Assuntos
Publicidade Direta ao Consumidor , Marketing de Serviços de Saúde , Transplante de Células-Tronco/efeitos adversos , Publicidade Direta ao Consumidor/ética , Publicidade Direta ao Consumidor/legislação & jurisprudência , Humanos , Marketing de Serviços de Saúde/ética , Marketing de Serviços de Saúde/legislação & jurisprudência , Segurança do Paciente , Medição de Risco , Transplante de Células-Tronco/ética , Transplante de Células-Tronco/legislação & jurisprudência , Estados Unidos , United States Food and Drug AdministrationRESUMO
BACKGROUND: We assessed the effect of excision repair cross-complementing group 1 (ERCC1) and x-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcomes with satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy. PATIENTS AND METHODS: Twenty-four patients were enrolled in this single arm study. The primary objective was to determine if the presence of ERCC1 Asn118Asn (N118N, 500C>T, rs11615) and XRCC1 Arg399Gln (R399Q, 1301G>A, rs25487) genetic variants might be associated with an impact on progression-free survival (PFS); secondary objectives included overall response, survival, and toxicity. RESULTS: After population stratification by race, white patients carrying heterozygous or variant genotypes at the ERCC1 C>T locus had a >3-fold longer median PFS (5.8 vs. 1.8 months; 2P = .18, adjusted) and 5-fold longer median overall survival (OS) (15.7 vs. 3.2 months; 2P = .010, adjusted) than did patients carrying only wild-type alleles. For the XRCC1 G>A variant, without regard to race, patients carrying the wild-type GG alleles had a longer PFS (9.3 months) than those carrying GA or AA alleles (2.7 months; 2P = .02). Similarly, those carrying GG alleles did not reach median OS, whereas those carrying GA or AA alleles had a median OS of 9.6 months (2P = .12, adjusted). Multivariable analysis by using Cox proportional hazards modeling demonstrated that only XRCC1 was associated with PFS. CONCLUSIONS: To our knowledge, this is the first prospective study to date in patients with metastatic castration-resistant prostate cancer that describes predictive germline polymorphisms of ERCC1 and XRCC1 for assessing the clinical activity of satraplatin.
Assuntos
Proteínas de Ligação a DNA/genética , Endonucleases/genética , Compostos Organoplatínicos/uso terapêutico , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Docetaxel , Resistencia a Medicamentos Antineoplásicos/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/farmacologia , Polimorfismo de Nucleotídeo Único , Prednisona/efeitos adversos , Prednisona/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Taxoides/uso terapêutico , Resultado do Tratamento , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
Nucleotide excision repair (NER) and base excision repair (BER) pathways are DNA repair pathways that are important in carcinogenesis and in response to DNA-damaging chemotherapy. ERCC1 and ERCC2 are important molecular markers for NER; XRCC1 and PARP1 are important molecular markers for BER. Functional polymorphisms have been described that are associated with altered expression levels of these genes and with altered DNA repair capability. We assayed genomic DNA from 156 Americans of European descent and 164 Americans of African descent for the allelic frequencies of specific polymorphisms of ERCC1 N118N (500C>T), ERCC1 C8092A, ERCC2 K751Q (2282A>C), XRCC1 R399Q (1301G>A), XRCC1 R194W (685C>T), and PARP1 V762A (2446T>C). Differences were observed between Americans of European descent and Americans of African descent in the allelic frequencies of the ERCC1 N118N polymorphism (P < 0.000001). Differences were also observed between these two ethnic groups for ERCC2 K751Q (P = < 0.006675), XRCC1 R399Q (P < 0.000001), and PARP1 V762A (P = 0.000001). The ERCC1 N118N polymorphic variant that is seen most commonly in Americans of European descent is associated with a measurable reduction in NER function. ERCC1-mediated reduction in NER functionality affects the repair of cisplatin-DNA lesions.