Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Precision oncology in metastatic colorectal cancer — from biology to medicine

Nature Reviews Clinical Oncology volume 18, pages 506–525 (2021)Cite this article

Subjects

Abstract

Remarkable progress has been made in the development of biomarker-driven targeted therapies for patients with multiple cancer types, including melanoma, breast and lung tumours, although precision oncology for patients with colorectal cancer (CRC) continues to lag behind. Nonetheless, the availability of patient-derived CRC models coupled with in vitro and in vivo pharmacological and functional analyses over the past decade has finally led to advances in the field. Gene-specific alterations are not the only determinants that can successfully direct the use of targeted therapy. Indeed, successful inhibition of BRAF or KRAS in metastatic CRCs driven by activating mutations in these genes requires combinations of drugs that inhibit the mutant protein while at the same time restraining adaptive resistance via CRC-specific EGFR-mediated feedback loops. The emerging paradigm is, therefore, that the intrinsic biology of CRC cells must be considered alongside the molecular profiles of individual tumours in order to successfully personalize treatment. In this Review, we outline how preclinical studies based on patient-derived models have informed the design of practice-changing clinical trials. The integration of these experiences into a common framework will reshape the future design of biology-informed clinical trials in this field.

Key points

  • The efficacy of targeted therapies in patients with solid tumours is largely unpredictable owing to intrinsic genetic complexity and a high level of tissue context specificity.

  • The development of patient-derived models that reflect the genetic heterogeneity of colorectal cancer (CRC) constitutes a successful platform for the development of targeted therapies.

  • These models have enabled the validation of retrospectively identified biomarkers in clinical trials and the optimization of prospective biomarkers to guide the selection of novel targeted therapies, such as those targeting HER2.

  • Longitudinal evaluations of the genomic evolution of CRC enabled by analysis of liquid biopsy samples have further increased the understanding of the mechanisms of resistance to targeted agents.

  • Investigations of resistance to targeted therapies have revealed convergence on CRC-specific feedback loops within the MAPK signalling pathway as a core mechanism of survival.

  • Co-inhibition with agents targeting EGFR and the specific oncogenic mutation has proved crucial in the clinical development of effective regimens for BRAF-mutant CRCs, and has also been demonstrated to be beneficial in the context of KRASG12C-mutant CRC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Relevant therapeutic targets in metastatic CRC.
Fig. 2: Strategies for the development of biomarker-based targeted therapies in metastatic CRC.
Fig. 3: Central role of EGFR–RAS–MAPK signalling in CRC.

Similar content being viewed by others

References

  1. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

    Article  CAS  Google Scholar 

  2. Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Remon, J. & Dienstmann, R. Precision oncology: separating the wheat from the chaff. ESMO Open 3, e000446 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Banerji, U. & Workman, P. Critical parameters in targeted drug development: the pharmacological audit trail. Semin. Oncol. 43, 436–445 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Yap, T. A., Sandhu, S. K., Workman, P. & de Bono, J. S. Envisioning the future of early anticancer drug development. Nat. Rev. Cancer 10, 514–523 (2010). A framework for evidence-based decision-making during drug discovery and development.

    Article  CAS  PubMed  Google Scholar 

  6. Prahallad, A. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Corcoran, R. B. et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2, 227–235 (2012). The first evidence of the mechanism of resistance to BRAF inhibitor in BRAF-mutant CRC through feedback reactivation of the EGFR-MAPK axis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Amodio, V. et al. EGFR blockade reverts resistance to KRAS G12C inhibition in colorectal cancer. Cancer Discov. 10, 1129–1139 (2020). A recent paper highlighting the mechanism of resistance to selective KRAS-G12C inhibitors in CRC through feedback reactivation of EGFR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Iorio, F. et al. A landscape of pharmacogenomic interactions in cancer. Cell 166, 740–754 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Najgebauer, H. et al. CELLector: genomics-guided selection of cancer in vitro models. Cell Syst. 10, 424–4326 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Drost, J. & Clevers, H. Organoids in cancer research. Nat. Rev. Cancer 18, 407–418 (2018).

    Article  CAS  PubMed  Google Scholar 

  12. Ballard, D. H., Boyer, C. J. & Alexander, J. S. Organoids – preclinical models of human disease. N. Engl. J. Med. 380, 1981–1982 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  13. van de Wetering, M. et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Hidalgo, M. et al. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov. 4, 998–1013 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Byrne, A. T. et al. Interrogating open issues in cancer precision medicine with patient-derived xenografts. Nat. Rev. Cancer 17, 254–268 (2017).

    Article  CAS  PubMed  Google Scholar 

  16. Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Rad, R. et al. A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention. Cancer Cell 24, 15–29 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bürtin, F., Mullins, C. S. & Linnebacher, M. Mouse models of colorectal cancer: past, present and future perspectives. World J. Gastroenterol. 26, 1394–1426 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Diaz, L. A. & Bardelli, A. Liquid biopsies: genotyping circulating tumor DNA. J. Clin. Oncol. 32, 579–586 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  20. 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. 70, 1–8 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Siravegna, G., Marsoni, S., Siena, S. & Bardelli, A. Integrating liquid biopsies into the management of cancer. Nat. Rev. Clin. Oncol. 14, 531–548 (2017).

    Article  CAS  PubMed  Google Scholar 

  22. Siravegna, G. et al. Plasma HER2 (ERBB2) copy number predicts response to HER2-targeted therapy in metastatic colorectal cancer. Clin. Cancer Res. 25, 3046–3053 (2019).

    Article  CAS  PubMed  Google Scholar 

  23. Parikh, A. R. et al. Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers. Nat. Med. 25, 1415–1421 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Khan, K. H. 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. 8, 1270–1285 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Parikh, A. R. et al. Serial ctDNA monitoring to predict response to systemic therapy in metastatic gastrointestinal cancers. Clin. Cancer Res. 26, 1877–1885 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nakamura, Y. et al. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat. Med. 26, 1859–1864 (2020).

    Article  PubMed  CAS  Google Scholar 

  27. Siravegna, G. et al. How liquid biopsies can change clinical practice in oncology. Ann. Oncol. 30, 1580–1590 (2019).

    Article  CAS  PubMed  Google Scholar 

  28. Ganesh, K. et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat. Rev. Gastroenterol. Hepatol. 16, 361–375 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ciardiello, D. et al. Immunotherapy of colorectal cancer: challenges for therapeutic efficacy. Cancer Treat. Rev. 76, 22–32 (2019).

    Article  CAS  PubMed  Google Scholar 

  30. Germano, G. et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 552, 116–120 (2017).

    Article  CAS  PubMed  Google Scholar 

  31. Rospo, G. et al. Evolving neoantigen profiles in colorectal cancers with DNA repair defects. Genome Med. 11, 42 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Germano, G., Amirouchene-Angelozzi, N., Rospo, G. & Bardelli, A. The clinical impact of the genomic landscape of mismatch repair-deficient cancers. Cancer Discov. 8, 1518–1528 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Olson, B., Li, Y., Lin, Y., Liu, E. T. & Patnaik, A. Mouse models for cancer immunotherapy research. Cancer Discov. 8, 1358–1365 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Segal, N. H. & Saltz, L. B. Translational considerations on the outlook of immunotherapy for colorectal cancer. Curr. Colorectal Cancer Rep. 11, 92–97 (2015).

    Article  Google Scholar 

  36. Dijkstra, K. K. et al. Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell 174, 1586–1598.e12 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chalabi, M. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 26, 566–576 (2020).

    Article  CAS  PubMed  Google Scholar 

  38. Wieduwilt, M. J. & Moasser, M. M. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell. Mol. Life Sci. 65, 1566 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mendelsohn J, B. J. The EGF receptor family as targets for cancer therapy. Oncogene 19, 6550–6565 (2000).

    Article  PubMed  CAS  Google Scholar 

  40. Salomon, D. S., Brandt, R., Ciardiello, F. & Normanno, N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit. Rev. Oncol. Hematol. 19, 183–232 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Wu, X., Fan, Z., Masui, H., Rosen, N. & Mendelsohn, J. Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J. Clin. Invest. 95, 1897–1905 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ciardiello, F. & Tortora, G. EGFR antagonists in cancer treatment. N. Engl. J. Med. 358, 1160–1174 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Van Cutsem, E. et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J. Clin. Oncol. 25, 1658–1664 (2007).

    Article  PubMed  CAS  Google Scholar 

  44. Saltz, L. B. et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J. Clin. Oncol. 22, 1201–1208 (2004). The first trial demonstrating the clinical efficacy of an anti-EGFR agent in mCRC.

    Article  CAS  PubMed  Google Scholar 

  45. Mendelsohn, J. & Baselga, J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J. Clin. Oncol. 21, 2787–2799 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Cunningham, D. et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 351, 337–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Jonker, D. J. et al. Cetuximab for the treatment of colorectal cancer. N. Engl. J. Med. 357, 2040–2048 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Chung, K. Y. et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J. Clin. Oncol. 23, 1803–1810 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Lièvre, A. et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66, 3992–3995 (2006).

    Article  PubMed  Google Scholar 

  50. Benvenuti, S. et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 67, 2643–2648 (2007). The first two works, with Lièvre et al., to show how the presence of activating RAS or RAF mutations impair the activity of anti-EGFR antibodies in a preclinical model.

    Article  CAS  PubMed  Google Scholar 

  51. Amado, R. G. et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 1626–1634 (2008). The first clinical report showing the lack of clinical activity of anti-EGFR antibodies in KRAS-mutated cancers.

    Article  CAS  PubMed  Google Scholar 

  52. Karapetis, C. S. et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359, 1757–1765 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Peeters, M. et al. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J. Clin. Oncol. 31, 759–765 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Segelov, E. et al. Response to cetuximab with or without irinotecan in patients with refractory metastatic colorectal cancer harboring the KRAS G13D mutation: Australasian Gastro-Intestinal Trials Group ICECREAM study. J. Clin. Oncol. 34, 2258–2264 (2016).

    Article  CAS  PubMed  Google Scholar 

  55. Siena, S. et al. Phase II open-label study to assess efficacy and safety of lenalidomide in combination with cetuximab in KRAS-mutant metastatic colorectal cancer. PLoS ONE 8, e62264 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Douillard, J.-Y. 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. 28, 4697–4705 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Bardelli, A. & Siena, S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J. Clin. Oncol. 28, 1254–1261 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. De Roock, W. C. 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. 11, 753–762 (2010).

    Article  PubMed  CAS  Google Scholar 

  59. Douillard, J.-Y. et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N. Engl. J. Med. 369, 1023–1034 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Di Nicolantonio, F. et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J. Clin. Oncol. 26, 5705–5712 (2008).

    Article  PubMed  CAS  Google Scholar 

  61. Jhawer, M. et al. PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 68, 1953–1961 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sartore-Bianchi, A. et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 69, 1851–1857 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. van Brummelen, E. M. J., de Boer, A., Beijnen, J. H. & Schellens, J. H. M. BRAF mutations as predictive biomarker for response to anti-EGFR monoclonal antibodies. Oncologist 22, 864–872 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Rowland, A. 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 112, 1888–1894 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Pietrantonio, F. et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur. J. Cancer 51, 587–594 (2015).

    Article  CAS  PubMed  Google Scholar 

  66. Smith, C. G. et al. Somatic profiling of the epidermal growth factor receptor pathway in tumors from patients with advanced colorectal cancer treated with chemotherapy ± cetuximab. Clin. Cancer Res. 19, 4104–4113 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Loupakis, F. et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br. J. Cancer 101, 715–721 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Peeters, M. et al. Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. Clin. Cancer Res. 19, 1902–1912 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Karapetis, C. S. et al. 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. 20, 744–753 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Orlandi, A. et al. BRAF in metastatic colorectal cancer: the future starts now. Pharmacogenomics 16, 2069–2081 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Van Cutsem, E. et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol. 27, 1386–1422 (2016).

    Article  PubMed  Google Scholar 

  72. Zhao, L. & Vogt, P. K. Helical domain and kinase domain mutations in p110α of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl Acad. Sci. USA 105, 2652–2657 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Day, F. L. et al. PIK3CA and PTEN gene and exon mutation-specific clinicopathologic and molecular associations in colorectal cancer. Clin. Cancer Res. 19, 3285–3296 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Prenen, H. et al. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin. Cancer Res. 15, 3184–3188 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Perrone, F. et al. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann. Oncol. 20, 84–90 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Huang, L. et al. Anti-epidermal growth factor receptor monoclonal antibody-based therapy for metastatic colorectal cancer: a meta-analysis of the effect of PIK3CA mutations in KRAS wild-type patients. Arch. Med. Sci. 10, 1–9 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Sepulveda, A. R. 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 the American Society of Clinical Oncology. J. Clin. Oncol. 35, 1453–1486 (2017).

    Article  CAS  PubMed  Google Scholar 

  78. Ciardiello, F. et al. Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): a randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX. Ann. Oncol. 27, 1055–1061 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Yonesaka, K. et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci. Transl. Med. 3, 99ra86 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Bardelli, A. et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 3, 658–673 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Scartozzi, M. et al. Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecan-cetuximab. Ann. Oncol. 23, 1706–1712 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Martinelli, E. et al. AXL is an oncotarget in human colorectal cancer. Oncotarget 6, 23281–23296 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Cardone, C. et al. AXL is a predictor of poor survival and of resistance to anti-EGFR therapy in RAS wild-type metastatic colorectal cancer. Eur. J. Cancer 138, 1–10 (2020).

    Article  CAS  PubMed  Google Scholar 

  84. De Robertis, M. et al. Dysregulation of EGFR pathway in EphA2 cell subpopulation significantly associates with poor prognosis in colorectal cancer. Clin. Cancer Res. 23, 159–170 (2017).

    Article  PubMed  CAS  Google Scholar 

  85. Martini, G. et al. EPHA2 is a predictive biomarker of resistance and a potential therapeutic target for improving antiepidermal growth factor receptor therapy in colorectal cancer. Mol. Cancer Ther. 18, 845–855 (2019).

    Article  CAS  PubMed  Google Scholar 

  86. Pietrantonio, F. et al. ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer. J. Natl Cancer Inst. 109, djx089 (2017).

    Article  CAS  Google Scholar 

  87. Cremolini, C. et al. Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclonal antibodies: the PRESSING case-control study. Ann. Oncol. 28, 3009–3014 (2017).

    Article  CAS  PubMed  Google Scholar 

  88. Morano, F. et al. Negative hyperselection of patients with RAS and BRAF wild-type metastatic colorectal cancer who received panitumumab-based maintenance therapy. J. Clin. Oncol. 37, 3099–3110 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532–536 (2012). The first report of the causative role of KRAS mutations in acquired resistance to anti-EGFR agents in CRC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bettegowda, C. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl. Med. 6, 224ra24 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Martini, G. et al. Resistance to anti-epidermal growth factor receptor in metastatic colorectal cancer: what does still need to be addressed? Cancer Treat. Rev. 86, 102023 (2020).

    Article  CAS  PubMed  Google Scholar 

  92. Misale S, A. S., Lamba, S., Siravegna, G., Lallo, A., Hobor, S. et al. Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer. Sci. Transl. Med. 6, 224ra26 (2014).

    Article  PubMed  CAS  Google Scholar 

  93. Russo, M. et al. Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer. Cancer Discov. 6, 147–153 (2016).

    Article  CAS  PubMed  Google Scholar 

  94. Troiani, T. N. S., Vitagliano, D., Morgillo, F., Capasso, A., Sforza, V. et al. Primary and acquired resistance of colorectal cancer cells to anti-EGFR antibodies converge on MEK/ERK pathway activation and can be overcome by combined MEK/EGFR inhibition. Clin. Cancer Res. 20, 3775–3786 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Siena, S. et al. Dynamic molecular analysis and clinical correlates of tumor evolution within a phase II trial of panitumumab-based therapy in metastatic colorectal cancer. Ann. Oncol. 29, 119–126 (2018).

    Article  CAS  PubMed  Google Scholar 

  96. Siravegna, G. et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat. Med. 21, 795–801 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Siravegna, G. et al. Radiologic and genomic evolution of individual metastases during HER2 blockade in colorectal cancer. Cancer Cell 34, 148–1627 (2018).

    Article  CAS  PubMed  Google Scholar 

  98. Van Emburgh, B. O. et al. Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer. Nat. Commun. 7, 13665 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Parseghian, C. M. et al. Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge. Ann. Oncol. 30, 243–249 (2019).

    Article  CAS  PubMed  Google Scholar 

  100. Cremolini, C. 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. 5, 343–350 (2019).

    Article  PubMed  Google Scholar 

  101. Martinelli, E. et al. Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives. Ann. Oncol. 31, 30–40 (2020).

    Article  CAS  PubMed  Google Scholar 

  102. Dienstmann, R. et al. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat. Rev. Cancer 17, 79–92 (2017).

    Article  CAS  PubMed  Google Scholar 

  103. Garrett, T. P. J. et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol. Cell 11, 495–505 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Siena, S. et al. Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann. Oncol. 29, 1108–1119 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Valtorta, E. et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod. Pathol. 28, 1481–1491 (2015).

    Article  CAS  PubMed  Google Scholar 

  106. Seo, A. N. et al. HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression. PLoS ONE 9, e98528 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Bertotti, A. et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 1, 508–523 (2011). This proof-of-concept work establishing the translational potential of PDXs and the potential targeted approach in HER2-amplified CRC.

    Article  CAS  PubMed  Google Scholar 

  108. Richman, S. D. 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. 238, 562–570 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Nam, S. K. et al. BRAF, PIK3CA, and HER2 oncogenic alterations according to KRAS mutation status in advanced colorectal cancers with distant metastasis. PLoS ONE 11, e0151865 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Ingold Heppner, B. et al. HER2/neu testing in primary colorectal carcinoma. Br. J. Cancer 111, 1977–1984 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Missiaglia, E. et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann. Oncol. 25, 1995–2001 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Laurent-Puig, P. et al. ERBB2 alterations a new prognostic biomarker in stage III colon cancer from a FOLFOX based adjuvant trial (PETACC8). Ann. Oncol. 27, vi151 (2016).

    Google Scholar 

  113. Raghav, K. P. S. et al. HER2 amplification as a negative predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer. J. Clin. Oncol. 34, 3517 (2016).

    Article  Google Scholar 

  114. Schuell, B., Gruenberger, T., Scheithauer, W., Zielinski, C. & Wrba, F. HER 2/neu protein expression in colorectal cancer. BMC Cancer 6, 123 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sun, S.-J. et al. High HER-2 protein levels correlate with clinicopathological features in colorectal cancer. J. Cancer Res. Ther. 12, 323–333 (2020).

    CAS  Google Scholar 

  116. Sartore-Bianchi, A. et al. HER2 positivity predicts unresponsiveness to EGFR-targeted treatment in metastatic colorectal cancer. Oncologist 24, 1395–1402 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Brannon, A. R. et al. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions. Genome Biol. 15, 454 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Kavuri, S. M. et al. HER2 activating mutations are targets for colorectal cancer treatment. Cancer Discov. 5, 832–841 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Loree, J. M. et al. Molecular landscape of ERBB2/ERBB3 mutated colorectal cancer. J. Natl Cancer Inst. 110, 1409–1417 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Leto, S. M. et al. Sustained inhibition of HER3 and EGFR is necessary to induce regression of HER2-amplified gastrointestinal carcinomas. Clin. Cancer Res. 21, 5519–5531 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Martin, V. et al. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients. Br. J. Cancer 108, 668–675 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Clark, J., 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 [abstract]. Proc. Am. Soc. Clin. Oncol. 22, 3584 (2003).

    Google Scholar 

  124. Ramanathan, R. K. 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. 22, 858–865 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Sartore-Bianchi, A. 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. 17, 738–746 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Sartore-Bianchi, A. et al. Central nervous system as possible site of relapse in ERBB2-positive metastatic colorectal cancer: long-term results of treatment with trastuzumab and lapatinib. JAMA Oncol. 6, 927–929 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Tosi, F. et al. Long-term clinical outcome of trastuzumab and lapatinib for HER2-positive metastatic colorectal cancer. Clin. Colorectal Cancer 19, 256–262.e2 (2020). Three papers reporting the results of the HERACLES-A trial, investigating the combination of trastuzumab and lapatinib in HER2+ mCRC.

    Article  PubMed  Google Scholar 

  128. Sartore-Bianchi, A. et al. Pertuzumab and trastuzumab emtansine in patients with HER2-amplified metastatic colorectal cancer: the phase II HERACLES-B trial. ESMO Open 5, e000911 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Sakai, K. et al. Pertuzumab, a novel HER dimerization inhibitor, inhibits the growth of human lung cancer cells mediated by the HER3 signaling pathway. Cancer Sci. 98, 1498–1503 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Lewis Phillips, G. D. et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 68, 9280–9290 (2008).

    Article  CAS  PubMed  Google Scholar 

  131. Ogitani, Y. et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin. Cancer Res. 22, 5097–5108 (2016).

    Article  CAS  PubMed  Google Scholar 

  132. Nakada, T. et al. Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. Bioorg. Med. Chem. Lett. 26, 1542–1545 (2016).

    Article  CAS  PubMed  Google Scholar 

  133. Siena, S. et al. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial. Lancet Oncol. (in the press).

  134. Meric-Bernstam, F. 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. 20, 518–530 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Nakamura, Y. et al. TRIUMPH: Primary efficacy of a phase II trial of trastuzumab (T) and pertuzumab (P) in patients (pts) with metastatic colorectal cancer (mCRC) with HER2 (ERBB2) amplification (amp) in tumour tissue or circulating tumour DNA (ctDNA): A GOZILA sub-study [abstract 526PD]. Ann. Oncol. 30 (Suppl. 5), v199–v200 (2019).

    Article  Google Scholar 

  136. Kulukian, A. et al. Preclinical activity of HER2-selective tyrosine kinase inhibitor tucatinib as a single agent or in combination with trastuzumab or docetaxel in solid tumor models. Mol. Cancer Ther. 19, 976–987 (2020).

    Article  CAS  PubMed  Google Scholar 

  137. Strickler, J. H. et al. Trastuzumab and tucatinib for the treatment of HER2 amplified metastatic colorectal cancer (mCRC): initial results from the MOUNTAINEER trial [abstract 527PD]. Ann. Oncol. 30 (Suppl. 5), v200 (2019).

    Article  Google Scholar 

  138. Hyman, D. M. et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 554, 189–194 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Grothey, A. et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381, 303–312 (2013).

    Article  CAS  PubMed  Google Scholar 

  140. Li, J. et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 16, 619–629 (2015).

    Article  CAS  PubMed  Google Scholar 

  141. Mayer, R. J. et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N. Engl. J. Med. 372, 1909–1919 (2015).

    Article  PubMed  Google Scholar 

  142. Xu, J. et al. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study. J. Clin. Oncol. 36, 350–358 (2018).

    Article  CAS  PubMed  Google Scholar 

  143. Tol, J., Nagtegaal, I. D. & Punt, C. J. BRAF mutation in metastatic colorectal cancer. N. Engl. J. Med. 361, 98–99 (2009).

    Article  CAS  PubMed  Google Scholar 

  144. Roth, A. D. et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J. Clin. Oncol. 28, 466–474 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Giannakis, M. et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 15, 857–865 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Clarke, C. N. & Kopetz, E. S. BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies. J. Gastrointest. Oncol. 6, 660–667 (2015).

    PubMed  PubMed Central  Google Scholar 

  147. Michaloglou, C., Vredeveld, L. C., Mooi, W. J. & Peeper, D. S. BRAF(E600) in benign and malignant human tumours. Oncogene 27, 877–895 (2008).

    Article  CAS  PubMed  Google Scholar 

  148. Sebolt-Leopold, J. S. & Herrera, R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat. Rev. Cancer 4, 937–947 (2004).

    Article  CAS  PubMed  Google Scholar 

  149. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

    Article  CAS  PubMed  Google Scholar 

  150. Maughan, T. S. 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 377, 2103–2114 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Samowitz, W. S. et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 65, 6063–6069 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. Tran, B. et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer 117, 4623–4632 (2011).

    Article  CAS  PubMed  Google Scholar 

  153. Richman, S. D. 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. Oncol. 27, 5931–5937 (2009).

    Article  CAS  PubMed  Google Scholar 

  154. Ogino, S. et al. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clin. Cancer Res. 18, 890–900 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Taieb, J. et al. Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer. J. Natl Cancer Inst. 109, djw272 (2017).

    Article  CAS  Google Scholar 

  156. Matos, I., Elez, E., Capdevila, J. & Tabernero, J. Emerging tyrosine kinase inhibitors for the treatment of metastatic colorectal cancer. Expert Opin. Emerg. Drugs 21, 267–282 (2016).

    Article  CAS  PubMed  Google Scholar 

  157. Sinicrope, F. A. et al. Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology 148, 88–99 (2015).

    Article  CAS  PubMed  Google Scholar 

  158. French, A. J. et al. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin. Cancer Res. 14, 3408–3415 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Lochhead, P. et al. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J. Natl Cancer Inst. 105, 1151–1156 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Morris, V. et al. Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. Clin. Colorectal Cancer 13, 164–171 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Jones, J. C. et al. Non-V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J. Clin. Oncol. 35, 2624–2630 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Cremolini, C. et al. BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis. Ann. Oncol. 26, 2092–2097 (2015).

    Article  CAS  PubMed  Google Scholar 

  163. Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Long, G. V. et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl. J. Med. 371, 1877–1888 (2014).

    Article  PubMed  CAS  Google Scholar 

  165. Kopetz, S. et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J. Clin. Oncol. 33, 4032–4038 (2015). The first study investigating BRAF inhibition in BRAF-mutant CRC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Gomez-Roca, C. A. et al. Encorafenib (Lgx818), an oral Braf inhibitor, in patients (pts) with Braf V600e metastatic colorectal cancer (Mcrc): results of dose expansion in an open-label, phase 1 study [abstract 535P]. Ann. Oncol. 25 (Suppl. 4), iv182 (2014).

    Article  Google Scholar 

  167. Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596–599 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Hyman, D. M. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373, 726–736 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Yaeger, R. et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin. Cancer Res. 21, 1313–1320 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Corcoran, R. B. et al. Efficacy and circulating tumor DNA (ctDNA) analysis of the BRAF inhibitor dabrafenib (D), MEK inhibitor trametinib (T), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E-mutated (BRAFm) metastatic colorectal cancer (mCRC) [abstract 455O]. Ann. Oncol. 27 (Suppl. 6), vi150 (2016).

    Article  Google Scholar 

  171. Corcoran, R. B. et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAF(V600E)-mutant colorectal cancer. Cancer Discov. 8, 428–443 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Bendell, J. C. et al. Efficacy and tolerability in an open-label phase I/II study of MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in combination in patients (pts) with BRAF V600E mutated colorectal cancer (CRC) [abstract]. J. Clin. Oncol. 32 (Suppl. 15), 3515 (2014).

    Article  Google Scholar 

  173. Corcoran, R. B. et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J. Clin. Oncol. 33, 4023–4031 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Corcoran, R. B. et al. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci. Signal. 3, ra84 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Kopetz, S. et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N. Engl. J. Med. 381, 1632–1643 (2019). Results from the BEACON-CRC phase III trial that led to the registration of cetuximab + encorafenib ± binimetinib in BRAF-mutant mCRC.

    Article  CAS  PubMed  Google Scholar 

  176. Grothey, A. et al. ANCHOR CRC: a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E-mutant metastatic colorectal cancer [abstract LBA-5]. Ann. Oncol. 31 (Suppl. 3), S242–S243 (2020).

    Article  Google Scholar 

  177. Mao, M. et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin. Cancer Res. 19, 657–667 (2013).

    Article  CAS  PubMed  Google Scholar 

  178. van Geel, R. et al. A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer. Cancer Discov. 7, 610–619 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Juric, D. et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature 518, 240–244 (2015).

    Article  CAS  PubMed  Google Scholar 

  180. Hong, D. S. et al. Phase IB study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with BRAFV600E mutation. Cancer Discov. 6, 1352–1365 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Ahronian, L. G. et al. Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations. Cancer Discov. 5, 358–367 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Yaeger, R. et al. Mechanisms of acquired resistance to BRAF V600E inhibition in colon cancers converge on RAF dimerization and are sensitive to its inhibition. Cancer Res. 77, 6513–6523 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Oddo, D. et al. Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer. Br. J. Cancer 117, 347–352 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Oddo, D. et al. Molecular landscape of acquired resistance to targeted therapy combinations in BRAF-mutant colorectal cancer. Cancer Res. 76, 4504–4515 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Pietrantonio, F. et al. MET-driven resistance to dual EGFR and BRAF blockade may be overcome by switching from EGFR to MET inhibition in BRAF-mutated colorectal cancer. Cancer Discov. 6, 963–971 (2016).

    Article  CAS  PubMed  Google Scholar 

  186. Rajagopalan, H. et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418, 934 (2002).

    Article  CAS  PubMed  Google Scholar 

  187. Tie, J. et al. Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int. J. Cancer 128, 2075–2084 (2011).

    Article  CAS  PubMed  Google Scholar 

  188. Fransen, K. et al. Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis 25, 527–533 (2004).

    Article  CAS  PubMed  Google Scholar 

  189. Cisowski, J., Sayin, V. I., Liu, M., Karlsson, C. & Bergo, M. O. Oncogene-induced senescence underlies the mutual exclusive nature of oncogenic KRAS and BRAF. Oncogene 35, 1328–1333 (2016).

    Article  CAS  PubMed  Google Scholar 

  190. Heidorn, S. J. et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140, 209–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Lavoie, H. et al. Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization. Nat. Chem. Biol. 9, 428–436 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Schram, A. M., Chang, M. T., Jonsson, P. & Drilon, A. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance. Nat. Rev. Clin. Oncol. 14, 735–748 (2017).

    Article  CAS  PubMed  Google Scholar 

  193. Sveen, A., Kopetz, S. & Lothe, R. A. Biomarker-guided therapy for colorectal cancer: strength in complexity. Nat. Rev. Clin. Oncol. 17, 11–32 (2020). A recent review focused on the role of biomarkers in the therapeutic management of mCRC.

    Article  PubMed  Google Scholar 

  194. Pulciani, S. et al. Oncogenes in solid human tumours. Nature 300, 539–542 (1982).

    Article  CAS  PubMed  Google Scholar 

  195. Créancier, L. et al. Chromosomal rearrangements involving the NTRK1 gene in colorectal carcinoma. Cancer Lett. 365, 107–111 (2015).

    Article  PubMed  CAS  Google Scholar 

  196. Hechtman, J. F. et al. Identification of targetable kinase alterations in patients with colorectal carcinoma that are preferentially associated with wild-type RAS/RAF. Mol. Cancer Res. 14, 296–301 (2016).

    Article  CAS  PubMed  Google Scholar 

  197. Ardini, E. et al. The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition. Mol. Oncol. 8, 1495–1507 (2014). The first report of the sensitivity of NTRK fusion-positive CRC to TRKA inhibition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Vaishnavi, A., Le, A. T. & Doebele, R. C. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 5, 25–34 (2015).

    Article  CAS  PubMed  Google Scholar 

  199. Drilon, A. 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. 7, 400–409 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Drilon, A. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 378, 731–739 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Hong, D. S. et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 21, 531–540 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Doebele, R. C. et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 21, 271–282 (2020).

    Article  CAS  PubMed  Google Scholar 

  203. FDA. FDA approves larotrectinib for solid tumors with NTRK gene fusions. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions-0 (2018).

  204. EMA. First ‘histology-independent’ treatment for solid tumours with a specific gene mutation. https://www.ema.europa.eu/en/news/first-histology-independent-treatment-solid-tumours-specific-gene-mutation (2019).

  205. Nathenson, M. et al. Activity of larotrectinib in patients with TRK fusion GI malignancies [abstract O-020]. Ann. Oncol. 29 (Suppl. 5), v107 (2018).

    Article  Google Scholar 

  206. Doebele, R.C. et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol. 21, 271–282 (2020).

    Article  CAS  PubMed  Google Scholar 

  207. Sgambato, A., Casaluce, F., Maione, P. & Gridelli, C. Targeted therapies in non-small cell lung cancer: a focus on ALK/ROS1 tyrosine kinase inhibitors. Expert. Rev. Anticancer. Ther. 18, 71–80 (2018).

    Article  CAS  PubMed  Google Scholar 

  208. Amatu, A. et al. Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer. Br. J. Cancer 113, 1730–1734 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Pietrantonio, F. et al. RET fusions in a small subset of advanced colorectal cancers at risk of being neglected. Ann. Oncol. 29, 1394–1401 (2018).

    Article  CAS  PubMed  Google Scholar 

  210. Weaver, A. & Bossaer, J. B. Fibroblast growth factor receptor (FGFR) inhibitors: a review of a novel therapeutic class. J. Oncol. Pharm. Pract. https://doi.org/10.1177/1078155220983425 (2020).

    Article  PubMed  Google Scholar 

  211. Pagani, F. et al. The landscape of actionable gene fusions in colorectal cancer. Int. J. Mol. Sci. 20, 5319 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  212. Drilon, A. et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann. Oncol. 27, 920–926 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Drilon, A. et al. A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov. 7, 963–972 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Russo, M. et al. Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer. Cancer Discov. 6, 36–44 (2016).

    Article  CAS  PubMed  Google Scholar 

  215. Cocco, E., Scaltriti, M. & Drilon, A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat. Rev. Clin. Oncol. 15, 731–747 (2018). A thorough review on the key discoveries in NTRK fusion-positive cancers and their treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Drilon, A. et al. Repotrectinib (TPX-0005) is a next-generation ROS1/TRK/ALK inhibitor that potently inhibits ROS1/TRK/ALK solvent- front mutations. Cancer Discov. 8, 1227–1236 (2018).

    Article  CAS  PubMed  Google Scholar 

  217. Cocco, E. et al. Resistance to TRK inhibition mediated by convergent MAPK pathway activation. Nat. Med. 25, 1422–1427 (2019). The first report that MAPK reactivation through parallel signalling participates to the onset of acquired resistance to NTRK inhibitors in gastrointestinal cancers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Pai, E. F. et al. Structure of the guanine-nucleotide-binding domain of the Ha-ras oncogene product p21 in the triphosphate conformation. Nature 341, 209–214 (1989).

    Article  CAS  PubMed  Google Scholar 

  219. Papke, B. & Der, C. J. Drugging RAS: know the enemy. Science 355, 1158–1163 (2017).

    Article  CAS  PubMed  Google Scholar 

  220. Schubbert, S., Shannon, K. & Bollag, G. Hyperactive Ras in developmental disorders and cancer. Nat. Rev. Cancer 7, 295–308 (2007).

    Article  CAS  PubMed  Google Scholar 

  221. Yuan, T. L. et al. Differential effector engagement by oncogenic KRAS. Cell Rep. 22, 1889–1902 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Hunter, J. C. et al. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol. Cancer Res. 13, 1325–1335 (2015).

    Article  CAS  PubMed  Google Scholar 

  223. Ihle, N. T. et al. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J. Natl. Cancer Inst. 104, 228–239 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J. & Der, C. J. Drugging the undruggable RAS: mission possible? Nat. Rev. Drug Discov. 13, 828–851 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Patricelli, M. P. et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 6, 316–329 (2016).

    Article  CAS  PubMed  Google Scholar 

  227. Janes, M. R. et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172, 578–589.e17 (2018).

    Article  CAS  PubMed  Google Scholar 

  228. Canon, J. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019).

    Article  CAS  PubMed  Google Scholar 

  229. Hallin, J. et al. The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 10, 54–71 (2020).

    Article  CAS  PubMed  Google Scholar 

  230. Govindan, R. et al. Phase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours [abstract 446PD]. Ann. Oncol. 30 (Suppl. 5), v163–v164 (2019).

    Article  Google Scholar 

  231. Strickler, J. et al. AMG 510, a novel small molecule inhibitor of KRAS G12C, for patients with advanced gastrointestinal cancers: results from the CodeBreak 100 phase 1 trial [abstract SO-24]. Ann. Oncol. 31 (Suppl. 3), S226 (2020).

    Article  Google Scholar 

  232. Hong, D. S. et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 393, 1207–1217 (2020). Summarizes, with Canon et al., Hallin et al., Govindan et al. and Strickler et al. (2020), the preclinical and clinical development of selective KRAS-G12C inhibitors.

    Article  Google Scholar 

  233. Nagasaka, M. et al. KRAS G12C game of thrones, which direct KRAS inhibitor will claim the iron throne? Cancer Treat. Rev. 84, 101974 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Lou, K. et al. KRAS G12C inhibition produces a driver-limited state revealing collateral dependencies. Sci. Signal. 12, 583 (2019).

    Article  CAS  Google Scholar 

  235. Misale, S. et al. KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin. Cancer Res. 25, 796–807 (2019).

    Article  CAS  PubMed  Google Scholar 

  236. Molina-Arcas, M. et al. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci. Transl. Med. 11, eaaw7999 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Lito P, R. N. & Solit, D. B. Tumor adaptation and resistance to RAF inhibitors. Nat. Med. 19, 1401–1409 (2013).

    Article  PubMed  CAS  Google Scholar 

  238. Simanshu, D. K., Nissley, D. V. & McCormick, F. RAS proteins and their regulators in human disease. Cell 170, 17–33 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Ryan, M. B. et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition. Clin. Cancer Res. 26, 1633–1643 (2020).

    Article  CAS  PubMed  Google Scholar 

  240. Schneider, G., Schmidt-Supprian, M., Rad, R. & Saur, D. Tissue-specific tumorigenesis: context matters. Nat. Rev. Cancer 17, 239–253 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Li, M. & Belmonte, J. C. I. Organoids — preclinical models of human disease. N. Engl. J. Med. 380, 569–579 (2019).

    Article  PubMed  Google Scholar 

  242. Yoshida, G. J. Applications of patient-derived tumor xenograft models and tumor organoids. J. Hematol. Oncol. 13, 1–16 (2020).

    Article  Google Scholar 

  243. Mainardi, S. et al. SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo. Nat. Med. 24, 961–967 (2018).

    Article  CAS  PubMed  Google Scholar 

  244. Deming, D. A. et al. A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer. Invest. New Drugs 34, 168–175 (2016).

    Article  CAS  PubMed  Google Scholar 

  245. Neto, J. M. F. et al. Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours. Nat. Commun. 11, 3157 (2020).

    Article  CAS  Google Scholar 

  246. Ozkan-Dagliyan, I. et al. Low-dose vertical inhibition of the RAF-MEK-ERK cascade causes apoptotic death of KRAS mutant cancers. Cell Rep. 31, 107764 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Dienstmann, R. et al. Evolving landscape of molecular prescreening strategies for oncology early clinical trials. JCO Precis. Oncol. 4, 505–513 (2020).

    Article  Google Scholar 

  248. Colomer, R. et al. When should we order a next generation sequencing test in a patient with cancer? EClinicalMedicine 25, 100487 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  249. Mosele, F. et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann. Oncol. 31, 1491–1505 (2020).

    Article  CAS  PubMed  Google Scholar 

  250. Mateo, J. et al. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann. Oncol. 29, 1895–1902 (2018). The ESCAT framework to rank genomic alterations on the basis of their actionability in cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Dickson, D. et al. The master observational trial: a new class of master protocol to advance precision medicine. Cell 180, 9–14 (2020).

    Article  CAS  PubMed  Google Scholar 

  252. Siena, S. et al. Pembrolizumab in MMR-proficient metastatic colorectal cancer pharmacologically primed to trigger dynamic hypermutation status: the ARETHUSA trial [abstract]. J. Clin. Oncol. 37 (Suppl. 15), TPS2659 (2019).

    Article  Google Scholar 

  253. Lonardi, S. et al. The PEGASUS trial: post-surgical liquid biopsy-guided treatment of stage III and high-risk stage II colon cancer patients [abstract]. J. Clin. Oncol. 38 (Suppl. 15), TPS4124 (2020).

    Article  Google Scholar 

  254. Andre, T. et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N. Engl. J. Med. 383, 2207–2218 (2020).

    Article  CAS  PubMed  Google Scholar 

  255. Overman, M. J. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 36, 773–779 (2018).

    Article  CAS  PubMed  Google Scholar 

  256. Arena, S. et al. A subset of colorectal cancers with cross-sensitivity to olaparib and oxaliplatin. Clin. Cancer Res. 26, 1372–1384 (2020).

    Article  CAS  PubMed  Google Scholar 

  257. Reilly, N. M., Novara, L., Di Nicolantonio, F. & Bardelli, A. Exploiting DNA repair defects in colorectal cancer. Mol. Oncol. 13, 681–700 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Mauri, G., Arena, S., Siena, S., Bardelli, A. & Sartore-Bianchi, A. The DNA damage response pathway as a land of therapeutic opportunities for colorectal cancer. Ann. Oncol. 31, 1135–1147 (2020).

    Article  CAS  PubMed  Google Scholar 

  259. Van Cutsem E, L. H. et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and ras mutations in colorectal cancer. J. Clin. Oncol. 33, 692–700 (2015).

    Article  PubMed  CAS  Google Scholar 

  260. Van Cutsem, E. et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009).

    Article  PubMed  Google Scholar 

  261. Bokemeyer, C. et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 27, 663–671 (2009).

    Article  CAS  PubMed  Google Scholar 

  262. Bokemeyer, C. et al. FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. Eur. J. Cancer 51, 1243–1252 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Tveit, K. M. 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. 30, 1755–1762 (2012).

    Article  CAS  PubMed  Google Scholar 

  264. Patterson, S. D. et al. Comprehensive analysis of KRAS and NRAS mutations as predictive biomarkers for single agent panitumumab (pmab) response in a randomized, phase III metastatic colorectal cancer (mCRC) study (20020408) [abstract]. J. Clin. Oncol. 31 (Suppl. 15), 3617 (2013).

    Article  Google Scholar 

  265. Seymour, M. T. 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. 14, 749–759 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Peeters, M. 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. 28, 4706–4713 (2010).

    Article  CAS  PubMed  Google Scholar 

  267. Peeters, 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. 21, 5469–5479 (2015).

    Article  CAS  PubMed  Google Scholar 

  268. Venook, A. P. 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 317, 2392–2401 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Innocenti, F. 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. 37, 1217–1227 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Heinemann, V. et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 15, 1065–1075 (2014).

    Article  CAS  PubMed  Google Scholar 

  271. Stintzing, S. 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. 17, 1426–1434 (2016).

    Article  CAS  PubMed  Google Scholar 

  272. Schwartzberg, L. S. et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J. Clin. Oncol. 32, 2240–2247 (2014).

    Article  CAS  PubMed  Google Scholar 

  273. Rivera, F. et al. Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int. J. Colorectal Dis. 32, 1179–1190 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  274. Ciardiello, F. 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. 25, 1756–1761 (2014).

    Article  CAS  PubMed  Google Scholar 

  275. Kopetz, S. et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). J. Clin. Oncol. 39, 285–294 (2017).

    Article  Google Scholar 

  276. Parikh, A. R. & Corcoran, R. B. Fast-TRKing drug development for rare molecular targets. Cancer Discov. 7, 934–936 (2017).

    Article  CAS  PubMed  Google Scholar 

  277. Park, J. J. H., Hsu, G., Siden, E. G., Thorlund, K. & Mills, E. J. An overview of precision oncology basket and umbrella trials for clinicians. CA Cancer J. Clin. 70, 125–137 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  278. Sidaway, P. MSI-H: a truly agnostic biomarker? Nat. Rev. Clin. Oncol. 17, 68 (2020).

    Article  PubMed  Google Scholar 

  279. Hyman, D. et al. Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi) [abstract]. Cancer Res. 79 (Suppl. 13), CT127 (2019).

    Article  Google Scholar 

  280. Jarow, J. P., Lurie, P., Ikenberry, S. C. & Lemery, S. Overview of FDA’s expanded access program for investigational drugs. Ther. Innov. Regul. Sci. 51, 177–179 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work is supported by Fondazione AIRC, Associazione Italiana per la Ricerca sul Cancro, Investigator Grants 20685 (S.S.), 21923 (A.B.), 21407 (F.D.N.) and 22802 (L.T.); Fondazione AIRC under 5 per Mille 2018-ID 21091 program (to A.B., F.D.N., S.M., S.S. and L.T); Instituto de Salud Carlos III through the project “AC15/00018” (co-funded by the European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future”) (J.T.). AIRC-CRUK-FC AECC Accelerator Award contract 22795 (A.B., L.T. and J.T); Fondazione Piemontese per la Ricerca sul Cancro-ONLUS, 5x1000 Ministero della Salute 2015 Project “STRATEGY” (F.D.N.); Fondazione Piemontese per la Ricerca sul Cancro-ONLUS, 5x1000 Ministero della Salute 2015 Project “IMMUNOGENOMICA” (A.B. and L.T.); BiLiGeCT - Progetto PON ARS01_00492 (A.B.); Fondazione Piemontese per la Ricerca sul Cancro-ONLUS, 5x1000 Ministero della Salute 2014 and 2016 (L.T.); H2020 grant agreement no. 754923 COLOSSUS (L.T. and J.T.); CORDIS Community Research and Development Information Service, Horizon 2020 (project ID 635342) grant, Molecularly Guided Trials with Specific Treatment Strategies in Patients with Advanced Newly Molecular Defined Subtypes of Colorectal Cancer (MoTriColor) (J.T.); and Fondazione Oncologia Niguarda Onlus, grant Terapia Molecolare dei Tumori (S.S.).

Author information

Author notes

  1. These authors contributed equally: Federica Di Nicolantonio, Pietro Paolo Vitiello

Authors and Affiliations

  1. Department of Oncology, University of Torino, Candiolo, Italy

    Federica Di Nicolantonio, Pietro Paolo Vitiello, Livio Trusolino & Alberto Bardelli

  2. Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy

    Federica Di Nicolantonio, Livio Trusolino & Alberto Bardelli

  3. Department of Precision Medicine, Medical Oncology Unit, University of Campania Luigi Vanvitelli, Naples, Italy

    Pietro Paolo Vitiello

  4. Istituto FIRC di Oncologia Molecolare, Milan, Italy

    Silvia Marsoni

  5. Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy

    Silvia Marsoni & Salvatore Siena

  6. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Salvatore Siena

  7. Vall d’Hebron University Hospital and Institute of Oncology, IOB-Quiron, UVic-UCC, Barcelona, Spain

    Josep Tabernero

  8. Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands

    Rene Bernards

Authors
  1. Federica Di Nicolantonio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pietro Paolo Vitiello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia Marsoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Salvatore Siena
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Josep Tabernero
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Livio Trusolino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rene Bernards
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alberto Bardelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.D.N., P.P.V., S.M., L.T. and A.B. researched data for this article, all authors made a substantial contribution to discussions of content, F.D.N., P.P.V., S.M., J.T., L.T., S.S. and A.B. wrote the manuscript, and all authors reviewed and/or edited the manuscript prior to submission.

Corresponding authors

Correspondence to Federica Di Nicolantonio or Alberto Bardelli.

Ethics declarations

Competing interests

P.P.V. has acted as a consultant of Biocartis and speaker for Merck. S.S. has acted as an advisor to Amgen, Bayer, BMS, Celgene, CheckmAb, Daiichi-Sankyo, Incyte, Merck, Novartis, Roche and Seattle Genetics. J.T. has acted as an advisor to Array BioPharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Foundation Medicine, Genentech, HalioDX SAS, Menarini, Merck Serono, Merus, MSD, Novartis, Peptomyc, Pfizer, Roche, Roche Diagnostics, Sanofi, Seattle Genetics, Servier, and Taiho Pharmaceutical. L.T. has acted as a speaker for AstraZeneca, Eli Lilly and Merck KGaA, and has received research grants from Menarini, Merus, Pfizer, Servier and Symphogen. R.B. is an employee of and holds shares in Agendia, holds shares in Oncosence, and has received research funding from Astex and Eli Lilly. A.B. has acted as an advisor to Biocartis, Guardant, Horizon Discovery, Illumina, Inivata, Neophore, Roche and Third Rock, declares ownership interests (including patents) in Phoremost and Neophore, and has received commercial research grants from Neophore. The remaining authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Clinical Oncology thanks T. Yoshino, B. Ma, T. Maughan, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Di Nicolantonio, F., Vitiello, P.P., Marsoni, S. et al. Precision oncology in metastatic colorectal cancer — from biology to medicine. Nat Rev Clin Oncol 18, 506–525 (2021). https://doi.org/10.1038/s41571-021-00495-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-021-00495-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer