Understanding Resistance to EGFR Inhibitors—Impact on Future Treatment Strategies

Deric L. Wheeler; Emily F. Dunn; Paul M. Harari

In This Article

Resistance to EGFR Antibodies

EGFR Expression as a Predictor of Response

In light of the high specificity of anti-EGFR monoclonal antibodies for the extracellular domain of EGFR, the initial assumption was that these agents would be most effective in tumors with robust overexpression of EGFR. Indeed, it was anticipated that expression levels of EGFR would serve as a predictive biomarker for the likelihood of response to cetuximab therapy, which would parallel the clinical paradigm in breast cancer, where women with breast cancer who have high HER2 receptor expression are more likely to respond to trastuzumab anti-HER2 therapy. However, early clinical studies did not confirm a correlation between EGFR expression level by immunohistochemistry and likelihood of response to EGFR inhibitor therapy.[104] In fact, Chung et al.[104] confirmed that several CRC patients who received cetuximab exhibited a major objective response despite the absence of measureable EGFR. Collectively, these studies suggest that immunohistochemistry-based assays measuring EGFR expression do not serve as a robust predictor for response to cetuximab therapy.

EGFR Copy Number as a Predictor of Response

Studies analyzing EGFR copy number have suggested that it may provide some predictive and prognostic value in CRC. Lièvre et al.[96] reported that increased EGFR copy number, assessed by chromogenic in situ hybridization, was significantly associated with objective tumor response to cetuximab therapy (P = 0.04). When EGFR copy number was measured by PCR, it was found that increased EGFR copy number was significantly associated with prolonged survival, indicating a potential prognostic value of EGFR copy number (P = 0.03).[105] Moroni et al.[106] analyzed EGFR copy number by fluorescence in situ hybridization and found a significant association between high EGFR copy number and response to both cetuximab and panitumumab (P = 0.01).[107]

KRAS Mutation as a Predictor of Response

KRAS mutation status in CRC has emerged as an important predictive biomarker that enables improved identification of patients more likely to respond to EGFR inhibitors. Lièvre et al.[96] reported in 2006 that KRAS with mutations at codon 12 or 13 might be predictive of resistance to cetuximab therapy. In this report, they analyzed 30 patients with metastatic CRC treated with cetuximab for KRAS, BRAF and PIK3CA mutations. KRAS mutations were found in 43% of tumors (13 tumors), and were significantly associated with resistance to cetuximab therapy (P = 0.002).[96] To confirm these findings, Di Fiore et al.[97] studied 59 patients with chemorefractory metastatic CRC treated with cetuximab plus chemotherapy. Direct sequencing SNaPshot® (Applied Biosystems, Foster City, CA, USA) and PCR-ligase assays determined KRAS mutations. KRAS mutations were highly predictive of resistance to cetuximab plus chemotherapy.[97] A larger study was performed to measure the KRAS mutation status in 113 patients with irinotecan-refractory metastatic CRC treated with cetuximab. The authors reported that KRAS wildtype is a strong predictor of significant increase in overall survival in this cohort of patients (P <0.001).[98]

In a seminal clinical report investigating KRAS mutational status, Van Cutsem et al.[56] investigated the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic CRC, and sought associations between the mutation status of KRAS and clinical response to cetuximab. In this study, 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone. First-line treatment with cetuximab plus FOLFIRI reduced the risk of disease progression compared with FOLFIRI alone, and the benefit of cetuximab was limited to patients with KRAS wildtype tumors.[56] Since the publication of these studies, several additional clinical trials have further strengthened these findings.[99–102,108] This collective body of work led to a Provisional Clinical Opinion from ASCO in 2009 stating that all patients with metastatic CRC who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA (clinical laboratory improvement amendments)-accredited laboratory. If codons 12 or 13 of KRAS are mutated, patients with metastatic CRC should not receive anti-EGFR antibody therapy as part of their treatment.[109]

In patients with metastatic CRC and wildtype KRAS, the expression of EGFR ligands has also shown promise as a predictor of response to cetuximab therapy. The first report showed that patients with increased expression of epiregulin and amphiregulin exhibited disease control.[110] Jacobs et al.[111] extended these findings and found that expression profiling of epiregulin and amphiregulin may predict both PFS and overall survival in those with KRAS wildtype metastatic CRC who are treated with cetuximab and irinotecan.