BRAF and RAS mutations as prognostic factors in metastatic colorectal cancer patients undergoing liver resection.
BACKGROUND
Despite major advances in the management of metastatic colorectal cancer (mCRC) with liver-only involvement, relapse rates are high and reliable prognostic markers are needed.


METHODS
To assess the prognostic impact of BRAF and RAS mutations in a large series of liver-resected patients, medical records of 3024 mCRC patients were reviewed. Eligible cases undergoing potentially curative liver resection were selected. BRAF and RAS mutational status was tested on primary and/or metastases by means of pyrosequencing and mass spectrometry genotyping assay. Primary endpoint was relapse-free survival (RFS).


RESULTS
In the final study population (N=309) BRAF mutant, RAS mutant and all wild-type (wt) patients were 12(4%), 160(52%) and 137(44%), respectively. Median RFS was 5.7, 11.0 and 14.4 months respectively and differed significantly (Log-rank, P=0.043). At multivariate analyses, BRAF mutant had a higher risk of relapse in comparison to all wt (multivariate hazard ratio (HR)=2.31; 95% CI, 1.09-4.87; P=0.029) and to RAS mutant (multivariate HR=2.06; 95% CI, 1.02-4.14; P=0.044). Similar results were obtained in terms of overall survival. Compared with all wt patients, RAS mutant showed a higher risk of death (HR=1.47; 95% CI, 1.05-2.07; P=0.025), but such effect was lost at multivariate analyses.


CONCLUSIONS
BRAF mutation is associated with an extremely poor median RFS after liver resection and with higher probability of relapse and death. Knowledge of BRAF mutational status may optimise clinical decision making in mCRC patients potentially candidate to hepatic surgery. RAS status as useful marker in this setting might require further studies.
Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Via Roma 67, 56126 Pisa, Italy.
M
M
Schirripa
Unit of Medical Oncology 1, Department of Medical Oncology, Oncology Institute of Veneto-IRCCS, via Gattamelata 64, 35128 Padova, Italy.
F
F
Bergamo
Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Via Roma 67, 56126 Pisa, Italy.
C
C
Cremolini
Department of Oncology, Azienda Ospedaliero-Universitaria 'Santa Maria della Misericordia', Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy.
M
M
Casagrande
Unit of Medical Oncology 1, Department of Medical Oncology, Oncology Institute of Veneto-IRCCS, via Gattamelata 64, 35128 Padova, Italy.
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S
Lonardi
Department of Oncology, Azienda Ospedaliero-Universitaria 'Santa Maria della Misericordia', Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy.
G
G
Aprile
Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School Of Medicine, University of Southern California, 1441 Eastlake Avenue, 90033 Los Angeles, California, USA.
D
D
Yang
Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Via Roma 67, 56126 Pisa, Italy.
F
F
Marmorino
Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Via Roma 67, 56126 Pisa, Italy.
G
G
Pasquini
Department of Surgery, Division of Pathology, University of Pisa, Via Roma 57, 56126 Pisa, Italy.
E
E
Sensi
Department of Surgery, Division of Pathology, University of Pisa, Via Roma 57, 56126 Pisa, Italy.
C
C
Lupi
Department of Laboratory Medicine, Division of Pathology, Azienda Ospedaliero-Universitaria 'Santa Maria della Misericordia', Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy.
G
G
De Maglio
Department of Surgery, Division of Pathology, University of Pisa, Via Roma 57, 56126 Pisa, Italy.
N
N
Borrelli
Department of Laboratory Medicine, Division of Pathology, Azienda Ospedaliero-Universitaria 'Santa Maria della Misericordia', Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy.
S
S
Pizzolitto
Department of Oncology, Azienda Ospedaliero-Universitaria 'Santa Maria della Misericordia', Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy.
G
G
Fasola
Unit of Immunology and of Oncological Molecular Diagnostics, Department of Oncological Diagnostics, Oncology Institute of Veneto-IRCCS, via Gattamelata 64, 35128 Padova, Italy.
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R
Bertorelle
Unit of Pathology, University Hospital of Padova, Via Gabelli 61, 35128 Padova, Italy.
M
M
Rugge
Department of Surgery, Division of Pathology, University of Pisa, Via Roma 57, 56126 Pisa, Italy.
G
G
Fontanini
Unit of Medical Oncology 1, Department of Medical Oncology, Oncology Institute of Veneto-IRCCS, via Gattamelata 64, 35128 Padova, Italy.
V
V
Zagonel
Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Via Roma 67, 56126 Pisa, Italy.
F
F
Loupakis
Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Via Roma 67, 56126 Pisa, Italy.
A
A
Falcone
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D011905:Genes, ras; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000556:secondary / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics
D014408:Biomarkers, Tumor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins