The impact of RAS mutation on the treatment strategy of colorectal cancer

Kirsten rat sarcoma (KRAS) is the most frequently mutated oncogene in colorectal cancer, being present in 30% of patients with localized disease and in almost half of the patients that develop metastatic disease. While the development of chemotherapy doublets and targeted therapy have improved survival in recent years, KRAS mutation still has a controversial role regarding its prognostic and predictive value both in the adjuvant and in the metastatic setting. The impact of KRAS mutation on treatment strategy remains to be better defined. The development of new KRAS inhibitors promising new treatment options is on the horizon.

[1]  T. Sjöblom,et al.  KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer , 2022, Frontiers in Oncology.

[2]  P. Jänne,et al.  First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1) , 2022, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  J. Tabernero,et al.  O-3 Characterization of KRAS mutation variants and prevalence of KRAS-G12C in gastrointestinal malignancies , 2021, Annals of Oncology.

[4]  T. Cenci,et al.  Discordance of KRAS Mutational Status between Primary Tumors and Liver Metastases in Colorectal Cancer: Impact on Long-Term Survival Following Radical Resection , 2021, Cancers.

[5]  Xiaohong Yan,et al.  KRYSTAL-2: A phase I/II trial of adagrasib (MRTX849) in combination with TNO155 in patients with advanced solid tumors with KRAS G12C mutation. , 2021 .

[6]  J. Desai,et al.  KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. , 2020, The New England journal of medicine.

[7]  P. LoRusso,et al.  One Step at a Time - Clinical Evidence That KRAS Is Indeed Druggable. , 2020, The New England journal of medicine.

[8]  J. Tímár,et al.  Molecular epidemiology and diagnostics of KRAS mutations in human cancer , 2020, Cancer and Metastasis Reviews.

[9]  Hongchuan Jin,et al.  Prognostic value of KRAS mutation status in colorectal cancer patients: a population-based competing risk analysis , 2020, PeerJ.

[10]  T. Zhou,et al.  Metformin selectively inhibits metastatic colorectal cancer with the KRAS mutation by intracellular accumulation through silencing MATE1 , 2020, Proceedings of the National Academy of Sciences.

[11]  N. Rosen,et al.  EGFR blockade reverts resistance to KRAS G12C inhibition in colorectal cancer. , 2020, Cancer discovery.

[12]  A. Jemal,et al.  Colorectal cancer statistics, 2020 , 2020, CA: a cancer journal for clinicians.

[13]  J. Desai,et al.  Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E–Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  D. S. Bhullar,et al.  Biomarker concordance between primary colorectal cancer and its metastases , 2019, EBioMedicine.

[15]  J. Shindoh,et al.  RAS Mutation Clinical Risk Score to Predict Survival After Resection of Colorectal Liver Metastases , 2017, Annals of surgery.

[16]  R. Danesi,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 , 2019, JAMA oncology.

[17]  Weontae Lee,et al.  β‐Catenin‐RAS interaction serves as a molecular switch for RAS degradation via GSK3β , 2018, EMBO reports.

[18]  B. Chabner,et al.  Application of Cell-free DNA Analysis to Cancer Treatment. , 2018, The New England journal of medicine.

[19]  D. Aust,et al.  Colon cancer molecular subtype intratumoral heterogeneity and its prognostic impact: An extensive molecular analysis of the PETACC-8. , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  M. Choti,et al.  Anatomical Resections Improve Disease-free Survival in Patients With KRAS-mutated Colorectal Liver Metastases , 2017, Annals of surgery.

[21]  P. Lyne,et al.  Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS , 2017, Science Translational Medicine.

[22]  A. Bardelli,et al.  Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer , 2016, Nature Communications.

[23]  M. Merlano,et al.  Prognostic and predictive biomarkers in metastatic colorectal cancer anti-EGFR therapy. , 2016, World journal of gastroenterology.

[24]  J Ricke,et al.  ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[25]  Jan Sundquist,et al.  Patterns of metastasis in colon and rectal cancer , 2016, Scientific Reports.

[26]  V. Heinemann,et al.  Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[27]  Long Bai,et al.  Comparison of KRAS mutation status between primary tumor and metastasis in Chinese colorectal cancer patients , 2016, Medical Oncology.

[28]  C. Camps,et al.  Molecular subtyping of colon cancer (CC) based on mutational status of RAS, BRAF, and DNA mismatch repair (MMR) proteins. Prognostic value. , 2016 .

[29]  P. Laurent-Puig,et al.  Prognostic Effect of BRAF and KRAS Mutations in Patients With Stage III Colon Cancer Treated With Leucovorin, Fluorouracil, and Oxaliplatin With or Without Cetuximab: A Post Hoc Analysis of the PETACC-8 Trial. , 2016, JAMA oncology.

[30]  J. Vauthey,et al.  RAS Mutation Predicts Positive Resection Margins and Narrower Resection Margins in Patients Undergoing Resection of Colorectal Liver Metastases , 2016, Annals of Surgical Oncology.

[31]  Ahmedin Jemal,et al.  Global Cancer Incidence and Mortality Rates and Trends—An Update , 2015, Cancer Epidemiology, Biomarkers & Prevention.

[32]  M. Cañadas-Garre,et al.  Molecular biomarkers in colorectal carcinoma. , 2015, Pharmacogenomics.

[33]  Beatriz Bellosillo,et al.  Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients , 2015, Nature Medicine.

[34]  Frank McCormick,et al.  KRAS as a Therapeutic Target , 2015, Clinical Cancer Research.

[35]  N. Goldstein,et al.  CCR 20th Anniversary Commentary: A Chimeric Antibody, C225, Inhibits EGFR Activation and Tumor Growth , 2015, Clinical Cancer Research.

[36]  D. Sargent,et al.  Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. , 2015, Gastroenterology.

[37]  M. D'Angelica,et al.  KRAS mutation influences recurrence patterns in patients undergoing hepatic resection of colorectal metastases , 2014, Cancer.

[38]  R. Salazar,et al.  Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[39]  S. Fesik,et al.  Drugging the undruggable RAS: Mission Possible? , 2014, Nature Reviews Drug Discovery.

[40]  Hartmut Link,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. , 2014, The Lancet. Oncology.

[41]  L. Collette,et al.  Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. , 2014, The Lancet. Oncology.

[42]  Liam O'Connor,et al.  Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer. , 2014, Cancer research.

[43]  Seung-Yong Jeong,et al.  KRAS Mutation is Associated with Worse Prognosis in Stage III or High-risk Stage II Colon Cancer Patients Treated with Adjuvant FOLFOX , 2014, Annals of Surgical Oncology.

[44]  Roland Seifert,et al.  Faculty Opinions recommendation of K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. , 2013 .

[45]  Kevan M. Shokat,et al.  K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions , 2013, Nature.

[46]  A. Russo,et al.  Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance? , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[47]  D. Sargent,et al.  Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. , 2012, JAMA.

[48]  T. Eberlein Association of KRAS p.G13D Mutation With Outcome in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer Treated With Cetuximab , 2012 .

[49]  D. Bar-Sagi,et al.  RAS oncogenes: weaving a tumorigenic web , 2011, Nature Reviews Cancer.

[50]  P. Carmeliet,et al.  Molecular mechanisms and clinical applications of angiogenesis , 2011, Nature.

[51]  I. Nagtegaal,et al.  KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients , 2011, British Journal of Cancer.

[52]  Sabine Tejpar,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. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2010, International journal of surgery.

[54]  J. Meyerhardt,et al.  KRAS Mutation in Stage III Colon Cancer and Clinical Outcome Following Intergroup Trial CALGB 89803 , 2009, Clinical Cancer Research.

[55]  D. Sargent,et al.  Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[56]  L. Mazzucchelli,et al.  Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant , 2009, British Journal of Cancer.

[57]  I. Floriani,et al.  High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practice. , 2008, The oncologist.

[58]  J. Downward,et al.  Many faces of Ras activation. , 2008, Biochimica et biophysica acta.

[59]  Dongsheng Tu,et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer. , 2008, The New England journal of medicine.

[60]  S. Veronese,et al.  Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  P. Laurent-Puig,et al.  K-Ras Mutations and Treatment Outcome in Colorectal Cancer Patients Receiving Exclusive Fluoropyrimidine Therapy , 2008, Clinical Cancer Research.

[62]  L. Ellis,et al.  VEGF-targeted therapy: mechanisms of anti-tumour activity , 2008, Nature Reviews Cancer.

[63]  Daniel J. Freeman,et al.  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  A. Lièvre,et al.  KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  R. Goldberg,et al.  Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[66]  Marc Peeters,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. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[67]  A. Lièvre,et al.  KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. , 2006, Cancer research.

[68]  H. Hollema,et al.  Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[69]  N. Petrelli,et al.  Hepatic resection: the last surgical frontier for colorectal cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[70]  Silvia Benvenuti,et al.  Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. , 2005, The Lancet. Oncology.

[71]  W. Scheithauer,et al.  Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  Armando Santoro,et al.  Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. , 2004, The New England journal of medicine.

[73]  J. Berlin,et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. , 2004, The New England journal of medicine.

[74]  D. Bishop,et al.  Molecular changes in the Ki-ras and APC genes in primary colorectal carcinoma and synchronous metastases compared with the findings in accompanying adenomas , 2003, Molecular pathology : MP.

[75]  C. Wilson,et al.  Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  M. Buyse,et al.  Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[77]  J. Pow-Sang,et al.  Antisense DNA inhibition of tumor growth induced by c-Ha-ras oncogene in nude mice. , 1993, Cancer research.

[78]  W. Bubb,et al.  Synthesis of 5-fluoropyrimidines , 1974 .

[79]  J. Folkman Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[80]  J. Higginson,et al.  International Agency for Research on Cancer. , 1968, WHO chronicle.