Abstract
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). 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. Higher IGF-1R, higher GRB(7), and lower INSIG(2) 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 GRB(7), and lower INSIG(2) expression, respectively. Lower IGF-1 expression was associated with a PFS benefit with cetuximab, whereas lower IGFBP(3) and INSR expression levels showed trends for a PFS benefit. Lower INSIG(2) 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 INSIG(2) 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). 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.
Highlights
Cetuximab is an anti–epidermal growth factor receptor (EGFR) monoclonal antibody that has antitumor efficacy in metastatic colorectal cancer; locoregionally advanced recurrent or metastatic squamous cell carcinoma of the head and neck [3, 4]; and advanced non–small cell lung cancer (NSCLC; ref. 5)
This study evaluated whether expression levels of the insulin-like growth factor-1 receptor (IGF-1R) pathway markers correlate with cetuximab benefit in patients with chemorefractory metastatic colorectal cancer (mCRC), including the subset of patients with wild-type K-Ras
This study indicates that there is a potential correlation between cetuximab benefit in mCRC and expression of certain markers in the IGF-1R pathway
Summary
Cetuximab is an anti–epidermal growth factor receptor (EGFR) monoclonal antibody that has antitumor efficacy in metastatic colorectal cancer (mCRC; refs. 1, 2); locoregionally advanced recurrent or metastatic squamous cell carcinoma of the head and neck [3, 4]; and advanced non–small cell lung cancer (NSCLC; ref. 5). That the presence of K-Ras exon-2 mutations (codons 12 and 13) predicts lack of cetuximab benefit in mCRC, both as single-agent therapy in patients who are refractory to chemotherapy and in combination with chemotherapy in treatment-na€ve patients [2, 6,7,8]. Whereas these original studies bundled all known exon-2 mutations as one single "resistance genotype," more recent studies have indicated that patients with tumors carrying the G13D mutation may benefit from therapy, suggesting that this mutation may not have the same effect as the rest on exon-2 [9, 10]. Not all patients with wild-type K-Ras benefit from cetuximab-based therapy, and further refinement of patient selection is desirable
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