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

Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p

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

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

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.Das deutsche Gesundheitswesen erlebt das Zeitalter der Zentrumsbildung und Zertifizierung. Krankenhäuser müssen ein Qualitätsmanagement mit externer Überprüfung einführen und ihre Behandlungsqualität weiterentwickeln. Dieser gesetzliche Anspruch kann nur durch Spezialisierung, Zentralisierung sowie Zentrums- und Netzwerkbildung mit interner und externer Interdisziplinarität erbracht werden. Vorreiter sind die zertifizierten Brustzentren nach den Kriterien der Deutschen Krebsgesellschaft (DKG) und der Deutschen Gesellschaft für Senologie (DGS). Parallel zu dieser Entwicklung nehmen bei zunehmend begrenzten Ressourcen im Gesundheitswesen die Forderungen nach Kosteneffektivität von medizinischen Leistungen zu, welche gesundheitsökonomische Analysen notwendig machen. Sowohl Zentrumsbildung als auch das Zertifizierungswesen wurden jedoch aus gesundheitsökonomischer Sicht bisher wenig untersucht. Allgemeine Langzeitqualitätsdaten, insbesondere zur Ergebnisqualität, aus den zertifizierten Brustzentren liegen noch nicht vor. Aktuell ist das zertifizierte Brustzentrum selbst kein nachgewiesener, eigenständiger Prognoseparameter für das Therapieergebnis. Jedoch wurde für einzelne Kriterien, deren Erfüllung Grundlage der Zertifizierung von Brustzentren ist, ein signifikanter positiver Einfluss auf die klinische Effektivität nachgewiesen. Demgegenüber steht ein erheblicher finanzieller Mehraufwand für zertifizierte Brustzentren. Da dieser aktuell nicht zusätzlich durch die Kostenträger vergütet wird, ist beim kleinsten möglichen Benefit für die Patientin durch zertifizierte Zentrumsstrukturen bereits eine Kosteneffektivtät gegeben. Ob zertifizierte Brustzentren bei Betrachtung der tatsächlich anfallenden Kosten, welche zurzeit meist durch weitere Abteilungen quersubventioniert werden, kosteneffektiv bleiben, ist unklar

Quality Assured Health Care in Certified Breast Centers and Improvement of the Prognosis of Breast Cancer Patients

Background: Increasing effort has been put in the implementation and certification of breast centers in order to establish standardized, quality assured health care for breast cancer patients. The aim of this analysis was to investigate whether patients treated in certified breast centers (CBC) have a favorable prognosis as compared to patients treated outside of certified breast treatment units. Patients and Methods: The data of 3,940 patients with invasive nonmetastatic breast cancer were analyzed with regard to differences in patient and tumor characteristics and crude overall survival according to diagnosis in or outside CBC in Middle Franconia, Germany. Patient, tumor, and follow-up data were obtained from the clinical cancer registry. Results: Patients in CBC were younger, and had lower disease stages and lower grading. Independent of the effects of these variables on overall survival, being treated at a CBC added to the prediction of overall survival. Patients treated at a CBC had a hazard ratio of 0.70 (95% confidence interval 0.52–0.93) in the adjusted Cox model. Conclusions: Independent from common prognostic factors, diagnosis and treatment of breast cancer at a CBC improves the prognosis of patients. It can be hypothesized that this effect is mediated through quality assured health care provided by the certification process.Hintergrund: In den vergangenen Jahren wurde die Etablierung von zertifizierten Brustzentren vorangetrieben, um eine standardisierte und qualitätsgesicherte Versorgung von Patientinnen mit einem Mammakarzinom zu gewährleisten. Die vorliegende Arbeit untersucht, ob Patientinnen mit einer Behandlung in einem zertifizierten Brustzentrum eine unterschiedliche Prognose im Vergleich zur Versorgung außerhalb zertifizierter Strukturen aufweisen. Patienten und Methoden: Die Daten von 3940 Patientinnen mit einem primären, nicht metastasierten Mammakarzinom des klinischen Krebsregisters Mittelfrankens wurden in Bezug auf anamnestische Faktoren, Tumorcharakteristika und Ergebnisqualität untersucht und mit der Versorgung in und außerhalb zertifizierter Brustzentren korreliert. Ergebnisse: Patientinnen im zertifizierten Brustzentrum waren jünger und hatten ein niedrigeres Tumorstadium und Grading. Unabhängig dieser Variablen hatte die Versorgung durch zertifizierte Brustzentren in einem adjustierten Cox-Modell einen signifikanten positiven Einfluss auf das Gesamtüberleben [Hazard Ratio 0,70 (95% Konfidenzintervall 0,52– 0,93)]. Schlussfolgerungen: Die Versorgung in einem zertifizierten Brustzentrum zeigt unabhängig von den klassischen Prognosefaktoren eine Verbesserung der Prognose von Mammakarzinompatientinnen. Dieses könnte durch die qualitätsgesicherten Versorgung basierend auf dem Zertifizierungsprozess erklärt werden

Prediction of pathological complete response and prognosis in patients with neoadjuvant treatment for triple-negative breast cancer

Abstract Background It has been reported that pathological complete response is an important surrogate marker for disease-free survival and overall survival in patients with triple-negative breast cancer. This study investigates predictors of the response to neoadjuvant platinum-based or anthracycline-based treatment, and of the prognosis, in patients with triple-negative breast cancer. Methods A total of 121 patients with triple-negative breast cancer received neoadjuvant treatment with either platinum or anthracycline between 2008 and 2013. Pathological complete response was assessed relative to different treatments using logistic regression models with age, clinical tumor stage, grading, and Ki-67 as predictors and interaction terms, to obtain adjusted and subgroup-specific results. The impact of the pathological complete response rate on disease-free survival and overall survival was also analyzed. Results The pathological complete response rate was higher after platinum/taxane treatment compared with anthracycline/taxane (50.0% vs. 41.8%), but this was not significant in the adjusted analysis (OR 1.44; 95% CI, 0.68 to 3.09). A high histological grade (G3) was a predictor for higher pathological complete response in platinum-based therapy (OR 2.27; 95% CI, 1.00 to 5.30). The effect of neoadjuvant chemotherapy on pathological complete response was significantly different for G1–2 vs. G3 (P interaction = 0.013), and additional subgroup-specific differences were noted. Pathological complete response was a predictor for improved disease-free survival and overall survival in both treatment groups, with and without platinum chemotherapy. Conclusions This retrospective study of patients with triple-negative breast cancer adds to the evidence that the treatment effect of platinum may be greatest particularly in G3 tumors. In addition, the effect of pathological complete response on the prognosis does not depend on the treatment used