Functional Polymorphisms in Xenobiotic Metabolizing Enzymes and Their Impact on the Therapy of Breast Cancer

Abstract

Breast cancer is the top cancer among women, and its incidence is increasing worldwide. Although the mortality tends to decrease due to early detection and treatment, there is great variability in the rates of clinical response and survival, which makes breast cancer one of the most appealing targets for pharmacogenomic studies. The recognition that functional CYP2D6 polymorphisms affect tamoxifen pharmacokinetics has motivated the attempts of using CYP2D6 genotyping for predicting breast cancer outcomes. In addition to tamoxifen, the chemotherapy of breast cancer includes combinations of cytotoxic drugs, which are substrates for various xenobiotic metabolizing enzymes. Because of these drugs’ narrow therapeutic window, it has been postulated that impaired biotransformation could lead to increased toxicity. In the present review, we performed a systematic search of all published data exploring associations between polymorphisms in xenobiotic metabolizing enzymes and clinical outcomes of breast cancer. We retrieved 43 original articles involving either tamoxifen or other chemotherapeutic protocols, and compiled all information regarding response or toxicity. The data indicate that, although CYP2D6 polymorphisms can indeed modify tamoxifen pharmacokinetics, CYP2D6 genotyping alone is not enough for predicting breast cancer outcomes. The studies involving other chemotherapeutic protocols explored a great diversity of pharmacogenetic targets, but the number of studies for each functional polymorphism is still very limited, with usually no confirmation of positive associations. In conclusion, the application of pharmacogenetics to predict breast cancer outcomes and to select one individual’s chemotherapeutic protocol is still far from clinical routine. Although some very interesting results have been produced, no clear practical recommendations are recognized yet.

Pharmacogenetic testing in oncology: a Brazilian perspective

“…Different aspects of the PGx of tamoxifen have been explored in a number of original studies in Brazilians, and Vianna-Jorge et al 70 published a careful overview of the impact of functional polymorphisms in metabolizing enzymes on the treatment of breast cancer. I will briefly comment on selected results from the original studies.…”

Pharmacogenomics research and clinical implementation in Brazil

“…Vianna‐Jorge et al published a careful overview of the impact of PGx polymorphisms on the therapy of breast cancer, whereas two other studies examined the frequency of selected CYP2D6 alleles on recurrence, and disease‐free survival in Brazilian women with breast cancer. The latter studies included relatively small cohorts (n = 80 and 58, respectively), genotyped limited numbers of known functional CYP2D6 variants and did not examine copy number variation, which collectively compromise the conclusions drawn.…”

Pharmacogenomics in Brazil

“…Only recently, recognition of this fact translated into PGx research on the clinical response to prescribed drugs in Brazilians, as illustrated in the following selected examples from studies carried out by Refargen groups: l Rosario Hirata studied the PGx of HMG-CoA reductase inhibitors [24][25][26] and clopidogrel [27] l Rosane Vianna-Jorge examined the impact of polymorphisms in the cyclooxygenase-2 gene and breast cancer risk and prognosis [28][29][30] l Vanessa Mattevi investigated the UGT1A1*28 variant allele as a predictor of severe hyperbilirubinemia in HIV-infected patients receiving highly active antiretroviral therapy (HAART) [31] l Adalberto Santos and Ândrea K. Ribeiro dos Santos, in collaboration with Mara Hutz, explored the association between N-acetyltransferase 2 (NAT2) haplotypes and the hepatotoxicity induced by antituberculosis drugs in Southern and Northern Brazilians, respectively [32,33] Our own studies covered the PGx of antipsychotics, HAART, immunosuppressants, L-thyroxine, levodopa, methylphenidate, nonsteroidal antiinflammatory agents (NSAIDs), statins, and warfarin. Only recently, recognition of this fact translated into PGx research on the clinical response to prescribed drugs in Brazilians, as illustrated in the following selected examples from studies carried out by Refargen groups: l Rosario Hirata studied the PGx of HMG-CoA reductase inhibitors [24][25][26] and clopidogrel [27] l Rosane Vianna-Jorge examined the impact of polymorphisms in the cyclooxygenase-2 gene and breast cancer risk and prognosis [28][29][30] l Vanessa Mattevi investigated the UGT1A1*28 variant allele as a predictor of severe hyperbilirubinemia in HIV-infected patients receiving highly active antiretroviral therapy (HAART) [31] l Adalberto Santos and Ândrea K. Ribeiro dos Santos, in collaboration with Mara Hutz, explored the association between N-acetyltransferase 2 (NAT2) haplotypes and the hepatotoxicity induced by antituberculosis drugs in Southern and Northern Brazilians, respectively [32,33] Our own studies covered the PGx of antipsychotics, HAART, immunosuppressants, L-thyroxine, levodopa, methylphenidate, nonsteroidal antiinflammatory agents (NSAIDs), statins, and warfarin.…”