Breast cancer is the most frequent type of cancer in women. Recent data suggest that lifestyle factors including dietary factors play a significant role in the development of and survival from breast cancer. In particular, there is convincing evidence that obesity is a potent risk factor for both cancer development and prognosis, increasing the risk for overall and breast cancer mortality by approximately 30%. In contrast, there is still only limited evidence that specific dietary patterns or dietary components affect breast cancer outcomes. However, current knowledge suggests that a healthy/Mediterranean-like diet characterized by high intake of fruit, vegetables, fiber, fish and unsaturated oils, particularly n-3 fatty acids, has a modest protective effect on breast cancer, whereas a typical Western diet characterized by high intake of total/saturated fat, refined carbohydrates, processed and red meat and low fiber intake is associated with modestly poorer outcome. Based on this evidence, weight control is a key recommendation for primary and secondary prevention of breast cancer. Adherence to a healthy/Mediterranean-like diet and avoidance of a Western diet may confer additional, although still unproven, benefit.
Breast cancer: development, survival/prognosis, mortality; Diet; Obesity
Considerable numbers of patients and physicians believe that micronutrients may be useful with respect to prevention and treatment of breast cancer. However, the analysis of the literature shows that basic information on nutritional demands in cancer patients is lacking. It is unknown whether there is an increased demand of micro-nutrients in cancer patients in general and if there is an even more increased demand during the various types of treatment. As a result, there are only limited positive findings. Higher calcium intake in premenopausal women and higher intake of vitamin D seem to be able to lower breast cancer incidence. Vitamin E (800 IU per day) was found to have a modest effect on hot flashes during tamoxifen treatment. However, there are potential side effects especially when micronutrients are administered in high or very high doses. There is increasing evidence that dose-effect relationships are not linear but U-shaped. It seems that two thresholds exist for adverse effect, one at low doses for undersupply, and another at high doses for toxicity. Thus, arbitrary high-dose administration of micronutrients should be avoided. Supplementation of normal doses seems to be safe and acceptable from the medical point of view.
Micronutrient; Multivitamin products; Supplement; Breast cancer; Prevention
Numerous epidemiological and case-control studies have proven the efficacy of physical activity in the prevention of breast cancer. In physically active subjects, the risk reduction averaged 25–30%. According to published data, 30–60 min of exercise per day at a moderate intensity is regarded as the optimal duration. Furthermore, physical activity plays an important role in the therapy of breast cancer, not only after finishing but already during treatment. Among experts, the evidence of a positive impact on the fatigue syndrome and on the quality of life is found sufficiently convincing. Now, the most recent investigations have shown that regular moderate exercise may bring about a prolongation of life. In the present publication, the most important background facts, potential mechanisms, and recommendations for the prevention and therapy of breast cancer are described.
Breast cancer; Prevention; Therapy; Physical activity; Mechanisms
Cohort trials have shown evidence that obesity and a low level of physical activity are not only associated with a higher risk of developing breast cancer, but also with an increased risk for recurrence and reduced survival in breast cancer patients. The SUCCESS C study is the first European trial to evaluate the effect of an intensive lifestyle intervention program on disease-free survival in women with early breast cancer and to examine the predictive value of selected biomarker candidates. A total of 3,547 women with early-stage, Her2/neu-negative breast cancer will be included. The first randomization will compare disease-free survival in patients treated with either 3 cycles of FEC (epirubicine, fluorouracil, cyclophosphamide), followed by 3 cycles of docetaxel or 6 cycles of docetaxel-cyclophosphamide, and thus assess the role of anthracycline-free chemotherapy. The second randomization compares disease-free survival in patients with a body mass index of 24–40 kg/m2 receiving either a telephone-based individualized lifestyle intervention program aiming at moderate weight loss or general recommendations for a healthy lifestyle alone. In addition, the study will evaluate the predictive role of cancer-associated and obesity-related biomarkers for the prediction of disease recurrence and survival. This SUCCESS C trial will provide valuable information on the effects of a lifestyle intervention program on the prognosis of early breast cancer patients.
Breast cancer; Obesity; Lifestyle intervention; Weight loss; Physical activity; Prognosis; Disease recurrence; Overall survival
To provide guidance for clinical practice on preferred standard palliative radiotherapy (RT) of different sites of metastasis for breast cancer patients based on current published evidence complemented by expert opinion.
The breast cancer expert panel of the German Society for Radiation Oncology (DEGRO) and members of the Working Party of Gynecologic Oncology (AGO) Breast Committee formulated recommendations based on the panel's interpretation of the level of evidence referring to the criteria of evidence-based medicine added to the AGO grades of recommendation.
For different types and sites of metastasis, distinct therapeutic goals (alleviation of symptoms, pain relief, local tumor control, prevention or improvement of neurological deficits, stabilization of the spine or other bones) require complex approaches considering individual factors (i.e. life expectancy, tumor progression at other sites). With regard to different therapeutic goals, different dose concepts and fractionation schedules, and single-versus multi-fraction palliative RT should be adapted individually.
RT is an effective tool in palliation treatment of bone metastasis (BM), cerebral metastasis (CM) and metastatic spinal cord compression (MSCC), or leptomeningeal carcinomatosis (LC) and plays a central role in an interdisciplinary approach. Preferred technique, targeting, and different dose schedules are described in detail in the DEGRO guidelines, which are also integrated in the updated 2010 AGO recommendations.
Metastatic breast cancer; Palliative radiation therapy; Bone metastasis; Cerebral metastasis; Metastatic spinal cord compression; Leptomeningeal carcinomatosis
Patients presenting with symptoms from unknown metastatic breast carcinoma are becoming increasingly uncommon. Perforated appendicitis from metastatic breast carcinoma is a rare entity with only a few published reports in the literature.
The case of a 76-year-old female patient who developed perforated appendicitis from previously unknown metastatic breast cancer is presented. During physical examination in the emergency department, a large left breast mass was palpated. The patient underwent an appendectomy and had no gross evidence of disease elsewhere in the intra-peritoneal cavity. Subsequent pathologic examination of the appendix revealed a lobular carcinoma.
The factors that influence the site of metastasis from breast cancer include estrogen receptor status and the subtype of carcinoma – ductal versus lobular.
Breast cancer; metastasized; Appendicitis
Sentinel lymph node biopsy (SLNB) is a widely accepted method to determine lymph node status in for instance breast cancer, cervical cancer, or cutaneous melanomas. Although injection of blue dyes facilitates successful detection of sentinel nodes, they have also been shown to cause adverse reactions.
A 62-year-old female patient was referred to the surgical department of the Atrium Medical Centre with a suspicious lesion located in the right breast, detected during population-based screening. Immediately after injection of patent blue V, the patient developed tachycardia on top of preexisting supraventricular tachycardia and showed an instant drop in blood pressure, after which cardiac arrest occurred. These clear symptoms of anaphylactic shock required prompt treatment, and the patient was treated accordingly.
Anaphylactic shock after injection of patent blue V remains a serious adverse event and warrants awareness. Immediate action with ephedrine, antihistamines, and subsequently corticosteroids can stabilize the patient. Tc-99m, isosulphan blue, and methylene blue can alternatively be used for SLNB, although also not without side effects.
Sentinel node; Patent blue; Anaphylactic shock; Breast cancer
Postmenopausal women are at an increased risk of osteopenia and osteoporosis due to the physiologic loss of the bone protective effects of estrogen. Additionally, disease-related risk factors also contribute to the increased fracture risk. To further complicate matters, one of the most common and severe safety issues associated with cancer therapies for breast cancer patients is bone loss and the associated increased risk of fractures. These facts underscore the need to carefully monitor bone mineral density in patients with endocrine-responsive breast cancer, and to consider adjuvant therapy that may help manage and/or prevent bone loss and fracture. Aromatase inhibitors (AIs) are now in widespread clinical use for women with hormone receptor-positive breast cancer and have replaced tamoxifen as the gold standard of care. AIs target the estrogen biosynthetic pathway and deprive tumor cells of the growth-promoting effects of estrogen. These treatments provide significant benefit to patients in terms of improved disease-free and overall survival. Adversely, there is a concern of an increased risk of bone loss with prolonged therapy consequently leading to an increased fracture risk. This manuscript will review the recent literature pertaining to AI-associated bone loss and discuss suggested management and preventative approaches that may help patients remain on therapy to derive the most clinical benefits.
Breast cancer; Fracture; Aromatase inhibitors; Bone loss; Bone mineral density
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
Morbidity and mortality in breast cancer patients are mainly caused by organ failure as a result of distant metastasis. The main target of metastatic disease is the skeleton (next to lungs and liver). Osseous metastases are diagnosed in 75-80% of all women who die due to breast cancer; and the skeleton is the primary metastatic target organ in more than half of these cases. In Germany, the incidence of breast cancer patients with newly diagnosed bone metastases is approximately 11–12,000 cases. Prevalence might amount to 40,000 cases of women with breast cancer and osseous metastases at a median survival time of 3–4 years. The treatment goal at this stage of the disease comprises improvement of quality of life, and reduction of bone pain and typical complications like fractures and hypercalcemia. By consistent use of bisphosphonates these goals can be accomplished. Bisphosphonates improve bone pain significantly and reduce the number of skeletal-related events in women with bone metastases. Bisphosphonates can be administered intravenously or orally, and are well tolerated. Nevertheless, there are side effects and complications including acute phase reaction, nephrotoxicity, osteonecrosis of the jaw, and gastrointestinal disturbances.
Bisphosphonates; Clodronate; Pamidronate; Ibandronate; Zoledronic acid; Breast cancer, Metastatic bone disease; Osteonecrosis of the jaw
A new understanding in the pathophysiology of bone led to the development of a fully human monoclonal antibody directed against RANK ligand (RANKL). Denosumab inhibits the interaction of RANKL with its receptor RANK, thereby suppressing osteoclast differentiation, function and survival. In this respect, denosumab mimics osteoprotegerin, the endogenous antagonist of RANKL. Recently, denosumab has been approved by the European Medicines Agency (EMEA) for the treatment of postmenopausal osteoporosis (PMO) and treatment-induced bone loss in breast and prostate cancer patients undergoing hormone ablation. Oncologic indications affecting bone are promising, but still under clinical evaluation. In clinical trials for PMO, denosumab has shown significant increases in bone mineral density (BMD) at various skeletal sites, decreases in bone turnover markers, and reductions in fracture risk. In head-tohead studies, denosumab proved to be superior to alendronate with regard to the increase in BMD. Considering clinical trial data, the risk-benefit profile of denosumab seems to be favorable since the rates of adverse events, serious adverse events, infections, malignancies and deaths were not higher compared to the control arms. In PMO, denosumab is applied subcutaneously as a 60-mg dose twice yearly. This administration scheme and route might have a high acceptance by patients and physicians.
Osteoporosis; Postmenopausal osteoporosis; Denosumab; Monoclonal antibody
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 stromal reaction may be one of the key factors in the development of breast carcinomas.
We report the case of an 80-year-old female patient who ignored a very slow growing, extensive scirrhous breast carcinoma for almost 20 years duration.
Histopathology analysis revealed a Scarff Bloom Richardson (SBR)3-grade, estrogen receptor (ER)-positive (80%), progesterone receptor (PR)-positive (10%), HER2/neu-negative, lobular-invasive, scirrhous breast carcinoma with large cells.
A strong peritumoral fibrous stromal reaction may explain the longstanding evolution of the tumor without any distant metastases.
Breast Cancer: scirrhous, Lobular
Myoid (muscular) hamartoma (MH) of the breast is a rare benign tumour-forming lesion composed of differentiated mammary glandular and stromal structures, fatty tissue, and areas of smooth muscle. It is considered to be a variant of mammary hamartoma.
We report the case of a 46-year-old woman with MH, and provide a literature review explaining the origin of smooth muscle cells. Histologically, the tumour consisted of fibrolipomatous stroma containing ductal and lobular structures of the mammary gland located mainly at the tumour borders. The glandular structures showed signs of micro- and macrocystic changes, apocrine metaplasia, and adenosis. The dominant feature was the presence of a fascicular formation of spindle cells, predominantly in central parts, with incursion between glandular structures. Immunohistochemically, foci of smooth muscle tissue were positive for desmin, smooth muscle actin, and h-caldesmon. Oestrogen and progesterone receptors (PR) showed positive expression which was markedly higher for PR. There was negative expression of CD34, S-100 protein, and CD10.
The origin of smooth muscle cells in MH is unknown. However, it is presumed to be derived from hormonally responsive breast stromal cells by smooth muscle metaplasia, based on evidence of hormone receptor expression in the lesion.
Breast; Hamartoma; Myoid; Muscular
The optimal sequence of systemic palliative chemotherapy in metastatic breast cancer is unknown.
We report the course of disease in a patient aged 24 years at the onset of disease, who was treated over 17 years for her metastatic ErbB2-positive breast cancer. Seventeen years ago, the patient was diagnosed to have invasive ductal breast cancer and underwent surgical treatment. She received 6 cycles of adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate, 5-fluorouracil). Twenty-eight months after the primary surgery, the patient developed a histologically verified lung metastasis, and subsequently received 8 different lines of chemotherapy, including high-dose cytotoxic therapy and stem cell support as well as trastu-zumab. In addition, she received 5 different types of antihormonal treatment. Due to the recent progression of her lung metastasis, 27 cycles of lapatinib and capecitabine were administered. A long-term partial response in the lung was observed.
Individualized systemic treatment with the tyrosine kinase inhibitor lapatinib and capecitabine in heavily pretreated patients with Her2-positive metastatic breast cancer may lead to effective palliation for almost 2 years despite extensive pretreatment.
Breast cancer; Palliative chemotherapy; Lapatinib Capecitabine; ErbB2-positivity; Her2-positivity
Bone metastases are common in breast cancer patients. Radiotherapy is safe and effective. This review aimes to contribute to the definition of the appropriate radiation regimens for different endpoints.
Material and Methods
Information was compiled by searching PubMed and MEDLINE databases including early-release publications. When possible, primary sources were quoted. Full articles were obtained. References were checked for additional material when appropriate.
Randomized trials and meta-analyses demonstrated that single-fraction radiotherapy with 1 × 8 Gy is as effective for pain relief as multi-fraction regimens such as 5 × 4 Gy or 10 × 3 Gy. Re-irradiation for recurrent pain is required more often after single-fraction radiotherapy. Re-irradiation with another single fraction is safe and effective. Multi-fraction long-course radiotherapy such as 10 × 3 Gy leads to better re-calcification and better local control of metastatic spinal cord compression (MSCC). Because both re-calcification and MSCC recurrences occur only several months after radiotherapy, long-course radiotherapy is particularly appropriate for patients with a favorable survival prognosis.
For uncomplicated painful bone metastases, single-fraction radiotherapy with 1 × 8 Gy may be considered the standard regimen. If re-calcification is a major goal, longer-course radiotherapy (i.e. 10 × 3 Gy) should be used. For MSCC, 10 × 3 Gy is preferable for patients with a favorable survival prognosis.
Bone metastases; Radiotherapy; Bone pain; Pathological fractures; Metastatic spinal cord compression
The population-based breast cancer screening program in Stockholm County was initiated in 1989. The program follows the recommendations issued by the Swedish Board of Health and Welfare, and is in agreement with guidelines from the European Commission. Individual data is available for all women in Stockholm County aged 40–69 years since initiation of the program in 1989. The participation rate exceeds 70%, the recall rate averages 3%, and the detection rate is 0.5%. The introduction of the breast cancer screening program in Stockholm County has reduced breast cancer mortality by 29% and among participants by 52%. The breast screening program is well organized and functioning, and well adapted to its purpose. Follow-up ensures a good quality process with the aim of reducing breast cancer mortality.
Breast cancer screening program; Organization; Quality assurance
B3 lesions comprise different histopathological entities that are considered benign but ‘of unknown biological potential’. These entities may act as risk indicators (for both breasts) or as non-obligatory precursors of malignancy. Being diagnosed at percutaneous breast biopsy, an additional risk of underestimate exists. Imaging appearances, histopathological appearance and risk of associated malignancy are presented. B3 lesions of high risk, which thus should usually be excised, include atypical ductal hyperplasia (ADH), pleomorphic or necrotic type of lobular neoplasia (LIN 3), and papillary lesions with atypias. Intermediate risk may be associated with classic lobular carcinoma in situ (LIN 2) or flat epithelial atypia (FEA), and low risk with radial sclerosing lesions (RSLs) and papillary lesions without atypias. LIN 1 is mostly an incidental finding acting as risk indicator. Follow-up is adequate if the initial diagnostic problem is solved. According to international guidelines, risk and subsequent recommendations should be discussed for each individual patient, taking into account biological risk, representative sampling, lesion size, lesion extent, percentage of lesion removal, other individual risks, and the possibility of surveillance. With vacuum-assisted breast biopsy (VABB), surgery may be avoided for more of the small lesions at low risk. Further data collection and diligent evaluation may help to better assess the individual risk, to better adapt treatment recommendations and avoid overtreatment.
B3 lesion; Biopsy; Underestimate; Atypical hyperplasia
Atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), and lobular neoplasia (LN) form a group of early precursor lesions that are part of the low-grade pathway in breast cancer development. This concept implies that the neoplastic disease process begins at a stage much earlier than in situ carcinoma. We have performed a review of the published literature for the upgrade risk to ductal carcinoma in situ or invasive carcinoma in open biopsy after a diagnosis of ADH, FEA, or LN in core needle biopsy. This has revealed the highest upgrade risk for ADH (28.2% after open biopsy), followed by LN (14.9%), and FEA (10.2%). With LN, the pleomorphic subtype is believed to confer a higher risk than classical LN. With all types of precursor lesions, careful attention must be paid to the clinicopathological correlation for the guidance of the clinical management. Follow-up biopsies are generally indicated in ADH, and if there is any radiological-pathological discrepancy, also in LN or FEA.
Breast cancer, precursor; Atypical ductal hyperplasia (ADH); Flat epithelial atypia (FEA); Lobular neoplasia (LN)
Ductal carcinoma is situ (DCIS) is the fastest growing subtype of breast cancer, mainly because of improved screening activities. In contrast to invasive disease, DCIS is a local process with excellent survival rates. Current treatment strategies include surgery, radiotherapy (RT) and anti-hormonal treatment. The selection of an individual risk-adapted therapeutic approach remains controversial. This relates especially to the extent of surgery and the therapeutic index of adjuvant RT and tamoxifen. Several new trials have been published or updated recently that address important clinical issues. There is an urgent need to get more insight into the biological behaviour of different subtypes of DCIS, and develop more targeted and individualized treatment strategies. So far, surgery appears to be the most effective treatment modality. A morphology-based treatment model that allows complete resection of certain DCIS lesions without further adjuvant measures has not been evaluated prospectively and deserves further evaluation.
Breast cancer; Ductal carcinoma in situ; Surgery; Radiotherapy; Tamoxifen
Ductal carcinoma in situ (DCIS) now represents up to 20% of breast cancer cases, yet its behaviour is still poorly understood. Morphological classifications go some way to predicting prognosis, but more sophisticated approaches are required to better tailor therapy to the individual. A number of biological molecules have been identified that appear to relate to prognosis and, in model systems, promote progression to invasive disease. Some of these, such as COX-2, provide real therapeutic opportunities, whilst other marker combinations are showing promise in categorising women according to risk. Gene expression studies have led to an emerging molecular classification of invasive breast cancer, and it is now evident that at least some of these molecular subtypes can be identified at the pre-invasive stage. The difference in frequency of these subtypes between DCIS and invasive cancer may hold clues as to the biological mechanisms underpinning disease transition. It is increasingly clear that the host microenvironment can have a major impact on disease behaviour, and as well as acting as potential predictive factors, the altered microenvironment phenotype also offers novel therapeutic opportunities.
DCIS; Linear progression; Parallel progression; Molecular classification; Microenvironment; Myoepithelial cells