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1.  Polymorphisms in the RANK/RANKL Genes and Their Effect on Bone Specific Prognosis in Breast Cancer Patients 
BioMed Research International  2014;2014:842452.
The receptor activator of NF-κB (RANK) pathway is involved in bone health as well as breast cancer (BC) pathogenesis and progression. Whereas the therapeutic implication of this pathway is established for the treatment of osteoporosis and bone metastases, the application in adjuvant BC is currently investigated. As genetic variants in this pathway have been described to influence bone health, aim of this study was the prognostic relevance of genetic variants in RANK and RANKL. Single nucleotide polymorphisms in RANK(L) (rs1054016/rs1805034/rs35211496) were genotyped and analyzed with regard to bone metastasis-free survival (BMFS), disease-free survival, and overall survival for a retrospective cohort of 1251 patients. Cox proportional hazard models were built to examine the prognostic influence in addition to commonly established prognostic factors. The SNP rs1054016 seems to influence BMFS. Patients with two minor alleles had a more favorable prognosis than patients with at least one common allele (HR 0.37 (95% CI: 0.17, 0.84)), whereas other outcome parameters remained unaffected. rs1805034 and rs35211496 had no prognostic relevance. The effect of rs1054016(RANKL) adds to the evidence that the RANK pathway plays a role in BC pathogenesis and progression with respect to BMFS, emphasizing the connection between BC and bone health.
doi:10.1155/2014/842452
PMCID: PMC3963378  PMID: 24729980
2.  Health Economics in Breast Cancer 
Breast Care  2013;8(1):5-6.
doi:10.1159/000346882
PMCID: PMC3971805  PMID: 24715836
3.  Economic Constraints – the Growing Challenge for Western Breast Cancer Centers 
Breast Care  2013;8(1):41-47.
Summary
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.
doi:10.1159/000348356
PMCID: PMC3971806  PMID: 24715842
Breast Cancer Center; Expenditures and costs; Process management; Process quality; Process efficiency; Health economics; Patient satisfaction; Clinical workflow; Breast cancer
4.  Extent of Primary Breast Cancer Surgery: Standards and Individualized Concepts 
Breast Care  2012;7(5):364-369.
Surgery is still a main therapeutic option in breast cancer treatment. Nowadays, methods of resection and reconstruction vary according to different tumors and patients. This review presents and discusses standards of care and arising questions on how radical primary breast cancer surgery should be according to different clinical situations. In most early breast cancer patients, breast conservation is the method of choice. The discussion on resection margins is still controversial as different studies show conflicting results. Modified radical mastectomy is the standard in locally advanced breast cancer patients, although there are different promising approaches to spare skin or even the nipple-areola complex. A sentinel node biopsy is the standard of care in clinically node-negative invasive breast cancer patients, whereas the significance of axillary lymphonodectomy seems to be questioned through a number of different findings. Although there are interesting findings to modify surgical approaches in very young or elderly breast cancer patients, it will always be an individualized approach if we do not adhere to current guidelines. Up to date, there are no special surgical procedures in BRCA mutation carriers or patients of high-risk families.
doi:10.1159/000343976
PMCID: PMC3518938  PMID: 24647774
Breast cancer surgery; Resection margins; Sentinel lymph node biopsy; Axillary lymphonodectomy
5.  Cost-Benefit Analysis of Endocrine Therapy in the Adjuvant Setting for Postmenopausal Patients with Hormone Receptor-Positive Breast Cancer, Based on Survival Data and Future Prices for Generic Drugs in the Context of the German Health Care System 
Breast Care  2011;6(5):381-389.
Background
Cost-effectiveness analyses have focused on aromatase inhibitors (AIs), but the results are inconsistent and disease-free survival has often been extrapolated to overall survival. The present study calculates the cost-effectiveness of 5 years of letrozole versus tamoxifen versus anastrozole in the context of the German health care system, using survival data from the Breast International Group (BIG) 1–98 study and the Arimidex, Tamoxifen, Alone or in Combination (ATAC) study and generic prices.
Materials and Methods
A hybrid model was developed that incorporates recurrence rates, overall survival, treatment costs and treatment-associated adverse events and the resulting costs. The basic assumption was that generic anastrozole would lead to a price reduction to 75% of the original price. Further analyses were carried out with 50% and 25% of the original prices for anastrozole and letrozole.
Results
The cost-benefit model showed a gain of 0.3124 or 0.0659 quality-adjusted life years (QALYs) for letrozole or anastrozole. Incremental costs of € 29,375.15/QALY for letrozole (100% of original price) were calculated and € 94,648.03/QALY for anastrozole (75% of original price). Marked increases in cost-effectiveness are observed with further decreases in price (anastrozole: 50% price € 54,715.17/QALY, 25% price € 14,779.57/QALY; letrozole 75% price € 20,988.59/QALY, 50% price € 12,602.03/QALY, 25% price € 4,215.46/QALY).
Conclusion
The present model including the inverse probability of censoring weighted analysis (IPCW) for letrozole and generic prices for both AIs shows that letrozole is cost effective.
doi:10.1159/000333118
PMCID: PMC3357170  PMID: 22619649
Letrozole; Anastrozole; Tamoxifen; Cost-effectiveness; QALY; BIG 1–98; ATAC
6.  FemZone trial: a randomized phase II trial comparing neoadjuvant letrozole and zoledronic acid with letrozole in primary breast cancer patients 
BMC Cancer  2014;14:66.
Background
The objective of this prospectively randomized phase II trial (Trial registration: EUCTR2004-004007-37-DE) was to compare the clinical response of primary breast cancer patients to neoadjuvant therapy with letrozole alone (LET) or letrozole and zoledronic acid (LET + ZOL).
Methods
Patients were randomly assigned to receive either LET 2.5 mg/day (n = 79) or the combination of LET 2.5 mg/day and a total of seven infusions of ZOL 4 mg every 4 weeks (n = 89) for 6 months. Primary endpoint was clinical response rate as assessed by mammogram readings. The study was terminated prematurely due to insufficient recruitment. We report here on an exploratory analysis of this data.
Results
Central assessment of tumor sizes during the treatment period was available for 131 patients (66 LET, 65 LET + ZOL). Clinical responses (complete or partial) were seen in 54.5% (95% CI: 41.8-66.9) of the patients in the LET arm and 69.2% (95% CI: 56.6-80.1) of those in the LET + ZOL arm (P = 0.106). A multivariate model showed an OR of 1.72 (95% CI: 0.83-3.59) for the experimental arm.
Conclusion
No increase in the clinical response rate was observed with the addition of ZOL to a neoadjuvant treatment regimen with LET. However a trend towards a better reponse in the LET + ZOL arm could be observed. This trend is consistent with previous studies that have investigated the addition of ZOL to chemotherapy, and it may support the evidence for a direct antitumor action of zoledronic acid.
doi:10.1186/1471-2407-14-66
PMCID: PMC3937056  PMID: 24499441
Zoledronic acid; Neoadjuvant treatment; Breast cancer; Letrozole; Aromatase inhibitors; Bisphosphonates
7.  Characterizing mammographic images by using generic texture features 
Introduction
Although mammographic density is an established risk factor for breast cancer, its use is limited in clinical practice because of a lack of automated and standardized measurement methods. The aims of this study were to evaluate a variety of automated texture features in mammograms as risk factors for breast cancer and to compare them with the percentage mammographic density (PMD) by using a case-control study design.
Methods
A case-control study including 864 cases and 418 controls was analyzed automatically. Four hundred seventy features were explored as possible risk factors for breast cancer. These included statistical features, moment-based features, spectral-energy features, and form-based features. An elaborate variable selection process using logistic regression analyses was performed to identify those features that were associated with case-control status. In addition, PMD was assessed and included in the regression model.
Results
Of the 470 image-analysis features explored, 46 remained in the final logistic regression model. An area under the curve of 0.79, with an odds ratio per standard deviation change of 2.88 (95% CI, 2.28 to 3.65), was obtained with validation data. Adding the PMD did not improve the final model.
Conclusions
Using texture features to predict the risk of breast cancer appears feasible. PMD did not show any additional value in this study. With regard to the features assessed, most of the analysis tools appeared to reflect mammographic density, although some features did not correlate with PMD. It remains to be investigated in larger case-control studies whether these features can contribute to increased prediction accuracy.
doi:10.1186/bcr3163
PMCID: PMC3446394  PMID: 22490545
8.  Circulating Micro-RNAs as Potential Blood-Based Markers for Early Stage Breast Cancer Detection 
PLoS ONE  2012;7(1):e29770.
Introduction
MicroRNAs (miRNAs, miRs) are a class of small, non-coding RNA molecules with relevance as regulators of gene expression thereby affecting crucial processes in cancer development. MiRNAs offer great potential as biomarkers for cancer detection due to their remarkable stability in blood and their characteristic expression in many different diseases. We investigated whether microarray-based miRNA profiling on whole blood could discriminate between early stage breast cancer patients and healthy controls.
Methods
We performed microarray-based miRNA profiling on whole blood of 48 early stage breast cancer patients at diagnosis along with 57 healthy individuals as controls. This was followed by a real-time semi-quantitative Polymerase Chain Reaction (RT-qPCR) validation in a separate cohort of 24 early stage breast cancer patients from a breast cancer screening unit and 24 age matched controls using two differentially expressed miRNAs (miR-202, miR-718).
Results
Using the significance level of p<0.05, we found that 59 miRNAs were differentially expressed in whole blood of early stage breast cancer patients compared to healthy controls. 13 significantly up-regulated miRNAs and 46 significantly down-regulated miRNAs in our microarray panel of 1100 miRNAs and miRNA star sequences could be detected. A set of 240 miRNAs that was evaluated by radial basis function kernel support vector machines and 10-fold cross validation yielded a specificity of 78.8%, and a sensitivity of 92.5%, as well as an accuracy of 85.6%. Two miRNAs were validated by RT-qPCR in an independent cohort. The relative fold changes of the RT-qPCR validation were in line with the microarray data for both miRNAs, and statistically significant differences in miRNA-expression were found for miR-202.
Conclusions
MiRNA profiling in whole blood has potential as a novel method for early stage breast cancer detection, but there are still challenges that need to be addressed to establish these new biomarkers in clinical use.
doi:10.1371/journal.pone.0029770
PMCID: PMC3252341  PMID: 22242178
9.  Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment 
BMC Cancer  2011;11:486.
Background
The pathological complete response (pCR) after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer.
Methods
Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible.
Results
Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1) and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4) and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9). The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells.
Conclusions
Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further.
doi:10.1186/1471-2407-11-486
PMCID: PMC3262864  PMID: 22081974

Results 1-9 (9)