Pharmacogenomic and Pharmacoproteomic Studies of Cetuximab in Metastatic Colorectal Cancer: Biomarker Analysis of a Phase I Dose-Escalation Study
Open accessAbstract
Purpose: This study assessed biomarkers for cetuximab efficacy in tissue samples collected during a phase I dose-escalation study exploring every second week administration of cetuximab as first-line therapy in patients with metastatic colorectal cancer (mCRC). Patients and Methods: Sixty-two patients received cetuximab monotherapy for 6 weeks, followed by cetuximab plus infusional fluorouracil, leucovorin, and irinotecan until disease progression. Patients in the control arm received cetuximab as a 400 mg/m 2 initial dose then 250 mg/m 2 per week; patients in the dose-escalation arms received 400 to 700 mg/m 2 every second week. Tumor and skin biopsies were taken for immunohistochemical and microarray expression analyses (tumor only) at baseline and week 4. Plasma was collected for proteomic analysis at baseline and week 4. KRAS tumor mutation status was assessed. Results: In subsets of paired skin samples from 35 patients, cetuximab treatment was associated with substantial downregulation of phospho(p)-EGFR, p-MAPK and proliferation and substantial upregulation of p27 Kip1 and p-STAT3 levels. No marked difference in these effects was noted for different schedules of administration and dose levels. In the cetuximab monotherapy phase, responses were seen only in patients whose tumors were wild-type for KRAS (eight of 29 v zero of 19 for KRAS mutant tumors; P = .015). Progression-free survival was longer for patients with KRAS wild-type compared with KRAS mutant tumors (log-rank P = .048). Genomics/proteomics analyses (42 and 45 patients, respectively) identified candidate biomarkers associated with response. Conclusion: Biomarker analysis supported the functional equivalence of weekly and every second week administration of cetuximab and provided further confirmation that patients with KRAS wild-type mCRC were those most likely to benefit from cetuximab treatment.
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High mRNA levels of either amphiregulin or epiregulin may predict a better response to cetuximab.
“while high mRNA levels of either amphiregulin or epiregulin may predict a better response [21, 116-119]”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [118]
High levels of TGF-α as well as HB-EGF could confer lack of sensitivity to cetuximab.
“high levels of TGF-α as well as HB-EGF could confer lack of sensitivity [107, 118].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [118]
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MethodImproving outcomes in colorectal cancer: Where do we go from here?
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Self-citationTroiani, T., Zappavigna, S., Martinelli, E., Addeo, S. R., Stiuso, P., Ciardiello, F., & Caraglia, M. (2013) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2012.756469 · Cited by 53 · see citing works
Self-citationFool’s gold, lost treasures, and the randomized clinical trial
Stewart, D. J., & Kurzrock, R. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-193 · Cited by 51 · see citing works
“Across a range of colorectal cancer and NSCLC studies, p-value for association of response with mutation status was usually more significant than association of overall survival with mutation status (Table 1) [35,36,52-70], in keeping with increased statistical power with a response endpoint.”
BackgroundCiardiello, F., Tejpar, S., Normanno, N., Mercadante, D., Teague, T., Wohlschlegel, B., & Cutsem, E. V. (2011) · Targeted Oncology · doi:10.1007/s11523-011-0181-x · Cited by 51 · see citing works
Self-citationPredictive and prognostic biomarkers with therapeutic targets in advanced colorectal cancer
Luo, H. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i14.3858 · Cited by 50 · see citing works
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“AREG- and EREG-induced upregulation of EGFR is not only a key mediator of intestinal neoplastic transformation, but also a positive predictor of sensitivity to EGFR inhibition in CRC [36-39].”
BackgroundMolecular pathways: sensitivity and resistance to anti-EGFR antibodies
Bertotti, A., & Sassi, F. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0848 · Cited by 45 · see citing works
“In particular, strong overexpression of TGFa has been shown to correlate with reduced sensitivity to cetuximab (24).”
BackgroundCirculating tumor cells as pharmacodynamic biomarker in early clinical oncological trials
Devriese, L. A., Voest, E. E., Beijnen, J. H., & Schellens, J. H. M. (2011) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2011.04.006 · Cited by 43 · see citing works
Analysis of Impact of Post-Treatment Biopsies in Phase I Clinical Trials
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Sequential research-related biopsies in phase I trials: acceptance, feasibility and safety
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Molecular Predictors of Response to Chemotherapy in Colorectal Cancer
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Self-citationFury, M. G., Sherman, E. J., Lisa, D., Agarwal, N., Algazy, K., Brockstein, B., Langer, C. J., Lim, D. W., Mehra, R., Rajan, S. K., et al. (2012) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2012.0144 · Cited by 40 · see citing works
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“An increased expression of high-affinity ligands, such as TGFa and HB-EGF, was also observed in a mouse colorectal cancer model with acquired resistance to cetuximab (14).”
BackgroundResultInfluentialMendelsohn, J. M., Prewett, M. C., Rockwell, P., & Goldstein, N. I. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2491 · Cited by 36 · see citing works
“A few reports have suggested that high expression of epiregulin and amphiregulin in tumors correlates with response to cetuximab in patients with colorectal cancer (10).”
TACE-dependent TGFα shedding drives triple-negative breast cancer cell invasion
Giricz, O., Calvo, V., Peterson, E. A., Abouzeid, C. M., & Kenny, P. A. (2013) · International Journal of Cancer · doi:10.1002/ijc.28295 · Cited by 35 · see citing works
A dual‐targeting antibody against EGFR‐VEGF for lung and head and neck cancer treatment
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Loupakis, F., Cremolini, C., Fioravanti, A., Orlandi, P., Salvatore, L., Masi, G., Schirripa, M., Di Desidero, T., Antoniotti, C., Canu, B., et al. (2014) · Targeted Oncology · doi:10.1007/s11523-013-0284-7 · Cited by 33 · see citing works
Development of Molecular Biomarkers in Individualized Treatment of Colorectal Cancer
Mattos‐Arruda, L. D., Dienstmann, R., & Tabernero, J. M. (2011) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2011.03.030 · Cited by 29 · see citing works
Self-citationTetraspanin 6 is a regulator of carcinogenesis in colorectal cancer
Andrijes, R., Hejmadi, R. K., Pugh, M., Rajesh, S., Novitskaya, V., Ibrahim, M., Overduin, M., Tselepis, C., Middleton, G., Győrffy, B., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2011411118 · Cited by 28 · see citing works
Nandal, S., & Burt, T. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18020448 · Cited by 26 · see citing works
“2010 [69] Cetuximab 1 mCRC Identifying biomarkers of cetuximab-responsive disease in plasma and tissue samples Immuno-assays for 97 proteins Candidate predictive biomarkers of response to cetuximab treatment were identified including inhibition of signaling proteins”
MethodCirculating pEGFR Is a Candidate Response Biomarker of Cetuximab Therapy in Colorectal Cancer
Κάτσιλα, Θ., Juliachs, M., Gregori, J., Macarulla, T. M., Villarreal, L., Bardelli, A., Torrance, C. J., Élez, E., Tabernero, J. M., & Villanueva, J. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0361 · Cited by 25 · see citing works
Self-citationMetabolomics as a tool for Personalizing Medicine: 2012 Update
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Giampieri, R., Scartozzi, M., Prete, M. D., Maccaroni, E., Bittoni, A., Faloppi, L., Bianconi, M., Cecchini, L., & Cascinu, S. (2013) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2013.05.008 · Cited by 24 · see citing works
Feedback activation of HER3 attenuates response to EGFR inhibitors in colon cancer cells
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Personalized treatment for advanced colorectal cancer: KRAS and beyond
Karapetis, C. S., & Patel, G. S. (2013) · Cancer Management and Research · doi:10.2147/cmar.s35025 · Cited by 20 · see citing works
Overview of biomarkers in metastatic colorectal cancer: Tumour, blood and patient-related factors
Clarke, S. J., Karapetis, C. S., Gibbs, P., Pavlakis, N., Desai, J., Michael, M., Tebbutt, N. C., Price, T. J., & Tabernero, J. M. (2012) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2012.06.001 · Cited by 21 · see citing works
“[61] Tabernero J, Cervantes A, Rivera F, et al.”
BackgroundSelf-citationPersonalised Treatment in Gastric Cancer: Myth or Reality?
Tarazona, N., Gambardella, V., Huerta, M., Roselló, S., & Cervantes, A. M. R. (2016) · Current Oncology Reports · doi:10.1007/s11912-016-0525-x · Cited by 20 · see citing works
Self-citationKogawa, T., Doi, A., Shimokawa, M., Fouad, T. M., Osuga, T., Tamura, F., Mizushima, T., Kimura, T., Abe, S., Ihara, H., et al. (2014) · Targeted Oncology · doi:10.1007/s11523-014-0322-0 · Cited by 19 · see citing works
Cost Estimates and Economic Implications of Expanded RAS Testing in Metastatic Colorectal Cancer
Kircher, S. M., Mohindra, N. A., & Nimeiri, H. S. (2014) · The Oncologist · doi:10.1634/theoncologist.2014-0252 · Cited by 18 · see citing works
Cho, W. C. S. (2011) · Expert Review of Proteomics · doi:10.1586/epr.10.108 · Cited by 18 · see citing works
Pharmacogenomic Contribution to Drug Response
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“This interaction between wild-type K-ras tumors and cetuximab benefit persisted when cetuximab monotherapy was given as a first-line therapy.(33) There are similar data for panitumumab and K-ras effect on tumor control.”
MethodAlternate dosing of cetuximab for patients with metastatic colorectal cancer.
Hubbard, J. M., & Alberts, S. R. (2013) · Europe PMC (PubMed Central) · Cited by 16 · see citing works
Ichikawa, W., Terashima, M., Ochiai, A., Kitada, K., Kurahashi, I., Sakuramoto, S., Katai, H., Sano, T., Imamura, H., & Sasako, M. (2016) · Gastric Cancer · doi:10.1007/s10120-016-0600-x · Cited by 15 · see citing works
Barry, G. S., Cheang, M. C. U., Chang, H. L., & Kennecke, H. F. (2016) · Oncotarget · doi:10.18632/oncotarget.8006 · Cited by 15 · see citing works
“A separate phase I doseescalation cetuximab trial in a KRAS wt mCRC cohort reported a non-overlapping set of 6 genes associated with response to EGFR inhibition, though the biological significance of these genes is currently unknown [13].”
BackgroundMethodPharmacokinetic and pharmacodynamic evaluation of panitumumab in the treatment of colorectal cancer
Lo, L. L., Patel, D., Townsend, A. R., & Price, T. J. (2015) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2015.1112787 · Cited by 14 · see citing works
“[95] Studies have shown that higher amphiregulin and epiregulin mRNA expression in KRAS WT patients treated with cetuximab was associated with better disease control rate.[96,97] Low expression of these ligands indicated that the tumour may be dependent on alternative signalling pathways, not solely RAS, and was assoc…”
BackgroundAn Assessment of Peptide Enrichment Methods Employing mTRAQ Quantification Approaches
Potier, D. N., Griffiths, J. R., Unwin, R. D., Walker, M. J., Carrick, E., Willamson, A. J. K., & Whetton, A. D. (2012) · Analytical Chemistry · doi:10.1021/ac300584y · Cited by 14 · see citing works
Bao, L., Guo, T., Wang, J., Zhang, K., & Bao, M. (2019) · Oncology Letters · doi:10.3892/ol.2019.11079 · Cited by 13 · see citing works
“Tumor patients with high expression levels of PPAN have been shown to respond more favorably to treatment with anti‐EGFR antibodies such as cetuximab (34).”
Caiazza, F., Elliott, L., Fennelly, D. W., Sheahan, K. D., Doherty, G. A., & Ryan, E. J. (2015) · Biomarkers in Medicine · doi:10.2217/bmm.15.5 · Cited by 12 · see citing works
Response Phenotype As a Predictive Biomarker to Guide Treatment With Targeted Therapies
Oxnard, G. R., & Schwartz, L. H. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.51.8365 · Cited by 9 · see citing works
Park, J. H., Kim, M. Y., Choi, I. S., Kim, J., Kim, J. W., Lee, K., & Kim, J. S. (2022) · PLoS ONE · doi:10.1371/journal.pone.0276497 · Cited by 9 · see citing works
“Proteomic analysis of mCRC patients treated with Cmab showed downregulation of phospho(p)-EGFR, p-MAPK, and proliferation and substantial upregulation of p27 and p-STAT3 levels [10].”
BackgroundKRAS mutational status of endoscopic biopsies matches resection specimens
Yang, Q., Schmidt, J., Soucy, G., Odze, R. D., Dejesa-Jamanila, L., Arnold, K., Kuslich, C. D., & Lash, R. H. (2012) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2012-200746 · Cited by 9 · see citing works
Pharmacodynamics of DT-IgG, a dual-targeting antibody against VEGF-EGFR, in tumor xenografted mice
Hurwitz, S. J., Zhang, H., Yun, S., Batuwangala, T. D., Steward, M., Holmes, S. D., Rycroft, D., Pan, L., Tighiouart, M., Shin, H. J. C., et al. (2011) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-011-1713-x · Cited by 9 · see citing works
Topic Evolution Analysis for Omics Data Integration in Cancers
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“It provided further confirmation that patients with KRAS wild-type metastatic colorectal cancer (mCRC) were those most likely to benefit from cetuximab treatment (Tabernero et al., 2010).”
BackgroundCetuximab Every 2 Weeks Versus Standard Weekly Dosing Administration Schedule
Bokemeyer, C., Ciardiello, F., Dubreuil, O., Guigay, J., Kasper, S., Pfeiffer, P., Pinto, C., Yamaguchi, K., Yoshino, T., Zielinski, C. C., et al. (2023) · Future Oncology · doi:10.2217/fon-2023-0282 · Cited by 8 · see citing works
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Impact of cetuximab in current treatment of metastatic colorectal cancer
Sotelo, M. J., Valera, J. S., & Díaz‐Rubio, E. (2014) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2014.883376 · Cited by 7 · see citing works
“Finally, while confirmation in additional studies is still awaited, the available evidence supports the hypothesis that the analysis of KRAS mutational status in conjunction with other biomarkers, such as EGFR gene copy number, levels of amphiregulin and epiregulin, mutations in BRAF, NRAS, PIK3CA or loss of PTEN expr…”
ResultPanitumumab for the Treatment of Metastatic Colorectal Cancer: A Review
Prete, M. D., Giampieri, R., Faloppi, L., Bianconi, M., Bittoni, A., Andrikou, K., & Cascinu, S. (2015) · Immunotherapy · doi:10.2217/imt.15.46 · Cited by 7 · see citing works
Chen, Y., Cao, D., Bi, F., Li, Q., & Qiu, M. (2014) · Medical Oncology · doi:10.1007/s12032-014-0935-2 · Cited by 6 · see citing works
“It also supported by biomarker analysis [14].”
Kazmi, F., Shrestha, N., Liu, T. F. D., Foord, T. H., Heesen, P., Booth, S. W., Dodwell, D. J., Lord, S., Yeoh, K., & Blagden, S. P. (2025) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd014872.pub2 · Cited by 7 · see citing works
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Self-citationVecchione, L., Saridaki, Z., & Tejpar, S. (2011) · Current Colorectal Cancer Reports · doi:10.1007/s11888-011-0112-3 · Cited by 4 · see citing works
Paracrine Network: Another Step in the Complexity of Resistance to EGFR Blockade?
Salazar, R., Capellá, G., & Tabernero, J. M. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1615 · Cited by 4 · see citing works
“tiated by Baker and colleagues (9) and Tabernero and colleagues (10), with the latter also suggesting that high TGFa expression was associated with a negative predictive”
BackgroundSelf-citationCetuximab dosing by rash—is the scaling of EVEREST meaningful?
Stintzing, S., & Lenz, H. (2012) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2012.142 · Cited by 3 · see citing works
Where now for anti-EGF receptor therapies in colorectal cancer?
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Resistance of Colorectal Tumors to Anti-EGFR Antibodies
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Metabonomics in Translational Research for Personalized Medicine and Nutrition
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“Elevated expression of epiregulin and amphiregulin has been shown in 50–60% of patients with mCRC and correlates with clinical benefit from cetuximab as monotherapy or in combination with chemotherapy [42,43].”
BackgroundOptimization of Anti-EGFR Treatment of Advanced Colorectal Cancer
Vecchione, L. (2014) · Current Colorectal Cancer Reports · doi:10.1007/s11888-014-0232-7 · Cited by 1 · see citing works
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Analysis and Interpretation of Pharmacoproteomic Data
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Identification of Biomarkers for Pharmacological Activity
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“Several genomics analyses based on DNA extraction and RNA expression profiling showed that KRAS mutation is a candidate marker associated with resistance to cetuximab treatment in CRC (De Roock et al. 2008; Lièvre et al. 2008; Tabernero et al. 2011).”
BackgroundBiomarkers in Metastatic Colorectal Cancer
Diakos, C. I., Charles, K. A., Chua, W. M., Howell, V. M., & Clarke, S. J. (2015) · Biomarkers in disease · doi:10.1007/978-94-007-7681-4_1 · Cited by 1 · see citing works
EGFR inhibitors in cancer treatment
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Self-citationResistance to the Anti-EGFR Therapy, Beyond KRAS, in Patients with Metastatic Colorectal Cancer
Saridaki, Z., & Souglakos, J. (2013) · Resistance to targeted anti-cancer therapeutics · doi:10.1007/978-1-4614-7654-2_6
- Authors
- Tabernero, J., Cervantes, A., Rivera, F., Martinelli, E., Rojo, F., von Heydebreck, A., Macarulla, T., Rodriguez-Braun, E., Eugenia Vega-Villegas, M., Senger, S., Ramos, F. J., Roselló, S., Celik, I., Stroh, C., Baselga, J., & Ciardiello, F.
- Affiliations
- Universitat Autònoma de Barcelona (ES)
- From the Medical Oncology Service, Pathology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona; Department of Hematology and Medical Oncology, Hospital Clinic Universitario, University of Valencia; Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, Santander, Spain; Division of Medical Oncology, Department of Experimental and Clinical Medicine “F. Magrassi and A. Lanzara,” Second University of Naples, Naples, Italy; and Merck KGaA,...
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2010-03-01
- Volume
- 28
- Issue
- 7
- Pages
- 1181-1189
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2163799638
- Cited by
- 110
- References
- 37
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 8 · 2015: 12 · 2014: 16 · 2013: 15 · 2012: 9
- FWCI
- 8.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- cetuximab, metastatic colorectal cancer, pharmacogenomics, pharmacoproteomics, predictive biomarkers, KRAS mutation status, EGFR signaling, MAPK signaling, STAT3, p27, dose escalation, treatment schedule, progression-free survival
- MeSH terms
- Cetuximab, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Humans, Immunohistochemistry, Mutation, Neoplasm Metastasis, Neoplasm Proteins, Pharmacogenetics, Proto-Oncogene Proteins, Biomarkers, Tumor, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), ras Proteins, Oligonucleotide Array Sequence Analysis, Proteomics, Intracellular Signaling Peptides and Proteins, Cyclin-Dependent Kinase Inhibitor p27, Antibodies, Monoclonal, Humanized, ErbB Receptors
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