RAC1b overexpression correlates with poor prognosis in KRAS/BRAF WT metastatic colorectal cancer patients treated with first-line FOLFOX/XELOX chemotherapy.
BACKGROUND
Chemotherapy is the principal treatment in metastatic colorectal cancer (mCRC) patients. RAC1b, a RAC1 spliced variant, is over-expressed in colorectal cancer (CRC), and impairs apoptosis by activation of nuclear-factor-KB. Since RAC1b has been associated with the BRAF(V600E) mutation, associated with poor prognosis in CRC, we evaluated the role of RAC1b expression as a predictor of chemotherapy efficacy in mCRC.


METHODS
We analysed KRAS and BRAF mutation, microsatellite instability and RAC1b expression in 157 mCRC patients treated with FOLFOX/XELOX in first-line therapy.


RESULTS
KRAS mutations were detected in 46 patients (34%), 10 patients were BRAF mutant (7%) and 79 were WT for both, KRAS and BRAF (59%). RAC1b overexpression was found in 30 patients (19%). In the multivariate analysis, BRAF mutational status was a poor prognostic factor for overall survival (OS); hazard ratio (HR), 2.78 (95% confidence interval (CI), 1.35-5.72; p=0.0057). RAC1b overexpression was a poor survival factor for OS (HR, 2.35; 95% CI, 1.2-4.59; p=0.01) and progression-free survival (PFS) (HR, 2.4; 95% CI, 1.2-4.78; p=0.01) in KRAS/BRAF WT mCRC patients.


CONCLUSIONS
RAC1b overexpression constitutes a marker of poor prognosis in KRAS/BRAF WT mCRC patients treated with first-line FOLFOX/XELOX therapy.
Department of Gastroenterology, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.
Virginia
V
Alonso-Espinaco
Pathology Department, Centre de Diagnòstic Biomèdic, Hospital Clinic, University of Barcelona, and Banc de Tumors-Biobanc Clinic-IDIBAPS, Spain.
Miriam
M
Cuatrecasas
Medical Oncology Department, Hospital Miguel Servet, Zaragoza, Spain.
Vicente
V
Alonso
Medical Oncology Department, Hospital Clínico de Zaragoza, Spain.
Pilar
P
Escudero
Medical Oncology Department, Hospital Clínic Barcelona, Spain.
Maribel
M
Marmol
Pathology Department, Hospital Miguel Servet, Zaragoza, Spain.
Carlos
C
Horndler
Pathology Department, Hospital Clinico Zaragoza, Spain.
Javier
J
Ortego
Medical Oncology Department, Hospital Clínic Barcelona, Spain.
Rosa
R
Gallego
Medical Oncology Department, Hospital Clínic Barcelona, Spain.
Jordi
J
Codony-Servat
Department of Epidemiology, Harvard Medical School of Public Health, Boston, USA.
Xabier
X
Garcia-Albeniz
Pathology Department, Centre de Diagnòstic Biomèdic, Hospital Clinic, University of Barcelona, and Banc de Tumors-Biobanc Clinic-IDIBAPS, Spain.
Pedro
P
Jares
Department of Gastroenterology, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.
Antoni
A
Castells
Bioinformatics Unit, CIBERehd, Barcelona, Catalonia, Spain.
Juan José
JJ
Lozano
Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
Rafael
R
Rosell
Medical Oncology Department, Hospital Clínic Barcelona, Spain. Electronic address: jmaurel@clinic.ub.es.
Joan
J
Maurel
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D005838:Genotype; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D010071:Oxaloacetates; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis* / Q000235:genetics; D018631:ras Proteins / Q000235:genetics*
C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D010071:Oxaloacetates; D011518:Proto-Oncogene Proteins; C107953:RAC1 protein, human; D003841:Deoxycytidine; D000069287:Capecitabine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D020830:rac1 GTP-Binding Protein; D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil
KRAS WT; Metastatic colorectal cancer patients; mRNA RAC1b overexpression