Endocrine therapy has become the most important systemic treatment

by Selleckchem | Mar 10 2014

Endocrine therapy has become the most important systemic treatment for women with estrogen receptor (ER)-positive breast cancer. Local aromatization of androgens to estrogens is the primary source of Imatinib estradiol in the breasts of postmenopausal women. Results of recent clinical trials have shown that third-generation aromatase inhibitors, such as anastrozole, letrozole and exemestane, are superior to tamoxifen in the treatment of postmenopausal women with either early stage or metastatic breast cancer. Thus, aromatase inhibitors are now considered to be the gold standard endocrine therapy in postmenopausal women in both adjuvant and metastatic settings. Characterization of the risk of recurrence for patients who receive aromatase inhibitors is important for the selection of treatment. Although recent analyses found multiple mechanisms of aromatase inhibitor resistance, factors predictive of the efficacy of aromatase inhibitors have not been identified.
Most studies analyzing prognostic factors ARN-509 in postmenopausal ER-positive breast cancer have been performed in patients treated with tamoxifen as adjuvant endocrine therapy or in patients treated with either tamoxifen or aromatase inhibitors. Therefore, biomarkers predicting outcome after adjuvant aromatase inhibitors, but not tamoxifen, are not completely understood. Furthermore, most prognostic markers and multigene scores, such as Ki-67 and recurrence score, are factors for predicting early recurrence. However, approximately half of all disease recurrences occur after 5 years of adjuvant endocrine therapy and prognostic factors might differ between early and late relapse in patients treated with adjuvant aromatase inhibitors.
Recent whole genome analysis identified the presence of a TP53 gene mutation in 12% of luminal A and 32% of luminal B breast cancers, although the frequency of TP53 gene mutation AGI5198 in luminal tumors is lower compared with basal-like (84%) or human epidermal growth factor receptor type 2 (HER2)-positive (75%) breast cancers. Functional p53 plays an important role in maintaining genomic stability, regulating the cell cycle and inducing apoptosis. As mutated p53 accumulates in the nucleus of tumor cells, immunohistochemical (IHC) staining for p53 is frequently used as a surrogate marker for p53 mutational status. We previously reported that 20% of ER-positive breast cancer patients showed p53 accumulation by IHC and that p53 accumulation predicted resistance to endocrine therapy and decreased post-relapse survival in metastatic breast cancer. We also investigated p53 expression in pretreatment biopsy tissues and post-treatment surgical specimens in postmenopausal patients with ER-positive breast cancer who were treated with exemestane as neoadjuvant endocrine therapy. Although p53 expression was low in most pretreatment tumors, expression levels of p53 were decreased in post-treatment specimens compared with the values in the pretreatment biopsies. Many studies have been performed on the prognostic and predictive value of p53 in breast cancer; however, the role of TP53 mutation and p53 accumulation has not yet been identified. It is suggested that the role of p53 alteration might differ according to breast cancer subtypes and treatments.