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Artificial Intelligence-Assisted Amphiregulin and Epiregulin IHC Predicts Panitumumab Benefit in RAS Wild-Type
Christopher J M Williams1,2, Jenny F Seligmann2, Faye Elliott2
1Division of Pathology and Data Analytics, University of Leeds, Leeds, United Kingdom.
Purpose:
High tumor mRNA levels of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are associated with anti-EGFR agent response in metastatic colorectal cancer (mCRC). However, ligand RNA assays have not been adopted into routine practice due to issues with analytic precision and practicality. We investigated whether AREG/EREG IHC could predict benefit from the anti-EGFR agent panitumumab.
Experimental Design:
Artificial intelligence algorithms were developed to assess AREG/EREG IHC in 274 patients from the PICCOLO trial of irinotecan with or without panitumumab (Ir vs. IrPan) in RAS wild-type mCRC. The primary endpoint was progression-free survival (PFS). Secondary endpoints were RECIST response rate (RR) and overall survival (OS). Models were repeated adjusting separately for BRAF mutation status and primary tumor location (PTL).
Results:
High ligand expression was associated with significant PFS benefit from IrPan compared with Ir [8.0 vs. 3.2 months; HR, 0.54; 95% confidence interval (CI), 0.37-0.79; P = 0.001]; whereas low ligand expression was not (3.4 vs. 4.4 months; HR, 1.05; 95% CI, 0.74-1.49; P = 0.78). The ligand-treatment interaction was significant (P interaction = 0.02) and remained significant after adjustment for BRAF-mutation status and PTL. Likewise, RECIST RR was significantly improved in patients with high ligand expression (IrPan vs. Ir: 48% vs. 6%; P < 0.0001) but not those with low ligand expression (25% vs. 14%; P = 0.10; P interaction = 0.01). The effect on OS was similar but not statistically significant.
Conclusions:
AREG/EREG IHC identified patients who benefitted from the addition of panitumumab to irinotecan chemotherapy. IHC is a practicable assay that may be of use in routine practice.
Insights
Immunohistochemistry (IHC) for amphiregulin (AREG) and epiregulin (EREG) ligands can identify metastatic colorectal cancer (mCRC) patients who benefit from panitumumab treatment, offering a practical clinical tool.
Area of Science:
- Oncology
- Molecular Diagnostics
- Colorectal Cancer Research
Background:
- High tumor mRNA levels of EGFR ligands AREG and EREG correlate with anti-EGFR therapy response in mCRC.
- Current RNA assays for these ligands face challenges in precision and practicality for routine clinical use.
Purpose of the Study:
- To evaluate if AREG/EREG immunohistochemistry (IHC) can predict patient benefit from panitumumab, an anti-EGFR agent.
- To assess the utility of IHC as a practical diagnostic tool in clinical settings.
Main Methods:
- Developed AI algorithms to analyze AREG/EREG IHC in 274 mCRC patients from the PICCOLO trial (irinotecan +/- panitumumab).
- Primary endpoint was progression-free survival (PFS); secondary endpoints included RECIST response rate (RR) and overall survival (OS).
- Analyses were adjusted for BRAF mutation status and primary tumor location.
Main Results:
- High AREG/EREG expression predicted significant PFS benefit with panitumumab addition (8.0 vs. 3.2 months; P=0.001), while low expression did not (3.4 vs. 4.4 months; P=0.78).
- The ligand-treatment interaction was significant (Pinteraction=0.02) and persisted after adjustments.
- RECIST RR was substantially improved in high-ligand expressors (48% vs. 6%; P<0.0001), with no significant benefit in low-ligand expressors (25% vs. 14%; P=0.10).
Conclusions:
- AREG/EREG IHC effectively identifies patients who gain benefit from panitumumab plus irinotecan chemotherapy.
- IHC represents a practicable assay suitable for integration into routine clinical practice for mCRC treatment selection.
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