PHARMACOGENETICS OF TAMOXIFEN ADJUVANT THERAPY AND ITS EFFICIACY: MDR1 POLYMORPHISMS IN CYP2D6 EXTENSIVE METABOLIZERS WITH BREAST CANCER

Konference: 2012 37th Congress ESMO – účast ČR

Kategorie: Nádorová biologie/imunologie/genetika a buněčná terapie; Zhoubné nádory prsu

Téma: Poster, Poster presentation II

Číslo abstraktu: 196P

Autoři: MUDr. Soňa Argalacsová; Doc. MUDr. Ondřej Slanař, Ph.D.; PharmDr. Hana Bakhouche (Vondráčková); RNDr. Marcela Dražďáková; MUDr. Olga Matoušková; prof. MUDr. Tomáš Zima, DrSc., MBA; prof. MUDr. Luboš Petruželka, CSc.

Background

The role of CYP2D6 polymorphisms in adjuvant breast cancer therapy has not been standardised until now. Recent pre-clinical evidence suggests that the active metabolite of tamoxifen, endoxifen, is a substrate for efflux pump P-glycoprotein (P-gp). The polymorphic MDR1 gene encoding the P-gp may thus represent a prognostic factor for the treatment outcome in addition to the previously studied pharmacogenetic factors. The aim of our study was to evaluate, if the polymorphisms within MDR1 gene and CYP2D6 gene alter tamoxifen adjuvant treatment efficacy in breast cancer.

Methods

Totally 252 women signed informed consent and participated in the study. After exclusion of poor metabolizers for CYP2D6, 227 women with estrogen receptor positive breast cancer were followed retrospectively for median period of 79 months. The primary analysis was conducted on time-to-event.

Results

The cumulative observed recurrence rate was approximately 26.5%. The Cox-proportional hazard regression model revealed C3435T polymorphism, age and clinical tumor size at the time of diagnosis as significant covariates affecting the event free survival. The patients carrying at least one variant allele 3435T in MDR1 gene had significantly longer time to event survival resulting in hazard ratio of 0.44 (95%CI 0.21-0.92) as compared with CC3435 patients. For the G2677T/A polymorphism, a non-significant trend suggesting that the wt homozygous may had worse treatment outcome as compared with the heterozygous or homozygous subjects for the variant alleles was noted. The respective median event free survival times were 93, 103, and 126 months.

Conclusions

Wild type homozygous genotype in MDR1 polymorphism C3435T predicts for worse treatment outcome of tamoxifen adjuvant therapy. This should be taken into account as a potential pharmacogenetic biomarker for the drug efficacy.

Disclosure

All authors have declared no conflicts of interest.


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Datum přednesení příspěvku: 30. 9. 2012