TY - JOUR
T1 - The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer
T2 - A systematic review and meta-analysis
AU - Therkildsen, Christina
AU - Bergmann, Troels K
AU - Henrichsen-Schnack, Tine
AU - Ladelund, Steen
AU - Nilbert, Mef
PY - 2014/7
Y1 - 2014/7
N2 - BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways in colorectal cancer is uncertain, which led us to systematically review the impact of alterations in KRAS (outside of exon 2), NRAS, BRAF, PIK3CA and PTEN in relation to the clinical benefit from anti-EGFR treatment.METHODS: In total, 22 studies that include 2395 patients formed the basis for a meta-analysis on alterations in KRAS exons 3 and 4, NRAS, BRAF, and PIK3CA and PTEN and outcome of anti-EGFR treatment. Odds ratios for objective response rate (ORR) and hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) were calculated.RESULTS: Mutations in KRAS exons 3 and 4, BRAF, PIK3CA and non-functional PTEN (mutations or loss of protein expression) significantly predicted poor ORR (OR = 0.26, OR = 0.29, OR = 0.39, and OR = 0.41, respectively). Significantly shorter PFS applied to mutations in KRAS exons 3 and 4 (HR = 2.19), NRAS (HR = 2.30) and BRAF (HR = 2.95) and non-functional PTEN (HR = 1.88). Significantly shorter OS applied to mutations in KRAS exons 3 and 4 (HR = 1.78), NRAS (HR = 1.85), BRAF (HR = 2.52), PIK3CA (HR = 1.43) and alterations in PTEN (HR = 2.09).CONCLUSIONS: Meta-analysis suggests that mutations in KRAS exons 3 and 4, NRAS, BRAF and PIK3CA and non-functional PTEN predict resistance to anti-EGFR therapies and demonstrates that biomarker analysis beyond KRAS exon 2 should be implemented for prediction of clinical benefit from anti-EGFR antibodies in metastatic colorectal cancer.
AB - BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways in colorectal cancer is uncertain, which led us to systematically review the impact of alterations in KRAS (outside of exon 2), NRAS, BRAF, PIK3CA and PTEN in relation to the clinical benefit from anti-EGFR treatment.METHODS: In total, 22 studies that include 2395 patients formed the basis for a meta-analysis on alterations in KRAS exons 3 and 4, NRAS, BRAF, and PIK3CA and PTEN and outcome of anti-EGFR treatment. Odds ratios for objective response rate (ORR) and hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) were calculated.RESULTS: Mutations in KRAS exons 3 and 4, BRAF, PIK3CA and non-functional PTEN (mutations or loss of protein expression) significantly predicted poor ORR (OR = 0.26, OR = 0.29, OR = 0.39, and OR = 0.41, respectively). Significantly shorter PFS applied to mutations in KRAS exons 3 and 4 (HR = 2.19), NRAS (HR = 2.30) and BRAF (HR = 2.95) and non-functional PTEN (HR = 1.88). Significantly shorter OS applied to mutations in KRAS exons 3 and 4 (HR = 1.78), NRAS (HR = 1.85), BRAF (HR = 2.52), PIK3CA (HR = 1.43) and alterations in PTEN (HR = 2.09).CONCLUSIONS: Meta-analysis suggests that mutations in KRAS exons 3 and 4, NRAS, BRAF and PIK3CA and non-functional PTEN predict resistance to anti-EGFR therapies and demonstrates that biomarker analysis beyond KRAS exon 2 should be implemented for prediction of clinical benefit from anti-EGFR antibodies in metastatic colorectal cancer.
U2 - 10.3109/0284186X.2014.895036
DO - 10.3109/0284186X.2014.895036
M3 - Review
C2 - 24666267
SN - 0284-186X
VL - 53
SP - 852
EP - 864
JO - Acta Oncologica
JF - Acta Oncologica
IS - 7
ER -
