A polymorphism of EGFR extracellular domain is associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximab-based treatment

Abstract

Background: Cetuximab, a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR), is currently used in metastatic colorectal cancer (mCRC), but predictive factors for therapeutic response are lacking. Mutational status of KRAS and EGFR, and EGFR copy number are potential determinants of cetuximab activity.

Methods: We analyzed tumor tissues from 32 EGFR-positive mCRC patients receiving cetuximab/irinotecan combination and evaluable for treatment response. EGFR copy number was quantified by fluorescence in situ hybridization (FISH). KRAS exon 1 and EGFR exons coding for extracellular regions were sequenced.

Results: Nine patients experienced an objective response (partial response) and 23 were considered as nonresponders (12 with stable disease and 11 with progressive disease). There was no EGFR amplification found, but high polysomy was noted in 2 patients, both of which were cetuximab responders. No EGFR mutations were found but a variant of exon 13 (R521K) was observed in 12 patients, 11 of which achieved objective response or stable disease. Progression-free and overall survivals were significantly better in patients with this EGFR exon 13 variant. KRAS mutations were found in 14 cases. While there was a trend for an increased KRAS mutation frequency in nonresponder patients (12 mutations out of 23, 52%) as compared to responder patients (2 out of 9, 22%), authentic tumor response or long-term disease stabilization was found in KRAS mutated patients.

Conclusion: This preliminary study suggests that: an increase in EGFR copy number may be associated with cetuximab response but is a rare event in CRC, KRAS mutations are associated with low response rate but do not preclude any cetuximab-based combination efficacy and EGFR exon 13 variant (R521K) may predict for cetuximab benefit.

Figure 1

Dual color FISH assays for probes of EGFR (green) and chromosome seven (CEP7, red). (A) Balanced disomy in healthy colorectal mucosa. (B) Balanced disomy in tumor of patient 15. (C) Balanced low polysomy in tumor of patient 4. (D) High polysomy in tumor of patient 1. (E) Amplification in a control tumor.

Figure 2

Survivals according to EGFR and KRAS genotypes. A/ Progression-free survival (PFS) (Left) and overall survival (OS) (Right) curves of patients with EGFR R521K variant and wild-type. B/ PFS (Left) and OS (Right) curves of patients with a KRAS-mutated and nonmutated tumor.

Figure 3

Objective partial responses to cetuximab-based treatment in patients with KRAS- mutated tumors. (A) Pre- and post-cetuximab CT scan showing partial tumor response allowing surgical resection to be performed in patient 6. (B) Pre- and post-cetuximab CT scan demonstrating a major tumor response to cetuximab-based treatment in patient 7.