The developments in gene expression analysis have made it possible to sub-classify hormone receptor-positive (luminal) breast cancer in different prognostic subgroups. This sub-classification is currently used in clinical routine as prognostic signature (e.g. 21-gene Onoctype DX®, 70-gene Mammaprint®). As yet, the optimal method for sub-classification has not been defined. Moreover, there is no evidence from prospective trials. This review explores widely used genomic signatures in luminal breast cancer, making a critical appraisal of evidence from retrospective/prospective trials. It is based on systematic literature search performed using Medline (accessed September 2013) and abstracts presented at the Annual Meeting of American Society of Clinical Oncology and San Antonio Breast Cancer Symposium.
Biomarker; Breast cancer; Gene expression; Prognostic markers; Luminal breast cancer
Triple-negative breast cancer (TNBC) is defined by a lack of hormone receptor expression as well as lack of overexpression/amplification of HER2/neu. Patients with TNBC show a significantly worse prognosis compared to patients with other breast cancer subtypes. TNBC, however, is a heterogeneous entity both with regard to clinical/pathological characteristics and molecular biology. This review summarizes the current data on TNBC with a particular focus on mutational and gene expression profiling and the association between TNBC and breast cancer stem cells.
Triple negative breast cancer, subtypes; Whole genome sequencing; RNA profiling; Heterogeneity
Following the completion of the human genome sequence at the beginning of the new millennium, a series of high-throughput methods have changed cancer research. Using these techniques, global analysis such as expression profiling could be carried out on a genomic scale. In breast cancer they led to the classification of the intrinsic subtypes, and the development of several prognostic and predictive ‘genomic tests’ for patient stratification. During the last 2 years we have faced a similar dramatic revolution with the introduction of next generation sequencing (NGS). These techniques allow sequencing of the complete human exome or whole genome with a cost reduction in the order of 10,000–100,000 fold. Consequently, the number of known cancer genome sequences exploded with more than 6,000 samples, published between 2011 and 2013. These studies have led to important and surprising discoveries both for basic cancer research and clinical applications. They relate to understanding the development of cancer as well as the heterogeneity of the disease, and how to use this information to guide the development and application of therapies. Although it is foreseeable that the sequencing surveys of neoplasms will soon conclude, their introduction into clinical practice is just beginning.
Gene expression profiling; Next-generation sequencing; Breast cancer, molecular subtypes; Cancer genome; Tumor heterogeneity
The main objective of following patients after the primary treatment of breast cancer is the detection of potentially curable events, particularly the detection of local recurrences and contralateral breast cancer. Additionally, medical counseling on therapies, psychosocial aspects, side effects of therapies, and lifestyle interventions is important to improve the quality of life. There is an ongoing discussion about whether early detection of asymptomatic metastasis could improve the course of disease. Today, the follow-up is still symptom-orientated. Intensified imaging and laboratory check-ups have not been beneficial for the patients’ survival. A follow-up in the first 2–3 years is recommended every 3 months. Because of the decreasing incidence of recurrence from year 4, 6-monthly screening intervals are recommended. The screening should include a history, physical examination, and a consultation. Routine diagnostic imaging – except for mammography/ultrasound – is not indicated in asymptomatic patients. Innovative therapies for patients with metastatic breast cancer have been introduced. Therefore, measures of an intensified follow-up could change in the future as novel endocrine combination or targeted therapies in molecular subtypes could significantly improve the survival in early detected metastasis. In the future, more individualized follow-up programs are conceivable. However, this idea is so far not supported by the available data.
Breast cancer follow-up; Imaging; Laboratory check-up; Lead time; Breast cancer subtypes
Many patients with cancer look for information on complementary or alternative medicine (CAM) and use various CAM methods. Women with breast cancer are amongst the most avid users. Patients in Europe prefer drug-bound CAM methods, which are prone to side effects and drug interactions. In order to reduce these risks, communication between the patient and the physician on CAM is indispensible. Yet, most patients do not discuss CAM in general and complementary drug therapy in particular with their oncologists and most oncologists themselves are not overly familiar with the topic. This article gives an overview on the most often used CAM methods with regard to breast cancer. The current state of the scientific evidence, the benefits and risks are summarized.
Complementary medicine; Alternative medicine; Supplements; Supportive therapy; Breast cancer; Evidence based medicine
Most scientific studies regarding physical activity in cancer patients involve breast cancer patients. It is apparent that physical activity during medical treatment and aftercare is not only feasible and safe but also effective. Current studies clearly show that regular and specific endurance and/or resistance training can reduce a number of side effects caused by medical treatment. Among others, improvements in physical performance, body composition, and quality of life as well as a reduction in fatigue, have been observed. Since inactivity appears to exacerbate lymphedema, patients with lymphedema are also encouraged to exercise. Few studies have been carried out regarding physical exercise in metastatic patients. However, experts in the field also recommend regular physical activity for patients with advanced-stage breast cancer.
Physical activity; Exercise; Breast cancer
Today, in cases of nipple discharge of unclear origin, the abundance of diagnostic procedures – a, diagnostic dilemma’ – becomes apparent, because unequivocal indications and a current, standardized examination sequence are presently not available. The diagnostic workup of patients with nipple discharge usually includes the clinical history, physical examination, mammography, ultrasonography, galactography, and nipple discharge cytology, but not ductoscopy.
In this review we analyze and discuss the possible role of ductoscopy in evaluating intraductal pathologies and its combined use with diagnostic imaging modalities. For this purpose, we reviewed and compared the results of the radiological, pathological, and surgical studies independently.
Currently, there is no solitary accurate modality to reach our definitive purpose. Being aware of the capability of each diagnostic modality may take us closer to our target. Therefore, adjunct and appropriate use of multiple imaging modalities and ductoscopy is necessary to evaluate patients with nipple discharge.
Ductoscopy; Imaging methods; Biopsy; Papilloma; Ductal carcinoma
The estrogen receptor (ER) and/or the human epidermal growth factor receptor 2 (HER2) signaling pathways are the dominant drivers of cell proliferation and survival in the majority of human breast cancers. As a result, targeting these pathways provides the most effective therapies in appropriately selected patients. Nevertheless, resistance to both endocrine and anti-HER2 therapies occurs frequently and represents a major clinical challenge. Compelling preclinical and clinical evidence relates this treatment resistance to the presence of a complex bidirectional molecular crosstalk between the ER and HER2 pathways. As a consequence, treatment strategies targeting either pathway are associated with up-regulation of the other one, ultimately resulting in resistance to therapy. Therefore, a more promising strategy to prevent or overcome either endocrine or anti-HER2 resistance at least in some tumors is to combine targeted treatments that simultaneously block both signaling pathways. Many clinical trials exploring this strategy have shown positive results, and many more are currently ongoing. Future clinical trials with appropriate patient selection, based on biomarker evaluation of primary tumors and possibly of recurrent lesions, are warranted for the optimization of individualized therapeutic strategies.
Estrogen Receptor; HER2; Crosstalk; Resistance
Breast cancer is the most common cancer among women. Up to 75% of breast cancers express the estrogen receptor (ER)α and/or the progesterone receptor (PR). Patients with hormone receptor-positive metastatic breast cancer are typically treated with endocrine therapy. Yet, not all patients with metastatic breast cancer respond to endocrine treatments and are considered to have primary (de novo) resistance. Furthermore, all patients who initially respond to endocrine treatment will eventually develop acquired resistance. Several mechanisms have been linked to the development of endocrine resistance, including reduced expression of ERα, altered regulation of the ER pathway, and activation of various growth factor signaling pathways, among them the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. This pathway is involved in critical processes including cell survival, proliferation, and angiogenesis, and plays a central role in breast cancer development. Recent laboratory and clinical data implicate this pathway as mediating endocrine resistance, and agents directed against critical components of this pathway are either already approved for clinical use in breast cancer patients or are currently being tested in clinical trials. In this review, we describe the interaction between the PI3K/Akt/mTOR pathway and the ER cascade, its role in mediating endocrine resistance, and the clinical implications of this interaction.
Hormone receptor-positive breast cancer; Estrogen receptor; Endocrine resistance; PI3K/mTOR pathway
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
Trastuzumab administered in combination with various chemotherapy regimens has led to outstanding improvements in both disease-free survival and overall survival. So far, thousands of patients have been treated in this way which has proven to be reasonably safe, with cardiac events being the predominant recognisable toxicity requiring surveillance. Notwithstanding the large cumulative experience of the oncology community in treating early HER2/neu-positive breast cancer with trastuzumab, some uncertainties remain, with key issues being the ideal time of chemotherapy administration and the optimal duration of trastuzumab therapy. This paper discusses these issues in the light of the recent updates of some of the pivotal clinical trials in the adjuvant context.
Early breast cancer; Adjuvant; HER2/neu-positive; Trastuzumab
The WHO Classification of Tumors of the Breast, 4th edition, is an update to the 3rd edition that was published in 2003, and covers all neoplastic and preneoplastic lesions of the breast. Changes to the 4th edition include new aspects and changes to the terminology that reflect our present-day knowledge of these lesions. Definitions for histopathological diagnosis are complemented by a description of clinical features, epidemiology, macroscopy, genetics, and prognostic and predictive features. In this review of the WHO classification, we have focused on invasive carcinomas, precursor lesions, and some benign epithelial proliferations.
Diagnostic criteria; Pathology; WHO classification; Breast Cancer
The humanized monoclonal antibody pertuzumab prevents the dimerization of HER2 with other HER receptors, in particular the pairing of the most potent signaling heterodimer HER2/HER3, thus providing a potent strategy for dual HER2 inhibition. It binds to the extracellular domain of HER2 at a different epitope than trastuzumab. Pertuzumab and trastuzumab act in a complementary fashion and provide a more complete blockade of HER2-mediated signal transduction than either agent alone. Phase II studies demonstrated that pertuzumab was generally well tolerated as a single agent or in combination with trastuzumab and/or cytotoxic agents, and implied an improved clinical efficacy of the combination of pertuzumab and trastuzumab in early and advanced HER2-positive breast cancer. Results of the pivotal phase III study CLEOPATRA in patients with HER2-positive metastatic breast cancer demonstrated that the addition of pertuzumab to first-line combination therapy with docetaxel and trastuzumab significantly prolonged progression-free and overall survival without increasing cardiac toxicity. Currently, the combination of both antibodies is being explored in the palliative setting as well as in the treatment of early HER2-positive breast cancer. Dual HER2 inhibition with the HER2 dimerization inhibitor pertuzumab and trastuzumab may change clinical practice in HER2-positive first-line metastatic breast cancer treatment.
HER2-positive; Dual inhibition; Breast cancer, metastatic; Pertuzumab; Trastuzumab
Since the introduction of the diagnosis-related groups (DRG) system with cost-related and entity-specific flat-rate reimbursements for all in-patients in 2004 in Germany, economics have become an important focus in medical care, including breast centers. Since then, physicians and hospitals have had to gradually take on more and more financial responsibilities for their medical care to avoid losses for their institutions. Due to financial limitations of resources, most medical services have to be adjusted to correlating revenues, which results in the development of a variety of active measures to understand, steer, and optimize costs, resources and related processes for breast cancer treatment. In this review, the challenging task to implement microeconomic management at the clinic level for breast cancer treatment is analyzed from breast cancer-specific publications. The newly developed economic management perspective is identified for different stakeholders in the healthcare system, and successful microeconomic projects and future aspects are described.
Breast cancer; Costs of treatment; Limited resources; Microeconomic solutions; Health economics
In this article, the position of the Professional Association of Practicing Gynecologic Oncologists e.V. (BNGO) on the health economics of medical breast cancer therapy is presented. The BNGO unites professionals and employees whose principal activity lies in highly specialized gynecologic oncology. In Germany, 139 specialists are united in 128 professional practices. According to § 12 of the Social Code, the oncological services provided by members must be ‘sufficient, effective and economical; they must not exceed what is necessary’. People who are covered by statutory health insurance in Germany are entitled to sufficient benefits. Sufficient measures are measures that benefit the patient with breast cancer and have a positive effect on the course of the disease. In § 35b of the Social Code, the benefit of the patient is defined as ‘improvement in health, shortening of the duration of illness, lengthening of lifespan, reduction of side effects and an improvement in the quality of life’. In the adjuvant situation, the ideal goal is healing; in the palliative situation, the most basic marker is overall survival, while surrogate markers are the progression-free interval, improved quality of life, or diminished symptoms. At the same time, the law on economic assessment stipulates ‘appropriateness and reasonableness of reimbursement by the insured community’.
Adjuvant therapy; Aromatase inhibitors; Chemotherapy; Systemic therapy; Therapy Costs
Breast cancer care in Western countries has reached a considerable level of quality and standardization, which has contributed to the decline in breast cancer mortality. Certified Breast Cancer Centers (BCC) represent an important element of this development. Related to changes in reimbursement and growing costs, BCC face economic constraints which ultimately could endanger the achievements of the past. Thus, BCC have to optimize their care strategies from an economic perspective, particularly by increasing efficiency but also by adapting their service portfolio. This could result in competitive advantages and additional revenue by increasing case numbers and extra charges to patients. Furthermore, an intensification of collaboration with the outpatient sector resulting in an integrated and managed ‘trans-sectoral’ care approach which could allow to shift unprofitable procedures to the outpatient sector – in the sense of a win-win situation for both sectors and without loss of care quality – seems reasonable. Structured and specialized consulting approaches can further be a lever to fulfill economic requirements in order to avoid cuts in medical care quality for the sake of a balanced budget. In this review, economic constraints of BCC with a focus on the German healthcare system and potential approaches to ameliorate these financial burdens are being discussed.
Breast Cancer Center; Expenditures and costs; Process management; Process quality; Process efficiency; Health economics; Patient satisfaction; Clinical workflow; Breast cancer
Breast cancer centres – certified in accordance with the criteria of the German Cancer Association and the German Mastology Association – are established throughout Germany. Although the setting up of centres and the subsequent need for certification are associated with a marked increase in costs, initial data show positive effects on quality. Certified centres are cost-effective from the point of view of health economics – they lead to improved quality in processes and results without creating any increase in costs for the funding bodies. However, the organization of the necessary structures, with interdisciplinary treatment, documentation and quality-assurance measures, requires considerable resources. Increasing consolidation of inpatient services is also involved, while shortening of the patients’ hospitalization periods is leading to reduced remuneration from the funding bodies. The current cost deficits, which have resulted from the increased resources required, need to be recouped through additional charges. It will only be possible to maintain the high quality achieved if additional charges become available to cover the centres’ added costs. Good data are increasingly becoming available as a basis for negotiations on charges – e.g., with regard to the quality of results and the National Cancer Plan – as well as clear support from patients.
Breast cancer; Certified centres; Economics; Health economics; Cost-effectiveness
Due to the impact of rising expenditures for the delivery of high-standard health care, further efforts supporting evidence-based, cost-efficient and patient-centered management in oncology are advised. This also concerns the treatment of patients with breast cancer. Reimbursement of diagnostic and/or therapeutic innovations in oncologic health care within the compulsory health insurances (CHIs) in Germany requests their evidence-based proof of benefit and medical need. Using selected examples in pharmacotherapy, recommendations to improve outpatient breast cancer care are discussed.
Compulsory health care insurance; Evidence-based pharmacotherapy; Breast cancer; Cost efficiency
The introduction of the Mammography Screening Program (MSP) in 2005 has changed the early detection of breast cancer in Germany significantly. We analyzed the frequency and ensuing health care costs of mammograms performed for the early detection of breast cancer before and after the introduction of the MSP. Furthermore, we analyzed the influence of the MSP on the demographics of physicians (gynecologists versus radiologists) performing mammograms in Germany. Whereas the number of ‘curative’ mammograms has decreased since the introduction of the MSP, 2 million ‘curative’ mammograms per year are still being performed in addition to the 4.6 million mammograms performed annually in the MSP at an additional health care cost of approximately €100 million per year. Only 12% of screening and ‘curative’ mammograms are being performed and evaluated by gynecologists.
Breast cancer; Mammography; Mammography screening; Health economics; Outpatient setting
Lymphedema is the major complication following breast cancer treatment and can persist long periods of time and affect breast cancer survivors’ quality of life. Accurate estimation of the risk factors for lymphedema is of significant importance. In this article we report the factors for secondary lymphedema among postmenopausal breast cancer patients after radical mastectomy in China.
Patients and Methods
A total of 126 consecutive postmenopausal breast cancer patients who received radical mastectomy were admitted to the Chongqing Breast Cancer Center between July 2009 and June 2010. Circumferential measurement was used to diagnose lymphedema.
Among the 126 postmenopausal women with breast cancer, 54 (42.9%) had lymphedema. Body mass index (BMI), lymph nodes status, and radiotherapy were associated with lymphedema. BMI ≥ 25 kg/m2 (adjusted odds ratio (OR) = 7.5; 95% confidence interval (CI) 2.8–20.1) and radiotherapy (adjusted OR = 3.0; 95% CI 2.0–9.2) were independent predictors of lymphedema.
BMI, lymph nodes status, and radiotherapy were the risk factors for lymphedema among Chinese postmenopausal breast cancer patients who underwent radical mastectomy. Clinicians should provide sufficient information for patients and their caregivers to prevent this complication, especially for those who are at high risk of developing lymphedema.
Breast cancer; Lymphedema; Nursing; Chinese women
Elderly breast cancer patients are underrepresented in clinical trials, leading to a lack of knowledge regarding their tolerance of modern chemotherapy regimens. In addition, physicians are often reluctant to treat older patients with chemotherapy due to potential side effects. This article summarizes the up-to-date literature on chemotherapy in elderly patients with breast cancer, evaluates the impact of the patients’ comorbidities and treatment alterations and aims to encourage treating patients adequately according to their disease in combination with the biological age rather than the chronological age alone. Finally, a short overview is given of the recruiting studies in Europe evaluating chemotherapy in elderly patients.
Adjuvant chemotherapy; Elderly patients; Breast cancer
Breast cancer in the elderly is a rising health care challenge. Under-treatment is common. While the proportion of older patients receiving adjuvant radiotherapy (RT) is rising, the proportion undergoing breast-conserving surgery without irradiation has also risen. The evidence base for loco-regional treatment is limited, reflecting the historical exclusion of older patients from randomised trials. The 2011 Oxford overview shows that the risk of first recurrence is halved in all age groups by adjuvant RT after breast-conserving surgery, although the absolute benefit in older ‘low-risk’ patients is small. There is level 1 evidence that a breast boost after breast-conserving surgery and whole-breast irradiation reduces local recurrence in older as in younger women, although in the former the absolute reduction is modest. Partial breast irradiation (external beam or intraoperative or postoperative brachytherapy) is potentially an attractive option for older patients, but the evidence base is insufficient to recommend it routinely. Similarly, shortened (hypofractionated) dose fraction schedules may be more convenient for older patients and are supported by level 1 evidence. There remains uncertainty about whether there is a subgroup of older low-risk patients in whom postoperative RT can be omitted after breast-conserving surgery. Biomarkers of ‘low risk’ are needed to refine the selection of patients for the omission of adjuvant RT. The role of postmastectomy irradiation is well established for ‘high-risk’ patients but uncertain in the intermediate-risk category of patients with 1–3 involved axillary nodes or node-negative patients with other risk factors where its role is investigational.
Breast cancer; Radiotherapy; Elderly
The aim of this study was to investigate the expression of caveolin-1 (Cav-1) in cancer-associated fibroblasts (CAFs) and to explore its correlation with clinicopathologic parameters and prognosis.
Materials and Methods
Cav-1 expression was detected in the stroma of 143 patients with breast cancer, 10 patients with ductal carcinoma in situ (DCIS), and 10 normal breast tissue samples.
Overexpression of stromal Cav-1 in breast cancer was associated with histological type, low histological grade, estrogen receptor (ER) negativity, and molecular subtypes. The expression rate of stromal Cav-1 in breast cancer (65.7%, 94/143) was significantly higher than that of DCIS (0%, 0/10) and normal breast tissue (0%, 0/10) (p = 0.000). A positive correlation was found between stromal Cav-1 and ER (p = 0.046, rs = 0.218). Stromal Cav-1 expression in luminal B was significantly higher than in basal-like type (p = 0.048). Furthermore, stromal expression of Cav-1 was significantly correlated with the 5-year survival rate (p = 0.029), and it was an independent prognostic factor (p = 0.009).
Cav-1 expression in CAFs was correlated with histological type, histological grade, ER status, and molecular subtypes in breast cancer. Stromal Cav-1 expression was an independent prognostic factor, and the absence or reduction of Cav-1 expression in stromal CAFs of invasive breast cancer predicts poor prognostic outcome.
Breast cancer; Cancer-associated fibroblasts; Biomarker; Gene; Prognosis
Breast cancer is a major cause of mortality worldwide. As the population ages and life expectancy increases, the burden of cancer on health services will increase. Older patients with breast cancer are becoming more suitable for surgery; tailored surgical techniques and increasing healthy life expectancy alongside improved assessment of patients are aiding this trend. Surgery is also becoming a favoured treatment of personal choice for older patient with breast cancer. Evidence shows that surgery is almost always feasible for the older patient with outcomes (survival, progression, and recurrence rates) comparable to younger groups and superior to non-surgical treatments. We aim to describe the current status of surgery for the older patient with breast cancer, showing it is an option that should not be denied. Surgery should always be considered regardless of age, after evaluation of co-morbidities.
Breast cancer; Surgery; Oncology; Geriatric; Elderly
Molecular classification of breast cancer (BC) and the evaluation of new biological markers such as estrogen receptor (ER), progesterone receptor (PR), ErbB2 (HER2) and topoisomerase 2a (Topo2a) status are claimed to be important parameters in the management of BC therapy. In case of heterogeneity between primary BC and metastatic site, this implies profound limitations of efficient systemic therapy. Therefore, it is essential to analyze whether biological markers of BC relate to identical expression profiles of metastatic lymph nodes (mLNs). We used paraffin-embedded tumor tissue from 119 patients with at least 1 mLN. Immunohistochemistry (IHC) was used to analyze ER, PR, HER2 and Topo2a. In addition, HER2 and Topo2a amplification was evaluated by fluorescence/chromogenic in situ hybridization (FISH/CISH) in all samples with a HER2 score of 2+/3+ by IHC. Overall, the percentage of discordant marker status in the BC and its mLN was 2.6% for ER, 3.5% for PR, 3.4% for HER2, and 3.4% for Topo2a. With FISH/CISH, the amplification rate for Topo2a and HER2 was concordant in all cases. Because there are no prospective studies, it remains unclear whether these discrepancies have an effect on patient survival.
Breast Cancer; Metastasis; Hormone receptor; HER2/neu; Topoisomerase 2a