title: Improvement of a predictive model in ovarian cancer patients submitted to platinum-based chemotherapy: implications of a GST activity profile.
abstract: OBJECTIVE
  The success of chemotherapy in ovarian cancer (OC) is directly associated with the broad variability in platinum response, with implications in patients survival. This heterogeneous response might result from inter-individual variations in the platinum-detoxification pathway due to the expression of glutathione-S-transferase (GST) enzymes. We hypothesized that GSTM1 and GSTT1 polymorphisms might have an impact as prognostic and predictive determinants for OC.
  
  
  METHODS
  We conducted a hospital-based study in a cohort of OC patients submitted to platinum-based chemotherapy. GSTM1 and GSTT1 genotypes were determined by multiplex PCR.
  
  
  RESULTS
  GSTM1-null genotype patients presented a significantly longer 5-year survival and an improved time to progression when compared with GSTM1-wt genotype patients (log-rank test, P = 0.001 and P = 0.013, respectively). Multivariate Cox regression analysis indicates that the inclusion of genetic information regarding GSTM1 polymorphism increased the predictive ability of risk of death after OC platinum-based chemotherapy (c-index from 0.712 to 0.833). Namely, residual disease (HR, 4.90; P = 0.016) and GSTM1-wt genotype emerged as more important predictors of risk of death (HR, 2.29; P = 0.039; P = 0.036 after bootstrap). No similar effect on survival was observed regarding GSTT1 polymorphism, and there were no statistically significant differences between GSTM1 and GSTT1 genotypes and the assessed patients' clinical-pathological characteristics.
  
  
  CONCLUSIONS
  GSTM1 polymorphism seems to have an impact in OC prognosis as it predicts a better response to platinum-based chemotherapy and hence an improved survival. The characterization of the GSTM1 genetic profile might be a useful molecular tool and a putative genetic marker for OC clinical outcome.
authors.affiliation: Oncology Department, Portuguese Institute of Oncology, Porto, Portugal.|ICBAS, Abel Salazar Institute for the Biomedical Sciences, Porto, Portugal.
authors.forename: Deolinda
authors.initials: D
authors.lastname: Pereira
authors.affiliation: Molecular Oncology and Viral Pathology Group-Research Center, Portuguese Institute of Oncology, Edifício Laboratórios. 4° piso, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.|FMUP, Faculty of Medicine, Porto University, Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Assis
authors.affiliation: ICBAS, Abel Salazar Institute for the Biomedical Sciences, Porto, Portugal.|Molecular Oncology and Viral Pathology Group-Research Center, Portuguese Institute of Oncology, Edifício Laboratórios. 4° piso, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.|Research Department, Portuguese League Against Cancer (NRNorte), Porto, Portugal.
authors.forename: Mónica
authors.initials: M
authors.lastname: Gomes
authors.affiliation: Molecular Oncology and Viral Pathology Group-Research Center, Portuguese Institute of Oncology, Edifício Laboratórios. 4° piso, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.|FMUP, Faculty of Medicine, Porto University, Porto, Portugal.|Research Department, Portuguese League Against Cancer (NRNorte), Porto, Portugal.
authors.forename: Augusto
authors.initials: A
authors.lastname: Nogueira
authors.affiliation: ICBAS, Abel Salazar Institute for the Biomedical Sciences, Porto, Portugal. ruimedei@ipoporto.min-saude.pt.|Molecular Oncology and Viral Pathology Group-Research Center, Portuguese Institute of Oncology, Edifício Laboratórios. 4° piso, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal. ruimedei@ipoporto.min-saude.pt.|Research Department, Portuguese League Against Cancer (NRNorte), Porto, Portugal. ruimedei@ipoporto.min-saude.pt.|CEBIMED, Faculty of Health Sciences, Fernando Pessoa University, Porto, Portugal. ruimedei@ipoporto.min-saude.pt.
authors.forename: Rui
authors.initials: R
authors.lastname: Medeiros
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017671:Platinum Compounds / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011379:Prognosis
chemical_list: D000970:Antineoplastic Agents; D005982:Glutathione Transferase; D017671:Platinum Compounds; C413545:glutathione S-transferase T1
keywords: Epithelial ovarian cancer; GST; Pharmacogenetic; Platinum-based chemotherapy; Polymorphism; Predictive value