Current treatment options in RAS mutant metastatic colorectal cancer patients: A meta-analysis of 14 randomized phase III trials
Open accessAbstract
Purpose: Although biomarkers for patients with metastatic colorectal cancer exist, the benefit patients with RAS mutated tumors derive from established regimens is unclear. Methods: Efficacy of therapeutic strategies available for RAS mutated patients (addition of chemotherapeutic agents and/or anti angiogenic agents) were investigated in fourteen randomized controlled phase III trials at trial level by meta-analysing individual study hazard ratios and 95% confidence intervals (95% CI) for overall survival (OS) and progression free survival (PFS). Results: 6810 of 10,748 patients (63.3%) were available (48.5% RAS wildtype, 51.5% RAS mutated). Across all treatment lines, additional treatment efficacy (chemotherapy and/or anti angiogenic agents) was significantly smaller in RAS mutated compared to wildtype tumors for OS and PFS. In detail, patients with RAS mutated metastatic colorectal cancer derived significant benefit in PFS but not in OS by the addition of either chemotherapy or anti angiogenic agents to the respective comparator. In patients with RAS wildtype metastatic colorectal cancer, PFS and OS were improved by the addition of chemotherapy or anti angiogenic agent. Conclusion: The therapeutic benefit of additional substances is less distinct in patients with RAS mutated as compared to RAS wildtype metastatic colorectal cancer, especially with regard to OS.
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In a meta-analysis of 14 phase III trials, improvement in OS was significantly more pronounced in RAS WT tumors than RAS mutant tumors across all included studies (p for interaction = 0.003).
“In a meta-analysis consisting of 14 phase III trials, the efficacy analysis aimed to compare outcomes between patients with wild and mutant tumors. The study demonstrated that the improvement in OS was significantly more pronounced in patients with RAS WT tumors than those with RAS mutant tumors across all included studies (p for interaction = 0.003) [41].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [41]
Addition of anti-angiogenic treatment was significantly less effective in RAS mutant tumors compared to wild-type tumors, with interaction effect (wt HR=0.78 vs mut HR=0.91).
“Furthermore, the addition of anti-angiogenic treatment was significantly less effective in RAS mutant tumors compared to wild-type tumors, with a notable interaction effect (wt: HR = 0.78 vs. mut: HR = 0.91) (Table 2).”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [41]
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Cites
Genetic Alterations during Colorectal-Tumor Development
Vogelstein, B., Fearon, E. R., Hamilton, S. R., Kern, S. E., Preisinger, A. C., Leppert, M., de Vries-Smits, A. M. M., & Bos, J. L. (1988) · New England Journal of Medicine · doi:10.1056/nejm198809013190901 · Cited by 6,704 · see citing works
Cunningham, D., Humblet, Y., Siena, S., Khayat, D., Bleiberg, H., Santoro, A., Bets, D., Mueser, M., Harstrick, A., Verslype, C., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa033025 · Cited by 5,035 · see citing works
ESMO consensus guidelines for the management of patients with metastatic colorectal cancer
Van Cutsem, E., Cervantes, A., Adam, R., Sobrero, A., Van Krieken, J. H., Aderka, D., Aranda Aguilar, E., Bardelli, A., Benson, A., Bodoky, G., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw235 · Cited by 3,421 · see citing works
Self-citationGrothey, A., Cutsem, E. V., Sobrero, A., Siena, S., Falcone, A., Ychou, M., Humblet, Y., Bouché, O., Mineur, L., Barone, C., et al. (2013) · The Lancet · doi:10.1016/s0140-6736(12)61900-x · Cited by 2,895 · see citing works
Panitumumab–FOLFOX4 Treatment and <i>RAS</i> Mutations in Colorectal Cancer
Douillard, J.-Y., Oliner, K. S., Siena, S., Tabernero, J., Burkes, R., Barugel, M., Humblet, Y., Bodoky, G., Cunningham, D., Jassem, J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1305275 · Cited by 2,263 · see citing works
Cetuximab for the Treatment of Colorectal Cancer
Jonker, D. J., O'Callaghan, C. J., Karapetis, C. S., Zalcberg, J. R., Tu, D., Au, H.-J., Berry, S. R., Krahn, M., Price, T., Simes, R. J., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa071834 · Cited by 1,904 · see citing works
Heinemann, V., von Weikersthal, L. F., Decker, T., Kiani, A., Vehling-Kaiser, U., Al-Batran, S.-E., Heintges, T., Lerchenmüller, C., Kahl, C., Seipelt, G., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70330-4 · Cited by 1,740 · see citing works
Self-citationCetuximab in the treatment of colorectal cancer.
Goldberg, R. M., Venook, A. P., & Schilsky, R. L. (2004) · PubMed · Cited by 1,518 · see citing works
Cremolini, C., Loupakis, F., Antoniotti, C., Lupi, C., Sensi, E., Lonardi, S., Mezi, S., Tomasello, G., Ronzoni, M., Zaniboni, A., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00122-9 · Cited by 1,092 · see citing works
Sobrero, A. F., Maurel, J., Fehrenbacher, L., Scheithauer, W., Abubakr, Y. A., Lutz, M. P., Vega-Villegas, M. E., Eng, C., Steinhauer, E. U., Prausová, J., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.13.1193 · Cited by 940 · see citing works
Benvenuti, S., Sartore-Bianchi, A., Di Nicolantonio, F., Zanon, C., Moroni, M., Veronese, S., Siena, S., & Bardelli, A. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4158 · Cited by 830 · see citing works
Li, J., Qin, S., Xu, R., Yau, T. C. C., Ma, B., Pan, H., Xu, J., Bai, Y., Chi, Y., Wang, L., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)70156-7 · Cited by 813 · see citing works
Kirsten ras mutations in patients with colorectal cancer: The multicenter “RASCAL” study
Andreyev, H. J. N., Norman, A. R., Clarke, P. A., Cunningham, D., & Oates, J. R. (1998) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/90.9.675 · Cited by 748 · see citing works
Richman, S. D., Seymour, M. T., Chambers, P., Elliott, F., Daly, C. L., Meade, A. M., Taylor, G., Barrett, J. H., & Quirke, P. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.22.4295 · Cited by 560 · see citing works
Modest, D. P., Ricard, I., Heinemann, V., Hegewisch-Becker, S., Schmiegel, W., Porschen, R., Stintzing, S., Graeven, U., Arnold, D., von Weikersthal, L. F., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw261 · Cited by 351 · see citing works
Self-citationBarault, L., Veyrie, N., Jooste, V., Corre, D. L., Chapusot, C., Ferraz, J., Lièvre, A., Cortet, M., Bouvier, A., Rat, P., et al. (2008) · International Journal of Cancer · doi:10.1002/ijc.23388 · Cited by 345 · see citing works
Hegewisch-Becker, S., Graeven, U., Lerchenmüller, C. A., Killing, B., Depenbusch, R., Steffens, C.-C., Al-Batran, S.-E., Lange, T., Dietrich, G., Stoehlmacher, J., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00042-x · Cited by 251 · see citing works
Hurwitz, H. I., Yi, J., Ince, W., Novotny, W. F., & Rosen, O. (2009) · The Oncologist · doi:10.1634/theoncologist.2008-0213 · Cited by 239 · see citing works
Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study
Andreyev, J. N., Norman, A. R., Cunningham, D., Oates, J. R., Dix, B. R., Iacopetta, B. J., Young, J. P., Walsh, T. P., Ward, R. L., Hawkins, N., et al. (2001) · British Journal of Cancer · doi:10.1054/bjoc.2001.1964 · Cited by 204 · see citing works
Leonard, J. P., Kolibaba, K. S., Reeves, J. A., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2017.73.2784 · Cited by 186 · see citing works
HB-EGF promotes angiogenesis in endothelial cells via PI3-kinase and MAPK signaling pathways
Mehta, V. B., & Besner, G. E. (2007) · Growth Factors · doi:10.1080/08977190701773070 · Cited by 156 · see citing works
Kubicka, S., Greil, R., André, T., Bennouna, J., Sastre, J., Van Cutsem, E., von Moos, R., Österlund, P., Reyes-Rivera, I., Müller, T., et al. (2013) · Annals of Oncology · doi:10.1093/annonc/mdt231 · Cited by 104 · see citing works
Cutsem, E. V., Mayer, R. J., Laurent, S., Winkler, R. E., Grávalos, C., Benavides, M., Longo-Muñoz, F., Portales, F., Ciardiello, F., Siena, S., et al. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2017.10.009 · Cited by 96 · see citing works
Aparicio, T., Ghiringhelli, F., Boige, V., Le Malicot, K., Taieb, J., Bouché, O., Phelip, J.-M., François, E., Borel, C., Faroux, R., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.75.2931 · Cited by 91 · see citing works
Goey, K. K. H., Elias, S. G., van Tinteren, H., Laclé, M. M., Willems, S. M., Offerhaus, G. J. A., de Leng, W. W. J., Strengman, E., ten Tije, A. J., Creemers, G. J. M., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx322 · Cited by 81 · see citing works
Baraniskin, A., Buchberger, B., Pox, C. P., Graeven, U., Holch, J. W., Schmiegel, W., & Heinemann, V. (2018) · European Journal of Cancer · doi:10.1016/j.ejca.2018.10.009 · Cited by 75 · see citing works
Self-citationObermannova, R. L., Cutsem, E. V., Yoshino, T., Bodoky, G., Prausová, J., García‐Carbonero, R., Ciuleanu, T., Alfonso, P., Portnoy, D. C., Cohn, A. L., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw402 · Cited by 71 · see citing works
Velour trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity.
Wirapati, P., Pomella, V., Vandenbosch, B., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2017.35.15_suppl.3538 · Cited by 56 · see citing works
Modest, D. P., von Weikersthal, L. F., Decker, T. W., Vehling‐Kaiser, U., Uhlig, J., Schenk, M., Freiberg‐Richter, J., Peuser, B., Denzlinger, C., Reddemann, C. P. G., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.18.00052 · Cited by 50 · see citing works
Self-citationPrice, T. J., Bruhn, M. A., Lee, C. K., Hardingham, J. E., Townsend, A. R., Mann, K. P., Simes, J., Weickhardt, A., Wrin, J. W., Wilson, K., et al. (2015) · British Journal of Cancer · doi:10.1038/bjc.2015.37 · Cited by 39 · see citing works
Velour trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity
Wirapati, P., Pomella, V., Vandenbosch, B., Kerr, P., Maiello, E., Jeffery Grahame, M., Curca, R.-O. D., Karthaus, M., Bridgewater, J. A., Mihailov, A. C., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx302.004 · Cited by 39 · see citing works
Hegewisch‐Becker, S., Nöpel‐Dünnebacke, S., Hinke, A., Graeven, U., Reinacher‐Schick, A., Hertel, J., Lerchenmuller, C. A., Killing, B., Depenbusch, R., Al‐Batran, S., et al. (2018) · European Journal of Cancer · doi:10.1016/j.ejca.2018.06.015 · Cited by 22 · see citing works
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Sütcüoğlu, O., Yıldırım, H. Ç., Almuradova, E., Günenç, D., & Yalçın, Ş. (2025) · Medicina · doi:10.3390/medicina61071202 · Cited by 10 · see citing works
- Authors
- Stahler, A., Heinemann, V., Ricard, I., von Einem, J. C., Giessen-Jung, C., Westphalen, C. B., Michl, M., Heinrich, K., Miller-Phillips, L., Jelas, I., Stintzing, S., & Modest, D. P.
- Affiliations
- LMU Klinikum (DE)
- German Cancer Research Center (DE)
- Stiftung Charité (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Corresponding author
- Stahler, Arndt
- ORCID
- Venue
- Journal of Cancer Research and Clinical Oncology
- Published
- 2020-06-19
- Volume
- 146
- Issue
- 8
- Pages
- 2077-2087
- ISSN
- 0084-5353 (ISSN-L)
- 0171-5216
- 1432-1335
- PMC
- PMC7324435
- OpenAlex
- W3036422969
- Cited by
- 21
- References
- 32
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 6 · 2021: 4
- FWCI
- 0.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Cancer Research and Clinical Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- RAS mutations, metastatic colorectal cancer, chemotherapy, angiogenesis inhibitors, overall survival, progression-free survival, treatment efficacy, biomarkers
- MeSH terms
- Antineoplastic Combined Chemotherapy Protocols, Humans, Mutation, Genes, ras, Colorectal Neoplasms, Randomized Controlled Trials as Topic, Clinical Trials, Phase III as Topic, ras Proteins, Angiogenesis Inhibitors
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