RESUMO
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.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Cetuximab , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Éxons , Humanos , Terapia de Alvo Molecular/métodos , Mutação , Panitumumabe , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas p21(ras) , Resultado do TratamentoRESUMO
The aim of this study was to investigate the value of serum human epididymis protein 4 (HE4) and HE4 tissue protein expression to predict tumor resistance to adjuvant chemotherapy, progression-free survival (PFS), and overall survival in patients with epithelial ovarian cancer (EOC). Consecutive inclusion of 198 patients diagnosed with EOC was conducted. Blood samples were collected prior to surgery and tissue samples during surgery. Patient data were registered prospectively in the Danish Gynecologic Cancer Database. The association between serum HE4 and HE4 tissue protein expression, resistance to adjuvant chemotherapy, PFS, and overall survival were analyzed in univariate analyses and in multivariate analyses adjusted for age, performance score, surgical outcome, stage, grade, and histological subtype. Serum HE4 levels predicted chemotherapy resistance, PFS, and overall survival correlated significantly (p < 0.001) in the univariate analyses; but after adjustment in a multivariate model, serum HE4 was insignificant, except in a subgroup analysis of postmenopausal women, where serum HE4 significantly predicted resistance to chemotherapy and progression-free survival. HE4 tissue protein expression predicted PFS (p = 0.022) and overall survival (p = 0.047) in the univariate analysis, while HE4 tissue protein expression failed to predict these outcomes in the adjusted multivariate analyses. Serum HE4 or HE4 tissue protein expression are not independent factors of chemotherapy resistance or survival in patients with EOC, but serum HE4 might predict chemotherapy resistance and PFS in postmenopausal women.