Overview and new strategies in metastatic breast cancer (MBC) for treatment of tamoxifen-resistant patients

symposium article Annals of Oncology 18 (Supplement 6): vi53–vi57, 2007 doi:10.1093/annonc/mdm225 Overview and new strategies in metastatic breast cancer (MBC) for treatment of tamoxifen-resistant patients V. Adamo*, M. Iorfida, E. Montalto, V. Festa, C. Garipoli, A. Scimone, M. Zanghı̀ & N. Caristi The treatment with aromatase inhibitors (AIs) and fulvestrant has been demonstrated to be active in a proportion of tamoxifen-resistant breast cancer patients, obtaining, in some cases, a long-term control of tumor growth. Results from clinical trials indicate that treatment with fulvestrant might either precede or follow AIs. However, the AIs are now replacing tamoxifen as first-line advanced and adjuvant therapies, and thus, other options following tamoxifen failure are required. Fulvestrant may be effective in this setting, even if there is also evidence of a lack of cross-resistance between nonsteroidal and steroidal AIs, resulting in the potential use of steroidal AIs following nonsteroidal AI failure and vice versa. Resistance mechanisms to these therapies appear to be related to a cross talk between estrogen receptor (ER) and growth factor-signaling cascades. Novel therapeutic approaches for ER+ patients, which combine hormonal agents and signal transduction inhibitors, have been developed to overcoming resistance. Several trials are now investigating signal transduction inhibitors combined with endocrine agents. This approach might provide efficient treatments and delay the onset of antihormone resistance, thereby significantly improving patient’s survival. Key words: metastatic breast cancer, new strategies, overview, resistance, tamoxifen, treatment introduction In postmenopausal women the majority of breast cancers expresses estrogen receptors (ERs) and/or progesterone receptors. These biological characteristics are associated with a better prognosis and are predictive of response to hormonal therapy. In these patients endocrine therapy represents the treatment of choice, resulting in a good antitumor activity with lesser adverse events compared with chemotherapy. Despite that, patients may present de novo or acquired resistance after various hormonal manipulations. Patients experiencing disease progression with a first-line hormonal therapy may benefit from other endocrine agents. Tamoxifen has been the standard endocrine therapy for many years, but most tumors finally become resistant to this drug [1]. Several trials have been conducted to explicate the optimal sequence and/or combination to improve hormonal treatment outcomes of breast cancer. Here, we review the data regarding on the mechanisms of tamoxifen resistance and the therapeutic strategies for overcoming or bypassing such resistance. molecular actions of ER To explain the mechanisms of resistance to hormonal therapy, we need to explicate the characteristics and molecular actions of *Correspondence to: Dr V. Adamo, U.O. Oncologia Medica e Terapie Integrate, A.O. Universitraria Policlinico G. Martino, via consolare valeria n.1, 98125 Messina, Italy. Tel: +390902213238; Fax: +390902213669; E-mail: ª 2007 European Society for Medical Oncology ER. Two different ER are known, ERa and ERb. The role of ERb in the ER-mediated signaling is not fully understood, and therefore the term ÔERÕ will refer to ERa. The ER presents an N-terminal domain with a region called AF1 (hormone-independent transcriptional activation function 1), a central DNA-binding domain and a C-terminal domain with a region called AF2 (hormone-dependent activation function 2). Binding of estrogens to ER causes a dissociation of the complex ER–heat shock proteins, ER conformational changes, dimerization and phosphorylation. The dimer complex binds to specific DNA sequences termed the estrogen response elements. The activation of transcription by ER involves the interaction of two transcription activation functions (AF1 and AF2). While AF2 is activated by estradiol and represents the classical genomic pathway of ER signaling, AF1 is activated by growth factor receptors such as Erb family and Insulin-like growth factor-I receptor (IGFR1) that act via the Mitogen-Activated Protein Kinase (MAPK) in a model called alternative nongenomic pathway [2]. The full transcriptional activity requires the recruitment of nuclear receptor coactivators and corepressors. However, nonclassical genomic pathways have been described regarding the interaction with other DNA-bound transcription factors such as Fos and Jun proteins on AP1 response elements [3], SP1 and other non- defined sites. The symposium article Department of Human Pathology, Medical Oncology and Integrated Therapies Unit, Policlinic Universitary ‘‘G. Martino’’ of Messina, Italy symposium article classical and non-classical modes of action of ER are ligand dependent. In addition, there are evidences that the ERs located in or near the cell membrane can interact with the growth factors receptor tyrosine kinases and kinases. The cross-talk between the ER and growth factor receptors travels in both directions. tamoxifen: mechanism of action and resistance Tamoxifen is a nonsteroidal triphenylethylene derivative, classified as a selective estrogen receptor modulator, and has been the mainstay of endocrine therapy in the ER+ breast cancer for the last 20 years. Tamoxifen binds to ER, with low affinity compared with estrogens, and the complex homodimerizes and translocates to the nucleus, where it inhibits coactivator binding and promotes corepressor binding, blocking the transcription of AF2, while AF1 remains active. The inhibition of AF2 explains the antagonist effect of tamoxifen in the breast, whereas partial agonist effect in bone, liver and the uterus results from the activation of AF1. The postulated mechanisms of resistance or insensitivity to endocrine therapy include the following: loss of ER in the tumor, ER mutations, enhancement of coactivators and inhibition of corepressors and cross talk between the ER and the growth factor receptor pathways [4]. Preclinical models and clinical trials indicate that overexpression of EGFR and HER-2 confers antiestrogen resistance [5, 6] by an increased cross-talk between ER and is associated with a poor prognosis [7]. treatment options following tamoxifen aromatase inhibitors Several studies have shown that ER continues to regulate tumor development in most endocrine-resistant cases, and two-thirds of patients who relapse on tamoxifen respond to aromatase inhibitors or to the pure ER antagonist fulvestrant. Aromatase inhibitors (AIs) have been developed to suppress activity of the cytochrome P450 enzyme aromatase in peripheral tissues, reducing circulating estradiol levels and eluding estradiol-induced transcription via nuclear and non-nuclear pathways. Third-generation AIs can be divided into two main classes, nonsteroidal (anastrozole, letrozole) and steroidal (exemestane), and subclassified according to the reversibility of their inhib (...truncated)