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. 2014 Feb 4;110(3):648-55.
doi: 10.1038/bjc.2013.753. Epub 2013 Dec 12.

Epiregulin gene expression as a biomarker of benefit from cetuximab in the treatment of advanced colorectal cancer

D J Jonker  1 , C S Karapetis  2 , C Harbison  3 , C J O'Callaghan  4 , D Tu  4 , R J Simes  5 , D P Malone  3 , C Langer  6 , N Tebbutt  7 , T J Price  8 , J Shapiro  9 , L L Siu  10 , R P W Wong  11 , G Bjarnason  12 , M J Moore  10 , J R Zalcberg  13 , S Khambata-Ford  3
Affiliations

Epiregulin gene expression as a biomarker of benefit from cetuximab in the treatment of advanced colorectal cancer

D J Jonker et al. Br J Cancer. .

Abstract

Background: Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy-refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression may further predict cetuximab benefit.

Methods: Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment-biomarker interaction.

Results: Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status ('co-biomarker')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P<0.0001), and median OS was 9.8 vs 5.1 months (HR 0.43; P<0.001) for cetuximab vs BSC, respectively. In the rest (n=246, 64%), PFS (HR 0.82; P=0.12) and OS (HR 0.90; P=0.45) were not significantly different. Test for treatment interaction showed a larger cetuximab effect on OS (HR 0.52; P=0.007) and PFS (HR 0.49; P=0.001) in the co-biomarker-positive group.

Conclusion: In pre-treated K-ras wild-type status colorectal cancer, patients with high EREG gene expression appear to benefit more from cetuximab therapy compared with low expression. Epiregulin as a selective biomarker requires further evaluation.

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Figures

Figure 1
Figure 1
Kaplan–Meier curves for OS by treatment for patients with K-ras wild-type status with (A) high EREG and (B) low EREG expression (using the minimum P-value threshold). Overall survival was improved with cetuximab in those with high EREG (P<0.0001) but not those with low EREG expression (P=0.81). The difference in treatment effect by subgroup was statistically significant (adjusted P-value for interaction P=0.041). (A) K-ras wild-type and high EREG expression (‘co-biomarker'-positive). (B) K-ras wild-type and low EREG expression.
Figure 2
Figure 2
Forest plot demonstrating HRs for death and progression by K-ras and EREG status. For this analysis, EREG was dichotomised using the minimum P-value threshold. Interaction testing was adjusted for baseline prognostic covariates. The greatest cetuximab treatment effects were observed in the co-biomarker-positive group (wild-type K-ras and high EREG status).
Figure 3
Figure 3
Kaplan–Meier curves for OS for K-ras wild-type status patients on the BSC arm by EREG expression status. Epiregulin status in this analysis was dichotomised using the prespecified threshold. Overall survival was not significantly correlated with low vs high EREG status (adjusted HR 0.82; 95% CI: 0.58 vs 1.15; P=0.24), suggesting that EREG expression is not a significant prognostic factor.
See this image and copyright information in PMC

References

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