The Clinical Benefit of Bevacizumab in Metastatic Colorectal Cancer Is Independent of K-ras Mutation Status: Analysis of a Phase III Study of Bevacizumab with Chemotherapy in Previously Untreated Metastatic Colorectal Cancer
Open accessAbstract
Purpose.: Mutations of the K-ras gene were identified as a prognostic marker in metastatic colorectal cancer (mCRC). In addition, emerging data suggest that K-ras mutations are a negative predictor of clinical benefit from anti–epidermal growth factor receptor treatment in mCRC. Previously reported data suggest that the longer overall survival (OS) observed with bevacizumab treatment in mCRC is independent of alterations in the Ras/Raf/Mek/Erk pathway. We conducted additional analyses to better describe the clinical benefit of bevacizumab treatment in mCRC relative to K-ras mutation status. Patients and Methods.: Additional statistical analyses were done with data from K-ras mutation analyses in 230 patients who were treated with irinotecan, fluorouracil, and leucovorin (IFL) in combination with either bevacizumab or placebo in a randomized phase III study. Following microdissection, tissue was subject to DNA sequencing to identify K-ras mutations in codons 12 and 13. Hazard ratios for the bevacizumab group relative to the control group were estimated from an unstratified Cox regression model. The median progression-free survival (PFS), OS times, and objective response rates were compared. Results.: K-ras status was assessed in 230 patients (28.3%). The median PFS was significantly longer in bevacizumab-treated patients with wild-type (wt)- (13.5 versus 7.4 months; hazard ratio 0.44, p < .0001) and mutant (m)-K-ras (9.3 versus 5.5 months; hazard ratio 0.41, p = .0008). A significantly higher response rate for IFL plus bevacizumab was observed only in wt-K-ras patients (60.0% versus 37.3%, p = .006) compared with 43.2% versus 41.2% in the m-K-ras group. Conclusion.: Bevacizumab provides significant clinical benefit in patients with mCRC expressing either mutant or wild-type K-ras.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Addition of bevacizumab to chemotherapy contributes to PFS regardless of KRAS mutation status.
“In studies evaluating the addition of bevacizumab to chemotherapy agents, the addition of bevacizumab contributes to PFS, regardless of KRAS mutation status [17,18].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [18]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer
Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., Berlin, J., Baron, A., Griffing, S., Holmgren, E., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032691 · Cited by 10,968 · see citing works
Self-citationTargeting RAS signalling pathways in cancer therapy
Downward, J. (2003) · Nature reviews. Cancer · doi:10.1038/nrc969 · Cited by 3,262 · see citing works
Amado, R. G., Wolf, M., Peeters, M., Van Cutsem, E., Siena, S., Freeman, D. J., Juan, T., Sikorski, R., Suggs, S., Radinsky, R., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.7116 · Cited by 3,207 · see citing works
<i>KRAS</i> Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer
Lièvre, A., Bachet, J.-B., Le Corre, D., Boige, V., Landi, B., Emile, J.-F., Côté, J.-F., Tomasic, G., Penna, C., Ducreux, M., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0191 · Cited by 2,229 · see citing works
Bokemeyer, C., Bondarenko, I., Makhson, A. M., Hartmann, J. T., Aparicio, J., de Braud, F., Donea, S., Ludwig, H., Schuch, G., Stroh, C., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.20.8397 · Cited by 1,629 · see citing works
Lièvre, A., Bachet, J., Boige, V., Cayre, A., Corre, D. L., Buc, E., Ychou, M., Bouché, O., Landi, B., Louvet, C., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.12.5906 · Cited by 1,456 · see citing works
Khambata-Ford, S., Garrett, C. R., Meropol, N. J., Basik, M., Harbison, C. T., Wu, S., Wong, T. W., Huang, X., Takimoto, C. H., Godwin, A. K., et al. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.10.5437 · Cited by 1,125 · 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
De Roock, W., Piessevaux, H., De Schutter, J., Janssens, M., De Hertogh, G., Personeni, N., Biesmans, B., Van Laethem, J.-L., Peeters, M., Humblet, Y., et al. (2008) · Annals of Oncology · doi:10.1093/annonc/mdm496 · Cited by 827 · see citing works
Di Fiore, F., Blanchard, F., Charbonnier, F., Le Pessot, F., Lamy, A., Galais, M. P., Bastit, L., Killian, A., Sesboüé, R., Tuech, J. J., et al. (2007) · British Journal of Cancer · doi:10.1038/sj.bjc.6603685 · Cited by 734 · see citing works
Cutsem, E. V., Láng, I., D’Haens, G., Moiseyenko, V. M., Załuski, J., Folprecht, G., Tejpar, S., Kisker, O., Stroh, C., & Rougier, P. R. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.26.15_suppl.2 · Cited by 372 · see citing works
Ahnen, D. J., Feigl, P., Quan, G., Fenoglio‐Preiser, C. M., Lovato, L., Bunn, P. A., Stemmerman, G. N., Wells, J. D., Macdonald, J. S., & Meyskens, F. L. (1998) · PubMed · Cited by 338 · see citing works
Association of k-ras, b-raf, and p53 Status With the Treatment Effect of Bevacizumab
Ince, W. L., Jubb, A. M., Holden, S. N., Holmgren, E. B., Tobin, P., Sridhar, M., Hurwitz, H. I., Kabbinavar, F. F., Novotny, W. F., Hillan, K. J., et al. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji174 · Cited by 318 · see citing works
Self-citationBokemeyer, C., Bondarenko, I., Hartmann, J. T., de Braud, F., Volovat, C. D., Nippgen, J., Stroh, C., Celik, I., & Koralewski, P. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.26.15_suppl.4000 · Cited by 240 · see citing works
K-ras and p16 Aberrations Confer Poor Prognosis in Human Colorectal Cancer
Esteller, M., González, S., Risques, R. A., Marcuello, E., Mangues, R., Germà, J. R., Herman, J. G., Capellá, G., & Peinado, M. A. (2001) · Journal of Clinical Oncology · doi:10.1200/jco.2001.19.2.299 · Cited by 234 · 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
Hypoxia Inducible Factor-1–Independent Pathways in Tumor Angiogenesis
Mizukami, Y., Kohgo, Y., & Chung, D. C. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-0111 · Cited by 185 · see citing works
Punt, C. J. A., Tol, J. A. M. G., Rodenburg, C. J., Cats, A., Creemers, G. J. M., Schrama, J. G., Erdkamp, F., Vos, A. H., Mol, L., & Antonini, N. F. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.26.15_suppl.lba4011 · Cited by 128 · see citing works
What do oncogenic mutations have to do with angiogenesis/vascular dependence of tumors?
Rak, J. W., Yu, J., Kerbel, R. S., & Coomber, B. L. (2002) · PubMed · Cited by 102 · see citing works
Issues in clinical trial design for tumor marker studies
Sargent, D. J., & Allegra, C. J. (2002) · Seminars in Oncology · doi:10.1053/sonc.2002.32898 · Cited by 60 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Hegde, P. S., Jubb, A. M., Chen, D., Li, N. F., Meng, Y. G., Bernaards, C., Elliott, R., Scherer, S. J., & Chen, D. S. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-2535 · Cited by 193 · 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
Current targeted therapies in the treatment of advanced colorectal cancer: a review
Moriarity, A., O’Sullivan, J., Kennedy, J., Mehigan, B., & McCormick, P. (2016) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834016646734 · Cited by 87 · see citing works
Price, 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
Ghimessy, Á. K., Gellert, Á., Schlegl, E., Hegedus, B., Raso, E., Barbai, T., Timar, J., Ostoros, G., Megyesfalvi, Z., Gieszer, B., et al. (2019) · Cancers · doi:10.3390/cancers11101514 · Cited by 27 · see citing works
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., et al. (2020) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-020-03290-y · Cited by 21 · see citing works
Sun, D.-C., Shi, Y., Wang, Y.-R., Lv, Y., Yan, H., Mao, H., Wang, Z.-K., Wu, Z.-Y., Shi, W.-W., & Dai, G.-H. (2017) · Scientific Reports · doi:10.1038/s41598-017-14669-2 · Cited by 16 · see citing works
Sütcüoğlu, O., Yıldırım, H. Ç., Almuradova, E., Günenç, D., & Yalçın, Ş. (2025) · Medicina · doi:10.3390/medicina61071202 · Cited by 10 · see citing works
- Authors
- Hurwitz, H. I., Yi, J., Ince, W., Novotny, W. F., & Rosen, O.
- Affiliations
- Duke University (US)
- Genentech (US)
- b Genentech, Inc., South San Francisco, California, USA
- Corresponding author
- Hurwitz, Herbert I.
- Venue
- The Oncologist
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-01-01
- Volume
- 14
- Issue
- 1
- Pages
- 22-28
- ISSN
- 1083-7159 (ISSN-L)
- 1549-490X
- OpenAlex
- W2171790106
- Cited by
- 239
- References
- 20
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 2 · 2020: 9 · 2019: 16 · 2018: 11 · 2017: 14 · 2016: 13 · 2015: 17 · 2014: 23 · 2013: 27 · 2012: 31
- FWCI
- 14.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Oncologist (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Sanofi
- Sunesis
- Genentech
- 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
- bevacizumab, metastatic colorectal cancer, irinotecan, 5-fluorouracil, leucovorin, progression-free survival, objective response rate, anti-EGFR therapy, prognostic factors, RAS/MAPK pathway
- MeSH terms
- Bevacizumab, Irinotecan, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Leucovorin, Female, Fluorouracil, Humans, Male, Middle Aged, Mutation, Predictive Value of Tests, Genes, ras, Colorectal Neoplasms, Disease-Free Survival, Angiogenesis Inhibitors, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
