In patients with hormone receptor-positive advanced breast cancer, response to endocrine therapy is frequently limited by endocrine resistance. One important mechanism of resistance is related to mammalian target of rapamycin (mTOR), a molecule involved in the activation of alternative signaling pathways. Preclinically, resensitization of endocrine resistance can be achieved by the addition of the mTOR inhibitor everolimus to endocrine therapy. Recent results of clinical trials confirmed the clinical activity of combining everolimus and endocrine therapy in neoadjuvant and advanced breast cancer. The BOLERO-2 trial demonstrated significant progression-free survival benefits for the addition of everolimus to exemestane. These data were the basis for the recent approval of everolimus in combination with exemestane for the treatment of advanced hormone r eceptor-positive breast cancer. In clinical practice, the following 3 patient groups are particularly suitable for this treatment: those with progression on aromatase inhibitor therapy, those who respond well to chemotherapy and might benefit from subsequent endocrine therapy, and those with non-aggressive tumor biology. Everolimus treatment requires careful clinical monitoring due to the potentially serious side effects, e.g. stomatitis and pneumonitis. It is also important to educate patients and physicians in order to increase their awareness of side effects. At present, everolimus is investigated in clinical trials.
Advanced breast cancer; Endocrine therapy; Endocrine resistance; mTOR inhibition; Everolimus; Exemestane
The 2013 St. Gallen Consensus Conference on early breast cancer provided mostly evidence-based, globally valid treatment recommendations for breast cancer care, with a broad spectrum of acceptable clinical practice. This report summarizes the results of the 2013 international panel voting procedures with regard to loco-regional and endocrine treatment, chemotherapy, targeted therapy as well as adjuvant bisphosphonate use. This report is not aimed to replace the official St. Gallen Consensus publication, some recommendations may even be altered in the final paper, but should serve a preliminary rapid report of this important meeting.
Early breast cancer; Bisphosphonates; Endocrine therapy; Chemotherapy; Surgery; Axillary dissection; Targeted therapy; Neoadjuvant therapy
At the first Austrian multidisciplinary expert panel on controversies in local treatment of breast cancer, 22 experts of all relevant disciplines discussed current areas of debate (surgery of the breast, surgery and pathology of the axilla, reconstructive surgery, radiotherapy, and imaging) in local therapy. The most controversial area of debate was the area of axillary surgery. The panel agreed that it was no longer necessary to perform completion axillary lymph node dissection (ALND) when micrometastases are diagnosed in the sentinel lymph node. The only prospective trial comparing patients with sentinel node macrometastases with or without completion ALND had to be terminated early due to failure in sufficient patient recruitment. As long as the frequently discussed issues have not been solved and in light of the lack of any clear level 1 evidence, the panel decided not to recommend omitting axillary dissection in patients with 1 or 2 macrometastases meeting the inclusion criteria of the ACOSOG Z0011 trial. The Austrian panel similarly decided not to recommend omitting axillary dissection in patients with macrometastases and low-risk breast cancer in general. These decisions reflect the increasing skepticism of the scientific community against rapidly shifting paradigms without sufficient and clear evidence.
Breast cancer: local therapy, surgery, radiotherapy; Expert panel
Bone metastases are usually associated with a variety of skeletal related events (SREs), a term covering both complications (pathological fractures, spinal cord compression) and the need for therapeutic intervention (radiotherapy, surgery to bone) for painful bone lesions and/or lesions carrying a high risk of fracture by which the patient's quality of life, functioning, and independence may be compromised. In view of the availability of improved therapeutic approaches for oncological diseases and the resulting improvements of median overall survival, the aim of preventing and delaying the occurrence of SREs becomes more important. To avoid, wherever possible, therapies requiring hospitalization, is another relevant goal. In recent years, bisphosphonates, along with available tumor-specific medication (chemotherapy, hormone therapy), constituted the standard of care for preventing skeletal complications in treating patients with bone metastases. Recently, a therapeutical alternative with potentially superior efficacy has been found in denosumab, a fully human monoclonal antibody that binds to the receptor activator of nuclear factor-κB ligand (RANKL), thus preventing osteoclast-mediated bone resorption and specifically interfering with bone metabolism.
Breast Cancer; Metastatic bone disease; Bisphosphonates; Denosumab; Osteonecrosis of the jaw
Adjuvant bisphosphonate therapy is increasingly used in postmenopausal breast cancer patients. This is based on level-one evidence that bisphosphonates, particularly zoledronic acid, can effectively prevent cancer treatment-induced bone loss in breast cancer patients receiving estradiol-lowering endocrine therapies such as aromatase inhibitors. Furthermore, emerging data from large clinical trials suggest that additional anticancer benefits can be derived due to a positive impact on the bone marrow microenvironment.
Breast cancer; Bone loss; Bisphosphonates, Adjuvant therapy
Breast cancer and bone health are closely linked. Early menopause induced by gonadotropin-releasing hormone analogues or chemotherapy as well as aromatase inhibitors reduce oestrogen levels, thereby causing cancer treatment-induced bone loss (CTIBL). Furthermore, bone metastases are commonly found in advanced disease. Current treatment options for bone lesions comprise systemic anti-tumour therapy, irradiation, surgery and bisphosphonates. The main mechanism of osteolysis, osteoclast activation, is induced by the RANK ligand and suppressed by osteoprotegerin (OPG). A human antibody targeting the RANK ligand, denosumab, had superior activity compared to OPG and was therefore further developed in the clinical setting. This article reviews clinical data on denosumab. Data were obtained by searching the Medline database and abstracts from the ASCO annual meeting, ASCO breast meeting, ECCO, ESMO, and the San Antonio Breast Cancer Symposium. Clinical trials have demonstrated that denosumab reduces markers of bone turnover, and suggest equal efficacy to bisphosphonates in reducing the rate of skeletal-related events. While overall fewer side effects were observed, a numerically increased rate of osteonecrosis of the jaw was reported. Denosumab was well tolerated, and clinical activity was similar to bisphosphonates in metastatic disease. Trials of denosumab in the prevention of CTIBL are ongoing.
Bisphosphonates; Bone metastases; Denosumab; Osteoporosis; Cancer treatment-induced bone loss
The 2011 St. Gallen Consensus Conference on early breast cancer provided mostly evidence-based treatment recommendations with a broad spectrum of acceptable clinical practice for global breast cancer care. This report summarizes the results of the 2011 international panel voting procedures with regard to locoregional and endocrine treatment, chemotherapy, targeted therapy as well as adjuvant bisphosphonate use.
Early breast cancer; Bisphosphonates; Endocrine therapy; Chemotherapy; Surgery; Targeted therapy; Neoadjuvant therapy
Endocrine therapy has become a key part in the adjuvant treatment of hormone responsive breast cancer. The positive effect on relapse risk reduction is well defined, but therapy is not free from bothersome side effects for which estrogen deprivation accounts to a great extent. Since endocrine therapy is usually prescribed for 5 years or longer to optimally display its protective effect, and because physical strain is missing, good tolerability and safety properties are important, particularly in low-risk patients. While tamoxifen has been the standard adjuvant endocrine treatment with well documented efficiency, it is increasingly replaced by third generation aromatase inhibitors due to their better effectiveness and tolerability. Because tamoxifen holds a risk for life-threatening adverse events such as endometrial cancer, pulmonary embolism, and stroke, its recommended duration of therapy is limited to 5 years, also because extension beyond that time did not produce a measurable advantage. While some side effects are present both with tamoxifen and aromatase inhibitors, differences in side effect profiles are well established. Although side effects of aromatase inhibitor-related therapy usually are mild and common to symptoms of menopause, misconception of the symptoms and their mechanism of action, as well as lack of knowledge about how to handle them, can easily lead to dangerous discontinuation of therapy.
Endocrine therapy; Breast cancer; Tamoxifen; Aromatase inhibitors; Anastrozole; Letrozole; Exemestane; Side effects; Tolerability; Safety
Endocrine adjuvant therapy is the best-described molecular targeted treatment and should therefore be used for all patients with endocrine-responsive breast cancer. Ta-moxifen for 5 years is standard of care and has proven efficacy in premenopausal patients. The combination of tamoxifen with ovarian function suppression and/or chemotherapy has been extensively tested, and some controversial approaches are used in clinical practice. Cessation or suppression of ovarian function appears to be beneficial for premenopausal patients. Particularly for premenopausal women with highly endocrine-responsive disease and/or low risk for relapse, the additional benefit of cytotoxic chemotherapy may be minor or nonexistent. While the use aromatase inhibitors is investigated in clinical trials, their application outside an academic trial setting cannot be recommended based on first available results. In contrast, the use of adjuvant bispho-sphonates may offer another strategy of further improving clinical outcomes in this important patient subgroup.
Breast cancer; Premenopausal patients; Endocrine treatment; Aromatase inhibitors; Bisphosphonates; Tamoxifen; LHRH agonists