Artificial Intelligence–Assisted Amphiregulin and Epiregulin IHC Predicts Panitumumab Benefit in RAS Wild-Type Metastatic Colorectal Cancer

Abstract

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 (Pinteraction = 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; Pinteraction = 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.

The Role of EREG/EGFR Pathway in Tumor Progression

“…Remarkably, high expression of EREG was suggested to fuel an oncogenic feedback loop that activates the EGFR/ERBB4 signaling cascade and was anticipated to be a therapeutic target in NSCLC [ 79 ]. Elevation of EREG has been shown to be a predictive biomarker of response to anti-EGFR therapies in mCRC and HNSCC patients [ 11 , 120 ]. Thus, the EGFR-specific ligands, such as EREG, have a significant effect on intracellular pathway and are strongly associated with response to anti-EGFR therapy.…”

Antibody-drug conjugates targeting EGFR ligand Epiregulin inhibit colorectal tumor growth irrespective ofRASmutational status

“…Notably, EREG-high status confers an overall survival advantage at earlier timepoints (Fig. 1F), which has been shown to be significant for KRAS wildtype patients who received anti-EGFR therapy (17,29). Analysis of a recent study of 18 matched primary tumors, synchronous liver metastases, and normal colonic epithelium (17 MSS and 1 MSI-H) showed EREG was significantly elevated in both primary tumors and their metastases (30).…”

Targeting epiregulin in the treatment-damaged tumor microenvironment restrains therapeutic resistance

“…Specifically, as a partial agonists of EGFR dimerization, EREG induces less stable EGFR dimers than other EGFR ligands such as EGF, while the weakened dimerization elicits more sustained EGFR signaling. In cancer clinics, upregulated EREG expression predicts a poor prognosis, but potentially benefits from therapies involving anti-EGFR agents such as panitumumab [ 65 , 66 ]. Unlike other EGFR ligands, EREG mimics EGFR mutations by sustaining EGFR-ERK pathway activation, while high EREG expression sensitizes tumors to treatment by the EGFR inhibitor erlotinib [ 65 ].…”