Abstract
Anti-EGFR mAbs cetuximab and panitumumab are routinely used for the treatment of patients with KRAS-wild type metastatic colorectal cancer (mCRC). However, in some patients their efficacy remains modest and with no clear association between the EGFR protein expression determined by PharmDx™ kit, and response to anti-EGFR therapies. Therefore, we investigated the relative expression and predictive value of wild-type EGFR (wtEGFR), mutated EGFRvIII and EGFR ligand proteins in mCRC patients treated with cetuximab. The expression levels of wtEGFR, EGFRvIII, and EGFR ligand were determined by immunohistochemistry (IHC) in 60 tumour specimens using specific antibodies. Sections were scored according to the percentage of positive tumour cells, intensity and cellular location of staining, and these were associated with response, overall survival (OS) and progression-free survival (PFS). At cut-off value > 5%, wtEGFR, and EGFRvIII were present in 44%, and 41%, betacellulin (BTC) in 72%, followed by epigen (67%), TGFα (58%), amphiregulin (34%), EGF (31%) of the cases, respectively and 96% of the wtEGFR positive cases had co-expression of at least one ligand. We found a significant association between the expression of wtEGFR and poor response to cetuximab. In addition, the co-expression of wtEGFR with one ligand at a cut-off value of > 5% and > 10% was associated with worse response to cetuximab (P = 0.021, and P = 0.005 respectively). We found a 3-fold and 5-fold increased risk of shorter OS with expression of BTC and epigen. Interestingly, the expression of wtEGFR and its co-expression with one or two ligands was associated with shorter PFS but not with OS. The relative expression of wtEGFR and its competing ligands, which is the target for therapeutic interventions with anti-EGFR antibodies, could serve as a more reliable predictive biomarker of response to therapy with anti-EGFR mAbs in mCRC patients and warrants further investigation in large prospective studies.
Highlights
Colorectal cancer remains one of the leading causes of cancer deaths worldwide [1]
We have previously shown that kits such as the epidermal growth factor receptor (EGFR) PharmDxTM, does not discriminate between the wild-type EGFR (wtEGFR) and EGFRvIII, and as such could have a major contribution to the lack of association between the expression of EGFR and response to anti-EGFR antibodies in such studies [13]
At present metastatic colorectal cancer (mCRC) patients are selected for antiEGFR monoclonal antibodies (mAbs) therapy provided their tumours do not harbour any RAS mutations, as no clear associations have yet been found between the expression of EGFR protein determined by immunohistochemistry and response to these inhibitors [4, 26,27,28]
Summary
Colorectal cancer remains one of the leading causes of cancer deaths worldwide [1]. In 2016, colorectal cancer is estimated to be the third most commonly diagnosed cancer (134,900) and the third leading cause of cancer deaths (49,190) in the USA [2], highlighting the need for developing more effective and less toxic therapeutic agents. We have previously shown that kits such as the EGFR PharmDxTM, does not discriminate between the wtEGFR and EGFRvIII, and as such could have a major contribution to the lack of association between the expression of EGFR and response to anti-EGFR antibodies in such studies [13]. This is of vital importance as the wtEGFR protein is the therapeutic target for antiEGFR antibodies and transmits the mitogenic action of competing autocrine and paracrine EGFR ligands [14]
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