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Improvement of a predictive model in ovarian cancer patients submitted to platinum-based chemotherapy: implications of a GST activity profile

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

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.

Conclusion

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.

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Acknowledgments

We would like to thank the Liga Portuguesa contra o Cancro-Centro Regional do Norte (Portuguese League against Cancer), Ministério da Saúde de Portugal (CFICS-45/2007), IPO-Porto (CI-IPOP-22-2015), and FCT (Fundação para a Ciência e Tecnologia). Joana Assis is a doctoral degree grant holder from FCT (SFRH/BD/98536/2013).

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    Authors and Affiliations

    1. Oncology Department, Portuguese Institute of Oncology, Porto, Portugal

      Deolinda Pereira

    2. ICBAS, Abel Salazar Institute for the Biomedical Sciences, Porto, Portugal

      Deolinda Pereira, Mónica Gomes & Rui Medeiros

    3. 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

      Joana Assis, Mónica Gomes, Augusto Nogueira & Rui Medeiros

    4. FMUP, Faculty of Medicine, Porto University, Porto, Portugal

      Joana Assis & Augusto Nogueira

    5. Research Department, Portuguese League Against Cancer (NRNorte), Porto, Portugal

      Mónica Gomes, Augusto Nogueira & Rui Medeiros

    6. CEBIMED, Faculty of Health Sciences, Fernando Pessoa University, Porto, Portugal

      Rui Medeiros

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    1. Deolinda Pereira
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    Correspondence to Rui Medeiros.

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    All procedures performed in the present study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. Deolinda Pereira and Rui Medeiros conceived or designed the study. Joana Assis, Mónica Gomes, and Augusto Nogueira performed research. Joana Assis, Deolinda Pereira, and Rui Medeiros analyzed data. Joana Assis and Deolinda Pereira wrote the paper.

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    The authors declare that they have no conflict of interests.

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    Deolinda Pereira and Joana Assis contributed equally to this work.

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    Pereira, D., Assis, J., Gomes, M. et al. Improvement of a predictive model in ovarian cancer patients submitted to platinum-based chemotherapy: implications of a GST activity profile. Eur J Clin Pharmacol 72, 545–553 (2016). https://doi.org/10.1007/s00228-016-2015-3

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