IJCEM Copyright © 2008-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Clin Exp Med 2013;6(7):552-561

Original Article
Influence of CYP3A4 genotypes in the outcome of serous ovarian cancer patients
treated with first-line chemotherapy: implication of a CYP3A4 activity profile

Joana Assis, Deolinda Pereira, Mónica Gomes, Dânia Marques, Inês Marques, Augusto Nogueira, Raquel Catarino, Rui Medeiros
Molecular Oncology Group–CI, Portuguese Institute of Oncology, Porto, Portugal; ICBAS, Abel Salazar Institute for the Biomedical
Sciences, University of Porto, Porto, Portugal; Oncology Department, Portuguese Institute of Oncology, Porto, Portugal; CEBIMED,
Faculty of Health Sciences of Fernando Pessoa University, Porto, Portugal; Research Department, Portuguese League against Cancer
(NRNorte), Porto, Portugal

Received June 7, 2013; Accepted July 10, 2013; Epub August 1, 2013; Published August 15, 2013

Abstract: CYP3A4 is a key enzyme involved in the metabolism of numerous compounds, such as paclitaxel, and its activity shows an
extensive inter-individual variation which can influence treatment response. The study’s purpose was to investigate the potential
predictive role of a CYP3A4 profile (CYP3A4*1B, rs2740574 and CYP3A4*22, rs35599367) in serous ovarian cancer patients treated
with first-line chemotherapy (paclitaxel and cisplatin or carboplatin), after cytoreductive surgery. CYP3A4*1B and CYP3A4*22 genotypes
were determined by Nested PCR-RFLP and Taqman® Allelic Discrimination, respectively. We observed that the mean survival rates
were statistically different according the patients CYP3A4 genotypes. The group of patients carrying the CYP3A4*1B G allele present a
decreased mean survival rate when compared with AA genotype patients (103.93 and 134.44 months, respectively, p = 0.010). This
result is consistent after multivariate Cox regression analysis (HR, 2.15; 95% CI, 1.03-4.52; p = 0.043). The combination of CYP3A4*1B
and CYP3A4*22 polymorphisms result in the definition of a CYP3A4 activity profile: the group of patients with a higher CYP3A4 activity
profile had significantly diminished survival when compared with patients with a lower CYP3A4 activity profile (101.06 and 134.44
months, respectively, p = 0.012). Multivariate Cox regression analysis revealed a diminished overall survival time for patients with
CYP3A4 high activity profile (HR, 2.29; 95% CI, 1.05-5.02; p = 0.038). The definition of a CYP3A4 activity profile resulted in the increase
of prediction ability, using Harrels’s concordance indexes (C-index from 0.617 to 0.626). To conclude, our results demonstrate an
association between CYP3A4*1B and a diminished overall survival of patients with serous ovarian cancer. The definition of a CYP3A4
activity profile proved to be benefic and the CYP3A4 high activity profile was associated with a lower overall survival. We consider that
the definition of a CYP3A4 activity profile might be useful as molecular marker for predicting the clinical outcome of serous ovarian
cancer patients. (IJCEM1306025).

Keywords: Serous ovarian cancer, CYP3A4, polymorphism, pharmacogenetic, paclitaxel, predictive value

Address correspondence to: Dr. Doutor Rui Medeiros, Instituto Português de Oncologia do Porto Francisco Gentil, EPE, Grupo de
Oncologia Molecular–CI, Edifício Laboratórios, 4° piso, Rua Dr. António Bernardino de Almeida, 4200-072 Porto. Tel: +351 22 508
4000; Fax: +351 22 508 4001; E-mail: ruimedei@ipoporto.min-saude.pt