Epidermal growth factor receptor intron 1 CA dinucleotide repeat polymorphism and survival of advanced gastric cancer patients treated with cetuximab plus modified FOLFOX6

Abstract

Cetuximab is a monoclonal antibody targeting epidermal growth factor receptor (EGFR). The present study investigated the association between germline genetic polymorphisms and the treatment outcome of cetuximab plus modified leucovovin, fluorouracil, and oxaliplatin (FOLFOX)6 chemotherapy in advanced gastric cancer (AGC). DNA from peripheral blood mononuclear cells of 38 patients enrolled in a phase II study of cetuximab plus modified FOLFOX6 were analyzed for 16 polymorphisms in eight genes (EGFR, epidermal growth factor, transforming growth factor-alpha (TGFA), thymidylate synthase, excision repair cross-complementation group 1, Xeroderma pigmentosum group D, and fragment c gamma receptors (FCGR)2A and 3A). The EGFR intron 1 CA repeat polymorphism was associated with survival. Twenty-one patients had low repeats (sum of both alleles <or=37), and 17 patients had high repeats (sum >or=38). Patients with low CA repeats had longer progression-free survival (adjusted hazard ratio [HR] 0.42 [95% confidence interval [CI] 0.19-0.96], P = 0.040) and overall survival (adjusted HR 0.40 [95% CI 0.16-0.99], P = 0.048) compared with patients with high CA repeats. In addition, the tumor EGFR expression was higher in patients with a lower number of CA repeats. The association between the CA repeat status and survival was not found in a separate cohort of AGC patients (n = 68) treated only with modified FOLFOX6. These results suggest that the EGFR intron 1 CA repeat polymorphism could be a useful, predictive biomarker of cetuximab efficacy in AGC and merits further investigation in randomized studies.

Figure 1

CA repeat length and tissue epidermal growth factor receptor (EGFR) expression. Tissue EGFR expression determined by immunohistochemistry was analyzed according to CA repeat length in the remaining allele in patients with at least one 20 repeat allele. Immunohistochemistry (IHC) score was derived by multiplying the staining intensity and percentage of positive cells. Spearman’s ρ‐value was –0.46 (ρ = 0.010).

Figure 2

Kaplan–Meier curves of overall survival in patients treated with cetuximab plus modified leucovovin, fluorouracil, and oxaliplotion 6 (mFOLFOX6) (A) and in another cohort of patients treated only with mFOLFOX6 (B). Adjusted hazard ratio (adjusted HR) and P‐values were calculated with the backward stepwise Cox regression analysis with baseline characteristics as covariates. (A) Adjusted HR 0.40 (0.16–0.99), P = 0.048. (B) P = not significant. Adjusted HR and P‐value are not given in patients treated only with mFOLFOX6 because the CA repeat status was removed during the stepwise analysis.