ABSTRACT: Growth factor receptor signaling plays a key role in endocrine resistance to therapy for metastatic breast cancer. These molecular
pathways provide a unique target for new therapeutic approaches to reverse resistance. In this review, we provide a background
discussion on the mechanisms of resistance, and then proceed to describe recent clinical trials involving the use of growth
factor receptor inhibitors to improve patient outcome in metastatic hormone receptor (HR)-positive breast cancer. We demonstrate
incremental improvements in outcome for patients with HR-positive metastatic breast cancer with combination therapy involving
growth factor inhibitors and endocrine therapies. It remains unclear which patients with HR-positive metastatic breast cancer
benefit from these combined approaches, and further research will focus on this issue. Understanding the mechanisms of endocrine
resistance will undoubtedly lead to the development of new agents that can improve outcome for patients with this disease.
KeywordsBreast cancer-Hormone resistance-Endocrine-Metastatic
Current Breast Cancer Reports 04/2012; 2(2):114-119.
Breast Cancer 04/2012; 8(4):265-274. · 1.36 Impact Factor
ABSTRACT: Tamoxifen (Fig. 1) is the endocrine treatment of choice for all stages of hormone-responsive breast cancer. Additionally tamoxifen
has been shown to reduce the incidence of cancer of the opposite breast (1) and has recently been demonstrated to prevent breast cancer (2). Although most women with hormone-responsive advanced breast cancer respond to tamoxifen, their disease eventually becomes
refractory to tamoxifen. These patients are known to respond to second-line hormonal therapies. In this chapter, we will focus
on new antiestrogens that are currently available or are being developed for use following tamoxifen failure. We have divided
these new agents into three groups according to their target-site specificity and molecular properties (3); tamoxifen-like agents, raloxifene-like agents, and pure antiestrogens.
12/2008: pages 195-212;
ABSTRACT: Tamoxifen (Nolvadex®) (Fig. 1), a nonsteroidal antiestrogen, is the endocrine treatment of choice for all stages of breast
cancer. The drug has ten million women years of clinical experience and is described by the World Health Organization (WHO)
as an essential treatment for breast cancer. The clinical pharmacology of tamoxifen has been studied in great detail because
it is continuing to be tested as a preventive for breast cancer in high-risk women (1). This strategy is based on three important facts. Firstly, tamoxifen prevents rat mammary carcinogenesis (2,3). Secondly, tamoxifen reduces the incidence of contralateral breast cancer (4) and thirdly, when the preliminary studies were started in 1986 (5), tamoxifen was believed to have a low incidence of side effects (6).
12/2008: pages 47-68;
ABSTRACT: Discovery of the estrogen receptors (ERs) has been critical for the development of endocrine therapy in breast cancer. Expression
of ER-?, the predominant isoform, in breast tumors of both pre- and postmenopausal women is a highly predictive marker for
response to antiestrogen treatment. Tamoxifen, an antiestrogen, that competitively blocks the actions of 17β-estradiol (E2), binds and activates ER-? in breast tumors and is used for treating all stages of breast cancer. Although tamoxifen is effective
in reducing recurrence fromER-positive early stage breast cancer, approximately 50% of patients do not benefit from its use,
because their breast cancers have intrinsic or de novo tamoxifen-resistance. Additionally, most patients that do initially benefit from tamoxifen, will develop acquired resistance
to the drug during the treatment regimen. Despite increasing use of the aromatase inhibitors as breast cancer therapies, tamoxifen
remains the hormonal therapy of choice in premenopausal women, and is the only hormonal therapy approved for breast cancer
prevention. Therefore, a current goal in breast cancer research is to elucidate the mechanisms of both intrinsic and acquired
resistance to tamoxifen and other antiestrogens in order to develop new therapeutic strategies to prevent and/or treat resistant
12/2005: pages 413-433;
ABSTRACT: Laboratory models for breast and endometrial cancer have had an enormous impact on the clinical development of antiestrogens.
Results from the DMBA-induced rat mammary cancer model has provided the scientific principles required to evaluate long-term
adjuvant tamoxifen therapy. Similarly, the athymic mouse model allowed the identification of clinically relevant mechanisms
of drug resistance to tamoxifen and a model system to test new agents for cross resistance. Additionally, the endometrial
cancer model has allowed the identification of agents that cause a slight increase in the risk of endometrial cancer long
before the data would have be available from clinical studies. However, it should be stressed that this model is really only
relevant for agents to be tested as preventives in normal women. The risks of developing endometrial cancer during tamoxifen
therapy are slight compared with the survival benefit in controlling breast cancer.
Finally the discovery of the carcinogenic potential of tamoxifen in the rat liver, 20 years after it was first introduced
into clinical practice, raises an interesting issue. If the studies of liver carcinogenicity had been completed and published
in the early 1970’s there would be no tamoxifen and tens of thousands of women with breast cancer would have died prematurely.
In fact there would have been no incentive to develop new agents as alternatives to tamoxifen or following tamoxifen failure.
Most importantly, we would not have any knowledge about the target-site or selective actions of antiestrogens. All the current
interest in selective estrogen receptor modulators (SERMs) is based on the huge clinical data base obtained by studying tamoxifen.
The success of tamoxifen as an agent that preserves bone density, lowers cholesterol and prevents contralateral breast cancer43 has become a classic example of a multimechanistic drug. These concepts have acted as a catalyst to develop new agents for
new applications. The laboratory studies of raloxifene44-46) provided the scientific rationale for the use of raloxifene as a preventive for osteoporosis47) but with the goal of preventing breast cancer in post-menopausal women48,49) (Fig 5). It is clear that the close collaboration between laboratory and clinical research has revolutionized the prospects
for women’s health care in the 21st century.
Breast Cancer 01/1998; 5(3):211-217. · 1.36 Impact Factor