1. Prognostic Value of BRAF, PI3K, PTEN, EGFR Copy Number, Amphiregulin and Epiregulin Status in Patients with KRAS Codon 12 Wild-Type Metastatic Colorectal Cancer Receiving First-Line Chemotherapy with Anti-EGFR Therapy.
- Author
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Llovet P, Sastre J, Ortega JS, Bando I, Ferrer M, García-Alfonso P, Donnay O, Carrato A, Jiménez A, Aranda E, León A, Grávalos C, Cámara JC, Feliú J, Sanchíz B, Caldés T, and Díaz-Rubio E
- Subjects
- Adult, Aged, Aged, 80 and over, Amphiregulin, Antineoplastic Combined Chemotherapy Protocols pharmacology, Class I Phosphatidylinositol 3-Kinases, Codon, Colorectal Neoplasms drug therapy, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, DNA Mutational Analysis, Disease-Free Survival, EGF Family of Proteins genetics, EGF Family of Proteins metabolism, Epiregulin genetics, Epiregulin metabolism, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Female, Gene Dosage, Gene Expression, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Multivariate Analysis, Mutation, Missense, Neoplasm Metastasis, PTEN Phosphohydrolase genetics, PTEN Phosphohydrolase metabolism, Phosphatidylinositol 3-Kinases genetics, Prognosis, Proportional Hazards Models, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins p21(ras) genetics, ROC Curve, Retrospective Studies, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colorectal Neoplasms genetics, DNA Copy Number Variations
- Abstract
Introduction: Mutational analysis of RAS is required for anti-epidermal growth factor receptor (EGFR) treatment for patients with metastatic colorectal cancer (mCRC). However, most patients with KRAS wild-type tumors still do not respond. Other molecules downstream of the EGFR may also play a role in resistance to EGFR therapies., Objective: Our objective was to investigate the clinical importance of biomarkers in relation to response, progression-free survival, and overall survival in patients with mCRC receiving first-line treatment with anti-EGFR therapy plus chemotherapy., Methods: We studied the EGFR pathway [EGFR, NRAS, BRAF, PIK3CA, phosphatase and tensin homolog (PTEN), amphiregulin (AREG), and epiregulin (EREG)] in 105 patients with mCRC KRAS codon 12 wild type. We analysed objective response, progression-free survival, and overall survival in molecularly defined subgroups of the patients receiving anti-EGFR therapy plus chemotherapy as first-line treatment., Results: We found a significant association between RAS wild-type, BRAF wild-type, EREG, and AREG overexpression and response to anti-EGFR therapy (p = 0.003, p = 0.015, p = 0.05, and p = 0.009, respectively). Progression-free survival and overall survival were lower in patients with RAS (p = 0.36 and p ≤ 0.001, respectively) or BRAF (p = 0.003 and p = 0.002, respectively) mutant tumors. Patients with EREG and AREG messenger RNA (mRNA) expression had longer survival than those with low-expression tumors; progression-free survival and overall survival were significant for AREG (p = 0.001 and p = 0.05, respectively). Patients with EGFR amplification tumors responded better to treatment and had better survival rates, although this was not significant. PIK3CA and PTEN were not associated with either response or survival. The multivariate logistic regression model for response showed only BRAF as a significant predictor after adjustment for the other covariates (p = 0.04, odds ratio 8.3, 95 % confidence interval 0.81-86.0)., Conclusions: RAS, BRAF, AREG, and EREG predict for efficacy of first-line anti-EGFR therapy in patients with mCRC.
- Published
- 2015
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