RESUMEN
BACKGROUND: Breast cancer susceptibility gene 1 (BRCA1) expression differentially affects outcome to platinum- and taxane-based chemotherapy. Mediator of DNA damage checkpoint protein 1 (MDC1), p53-binding protein 1 (53BP1), multiple myeloma SET domain (MMSET) and ubiquitin-conjugating enzyme 9 (UBC9) are involved in DNA repair and could modify the BRCA1 predictive model. METHODS: Mediator of DNA damage checkpoint protein 1, 53BP1, MMSET and UBC9 mRNA were assessed in gastric tumours from patients in whom BRCA1 levels had previously been determined. RESULTS: In vitro chemosensitivity assay, MMSET levels were higher in docetaxel-sensitive samples. In a separate cohort, survival was longer in those with low MMSET (12.3 vs 8.8 months; P=0.04) or UBC9 (12.4 vs 8.8 months; P=0.01) in patients receiving only folinic acid, fluorouracil (5-FU) and oxaliplatin (FOLFOX). Conversely, among patients receiving second-line docetaxel, longer survival was associated with high MMSET (19.1 vs 13.9 months; P=0.003). Patients with high MMSET and BRCA1 attained a median survival of 36.6 months, compared with 13.9 months for those with high BRCA1 and low MMSET (P=0.003). In the multivariate analyses, low MMSET (hazard ratio (HR), 0.59; P=0.04) and low UBC9 (HR, 0.52; P=0.01) levels were markers of longer survival to first-line FOLFOX, whereas palliative surgery (HR, 2.47; P=0.005), low BRCA1 (HR, 3.17; P=0.001) and low MMSET (HR, 2.52; P=0.004) levels were markers of shorter survival to second-line docetaxel. CONCLUSIONS: Breast cancer susceptibility gene 1, MMSET and UBC9 can be useful for customising chemotherapy in gastric cancer patients.
Asunto(s)
Adenocarcinoma/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , N-Metiltransferasa de Histona-Lisina/genética , Proteínas Represoras/genética , Neoplasias Gástricas/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteínas de Ciclo Celular , Docetaxel , Femenino , Fluorouracilo/uso terapéutico , Expresión Génica , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Estimación de Kaplan-Meier , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Compuestos Organoplatinos/uso terapéutico , Modelos de Riesgos Proporcionales , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Represoras/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Taxoides/administración & dosificación , Transactivadores/genética , Transactivadores/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53 , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo , Adulto JovenRESUMEN
BACKGROUND: neoadjuvant chemotherapy has shown a modest benefit in muscle-invasive bladder cancer patients; however, the subset of patients most likely to benefit has not been identified. BRCA1 plays a central role in DNA repair pathways and low BRCA1 expression has been associated with sensitivity to cisplatin and longer survival in lung and ovarian cancer patients. PATIENTS AND METHODS: we assessed BRCA1 messenger RNA expression levels in paraffin-embedded pre-treatment tumor samples obtained by transurethral resection from 57 patients with locally advanced bladder cancer subsequently treated with neoadjuvant cisplatin-based chemotherapy. BRCA1 levels were divided into terciles and correlated with pathological response and survival. RESULTS: a significant pathological response (pT0-1) was attained in 66% (24 of 39) of patients with low/intermediate BRCA1 levels compared with 22% (4 of 18) of patients with high BRCA1 levels (P = 0.01). Median survival was 168 months in patients with low/intermediate levels and 34 months in patients with high BRCA1 levels (P = 0.002). In the multivariate analysis for survival, only BRCA1 expression levels and lymphovascular invasion emerged as independent prognostic factors. CONCLUSIONS: our data suggest that BRCA1 expression may predict the efficacy of cisplatin-based neoadjuvant chemotherapy and may help to customize therapy in bladder cancer patients.
