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Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials
Open accessAbstract
IMPORTANCE: Metastatic colorectal cancer (mCRC) is heterogeneous, and primary tumors arising from different regions of the colon are clinically and molecularly distinct. OBJECTIVE: To examine the prognostic and predictive value of primary tumor location in patients with RAS wild-type (wt) mCRC treated with first-line fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab in the Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial and FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment For Patients With Metastatic Colorectal Cancer (FIRE-3) trial. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective analysis patients with RAS wt metastatic colorectal cancer from the CRYSTAL and FIRE-3 trials were classified as having left-sided or right-sided mCRC, defined, respectively, as patients whose tumors originated in the splenic flexure, descending colon, sigmoid colon, or rectum vs appendix, cecum, ascending colon, hepatic flexure, or transverse colon. MAIN OUTCOMES AND MEASURES: Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were assessed according to tumor location and treatment arm. RESULTS: In the RAS wt populations of the CRYSTAL and FIRE-3 trials, patients with left-sided tumors (n = 142 and n = 157, respectively) had markedly superior PFS, OS, and ORR compared with patients with right-sided tumors (n = 33 and n = 38, respectively). Among CRYSTAL and FIRE-3 study patients with RAS wt left-sided tumors, FOLFIRI plus cetuximab significantly improved OS relative to the respective comparators (FOLFIRI and FOLFIRI plus bevacizumab); in contrast, in RAS wt patients with poor-prognosis right-sided tumors, limited efficacy benefits were observed upon the addition of cetuximab to FOLFIRI in CRYSTAL, and comparable outcomes were observed between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab arms of FIRE-3. A significant interaction was observed between primary tumor location and treatment for OS (CRYSTAL: hazard ratio [HR], 1.95; 95% CI, 1.09-3.48 and FIRE-3: HR, 0.40; 95% CI, 0.23-0.70) within the RAS wt populations of both studies in multivariable models that also included sex, prior adjuvant therapy, and BRAF mutational status. CONCLUSIONS AND RELEVANCE: In the RAS wt populations of CRYSTAL and FIRE-3, patients with left-sided tumors had a markedly better prognosis than those with right-sided tumors. First-line FOLFIRI plus cetuximab clearly benefitted patients with left-sided tumors (vs FOLFIRI or FOLFIRI plus bevacizumab, respectively), whereas patients with right-sided tumors derived limited benefit from standard treatments. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: CRYSTAL, NCT00154102, and FIRE-3, NCT00433927.
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“bevacizumab is effective regardless of RAS gene status”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [39]
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Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D., Skora, A. D., Luber, B. S., Azad, N. S., Laheru, D., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500596 · Cited by 9,377
The consensus molecular subtypes of colorectal cancer
Guinney, J., Dienstmann, R., Wang, X., de Reyniès, A., Schlicker, A., Soneson, C., Marisa, L., Roepman, P., Nyamundanda, G., Angelino, P., et al. (2015) · Nature Medicine · doi:10.1038/nm.3967 · Cited by 5,170
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Van Cutsem, E., Köhne, C.-H., Hitre, E., Zaluski, J., Chang Chien, C.-R., Makhson, A., D'Haens, G., Pintér, T., Lim, R., Bodoky, G., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0805019 · Cited by 3,877
Self-citationVan Cutsem, E., Köhne, C.-H., Láng, I., Folprecht, G., Nowacki, M. P., Cascinu, S., Shchepotin, I., Maurel, J., Cunningham, D., Tejpar, S., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.33.5091 · Cited by 1,882
Self-citationHeinemann, 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
Self-citationVan Cutsem, E., Lenz, H.-J., Köhne, C.-H., Heinemann, V., Tejpar, S., Melezínek, I., Beier, F., Stroh, C., Rougier, P., van Krieken, J. H., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.4812 · Cited by 789
Self-citationPowell, A. E., Wang, Y., Li, Y., Poulin, E. J., Means, A. L., Washington, M. K., Higginbotham, J. N., Juchheim, A., Prasad, N., Levy, S. E., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.042 · Cited by 694
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Missiaglia, E., Jacobs, B., D’Ario, G., Narzo, A. F. D., Soneson, C., Budínská, E., Popovici, V. C., Vecchione, L., Gerster, S., Yan, P., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu275 · Cited by 646
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Loupakis, F., Yang, D., Yau, L., Feng, S., Cremolini, C., Zhang, W., Maus, M. K. H., Antoniotti, C., Langer, C., Scherer, S. J., et al. (2015) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dju427 · Cited by 477
Self-citationBrule, S. Y., Jonker, D. J., Karapetis, C. S., O’Callaghan, C. J., Moore, M. J., Wong, R. P. W., Tebbutt, N. C., Underhill, C. R., Yip, D., Zalcberg, J. R., et al. (2015) · European Journal of Cancer · doi:10.1016/j.ejca.2015.03.015 · Cited by 335
Venook, A. P., Niedzwiecki, D., Innocenti, F., Fruth, B. F., Greene, C. C., O’Neil, B. H., Shaw, J. E., Atkins, J. N., Horvath, L. E., Polite, B. N., et al. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2016.34.15_suppl.3504 · Cited by 335
Self-citationvon Einem, J. C., Heinemann, V., von Weikersthal, L. F., Vehling‐Kaiser, U., Stauch, M. B., Hass, H. G., Decker, T. W., Klein, S., Held, S., Jung, A., et al. (2014) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-014-1678-3 · Cited by 112
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LaPointe, L. C., Dunne, R. A., Brown, G. S., Worthley, D. L., Molloy, P. L., Wattchow, D. A., & Young, G. P. (2007) · Physiological Genomics · doi:10.1152/physiolgenomics.00185.2006 · Cited by 90
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Boisen, M. K., Johansen, J. S., Dehlendorff, C., Larsen, J. S., Østerlind, K., Hansen, J., Nielsen, S. E., Pfeiffer, P., Tarpgaard, L. S., Holländer, N. H., et al. (2013) · Annals of Oncology · doi:10.1093/annonc/mdt253 · Cited by 88
Sinicrope, F. A., Mahoney, M. R., Yoon, H. H., Smyrk, T. C., Thibodeau, S. N., Goldberg, R. M., Nelson, G. D., Sargent, D. J., & Alberts, S. R. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0527 · Cited by 84
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Wang, F., Bai, L., Liu, T.-S., Yu, Y.-Y., He, M.-M., Liu, K.-Y., Luo, H., Zhang, D.-S., Jin, Y., Wang, F., et al. (2015) · 癌症：英文版 · doi:10.1186/s40880-015-0022-x · Cited by 76
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Zhang, Y., Ma, J., Zhang, S., Deng, G., Wu, X., He, J., Pei, H., Shen, H., & Zeng, S. (2015) · International Journal of Colorectal Disease · doi:10.1007/s00384-015-2273-z · Cited by 55
Modest, D. P., Schulz, C. U., von Weikersthal, L. F., Quietzsch, D., von Einem, J. C., Schalhorn, A., Vehling‐Kaiser, U., Laubender, R. P., Giessen, C. A., Stintzing, S., et al. (2013) · Anti-Cancer Drugs · doi:10.1097/cad.0000000000000041 · Cited by 48
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Sunakawa, Y., Ichikawa, W., Tsuji, A., Denda, T., Segawa, Y., Negoro, Y., Shimada, K., Kochi, M., Nakamura, M., Kotaka, M., et al. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2016.34.4_suppl.613 · Cited by 6
Loupakis, F., Yang, D., Zhang, W., Cremolini, C., Wakatsuki, T., Salvatore, L., Antoniotti, C., Aprile, G., Schirripa, M., Ricci, V., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.30.15_suppl.3549 · Cited by 2
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He, W., Yang, Q., Jiang, C., Liao, F., Liu, S.-S., & Xia, L. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2016.34.4_suppl.683 · Cited by 2
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Arnold, D., Lueza, B., Douillard, J.-Y., Peeters, M., Lenz, H., Venook, A. P., Heinemann, V., Cutsem, E. V., Pignon, J., Tabernero, J. M., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx175 · Cited by 853
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Metadata
- Authors
- Tejpar, S., Stintzing, S., Ciardiello, F., Tabernero, J., Van Cutsem, E., Beier, F., Esser, R., Lenz, H.-J., & Heinemann, V.
- Affiliations
- Universitair Ziekenhuis Leuven (BE)
- Ludwig-Maximilians-Universität München (DE)
- University of Campania "Luigi Vanvitelli" (IT)
- Universitat Autònoma de Barcelona (ES)
- Digestive Oncology, University Hospitals Leuven and KULeuven, Leuven, Belgium
- Merck KGaA, Darmstadt (Germany) (DE)
- University of Southern California (US)
- Corresponding author
- Tejpar, Sabine
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2017-02-01
- Volume
- 3
- Issue
- 2
- Pages
- 194
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC7505121
- OpenAlex
- W2531319683
- Cited by
- 709
- References
- 24
- Citations by year
- 2026: 19 · 2025: 35 · 2024: 64 · 2023: 48 · 2022: 70 · 2021: 89 · 2020: 85 · 2019: 97 · 2018: 102 · 2017: 96
- FWCI
- 53.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Funders
- National Cancer Institute (P30CA014089)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- metastatic colorectal cancer, RAS wild-type, primary tumor site, cetuximab, FOLFIRI, bevacizumab, first-line therapy, progression-free survival, overall survival, objective response rate, predictive biomarkers, CRYSTAL trial, FIRE-3 trial, EGFR inhibition
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