Abstract
Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin‐binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment‐by‐marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild‐type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild‐type (WT) patients (chemo HR = 0.98, 95% CI = 0.74–1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05–2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02–2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67–1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68–13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31–2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88–1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32–1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab.
Highlights
Colorectal cancer (CRC) is one of the most common cancers in both men and women, and remains one of the leading causes of cancer-related death worldwide [1]
KRAS mutation analysis was performed in the CALGB/ Alliance molecular reference laboratory of Dr Greg
In the KRAS WT group, CD73 levels were predictive of PFS benefit from cetuximab (Fig. 5, panel B) and overall survival (OS) benefit from cetuximab (Fig. 5, panel C)
Summary
Colorectal cancer (CRC) is one of the most common cancers in both men and women, and remains one of the leading causes of cancer-related death worldwide [1]. Therapies targeting the activation and signaling of epidermal growth factor receptor (EGFR/HER1/ERBB1) have improved outcomes, but essentially all patients will develop treatment resistance and progress [3, 4]. Improving outcomes in these patients is predicated on refining our understanding of the relationship between receptor expression and downstream signaling pathways. Hetero-dimerization between members of this RTK family provides specificity to the downstream signaling initiated by the ligands that bind these receptors, and provides potential avenues for resistance to cetuximab, as well as other agents, that target the activity of a single member of this receptor family [7, 8]
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