Patricia Llovet1, Javier Sastre2,3, Julián Sanz Ortega4, Inmaculada Bando1, Milagros Ferrer4, Pilar García-Alfonso5, Olga Donnay6, Alfredo Carrato7, Ana Jiménez8, Enrique Aranda9, Ana León10, Cristina Grávalos11, Juan Carlos Cámara12, Jaime Feliú13, Bárbara Sanchíz2,3, Trinidad Caldés1, Eduardo Díaz-Rubio14,15. 1. Laboratory of Molecular Oncology, Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain. 2. Medical Oncology Department, Fundación Investigación Biomédica, Hospital Clínico San Carlos, c/ Martin Lagos s/n, 28040, Madrid, Spain. 3. Department of Medicine, Facultad de Medicina, Universidad Complutense, Madrid, Spain. 4. Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain. 5. Department of Medical Oncology, Hospital Gregorio Marañón, Madrid, Spain. 6. Department of Medical Oncology, Hospital La Princesa, La Paz, Madrid, Spain. 7. Department of Medical Oncology, Hospital Ramón y Cajal, Madrid, Spain. 8. Department of Medical Oncology, Hospital Getafe, Madrid, Spain. 9. Department of Medical Oncology, Hospital Reina Sofía, Córdoba, Spain. 10. Department of Medical Oncology, Fundación Jiménez Díaz, Madrid, Spain. 11. Department of Medical Oncology, Hospital 12 de Octubre, Madrid, Spain. 12. Department of Medical Oncology, Hospital Alcorcón, Madrid, Spain. 13. Department of Medical Oncology, Hospital La Paz, Madrid, Spain. 14. Medical Oncology Department, Fundación Investigación Biomédica, Hospital Clínico San Carlos, c/ Martin Lagos s/n, 28040, Madrid, Spain. eduardo.diazrubio@salud.madrid.org. 15. Department of Medicine, Facultad de Medicina, Universidad Complutense, Madrid, Spain. eduardo.diazrubio@salud.madrid.org.
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.
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.
Authors: F Perrone; A Lampis; M Orsenigo; M Di Bartolomeo; A Gevorgyan; M Losa; M Frattini; C Riva; S Andreola; E Bajetta; L Bertario; E Leo; M A Pierotti; S Pilotti Journal: Ann Oncol Date: 2008-07-31 Impact factor: 32.976
Authors: F Cappuzzo; G Finocchiaro; E Rossi; P A Jänne; C Carnaghi; C Calandri; K Bencardino; C Ligorio; F Ciardiello; T Pressiani; A Destro; M Roncalli; L Crino; W A Franklin; A Santoro; M Varella-Garcia Journal: Ann Oncol Date: 2007-10-31 Impact factor: 32.976
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Authors: J B Baker; D Dutta; D Watson; T Maddala; B M Munneke; S Shak; E K Rowinsky; L-A Xu; C T Harbison; E A Clark; D J Mauro; S Khambata-Ford Journal: Br J Cancer Date: 2011-01-04 Impact factor: 7.640
Authors: Daniel R Owen; Hui-Li Wong; Melika Bonakdar; Martin Jones; Christopher S Hughes; Gregg B Morin; Steven J M Jones; Daniel J Renouf; Howard Lim; Janessa Laskin; Marco Marra; Stephen Yip; David F Schaeffer Journal: Cold Spring Harb Mol Case Stud Date: 2018-04-02