RESUMEN
PURPOSE: Genetic variants in genes involved in the distribution, metabolism, accumulation or repair of lesions are likely to influence the response of drugs used in the treatment of Head and Neck Cancer (HNC). We examine the effect of 36 SNPs on clinical outcomes in patients with locally advanced HNC who were receiving platinum-based chemoradiotherapy (CRT). METHODS: These SNPs were genotyped in 110 patients using the iPLEX Gold assay on the MassARRAY method in blood DNA samples and used Kaplan-Meier and Cox regression analyses to compare genotype groups with the survival. RESULTS: Two SNPs, rs717620 (ABCC2) and rs12934241 (MMP2) were strongly associated with overall survival (OS) and disease-free survival (DFS). At a median follow-up of 64.4 months, the allele A of rs717620 (ABCC2) had an increased risk of disease progression {hazard ratio [HR] = 1.79, p = 0.0018} and death (HR = 2.0, p = 0.00027). ABCC2 was associated with OS after a Bonferroni adjustment for multiple testing. The MMP2 rs12934241-T allele was associated with an increased risk of worse OS and DFS (p = 0.0098 and p = 0.0015, respectively). One SNP of ABCB1 and three SNPs located in the ERCC2 gene showed an association with response in the subgroup of HNC patients treated with definitive CRT. CONCLUSIONS: Our findings highlight the potential usefulness of SNPs in different genes involved in drug metabolism and repair DNA to predict the response and survival to CRT. ABCC2 is a potential predictor of OS in patients with HNC.
Asunto(s)
Quimioradioterapia , Neoplasias de Cabeza y Cuello/terapia , Metaloproteinasa 2 de la Matriz/genética , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos/genética , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Frecuencia de los Genes , Haplotipos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Resultado del TratamientoRESUMEN
We studied the predictive value for response and toxicity of functional polymorphisms in genes involved in the oxaliplatin/fluorouracil pathway in colorectal cancer patients. One hundred and twenty-seven (127) patients were treated with curative intended surgery followed by adjuvant chemotherapy with FOLFOX (fluorouracil, leucovorin and oxaliplatin) regimen. The median age was 65.53 (27-80) years (66.9% male, 59.1% rectum). The median follow-up was 8.5 years (IQR, 4.1-9.4). At the end of follow-up, 59 patients (46.5%) had relapsed or died in the whole study population. We did find that XRCC1GG genotype is associated with a higher risk of developing haematologic toxicity. Furthermore, we report a significant association of the TS 3'UTR 6 bp/6 bp polymorphism and the XRCC1 rs25487 with a higher risk of developing anaemia and diarrhoea, respectively. On the other hand, none of the studied polymorphisms showed clinically relevant association with disease-free survival and overall survival or early failure to adjuvant FOLFOX therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Quimioterapia Adyuvante , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/cirugía , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Endonucleasas/genética , Endonucleasas/metabolismo , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/farmacocinética , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Leucovorina/farmacocinética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/farmacocinética , Oxaliplatino/administración & dosificación , Oxaliplatino/efectos adversos , Oxaliplatino/farmacocinética , Polimorfismo Genético , Regiones Promotoras Genéticas , Timidilato Sintasa/genética , Timidilato Sintasa/metabolismoRESUMEN
BACKGROUND: Platinum-based chemoradiotherapy (CRT) is the standard treatment for locally advanced head and neck squamous-cell carcinomas (HNSCC), and most patients experience serious toxicities. The aim of this study was to investigate the association between candidate genes involved in radiation/platinum pathways and acute toxicity of CRT to determine the predictive value of these polymorphisms for toxicity. METHODS: Thirty-six selected single nucleotide polymorphisms (SNPs) in 29 genes were genotyped in 110 patients treated with cisplatin-based CRT. DNA was obtained from blood samples, and SNP analysis was performed using a MassARRAY iPLEX Gold (Sequenom) method. RESULTS: Patients with ERCC1 rs11615-C allele (P = .0066), ERCC1 rs735482-C allele (P = .0204), and ERCC4 rs1799801-C allele (P = .0286) had lower risk of grade 2-3 hematologic toxicity. In addition, the presence of G allele of GSTP1 was associated with a significantly lower risk of severe dysphagia (P = .0004). CONCLUSION: Polymorphisms in ERCC1 and GSTP1 may act as prognostic factors of acute toxicity during treatment with CRT in HNSCC patients.
