Searching for the responsiveness to hormonotherapy by molecular genetic studies (polimorphisms of CYP2D6) in er positive breast cancer patients

SEARCHING FOR THE RESPONSIVENESS TO HORMONOTHERAPY BY MOLECULAR GENETIC STUDIES (Polimorphisms of CYP2D6) IN ER POSITIVE BREAST CANCER PATIENTS 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 genetic studies. The selective estrogen receptor modulator tamoxifen has been used for more than three decades for the treatment, and more recently prevention of breast cancer in women of all ages. Tamoxifen is a pro-drug and requires 'metabolic activation' catalyzed by cytochorome P450 (CYP) enzymes. CYP2D6 is the key enzim responsible for the conversion of N- desmetyl tamoxifen to endoxifen. Single nucleotid plemorphism in the CYP2D6 gene are not uncommon, and some pleomorphisms associated with reduced, null or increased activity. The patients who carrying two wild type CYP2D6 alleles (CYP2D6*1/*1) called extensive metabolizers (normal activity). Different combination of these polimorfic (variant) alleles cause to poor metabolizer (reduced or null enzym activity), ıntermediate metabolizer (reduced enzyme activity) and ultrarapid metabolizer (increased enzym activity) fenotypes. These fenoypes. These fenotypes are associated with worse clinical breast cancer outcome in patients who taking tamoxifen in adjuvan setting. The ethnic variations are common in CYP2D6 and the enzym activity can also be reduced by concomitant use of drugs for or example antidepresans used for psychiatric conditions or to relieve hot flashes, and these should be avoided in tamoxifen users whenever possible. In the present study we aimed to provide an overview on the current data and search the genetic polimorphisms in CYP2D6. We want to explain the clinical implication of CYP2D6 genotyping on hormonotherapy. This study including 47 breast cancer patients who are using tamoxifen in adjuvan setting. All patients have ER positive tumors. The patients are choosen 105 from the patients who are diagnosed in Medical Pathology Department of Akdeniz University Faculty of Medicine and follow up by the Oncology Department of same faculty, between the years 2002-2012. The study population include 26 patients who are have disease progression (recurrence /metastasis) and the control group include 21 patients who are in remission with hormonotherapy. The patients DNA analyzed for CYP2D6 polimorfisms by using FFPE (Autogenomics Infinity Biofilm Microarray CYP2D6 I). Gene polymorphisms and clinical characteristics of patients were compared. Chi-Square, KruskalWallis and Man- Whitney – U tests were used to compare categorical measures between the two groups. The mean follow up time is 60 months. We find CYP2D6 *4/*10 genotype in two premenaposal patients, and CYP2D6*2/*XN genotype in a postmenaposal patients. Each of them show disease progression. There was no polimorphism in control group patients who are in remission with hormonotherapy. There was no association between polimorphisms and tumor characteristics such as PR and Cerb-B2 situation, size, grade and stage. Time to progression is shorther in patients who have polimorfic genotypes (p=0.02). Between CYP2D6 genetic polymorphism with the various parameters of the disease in patients using tamoxifen, no significant relationship were observed between CYP2D6 genotypes with the pathological features of cancer. Based on the results we can say polimorphisms in CYP2D6 are very rare in Turks. The progression time is shorther in patients who have polimorfic genotypes but the definitive evidence that would change routine clinical practice not yet available. We think the postmenopozal patients can tested for CYP2D6 polimorphisms before the tamoxifen therapy for predict to efficacy of the drug, but tamoxifen still seems the best option for hormonotherapy in premenaposal and the patients who have intraductal carcinoma. Key words: Breast cancer, CYP2D6, sitP450, endocrine therapy, tamoxifen, aromatase inhibitors