Revista:
EUROPEAN JOURNAL OF CANCER
ISSN:
0959-8049
Año:
2012
Vol.:
48
N°:
12
Págs.:
1774-1780
Background: The immunoglobulin G1 (IgG(1)) monoclonal antibody (MoAb) Cetuximab is active in metastatic colorectal cancer (mCRC) as first or subsequent lines of therapy. Efficacy seems restricted to KRAS wild-type tumours. IgG(1) may also induce antibody dependent cell mediated citotoxicity (ADCC) by recruitment of immune effector cells. ADCC is influenced by Fc gamma receptor (Fc gamma R) polymorphisms. We investigated the association of Fc gamma R polymorphisms and disease control rate (DCR) in mCRC patients treated with chemotherapy plus Cetuximab. Patients and methods: Tumour tissues from 106 patients were screened for KRAS codon 12 and 13 mutations using a sensitive multiplex assay (DxS, Manchester, United Kingdom). NRAS (codons: 12, 13 and 61), PI3K (exon 20) and BRAF (exon 15) were analysed by direct sequencing. Fc gamma RIIa and Fc gamma RIIIa polymorphisms were genotyped by TaqMan assays. Results: DCR was significantly higher in KRAS wild-type tumours (61% versus 39%, p - 0.049). In epidermal growth factor receptor (EGFR) downstream-mutated mCRC patients, those harbouring an Fc gamma RIIa H/H genotype had a higher DCR than alternative genotypes (67% versus 33%, p = 0.017). By multivariate analysis, Fc gamma RIIa-131H/H remained significantly correlated with DCR (p = 0.008). Conclusion: Fc gamma R polymorphisms may play a role in the clinical efficacy of Cetuximab in EGFR downstream mutated mCRC patients. Further research into Cetuximab immune-based mechanisms in KRAS-mutated patients seems warranted. (C) 2012 Elsevier Ltd. All rights reserved.
Revista:
BRITISH JOURNAL OF CANCER
ISSN:
0007-0920
Año:
2010
Vol.:
102
N°:
6
Págs.:
987 - 994
BACKGROUND: A dose-finding study was performed to evaluate the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and the recommended dose (RD) of escalating the doses of capecitabine and fixed doses of irinotecan and oxaliplatin on a biweekly schedule for metastatic colorectal cancer patients (mCRC). A pharmacogenomic analysis was performed to investigate the association between SNPs and treatment outcome. METHODS: Eighty-seven chemotherapy-naive mCRC patients were recruited through a two-step study design; 27 were included in the dose-finding study and 60 in the pharmacogenomic analysis. Oxaliplatin (85 mg m(-2)) and CPT-11 (150 mg m(-2)), both on day 1, and capecitabine doses ranging from 850 to 1500 mg m(-2) bid on days 1-7 were explored. Peripheral blood samples were used to genotype 13 SNPs in 10 genes related to drug metabolism or efficacy. Univariate and multivariate Cox analysis was performed to examine associations between SNPs, ORR and PFS. RESULTS: The capecitabine RD was 1000 mg m(-2) bid. Diarrhoea and neutropenia were the DLTs. After a median follow-up of 52.5 months, the median PFS and OS were 12 (95% CI; 10.6-13.4) and 27 months (95% CI; 17.2-36.8), respectively. The GSTP1-G genotype, the Kohne low-risk category and use of a consolidation approach strongly correlated with decreased risk of progression. Patients with all favourable variables showed a median PFS of 42 months vs 3.4 months in the group with all adverse factors. A superior clinical response was obtained in patients with one GSTP1-G allele as compared with GSTP1-AA carriers (P = 0.004). CONCLUSION: First-line therapy with oxaliplatin, irinotecan and capecitabine is efficient and well-tolerated. The GSTP1 polymorphism A > G status was significantly associated with ORR and PFS in mCRC treated with this triplet therapy. British Journal of Cancer (2010) 102, 987-994. doi:10.1038/sj.bjc.6605595 www.bjcancer.com Published online 9 March 2010 (C) 2010 Cancer Research UK