Circulating Micro-RNAs as Potential Blood-Based Markers for Early Stage Breast Cancer Detection

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

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

Analysis of motives and patient satisfaction in oncological second opinions provided by a certified university breast and gynecological cancer center

Abstract Purpose Second opinions in oncology are becoming increasingly important in an era of more complex treatments and a growing demand for information by patients. Therefore, we analyzed their effects and influencing factors like patients’ motives, subjective extent of information and satisfaction with communications. Methods This prospective study evaluated second opinions for patients with breast cancer or gynecological malignancy. The patients received a questionnaire before and two months after, which inquired expectations, reasons, and satisfaction with the second opinion and the attending physicians. Results A total of 164 patients were included and the majority had breast cancer (75.0%). Receiving the second opinion made 89.7% feel better informed, their need for information decreased (from 75.3% to 39.2%, P < 0.0001), and satisfaction with doctor–patient communications increased (from 61.9 to 91.8%, P = 0.0002). There were various reasons for requesting a second opinion, e.g., the extremely stressful situation of a cancer diagnosis, hope for change in the treatment recommendation or dissatisfaction with the initial physicians. Conclusions Second opinions can lead to significantly greater patient satisfaction, meeting the need for information and leading to better management of patients in the extremely stressful situation of a cancer diagnosis. Doctor–patient communications play a key role

The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients

We have utilized a two-stage study design to search for SNPs associated with the survival of breast cancer patients treated with adjuvant chemotherapy. Our initial GWS data set consisted of 805 Finnish breast cancer cases (360 treated with adjuvant chemotherapy). The top 39 SNPs from this stage were analyzed in three independent data sets: iCOGS (n=6720 chemotherapy-treated cases), SUCCESS-A (n=3596), and POSH (n=518). Two SNPs were successfully validated: rs6500843 (any chemotherapy; per-allele HR 1.16, 95% C.I. 1.08-1.26, p=0.0001, p((adjusted))=0.0091), and rs11155012 (anthracycline therapy; per-allele HR 1.21, 95% C.I. 1.08-1.35, p=0.0010, p((adjusted))=0.0270). The SNP rs6500843 was found to specifically interact with adjuvant chemotherapy, independently of standard prognostic markers (p((interaction))=0.0009), with the rs6500843-GG genotype corresponding to the highest hazard among chemotherapy-treated cases (HR 1.47, 95% C.I. 1.20-1.80). Upon trans-eQTL analysis of public microarray data, the rs6500843 locus was found to associate with the expression of a group of genes involved in cell cycle control, notably AURKA, the expression of which also exhibited differential prognostic value between chemotherapy-treated and untreated cases in our analysis of microarray data. Based on previously published information, we propose that the eQTL genes may be connected to the rs6500843 locus via a RBFOX1-FOXM1 -mediated regulatory pathway.Peer reviewe

SNP-SNP interaction analysis of NF-kappa B signaling pathway on breast cancer survival

In breast cancer, constitutive activation of NF-kappa B has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-kappa B pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI= 3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI= 0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-kappa B pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.Peer reviewe

Pain perception and detailed visual pain mapping in breast cancer survivors

International audienceChronic pain and neural irritation after breast surgery and radiation are still relevant sequelae of the treatment. Pain quantification and localization in patient groups are difficult to standardize. In order to quantify and localize pain in a group of breast cancer patients, a Java-based program was developed to visualize the frequency of pain in “pain maps.” A questionnaire with structured questions on the perception of pain included pictograms of a body to mark possible pain areas. A group of 343 breast cancer survivors completed the questionnaires. The image information was digitalized and processed using a Java applet. Gray-scale summation pictures with numbers from “0,” indicating black (100% pain), to “255,” indicating white (0% pain), were generated. The visualization of pain by creating pain maps revealed the location of pain in breast cancer survivors on pictograms of the body. Analyzing the total number of pixels, in which pain was stated, made it possible to compare pain areas in several subgroups, showing that patients after mastectomy versus breast-conserving therapy (3,011 vs. 2,224 pixels), and patients with lymphedema versus patients without lymphedema (3,010 vs. 2,239 pixels), have larger pain areas. This study presents a method of visualizing pain areas and assigning them to a pictogram of the body in a sample of breast cancer patients. The method is easy to use and could help generate pain maps in several types of disease

Relevance of Health Economics in Breast Cancer Treatment - the View of Certified Breast Centres and Their Patients

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.Es ist unbestritten, dass wir im Zeitalter der zertifizierten Zentren leben. Im Bereich der Senologie sind insbesondere die zertifizierten Brustkrebszentren nach den Kriterien der Deutschen Krebsgesellschaft e.V. und der Deutschen Gesellschaft für Senologie e.V. flächendeckend etabliert. Auch wenn die Zentrumsbildung mit nachfolgender Zertifizierung mit deutlichen Mehrkosten verbunden ist, zeigen erste Daten auf, dass sich diese positiv auf die Ergebnisqualität auswirken. In Bezug auf die Gesundheitsökonomie sind zertifizierte Zentren aus der Sicht des Gesundheitswesens kosteneffektiv - es wird eine Verbesserung der Prozess- und Ergebnisqualität erreicht, ohne dass die Kostenträger Mehrkosten haben. Demgegenüber besteht ein enormer Ressourcenaufwand für Organisation der Strukturen, interdisziplinäre Betreuung, psychoonkologische Versorgung, sozialmedizinische Beratung, Dokumentation und Qualitätssicherung. Des Weiteren erfolgt eine zunehmende Konzentration der stationären Leistungen. Dem gegenüber werden durch Kürzungen der Verweildauer der Patientinnen durch die Kostenträger Abzüge der Honorierung erzwungen. Die aktuell fehlende Kostendeckung der zertifizierten Brustkrebszentren muss durch spezifische Zuschläge ausgeglichen werden. Diese fehlen allerdings größtenteils. Auf lange Sicht wird die hohe Qualität jedoch nur aufrechterhalten werden können, wenn Zuschläge den Mehraufwand der Zentren abdecken. Für die Verhandlungen dieser Zuschläge besteht mittlerweile eine zunehmend gute Datenlage, z.B. in Hinblick auf die Ergebnisqualität und den Nationalen Krebsplan, als auch eine deutliche Unterstützung durch die Patientinnen

Are Certified Breast Centers Cost-Effective?

The German health care system has entered an era of specialist centers and certification. Hospitals are required to introduce quality management with external monitoring, refining and improving their quality of treatment. These statutory requirements can only be met through specialization, centralization, and establishing centers and networks with internal and external interdisciplinary collaboration. The breast centers certified according to the criteria of the German Cancer Society (DKG) and German Society for Mastology (DGS) are pioneers here. Simultaneously, there are increasing demands for more cost-effective medical services despite limited resources – making economic analysis of health care provision necessary. Few economic studies of the centers and certification system have been conducted, however. General long-term quality data, particularly for results, are not yet available from certified breast centers. At present, a certified breast center is not itself a proven independent prognostic parameter for treatment results. However, the individual criteria required for breast center certification show a significant positive influence on clinical efficacy. Certified breast centers involve substantial extra costs that are not reimbursed by funding bodies, so the slightest potential benefit for patients from certified centers already appears cost-effective. When the actual costs, currently usually subsidized by other departments, are considered, it is unclear whether certified breast centers remain cost-effective