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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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“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]
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“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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“Activating mutations in KRAS (exon 2, 3 and 4) and NRAS (exon 2 , 3 and 4) occur in about 55% of metastatic CRC, while mutations in HRAS seem to occur infrequently [59-67].”
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“In fact, in 045 clinical trial, TGFα mRNA levels were significantly elevated in the tumors from metastatic CRC patients with disease progression after cetuximab therapy as compared to patient with clinical response (47).”
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“Few patients carrying KRAS-mutated tumors were responsive to cetuximab and panitumumab treatment [151].”
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“Different EGFR-specific ligands could differently influence the clinical activity of cetuximab: while high mRNA levels of either amphiregulin or epiregulin may predict a better response [21, 116-119], high levels of TGF-α as well as HBEGF could confer lack of sensitivity [107, 118].”
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MicroRNA-505 functions as a tumor suppressor in endometrial cancer by targeting TGF-α
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“Interestingly, overexpression of TGF-α could interact with mesenchymal-to-epithelial transition (MET) and contribute to cetuximab resistance in patients with colorectal cancer [35, 36].”
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“In addition, we showed here that Sym004 is highly efficient at blocking colorectal cancer cell line growth in the presence of the high-affinity ligands EGF and TGFα, factors known to be both upregulated in response to anti-EGFR antibody treatment and determinants of EGFR inhibitor resistance (13).”
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“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.”
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“In particular, strong overexpression of TGFa has been shown to correlate with reduced sensitivity to cetuximab (24).”
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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).”
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“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).”
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Cost Estimates and Economic Implications of Expanded RAS Testing in Metastatic Colorectal Cancer
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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.”
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“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
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“[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
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“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).”
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“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
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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
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ResultPanitumumab for the Treatment of Metastatic Colorectal Cancer: A Review
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“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”
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BackgroundOptimization of Anti-EGFR Treatment of Advanced Colorectal Cancer
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BackgroundBiomarkers in Metastatic Colorectal Cancer
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Metadata
- 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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