EGFR Protein Expression in KRAS Wild-Type Metastatic Colorectal Cancer Is Another Negative Predictive Factor of the Cetuximab Therapy

Abstract

The selection of colorectal cancer patients for anti-epidermal growth factor receptor (EGFR) antibody therapy is based on the determination of their RAS mutation status-a strongly negative predictive factor-since the protein target, EGFR, is not a reliable predictor of therapeutic response. In this study, we revisited the EGFR protein issue using a cohort of 90 patients with KRAS exon2 wild-type colorectal cancer who have been treated with cetuximab therapy. Twenty-nine of these patients had metastatic tissue available for analysis. The level of EGFR protein expression in the patients was determined by immunohistochemistry and evaluated by H-score (HS) methodology. Progression-free survival (PFS) and overall survival (OS) of the patients were determined according to the EGFR-HS ranges of both the primary and metastatic tissues using Kaplan-Meyer statistics. In the case of primary tumors, EGFR scores lower than HS = 200 were associated with significantly longer OS. In the case of metastatic tissues, all levels lower than the EGFR-HS range chosen were associated with significantly longer OS. These results are explained by the fact that metastatic tissues rarely maintained the expression levels of the primary tumors. On the other hand, high EGFR expression levels in either primary tumors or metastatic tissues were associated with multiple metastatic disease. This suggests a negative prognostic role of EGFR expression. However, in a multivariate analysis, one-sidedness remained a strong independent predictive factor of survival. Previous studies demonstrated that the EGFR expression level depends on sidedness. Therefore, a subgroup analysis of the left-and right-sided cases was performed on both primary and metastatic tissues. In the case of metastic tissues, an analysis confirmed a better OS in low EGFR protein-expressing cases than in high EGFR protein-expressing cases. Collectively, these data suggest that EGFR protein expression is another negative predictive factor of the efficacy of cetuximab therapy of KRAS exon2 wild-type colorectal cancer.

Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer

“…This model may also explain why Tspan6-expressing right-sided CRC in the COIN cohort responded to the cetuximab-based therapy. Previous studies demonstrated that the right-sided tumors express higher levels of EGFR ( 23 ) and, consequently, were less sensitive to the cetuximab-based treatments ( 24 ). Our data suggest that the increased expression of EGFR in those tumors will be responsive to the treatment if cancer cells express Tspan6, which suppresses secretion of TGF-α.…”

Influence of location-dependent sex difference on PD-L1, MMR/MSI, and EGFR in colorectal carcinogenesis

“…Anti-EGFR therapies have demonstrated improved efficacy and survival benefits when combined with chemotherapy, and these combinations of chemotherapy plus anti-EGFR mAb or anti-vascular endothelial growth factor mAb are widely used in the current clinical settings as first-line treatment options for advanced CRC [ 51 ]. Notably, several studies identified that distal CRCs having lower EGFR expression showed better prognosis to anti-EGFR therapies compared to those proximal [ 52 , 53 ]. Likewise, in an attempt to enhance the response to immunotherapy in CRC, several clinical trials are currently investigating the therapeutic effects of drug combinations, such as ICIs with chemotherapy and/or targeted agents [ 9 ].…”

Protein Arginine Methyltransferase 5 as a Therapeutic Target for KRAS Mutated Colorectal Cancer

“…Cetuximab, a monoclonal antibody that binds to the extracellular domain of EGFR and prevents ligands from binding, was therefore developed as a treatment for CRC [ 7 ]. Cetuximab, however, was later determined to be detrimental for CRC patients with a mutated KRAS gene [ 8 , 9 ].…”