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.
BACKGROUND
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.
Laboratory of Molecular Oncology, Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.
Patricia
P
Llovet
Medical Oncology Department, Fundación Investigación Biomédica, Hospital Clínico San Carlos, c/ Martin Lagos s/n, 28040, Madrid, Spain.|Department of Medicine, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
Javier
J
Sastre
Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain.
Julián Sanz
JS
Ortega
Laboratory of Molecular Oncology, Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.
Inmaculada
I
Bando
Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain.
Milagros
M
Ferrer
Department of Medical Oncology, Hospital Gregorio Marañón, Madrid, Spain.
Pilar
P
García-Alfonso
Department of Medical Oncology, Hospital La Princesa, La Paz, Madrid, Spain.
Olga
O
Donnay
Department of Medical Oncology, Hospital Ramón y Cajal, Madrid, Spain.
Alfredo
A
Carrato
Department of Medical Oncology, Hospital Getafe, Madrid, Spain.
Ana
A
Jiménez
Department of Medical Oncology, Hospital Reina Sofía, Córdoba, Spain.
Enrique
E
Aranda
Department of Medical Oncology, Fundación Jiménez Díaz, Madrid, Spain.
Ana
A
León
Department of Medical Oncology, Hospital 12 de Octubre, Madrid, Spain.
Cristina
C
Grávalos
Department of Medical Oncology, Hospital Alcorcón, Madrid, Spain.
Juan Carlos
JC
Cámara
Department of Medical Oncology, Hospital La Paz, Madrid, Spain.
Jaime
J
Feliú
Medical Oncology Department, Fundación Investigación Biomédica, Hospital Clínico San Carlos, c/ Martin Lagos s/n, 28040, Madrid, Spain.|Department of Medicine, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
Bárbara
B
Sanchíz
Laboratory of Molecular Oncology, Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.
Trinidad
T
Caldés
Medical Oncology Department, Fundación Investigación Biomédica, Hospital Clínico San Carlos, c/ Martin Lagos s/n, 28040, Madrid, Spain. eduardo.diazrubio@salud.madrid.org.|Department of Medicine, Facultad de Medicina, Universidad Complutense, Madrid, Spain. eduardo.diazrubio@salud.madrid.org.
Eduardo
E
Díaz-Rubio
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D066258:Amphiregulin; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases; D003062:Codon; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D066255:EGF Family of Proteins / Q000235:genetics / Q000378:metabolism; D066260:Epiregulin / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012372:ROC Curve; D012189:Retrospective Studies; D016896:Treatment Outcome
C587848:AREG protein, human; D066258:Amphiregulin; D003062:Codon; D066255:EGF Family of Proteins; C587880:EREG protein, human; D066260:Epiregulin; C117307:KRAS protein, human; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras)