] [PMC]

62.

Kopetz S, McDonough SL, Morris VK, Lenz HJ, Magliocco AM, Atreya CE, 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. [DOI]

63.

Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381:1632–43. [DOI] [PubMed]

64.

Zhang L. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part II. The utility of microsatellite instability testing. J Mol Diagn. 2008;10:301–7. [DOI] [PubMed] [PMC]

65.

Ward R, Meagher A, Tomlinson I, O’Connor T, Norrie M, Wu R, et al. Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut. 2001;48:821–9. [DOI] [PubMed] [PMC]

66.

Graham DM, Coyle VM, Kennedy RD, Wilson RH. Molecular subtypes and personalized therapy in metastatic colorectal cancer. Curr Colorectal Cancer Rep. 2016;12:141–50. [DOI] [PubMed] [PMC]

67.

Ashktorab H, Ahuja S, Kannan L, Llor X, Ellis NA, Xicola RM, et al. A meta-analysis of MSI frequency and race in colorectal cancer. Oncotarget. 2016;7:34546–57. [DOI] [PubMed] [PMC]

68.

Luchini C, Bibeau F, Ligtenberg MJL, Singh N, Nottegar A, Bosse T, et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol. 2019;30:1232–43. [DOI] [PubMed]

69.

Guastadisegni C, Colafranceschi M, Ottini L, Dogliotti E. Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur J Cancer. 2010;46:2788–98. [DOI] [PubMed]

70.

Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69–74. [DOI] [PubMed]

71.

Le DT, Durham JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20. [DOI] [PubMed] [PMC]

72.

Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13. [DOI] [PubMed] [PMC]

73.

Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182–91. [DOI] [PubMed] [PMC]

74.

Fabrizio DA, George TJ Jr, Dunne RF, Frampton G, Sun J, Gowen K, et al. Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition. J Gastrointest Oncol. 2018;9:610–7. [DOI] [PubMed] [PMC]

75.

Schrock AB, Ouyang C, Sandhu J, Sokol E, Jin D, Ross JS, et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol. 2019;30:1096–103. [DOI] [PubMed]

76.

Siena S, Sartore-Bianchi A, Marsoni S, Hurwitz HI, McCall SJ, Penault-Llorca F, et al. Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann Oncol. 2018;29:1108–19. [DOI] [PubMed] [PMC]

77.

Ross JS, Fakih M, Ali SM, Elvin JA, Schrock AB, Suh J, et al. Targeting HER2 in colorectal cancer: the landscape of amplification and short variant mutations in ERBB2 and ERBB3. Cancer. 2018;124:1358–73. [DOI] [PubMed] [PMC]

78.

Seo AN, Kwak Y, Kim DW, Kang SB, Choe G, Kim WH, et al. Her2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression. PLoS One. 2014;9:e98528. [DOI] [PubMed] [PMC]

79.

Ingold Heppner B, Behrens HM, Balschun K, Haag J, Krüger S, Becker T, et al. HER2/neu testing in primary colorectal carcinoma. Br J Cancer. 2014;111:1977–84. [DOI] [PubMed] [PMC]

80.

Missiaglia E, Jacobs B, D’Ario G, Di Narzo AF, Soneson C, Budinska E, et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol. 2014;25:1995–2001. [DOI] [PubMed]

81.

Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, 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;17:738–46. [DOI] [PubMed]

82.

Raghav KPS, Overman MJ, Yu R, Meric-Bernstam F, Menter D, Kee BK, et al. HER2 amplification as a negative predictor biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer. J Clin Oncol. 2016;34:15_suppl 3517. [DOI]

83.

Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3:99ra86. [DOI]

84.

Martin V, Landi L, Molinari F, Fountzilas G, Geva R, Riva A, et al. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients. Br J Cancer. 2013;108:668–75. [DOI] [PubMed] [PMC]

85.

Sartore-Bianchi A, Amatu A, Porcu L, Ghezzi S, Lonardi S, Leone F, et al. HER2 positivity predicts unresponsiveness to EGFR-targeted treatment in metastatic colorectal cancer. Oncologist. 2019;24:1395–402. [DOI] [PubMed] [PMC]

86.

Hainsworth JD, Meric-Bernstam F, Swanton C, Hurwitz H, Spigel DR, Sweeney C, et al. Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from MyPathway, an open-label, phase IIa multiple basket study. J Clin Oncol. 2018;36:536–42. [DOI] [PubMed]

87.

Ramanathan RK, Hwang JJ, Zamboni WC, Sinicrope FA, Safran H, Wong MK, et al. Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A phase II trial. Cancer Invest. 2004;22:858–65. [DOI] [PubMed]

88.

Clark JW, Niedzwiecki D, Hollis D, Mayer R. Phase-II trial of 5-fluororuacil (5-FU), leucovorin (LV), oxaliplatin (Ox), and trastuzumab (T) for patients with metastatic colorectal cancer (CRC) refractory to initial therapy. Onkologie. 2003;26 suppl 3:13–46. [DOI] [PubMed]

89.

Meric-Bernstam F, Hurwitz H, Raghav KPS, McWilliams RR, Fakih M, VanderWalde A, 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;20:518–30. [DOI] [PubMed] [PMC]

90.

Siravegna G, Sartore-Bianchi A, Nagy RJ, Raghav K, Odegaard JI, Lanman RB, et al. Plasma HER2 (ERBB2) copy number predicts response to HER2-targeted therapy in metastatic colorectal cancer. Clin Cancer Res. 2019;25:3046–53. [DOI] [PubMed]

91.

Martinelli E, Troiani T, Sforza V, Martini G, Cardone C, Vitiello PP, et al. Sequential HER2 blockade as effective therapy in chemorefractory, HER2 gene-amplified, RAS wild-type, metastatic colorectal cancer: learning from a clinical case. ESMO Open. 2018;3:e000299. [DOI] [PubMed] [PMC]

92.

Kavuri SM, Jain N, Galimi F, Cottino F, Leto SM, Migliardi G, et al. HER2 activating mutations are targets for colorectal cancer treatment. Cancer Discov. 2015;5:832–41. [DOI] [PubMed] [PMC]

93.

Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018;554:189–94. [DOI] [PubMed] [PMC]

94.

De Luca A, Maiello MR, D’Alessio A, Pergameno M, Normanno N. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets. 2012;16 Suppl 2:S17–27. [DOI]

95.

Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501. [DOI] [PubMed]

96.

Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004;64:7678–81. [DOI] [PubMed]

97.

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554. [DOI] [PubMed]

98.

De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, 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;11:753–62. [DOI] [PubMed]

99.

Rosty C, Young JP, Walsh MD, Clendenning M, Sanderson K, Walters RJ, et al. PIK3CA activating mutation in colorectal carcinoma: associations with molecular features and survival. PLoS One. 2013;8:e65479. [DOI] [PubMed] [PMC]

100.

Mei ZB, Duan CY, Li CB, Cui L, Ogino S. Prognostic role of tumor PIK3CA mutation in colorectal cancer: a systematic review and meta-analysis. Ann Oncol. 2016;27:1836–48. [DOI] [PubMed] [PMC]

101.

Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367:1596–606. [DOI] [PubMed] [PMC]

102.

Domingo E, Church DN, Sieber O, Ramamoorthy R, Yanagisawa Y, Johnstone E, et al. Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol. 2013;31:4297–305. [DOI] [PubMed]

103.

Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009;69:1851–7. [DOI] [PubMed]

104.

Ogino S, Nosho K, Kirkner GJ, Shima K, Irahara N, Kure S, et al. PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol. 2009;27:1477–84. [DOI] [PubMed] [PMC]

105.

Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, et al. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol. 2009;20:84–90. [DOI] [PubMed]

106.

Sood A, McClain D, Maitra R, Basu-Mallick A, Seetharam R, Kaubisch A, et al. PTEN gene expression and mutations in the PIK3CA gene as predictors of clinical benefit to anti-epidermal growth factor receptor antibody therapy in patients with KRAS wild-type metastatic colorectal cancer. Clin Colorectal Cancer. 2012;11:143–50. [DOI] [PubMed] [PMC]

107.

Ciardiello F, Normanno N, Maiello E, Martinelli E, Troiani T, Pisconti S, et al. Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial. Ann Oncol. 2014;25:1756–61. [DOI] [PubMed]

108.

Souglakos J, Philips J, Wang R, Marwah S, Silver M, Tzardi M, et al. Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009;101:465–72. [DOI] [PubMed] [PMC]

109.

Pietrantonio F, Di Nicolantonio F, Schrock AB, Lee J, Tejpar S, Sartore-Bianchi A, et al. ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer. J Natl Cancer Inst. 2017;109. [DOI]

110.

Pietrantonio F, Di Nicolantonio F, Schrock AB, Lee J, Morano F, Fuca G, et al. RET fusions in a small subset of advanced colorectal cancers at risk of being neglected. Ann Oncol. 2018;29:1394–401. [DOI] [PubMed]

111.

Russo M, Misale S, Wei G, Siravegna G, Crisafulli G, Lazzari L, et al. Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer. Cancer Discov. 2016;6:36–44. [DOI] [PubMed]

112.

Yaeger R, Shah MA, Miller VA, Kelsen JR, Wang K, Heins ZJ, et al. Genomic alterations observed in colitis-associated cancers are distinct from those found in sporadic colorectal cancers and vary by type of inflammatory bowel disease. Gastroenterology. 2016;151:278–87. [DOI] [PubMed] [PMC]

113.

Kloosterman WP, Coebergh van den Braak RRJ, Pieterse M, van Roosmalen MJ, Sieuwerts AM, Stangl C, et al. A systematic analysis of oncogenic gene fusions in primary colon cancer. Cancer Res. 2017;77:3814–22. [DOI] [PubMed]

114.

Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15:731–47. [DOI] [PubMed] [PMC]

115.

Cichowski K, Jacks T. NF1 tumor suppressor gene function: narrowing the GAP. Cell. 2001;104:593–604. [DOI] [PubMed]

116.

de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science. 2014;346:251–6. [DOI] [PubMed] [PMC]

117.

Mei Z, Shao YW, Lin P, Cai X, Wang B, Ding Y, et al. SMAD4 and NF1 mutations as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese metastatic colorectal cancer patients. BMC Cancer. 2018;18:479. [DOI] [PubMed] [PMC]

118.

Rachiglio AM, Lambiase M, Fenizia F, Roma C, Cardone C, Iannaccone A, et al. Genomic profiling of KRAS/NRAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patients reveals novel mutations in genes potentially associated with resistance to anti-EGFR agents. Cancers. 2019;11:E859. [DOI] [PubMed] [PMC]

119.

Woolston A, Khan K, Spain G, Barber LJ, Griffiths B, Gonzalez-Exposito R, et al. Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer. Cancer Cell. 2019;36:35–50. [DOI] [PubMed] [PMC]

120.

Russo M, Siravegna G, Blaszkowsky LS, Corti G, Crisafulli G, Ahronian LG, et al. Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer. Cancer Discov. 2016;6:147–53. [DOI] [PubMed] [PMC]

121.

Bertotti A, Papp E, Jones S, Adleff V, Anagnostou V, Lupo B, et al. The genomic landscape of response to EGFR blockade in colorectal cancer. Nature. 2015;526:263–7. [DOI] [PubMed] [PMC]

122.

Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013;45:136–44. [DOI] [PubMed] [PMC]

123.

Domingo E, Freeman-Mills L, Rayner E, Glaire M, Briggs S, Vermeulen L, et al. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study. Lancet Gastroenterol Hepatol. 2016;1:207–16. [DOI] [PubMed]

124.

Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D, Ng S, et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell. 2014;158:929–44. [DOI] [PubMed] [PMC]

125.

Budinska E, Popovici V, Tejpar S, D’Ario G, Lapique N, Sikora KO, et al. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J Pathol. 2013;231:63–76. [DOI] [PubMed] [PMC]

126.

Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013;19:619–25. [DOI] [PubMed] [PMC]

127.

Marisa L, de Reyniès A, Duval A, Selves J, Gaub MP, Vescovo L, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013;10:e1001453. [DOI] [PubMed] [PMC]

128.

Perez-Villamil B, Romera-Lopez A, Hernandez-Prieto S, Lopez-Campos G, Calles A, Lopez-Asenjo JA, et al. Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior. BMC Cancer. 2012;12:260. [DOI] [PubMed] [PMC]

129.

Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6. [DOI] [PubMed] [PMC]

130.

Song N, Pogue-Geile KL, Gavin PG, Yothers G, Kim SR, Johnson NL, et al. Clinical outcome from oxaliplatin treatment in stage II/III colon cancer according to intrinsic subtypes: secondary analysis of NSABP C-07/NRG oncology randomized clinical trial. JAMA Oncol. 2016;2:1162–9. [DOI] [PubMed] [PMC]

131.

Lenz HJ, Ou FS, Venook AP, Hochster HS, Niedzwiecki D, Goldberg RMJ, et al. Impact of consensus molecular subtype on survival in patients with metastatic colorectal cancer: results from CALGB/ SWOG 80405 (Alliance). J Clin Oncol. 2019;37:1876–85. [DOI] [PubMed] [PMC]

132.

Stintzing S, Wirapati P, Lenz HJ, Neureiter D, Fischer von Weikersthal L, Decker T, et al. Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab: analysis of the FIRE-3 (AIO KRK 0306) study. Ann Oncol. 2019;30:1796–803. [DOI] [PubMed] [PMC]

133.

Aderka D, Stintzing S, Heinemann V. Explaining the unexplainable: discrepancies in results from the CALGB/SWOG 80405 and FIRE-3 studies. Lancet Oncol. 2019;20:e274–83. [DOI] [PubMed]

134.

Morano F, Corallo S, Lonardi S, Raimondi A, Cremolini C, Rimassa L, 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;37:3099–110. [DOI] [PubMed] [PMC]

135.

Normanno N, Cervantes A, Ciardiello F, De Luca A, Pinto C. The liquid biopsy in the management of colorectal cancer patients: current applications and future scenarios. Cancer Treat Rev. 2018;70:1–8. [DOI] [PubMed]

136.

Marisa L, Svrcek M, Collura A, Becht E, Cervera P, Wanherdrick K, 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. [DOI]