Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer

Huang, Fei; Xu, Li-an; Khambata-Ford, Shirin

doi:10.1158/1078-0432.ccr-11-1135

Cited by 33Colorectal Cancer Treatments and StudiesGrowth Hormone and Insulin-like Growth FactorsHER2/EGFR in Cancer Research

Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer

Huang, Fei, Xu, Li-an, Khambata-Ford, Shirin·2012·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-11-1135

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Abstract

Purpose: This study examined potential correlations between markers related to the insulin-like growth factor-1 receptor (IGF-1R) pathway and clinical benefit from the anti–epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in metastatic colorectal cancer (mCRC). Experimental Design: Gene expression profiles for 70 pretreatment specimens from metastatic lesions of patients with chemorefractory mCRC receiving cetuximab monotherapy were analyzed using 74 predefined Gene-Chip probesets representing 33 unique IGF-1R pathway markers to determine correlations with progression-free survival (PFS) and disease control rate. Results: Higher IGF-1R, higher GRB7, and lower INSIG2 expression were associated with longer PFS with cetuximab in univariate analyses, particularly in patients with wild-type K-Ras tumors: median, 122 versus 60 days (P = 0.01), 122 versus 57 days (P = 0.011), and 57 versus 156 days (P < 0.0001), favoring higher IGF-1R, higher GRB7, and lower INSIG2 expression, respectively. Lower IGF-1 expression was associated with a PFS benefit with cetuximab, whereas lower IGFBP3 and INSR expression levels showed trends for a PFS benefit. Lower INSIG2 expression (vs. higher expression) was associated with greater PFS in the high epiregulin-expressing group (P = 0.001), but not in the low-expressing cohort suggesting an effect independent from the previously reported effect of epiregulin expression. Lower INSIG2 expression was also associated with higher disease control rate in the overall population (51.4% vs. 11.4%; P = 0.001) and wild-type K-Ras subset (76.2% vs. 18.2%; P < 0.0001). Conclusions: These results suggest that markers of the IGF-1R pathway may play a role in predicting benefit from cetuximab therapy in mCRC. Additional clinical studies are warranted to validate these findings. Clin Cancer Res; 18(4); 1156–66. ©2012 AACR.

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“The activation of compensatory feedback loops of EGFR, such as erb-b2 receptor tyrosine kinase 2 (ERBB2), MET and insulin-like growth factor 1 receptor (IGF-1R), has been shown to interfere with EGFR inhibitor treatment [12–14].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [14]

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Horndler, C., Gallego, R., García‐Albéniz, X., et al. (2011) · Cancer Biology & Therapy · doi:10.4161/cbt.11.2.13839 · Cited by 7 · see citing works

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Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies
Zhou, J., Ji, Q., & Li, Q. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02130-2 · Cited by 246 · see citing works
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Gene Expression Markers of Efficacy and Resistance to Cetuximab Treatment in Metastatic Colorectal Cancer: Results from CALGB 80203 (Alliance)
Cushman, S. M., Jiang, C., Hatch, A. J., Shterev, I. D., Sibley, A. B., Niedzwiecki, D., Venook, A. P., Owzar, K., Hurwitz, H. I., & Nixon, A. B. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2313 · Cited by 84 · see citing works
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Hebbar, M., Wacrenier, A., Desauw, C., Romano, O., Cattan, S., Triboulet, J., & Pruvot, F. (2006) · Anti-Cancer Drugs · doi:10.1097/01.cad.0000217425.44584.9f · Cited by 110 · see citing works
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Cetuximab in Patients with Non-Small Cell Lung Cancer and EGFR Exon 20 Insertion Alterations.
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Authors: Huang, F., Xu, L.-A., & Khambata-Ford, S.
Affiliations: Bristol-Myers Squibb (United States) (US)
Authors' Affiliation: Bristol-Myers Squibb Co., Princeton, New Jersey
ORCID: Huang, Fei
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2012-02-14
Volume: 18
Issue: 4
Pages: 1156-1166
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-11-1135
OpenAlex: W2143476323
Cited by: 33
References: 64
Citations by year: 2023: 3 · 2022: 2 · 2021: 2 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 5 · 2014: 4 · 2013: 4 · 2012: 2
FWCI: 2.37
Type: journal article
Language: en
Open access: closed
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords: cetuximab, metastatic colorectal cancer, gene expression biomarkers, anti-EGFR monoclonal antibody, progression-free survival, disease control rate, KRAS wild-type, Grb7, INSIG2, epiregulin, insulin-like growth factor I, IGFBP-3, insulin receptor, predictive biomarkers
MeSH terms: Cetuximab, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Agents, Female, Humans, Insulin-Like Growth Factor I, Male, Membrane Proteins, Middle Aged, Mutation, Neoplasm Metastasis, Proto-Oncogene Proteins, Receptor, Insulin, Biomarkers, Tumor, Colorectal Neoplasms, Signal Transduction, Antigens, CD, Gene Expression, Survival Analysis, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Receptor, IGF Type 1, ras Proteins, Insulin-Like Growth Factor Binding Protein 3, Gene Expression Profiling, Intracellular Signaling Peptides and Proteins, GRB7 Adaptor Protein, Antibodies, Monoclonal, Humanized

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Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer

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