RESUMEN
BACKGROUND: Variations in urothelial carcinoma (UC) response to platinum chemotherapy are common and frequently attributed to genetic and epigenetic variations of somatic DNA. We hypothesized that variations in germline DNA may contribute to UC chemosensitivity. PATIENTS AND METHODS: DNA from 210 UC patients treated with platinum-based chemotherapy was genotyped for 80 single nucleotide polymorphisms (SNPs). Logistic regression was used to examine the association between SNPs and response, and a multivariable predictive model was created. Significant SNPs were combined to form a SNP score predicting response. Eleven UC cell lines were genotyped as validation. RESULTS: Six SNPs were significantly associated with 101 complete or partial responses (48%). Four SNPs retained independence association and were incorporated into a response prediction model. Each additional risk allele was associated with a nearly 50% decrease in odds of response [odds ratio (OR) = 0.51, 95% confidence interval 0.39-0.65, P = 1.05 × 10(-7)). The bootstrap-adjusted area under the curves of this model was greater than clinical prognostic factors alone (0.78 versus 0.64). The SNP score showed a positive trend with chemosensitivity in cell lines (P = 0.115). CONCLUSIONS: Genetic variants associated with response of UC to platinum-based therapy were identified in germline DNA. A model using these genetic variants may predict response to chemotherapy better than clinical factors alone.
Asunto(s)
Carboplatino/uso terapéutico , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Femenino , Estudios de Asociación Genética , Variación Genética , Genotipo , Mutación de Línea Germinal/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Resultado del Tratamiento , Neoplasias Urológicas/mortalidad , Urotelio/patologíaRESUMEN
BACKGROUND: The differential impact of the number of prior lines of therapy and the setting of prior therapy (perioperative or metastatic) is unclear in advanced urothelial carcinoma. PATIENTS AND METHODS: Ten phase II trials of salvage chemotherapy, biologic agent therapy, or both, enrolling 731 patients, were available. Data on the number of prior lines of therapy and the setting of prior therapy were required in addition to known previously recognized prognostic factors: time from prior chemotherapy, hemoglobin level, performance status, and liver metastasis status. Cox proportional hazards regression was used to evaluate the association of the number of prior lines and prior perioperative therapy with overall survival (OS) as the primary clinical endpoint. Trial was a stratification factor. RESULTS: A total of 711 patients were evaluable. The overall median progression-free survival and OS were 2.7 and 6.8 months, respectively. The number of prior lines was 1 in 559 patients (78.6%), 2 in 111 (15.6%), 3 in 29 (4.1%), 4 in 10 (1.4%), and 5 in 2 (0.3%). Prior perioperative chemotherapy was given to 277 (39.1%) and chemotherapy for metastatic disease to 454 (64.1%). The number of prior lines was not independently associated with OS (hazard ratio, 0.99; 95% CI, 0.86-1.14). Prior perioperative chemotherapy was a favorable factor for OS on univariate but not multivariate analysis. CONCLUSION: The number of prior lines of therapy and prior perioperative chemotherapy were not independently prognostic in patients with urothelial carcinoma receiving salvage therapy. Adoption of these data in salvage therapy trials should enhance accrual, the interpretability of results, and drug development.