Tamoxifen nel trattamento del carcinoma mammario: studio dei fattori predittivi di risposta

Breast cancer is the tumor with highest incidence in women and the first leading cause of mortality in Western countries. The estrogen receptor positive breast cancer subtype is the most frequent (60-80%) and for its treatment the selective estrogen receptor modulator tamoxifen can be used. Tamoxifen efficacy is widely recognized in the adjuvant setting (post-surgical) of early stages tumors, however, in a significant percentage of patients disease recurs. The aim of our study was to investigate possible factors contributing to the therapeutic failure of tamoxifen treatment in invasive non-metastatic estrogen receptor positive breast cancer patients. Tamoxifen is a pro-drug extensively metabolized by the hepatic cytochrome P450 CYP2D6 into more active and powerful metabolites compared to the parental drug. Among these it has been recently taken into special account the active metabolite endoxifen, which is considered the main responsible for the therapeutic response because of its high affinity for the molecular target, the estrogen receptor alpha (Erα) and because it shows higher plasma levels compared to the similarly active metabolite 4-idrossitamoxifen. Several studies have demonstrated that the gene of CYP2D6 enzyme is highly polymorphic in the population, due to variations in the gene sequence which result in functional alterations, with partial reduction or total elimination of the enzymatic activity. However, the inter-individual differences in endoxifen exposure, clinically observed, are not only explained by CYP2D6 gene polymorphisms, as its activity is significantly influenced also by environmental causes (such as drugs that inhibit the enzyme). Hence the need to identify new ways to predict individual ability of patients to activate tamoxifen, keeping endoxifen plasma levels as a reference parameter. The latter cannot be directly used to estimate the metabolic capacity of CYP2D6 when mostly needed, thas is before or in the early phases of drug treatment, because, due to the prolonged half-life of the drug and its derivatives, the achievement of steady state plasma levels (indicative of concentrations to which patients are exposed for five years of therapy) takes an average of four months. Finally, in addition to the exposure to the active metabolite, another predictive factor of response may include the molecular target of the drug, the estrogen receptor. It has been confirmed by numerous studies that in tumor and healthy mammary tissue estrogen receptor splicing isoforms of Erα and Erβ are coexpressed with the full-length proteins. Recently, an in vitro study revealed that the wild-type Erβ enhanced the antiestrogenic action of endoxifen. For the evaluation of the individual capacity in tamoxifen activation, to overcome genotyping limitations, two strategies were used: the phenotyping test of CYP2D6 by the probe drug dextromethorphan and the determination of endoxifen plasma levels at the first month (previous to the steady state). We have shown that the results of phenotyping test and levels of endoxifen at the first month are significantly associated with endoxifen steady state levels and both can be considered as informative tools to know the metabolic status of the individual patient. The influence of polymorphisms on endoxifen plasma levels was confirmed by genetic analysis of the CYP2D6 in our population; the genotyping results were also significantly associated with those of phenotyping test. The possible role of an estrogen receptor isoform, Erβ2, on the activity of endoxifen was evaluated, in vitro, by monitoring the transcription of two estrogens sensitive genes. Through analysis of expression of IL20 and ADORA1 it was found that, in the presence of concentrations of endoxifen of 40nM for prolonged time (24h), the isoform Erβ2, co-expressed with Erα, reduced the inhibitory action of endoxifen compared to the presence of only Erα

Guida dello studente per la Facoltà di Ingegneria. Anno accademico 1981-1982

La Guida delinea il complesso dell’offerta formativa della Facoltà di Ingegneria, in diversi anni accademici, indicando le modalità di accesso ai Corsi di studio, i piani didattici e i programmi degli insegnamenti

Guida dello studente per la Facoltà di Ingegneria. Anno accademico 1979-1980

La Guida delinea il complesso dell’offerta formativa della Facoltà di Ingegneria, in diversi anni accademici, indicando le modalità di accesso ai Corsi di studio, i piani didattici e i programmi degli insegnamenti

Guida dello studente per la Facoltà di Ingegneria. Anno accademico 1980-1981

La Guida delinea il complesso dell’offerta formativa della Facoltà di Ingegneria, in diversi anni accademici, indicando le modalità di accesso ai Corsi di studio, i piani didattici e i programmi degli insegnamenti