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PDF file - 182K, Supplemental Figure 1. B cells activated with IL-21 and anti-BCR secrete enzymatically active granzyme B. Supplemental Figure 2. Interleukin 21 in the absence of B cells does not suppress T cell proliferation. Supplemental Figure 3. GrB-secreting B cells do not induce apoptosis in T cells. Supplemental Figure 4. IL-10, CD25 and IDO are expressed on IL-21-induced GrB+ Breg, but not on GrB- B cells. Supplemental Figure 5. IL-2 retitration has no significant effect on the suppression of CD4+ T cell proliferation by GrB-secreting B cells. Supplemental Figure 6. IL-21-induced GrB secretion by B cells depends on TLR7 and TLR9 signaling. Supplemental Figure 7. B cells in the microenvironment of solid tumors sporadically express IL-10.

MOV file - 3136K, Supplemental Video 1. B cells transfer active GrB to T cells.

Background Current research in breast cancer focuses on individualization of local and systemic therapies with adequate escalation or de-escalation strategies. As a result, about two-thirds of breast cancer patients can be cured, but up to one-third eventually develop metastatic disease, which is considered incurable with currently available treatment options. This underscores the importance to develop a metastatic recurrence score to escalate or de-escalate treatment strategies. Patients and methods Data from 10,499 patients were available from 17 clinical cancer registries (BRENDA-project [1]. In total, 8566 were used to develop the BRENDA-Index. This index was calculated from the regression coefficients of a Cox regression model for metastasis-free survival (MFS). Based on this index, patients were categorized into very high, high, intermediate, low, and very low risk groups forming the BRENDA-Score. Bootstrapping was used for internal validation and an independent dataset of 1883 patients for external validation. The predictive accuracy was checked by Harrell’s c-index. In addition, the BRENDA-Score was analyzed as a marker for overall survival (OS) and compared to the Nottingham prognostic score (NPS). Results: Intrinsic subtypes, tumour size, grading, and nodal status were identified as statistically significant prognostic factors in the multivariate analysis. The five prognostic groups of the BRENDA-Score showed highly significant (p &lt, 0.001) differences regarding MFS:low risk: hazard ratio (HR) = 2.4, 95%CI (1.7–3.3), intermediate risk: HR = 5.0, 95%CI.(3.6–6.9), high risk: HR = 10.3, 95%CI (7.4–14.3) and very high risk: HR = 18.1, 95%CI (13.2–24.9). The external validation showed congruent results. A multivariate Cox regression model for OS with BRENDA-Score and NPS as covariates showed that of these two scores only the BRENDA-Score is significant (BRENDA-Score p &lt, 0.001, NPS p = 0.447). Therefore, the BRENDA-Score is also a good prognostic marker for OS. Conclusion: The BRENDA-Score is an internally and externally validated robust predictive tool for metastatic recurrence in breast cancer patients. It is based on routine parameters easily accessible in daily clinical care. In addition, the BRENDA-Score is a good prognostic marker for overall survival. Highlights: The BRENDA-Score is a highly significant predictive tool for metastatic recurrence of breast cancer patients. The BRENDA-Score is stable for at least the first five years after primary diagnosis, i.e., the sensitivities and specificities of this predicting system is rather similar to the NPI with AUCs between 0.76 and 0.81 the BRENDA-Score is a good prognostic marker for overall survival.

ZusammenfassungDie AWMF und ihre Fachgesellschaften nehmen eine zunehmende Dominanz betriebswirtschaftlicher Ziele im stationären Gesundheitssektor wahr, die sich negativ auf die Patientenversorgung auswirken. Während eine angemessene, effiziente und gerechte Mittelverwendung geboten ist, belastet „Ökonomisierung“ Ärzte und Pflegende sowie die weiteren Gesundheitsberufe.Die AWMF hat zusammen mit Fachgesellschaftsvertretern Ursachen analysiert und Maßnahmen für eine wissenschaftliche, patientenzentrierte und ressourcenbewusste Medizin erarbeitet. Es bestehen Fehlanreize durch Vergütung, Zahl und Ausstattung von Krankenhäusern bzw. Fachabteilungen und deren Grundfinanzierung. Maßnahmen werden für die Patient–Arzt-Ebene, das Krankenhausmanagement, die Planung sowie Finanzierung von Krankenhäusern einschließlich der Vergütung stationärer Leistungen vorgeschlagen. Dabei bedarf es der gemeinsamen Anstrengung aller Akteure, um den Patienten und seine Gesundheit wieder in den Mittelpunkt zu stellen.

Das onkologische Leitlinienprogramm, das im Nationalen Krebsplan gefordert und gemeinsam von der Deutschen Krebshilfe, der Deutschen Krebsgesellschaft und der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften getragen wird, wurde gerade 10 Jahre alt. Mit seiner Zielsetzung, fur alle relevanten onkologischen Entitaten Leitlinien der hochsten methodischen Entwicklungsstufe (S3) zu erstellen, war das Programm sehr erfolgreich: Uber 90 % aller Tumorentitaten sind durch das Programm abgedeckt. Fur viele Entitaten gibt es daruber hinaus auch Patientenleitlinien. Die rasante Entwicklung insbesondere im Bereich der Therapie onkologischer Erkrankungen erfordert neue Instrumente zur Aktualisierung und Kommunikation von Leitlinien, wie sie im Amendment-Verfahren, den „living guidelines“ und der Leitlinien-App umgesetzt werden. Eine weitere Herausforderung besteht in der Nutzbarmachung von Daten aus der Versorgung, insbesondere aus den zertifizierten Zentren und den Krebsregistern, fur die Leitlinien.

Background This study examined the association between cognitive impairment and guideline adherence for application of chemotherapy in older patients with breast cancer. Patients and methods In the prospective multicenter cohort study BRENDA II, patients aged ≥65 years with primary breast cancer were sampled over a period of 4 years (2009-2012). A multiprofessional team (tumor board) discussed recommendation for adjuvant chemotherapy according to the German S3 guideline. Cognitive impairment was screened by the clock-drawing test (CDT) prior to adjuvant treatment. Results Two hundred and sixty-three patients were included in the study and CDT data were available for 193 patients. Thirty-one percent of the patients had cognitive impairment with different degree of severity. In high-risk patients (n = 61) tumor board recommendation in favor of chemotherapy was 90% and in intermediate-risk patients (n = 170) 27%. Not receiving recommendation for chemotherapy in spite of guideline recommendation was more frequent in patients with cognitive impairment (67%) vs patients without cognitive impairment (46%) with P = 0.02 (OR 2.4, 95% confidence interval (CI) 1.2-4.9). Age, education, migration background and comorbidities were not associated with chemotherapy recommendation by the tumor board among cognitively impaired patients. Once the tumor board had recommended chemotherapy, application of chemotherapy was similar in both groups of patients with or without cognitive impairment. Conclusion Almost one third of older patients with breast cancer are affected by cognitive impairment prior to adjuvant treatment. In these patients, cognitive impairment was associated with tumor board decision against chemotherapy in spite of a positive guideline recommendation.

This study examined 5-year overall, recurrence and distant metastasis-free survival (OS, RFS, MFS) of high- and intermediate-risk breast cancer (BC) patients who declined guideline-recommended adjuvant chemotherapy (CHT).In the prospective multicenter cohort study BRENDA II, patients with primary BC were sampled over a period of four years (2009-2012). A multi-professional team (tumorboard) discussed recommendation for adjuvant CHT according to the German guideline. Potential differences in 5 year survival were analyzed using Kaplan-Meier curves and Cox regression. The hazard ratios (HR) were adjusted for age, Charlson Comorbidity Score, American Society of Anesthesiologist (ASA) physical status classification, and endocrine therapy.A total of 759 patients were enrolled of which 688 could receive CHT according to the guidelines (n = 219 had a clear indication, in n = 304 it was possible). For 360 patients, the tumorboard advised to perform CHT, for 304 it advised against and in 24 cases, no decision was documented. Of those with a positive suggestion, 83% received CHT. Until 5 years after diagnosis, 57 patients were deceased, 41 had at least one distant metastasis and 29 a recurrence. There was no evidence for differences in OS and MFS in patients who declined CHT despite tumorboard recommendation (HR 3.5, 95% CI 0.8-15.1 for OS, HR 1.9, 95% 0.6-6.6 for MFS). Patients who received CHT had significantly better 5-year RFS compared to those who declined (HR 0.3, 95% CI 0.1-0.9, p = 0.03). There was no evidence for different survival in those who had no CHT because of comorbidity and those who declined actively, neither for OS, MFS nor RFS.The prospective BRENDA II study demonstrates benefit in RFS by guideline adherence in adjuvant breast cancer treatment, indicating prospectively the value of internationally validated guidelines in breast cancer care.

Background Radiotherapy (RT) is of critical importance in the locoregional management of early breast cancer. Although RT is routinely used following breast conserving surgery (BCS), patients may occasionally be effectively treated with BCS alone. Currently, the selection of patients undergoing BCS who do not need breast irradiation is under investigation. With the advancement of personalized medicine, there is an increasing interest in reduction of aggressive treatments especially in older women. The primary objective of this study was to identify elderly patients who may forego breast irradiation after BCS without measurable consequences on local tumor growth and survival. Methods We analyzed 2384 early breast cancer patients aged 70 and older who were treated in 17 German certified breast cancer centers between 2001 and 2009. We compared RT versus no RT after guideline adherent (GA) BCS. The outcomes studied were breast cancer recurrence (RFS) and breast cancer-specific survival (BCSS). Low-risk patients were defined by luminal A, tumor size T1 or T2 and node-negative whereas higher-risk patients were defined by patients with G3 or T3/T4 or node-positive or other than Luminal A tumors. To test if there is a difference between two or more survival curves, we used the Gp family of tests of Harrington and Fleming. Results The median age was 77 yrs (mean 77.6±5.6 y) and the median observation time 46 mths (mean 48.9±24.8 mths). 950 (39.8%) patients were low-risk and 1434 (60.2%) were higher-risk. 1298 (54.4%) patients received GA BCS of which 85.0% (1103) received GA-RT and only 15% (195) did not. For low-risk patients with GA-BCS there were no significant differences in RFS (log rank p = 0.651) and in BCSS (p = 0.573) stratified by GA-RT. 5 years RFS in both groups were > 97%. For higher-risk patients with GA-BCS we found a significant difference (p

Certified multi-disciplinary breast cancer centres (CBCs) have been established worldwide. Development of CBCs, guideline-adherent systemic therapy and surgical management should now show an impact on outcomes. This analysis aimed to investigate whether guideline adherence (GA) rates, relapse-free survival (RFS) and overall survival (OS) have significantly improved at CBCs compared to the pre-certification period.8323 patients with primary breast cancer were treated in 17 German CBCs, which had been certified between 2003 and 2007 [2003 (n = 1), 2004 (n = 6), 2005 (n = 3), 2006 (n = 6) and 2007 (n = 1)]. 3544 patients (42.6%) were treated before certification and 4779 patients (57.4%) after certification.A highly significant (p 0.001) difference in 100%-GA was found between the various hospitals before certification (min 25.0%; max 54.6%). In 2008, when all participating hospitals were certified, the GA rate was 61.8% (min 39.5%, max 74.4%) and 69.2% (min 45.9%, max 86.4%) for patients75 y (n = 6675). The difference between pre-certification 100%-GA (46.9%) and post-certification (57.2%) was highly significant (p 0.001). RFS and OS were both significantly better after certification compared to the pre-certification period (RFS: HR = 0.79; 95% CI: 0.68-0.92; p = 0.003; OS: HR = 0.75; 95% CI: 0.65-0.85; p 0.001). 5-year RFS (OS) of patients75 y was 89.6% (85.4%) pre-certification and 91.4% (89.5%) post-certification. Since improvement in GA and outcomes correlated as well, GA remains a highly significant prognostic factor for RFS and OS regardless of NPI, intrinsic subtype and adjuvant systemic therapy. This suggests that the certification process is strongly associated with improvements in outcome.

The Z0011 trial has fundamentally changed axillary management in breast cancer patients. However, some important questions remain, like the role of extracapsular nodal extension (ENE) in positive sentinel nodes and the need for further axillary treatment. In this retrospective cohort study, we reviewed and analyzed data from 342 clinically node negative (cN0) breast cancer patients with a positive sentinel node and subsequent axillary lymph node dissection (ALND) from the BRENDA data base. The 104 (30.4%) ENE positive patients had a significantly higher proportion of ≥3 positive axillary lymph nodes (65.0%) compared to ENE negative patients with a positive sentinel node (21.4%). Likewise, ENE positive patients had significantly more often lymph node metastasis size >2 mm (96.2%) than ENE negative patients (72.7%). T1 status was observed significantly more often in ENE negative patients (53.2%) than in ENE positive patients (24.0%). While ENE was linked to worse overall survival in univariate analysis, this effect disappeared when adjusting for nodal status, age, and comorbidities in multivariate analysis. ENE of the sentinel node is an important predictor for nonsentinel lymph node involvement. We suggest that ENE influences survival only via a higher number of positive nodes - one of the most predictive parameters for survival outcome in breast cancer.

Objective: To identify subgroups of patients with pT1 pN0 breast cancer (BC) who might not profit from adjuvant systemic therapy (AST). Methods: Data of 3,774 pT1 pN0 BC patients from 17 certified BC centres within the BRENDA study group were collected between 1992 and 2008 and retrospectively analysed. Uni- and multivariate analyses were performed using Kaplan-Meier methods and Cox regression models. Results: 279 (7.4%) of the pT1 pN0 BC patients were T1a, 944 (25.0%) were T1b and 2,551 (67.6%) were T1c. There was no significant difference (p > 0.1) in recurrence-free survival (RFS)/overall survival (OAS) between patients with pT1a, pT1b, and T1c. Patients receiving any type of AST had a better outcome compared to women without AST after adjusting for age, tumour size, and intrinsic subtypes (RFS: p < 0.001; OAS: p < 0.001). AST was the most important prognostic parameter for RFS followed by intrinsic subtypes and age. Conclusion: Patients with pT1 pN0 BC profit from AST independently of molecular subtypes, tumour size, age or comorbidity, with 5-year RFS of more than 95%. The correct definition of subgroups of patients who do not need AST is still an open question.

The AWMF and its medical societies perceive an increasing dominance of economic targets in the hospital health care sector, leading to impairment of patient care. While resource use in health care should be appropriate, efficient and fairly allocated, "economization" creates a burdensome situation for physicians, nurses and other health care professionals.The AMWF and the medical societies studied causes and developed measures for a scientific, patient-centred and resource-conscious medical care. Disincentives due to the remuneration system, number and equipment of hospitals resp. specialist departments and their basic funding need to be overcome. Proposed actions relate to the patient-doctor-level, the management level of hospitals and the level of planning and financing hospitals including compensation of hospital care. To place patients and their health in the forefront again, joint efforts of all stakeholders in health care are needed.Die AWMF und ihre Fachgesellschaften nehmen eine zunehmende Dominanz betriebswirtschaftlicher Ziele im stationären Gesundheitssektor wahr, die sich negativ auf die Patientenversorgung auswirken. Während eine angemessene, effiziente und gerechte Mittelverwendung geboten ist, belastet „Ökonomisierung“ Ärzte und Pflegende sowie die weiteren Gesundheitsberufe.Die AWMF hat zusammen mit Fachgesellschaftsvertretern Ursachen analysiert und Maßnahmen für eine wissenschaftliche, patientenzentrierte und ressourcenbewusste Medizin erarbeitet. Es bestehen Fehlanreize durch Vergütung, Zahl und Ausstattung von Krankenhäusern bzw. Fachabteilungen und deren Grundfinanzierung. Maßnahmen werden für die Patient–Arzt-Ebene, das Krankenhausmanagement, die Planung sowie Finanzierung von Krankenhäusern einschließlich der Vergütung stationärer Leistungen vorgeschlagen. Dabei bedarf es der gemeinsamen Anstrengung aller Akteure, um den Patienten und seine Gesundheit wieder in den Mittelpunkt zu stellen.

Background The decision making process for axillary dissection has changed in recent years for patients with early breast cancer and positive sentinel lymph nodes (LN). The question now arises, what is the optimal surgical treatment for patients with positive axillary LN (pN+). This article tries to answer the following questions: (1) Is there a survival benefit for breast cancer patients with 3 or more positive LN (pN3+) and with more than 10 removed LN? (2) Is there a survival benefit for high risk breast cancer patients (triple negative or Her2 + breast cancer) and with 3 or more positive LN (pN3+) with more than 10 removed LN? (3) In pN + patients is the prognostic value of the lymph node ratio (LNR) of pN+/pN removed impaired if 10 or less LN are removed? Methods A retrospective database analysis of the multi center cohort database BRENDA (breast cancer under evidence based guidelines) with data from 9625 patients from 17 breast centers was carried out. Guideline adherence was defined by the 2008 German National consensus guidelines. Results 2992 out of 9625 patients had histological confirmed positive lymph nodes. The most important factors for survival were intrinsic sub types, tumor size and guideline adherent chemo- and hormonal treatment (and age at diagnosis for overall survival (OAS)). Uni-and multivariable analyses for recurrence free survival (RFS) and OAS showed no significant survival benefit when removing more than 10 lymph nodes even for high-risk patients. The mean and median of LNR were significantly higher in the pN+ patients with ≤10 excised LN compared to patients with > 10 excised LN. LNR was in both, uni-and multivariable, analysis a highly significant prognostic factor for RFS and OAS in both subgroups of pN + patients with less respective more than 10 excised LN. Multivariable COX regression analysis was adjusted by age, tumor size, intrinsic sub types and guideline adherent adjuvant systemic therapy. Conclusion The removal of more than 10 LN did not result in a significant survival benefit even in high risk pN + breast cancer patients.

BackgroundIn this study based on the BRENDA data, we investigated the impact of endocrine ± chemotherapy for luminal A, nodal positive breast cancer on recurrence free (RFS) and overall survival (OS). In addition, we analysed if tumor size of luminal A breast cancer influences survival in patients with the same number of positive lymph nodes.MethodsIn this retrospective multi-centre cohort study data of 1376 nodal-positive patients with primary diagnosis of luminal A breast cancer during 2001-2008 were analysed. The results were stratified by therapy and adjusted by age, tumor size and number of affected lymph nodes.ResultsIn our study population, patients had a good to excellent prognosis (5-year RFS: 91% and tumorspecific 5-year OS 96.5%). There was no significant difference in RFS stratified by patients with only endocrine therapy and with endocrine plus chemo-therapy. Patients with 1-3 affected lymph nodes had no significant differences in OS treated only with endocrine therapy or with endocrine plus chemotherapy, independent of tumor size. Patients with large tumors and more than 3 affected lymph nodes had a significant worse survival as compared to the small tumors. However, despite the worse prognosis of those, adjuvant chemotherapy failed in order to improve RFS.ConclusionsAccording to our data, nodal positive patients with luminal A breast cancer have, if any, a limited benefit of adjuvant chemotherapy. Tumor size and nodal status seem to be of prognostic value in terms of survival, however both tumor size as well as nodal status were not predictive for a benefit of adjuvant chemotherapy.

The development of metastases is the most aggressive attribute of breast cancer. In this retrospective multicenter study, we evaluated if and how the different pathological breast cancer subtypes influence the spreading of tumor cells, the development of metastasis and the survival of breast cancer patients. This retrospective German multicenter study is based on the BRENDA collective including 9625 breast cancer patients treated in the adjuvant setting. We used the χ 2 tests for the analysis of the categorical variables between groups of patients with different sites of metastasis. Survival distributions and median survival times were estimated using the Kaplan–Meier product-limit method. The log-rank test was applied to compare survival rates. The Cox proportional hazards model was used to estimate the hazard ratio and confidence intervals. 886 women developed metastases during a time interval of 53 months after primary diagnosis. Luminal A tumor patients were more likely to get bone metastases than lung, liver or CNS metastases. Patients with a triple-negative subtype were, however, the least affected by metastasis in the skeleton. They were most likely to develop visceral metastases. Location, numbers of metastases herein and the subtype influenced the overall survival (OAS). Altogether, the best OAS was found in patients with the luminal A subtype, the worst in patients with the triple-negative subtype. Knowledge of the typical metastatic pattern of the subtypes of breast cancer will help to personalize therapeutic options and follow-up examinations of cancer patients.

Purpose: The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC). Methods: This randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m² doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m² every 28 days or capecitabine 1250 mg/m² twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP). Results: 210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838–1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31). Conclusion: Both PLD and capecitabine are effective first-line agents for MBC.

Das Mammakarzinom ist der haufigste maligne Tumor der Frau weltweit. Aufgrund der hohen Patientinnenzahlen existiert eine Vielzahl von Studien, die die gesamte Diagnostik und Therapie der Erkrankung in viele Facetten gliedern und daher schwer zu uberblicken sind. Aktuelle Aspekte beziehen sich vor allem auf die primare Pravention der Erkrankung sowie die prognostischen und pradiktiven Parameter. Zudem existieren neue Empfehlungen fur die operative, die adjuvante endokrine und zytostatische Therapie sowie die neo-adjuvante zytostatische Behandlung. Wir bringen Sie auf den neuesten Stand.

This study aims to answer the questions where breast cancer patients in Germany receive follow-up care (with what types of doctors) and what are the long-term problems and treatment regrets of breast cancer patients. In the prospective multicenter cohort study BRENDA II (“Breast Cancer under Evidence-Based Guidelines”), 456 patients with primary breast cancer were sampled consecutively over a period of 4 years (2009–2012) and contacted again 5 years after surgery. Long-term problems were elicited on a 4-point Likert scale ranging from 0 (‘not at all’) to 3 (‘very much’). 82% of the patients receive follow-up (FU) at the private practice gynecologist. In 22%, the initial treating hospital is involved in the FU, and in 20% the general practitioner does this (multiple answers possible). Long-term problems attributed to the treatment were most often related to endocrine therapy (mean 1.29) and to chemotherapy (mean 0.94). Most of the patients were happy to have had radiotherapy (95%). For chemotherapy, endocrine therapy, and antibody therapy, the satisfaction for the treatment decision was 87%, 87%, and 84% respectively. Among patients who reported they regretted having undergone a recommended treatment, it was most often for endocrine therapy (5%) and chemotherapy (4%). In Germany, different specialists are involved in the patients’ FU care for BC. The detection of long-term problems due to BC treatment is an essential part of FU care.

Background Breast cancer is the most common cancer in women. The German S3 guideline of 2012 has now been updated to take account of advances in the early detection, diagnostic evaluation, treatment, and follow-up care of this disease. Methods The updating process was based on the adaptation of identified source guidelines and on reviews of the scientific evidence. A systematic search in multiple literature databases was carried out, and the full texts of the selected articles were evaluated. Suggested recommendations were then proposed by interdisciplinary working groups and modified and graded in a nominal consensus procedure. Results The value of mammographic screening is confirmed in the updated guideline. As for the diagnostic evaluation of breast cancer, computed tomography is recommended for staging in patients with a high risk of recurrence, in addition to conventional methods. As for surgical treatment, the evidence supporting locoregional surgery for primary breast cancer now affords an opportunity for de-escalation: complete resection yields the best outcome, but a safety margin of several millimeters is not necessary. Axillary dissection is no longer recommended except in certain defined situations. Radiotherapeutic approaches consist of hypofractionated applications. Adjuvant systemic therapy is indicated for patients in certain high-risk situations defined by a constellation of factors including tumor grade, patient age, node status, Ki-67 antigen expression, hormone receptor status, and human epidermal growth factor receptor 2 (HER2) status. All patients with hormone receptor-positive breast cancer should receive endocrine therapy. The indication for chemotherapy and/or anti-HER2 therapy should be determined in consideration of the expected benefit and side effects. Conclusion Consistent implementation of the recommendations in the newly updated guideline can help lessen morbidity and mortality from breast cancer. The actual extent to which breast cancer guidelines are implemented should be a topic of future research.

Geburtshilfe und Frauenheilkunde 78(11), 1056-1088 (2018). doi:10.1055/a-0646-4630, Published by Thieme, New York, NY

Purpose This study examined the frequency of psychiatric co-morbidity in patients with breast cancer, its changes over time and predictors for these changes. Methods In a prospective study with measurements before surgery (t1, baseline), 1 month (t2) and 8 months thereafter (t3) using the Patient Health Questionnaire, we examined the course of psychiatric co-morbidity in breast cancer patients. The co-morbidity courses were grouped into healthy (no co-morbidity during the study), acute (co-morbidity at t1 and/or t2, but not at t3), emerging (no co-morbidity at t1, but at t3) and chronic (co-morbidity at t1 and t3). Results Of the 598 participants, 19% had acute, 10% emerging and 9% chronic psychiatric co-morbidity. Acute co-morbidity was more common in patients with poor quality of life (odds ratio (OR) 9.6, 95% confidence interval (CI) 4.4–20.8) and somatic co-morbidity (OR 3.8, CI 1.1–12.4). Patients who perceived support from their doctors had acute co-morbidity less frequently (OR 0.7, CI 0.5–1.0). Emerging co-morbidity occurred more often in younger patients (OR 2.4, CI 1.2–4.7) and in patients with another cancer in their own (OR 2.0, CI 1.1–3.9) or family (OR 2.1, CI 1.1–4.3) histories, less often in patients with support from doctors (OR 0.6, CI 0.4–1.0). Chronic co-morbidity was related to poor quality of life (OR 12.1, CI 3.6–39.9). Conclusion We found acute and emerging psychiatric co-morbidities less often in patients who reported having a supportive doctor–patient relationship. Patients that require psycho-oncological support often have poor quality of life and have experienced cancer before. Copyright © 2015 John Wiley & Sons, Ltd.

Treatment side effects, comorbidities, and guideline-adherent treatment (GL+) influence the oncologic outcome of older breast cancer patients (oBCP) (age ≥ 70 years). The focus of this analysis was to investigate the associations among tumor characteristics, guideline adherence, and outcome and to compare these associations between younger breast cancer patients (yBCP) (age 50-69 years) and oBCP.This is a retrospective multicenter cohort study with 17 participating certified breast cancer centers. The analysis of 10,897 patient records collected from 1992 to 2008 for GL+ and clinical outcome was performed. Tumor and patient characteristics and their associations with GL+ were compared between oBCP and yBCP.Nonguideline-adherent treatment (GL-) was associated with higher tumor stages and comorbidities. This effect was stronger in the oBCP group (P .001). GL+ was significantly more common in yBCP than in oBCP (P .001). The oBCP had significantly higher tumor stages, including tumor size (P .001), nodal status (P .001), and positive hormone receptors (P = .001). Tumor grading was lower (P = .001), and HER2neu overexpression was less frequent (P = .003) in oBCP. Overall survival and disease-free survival are significantly impaired if GL- occurred in patients with breast cancer independently of age.GL- is associated with decreased disease-free survival and overall survival in both age groups. GL+ decreases advanced tumor characteristics in all age groups but significantly more in oBCP. If patients received GL+, we were unable to detect a statistical significant difference in the survival parameters.

The purpose of this retrospective multicenter study was to resolve the pseudo-paradox that the clinical outcome of women affected by breast cancer has improved during the last 20 years irrespective of whether they were treated in accordance with clinical guidelines or not. This retrospective German multicenter study included 9061 patients with primary breast cancer recruited from 1991 to 2009. We formed subgroups for the time intervals 1991–2000 (TI1) and 2001–2009 (TI2). In these subgroups, the risk of recurrence (RFS) and overall survival (OS) were compared between patients whose treatment was either 100 % guideline-conforming or, respectively, non-guideline-conforming. The clinical outcome of all patients significantly improved in TI2 compared to TI1 [RFS: p

Purpose The tumor biology of older breast cancer patients (oBCP) is usually less aggressive, however applied adjuvant treatment is often less potent resulting in an impaired disease free survival and overall survival in this group. This study tries to answer the following questions for the biological subtypes of oBCP (70+ y): (1) Is there a significant difference in the distribution of the biological subtypes of oBCP vs younger breast cancer patients (yBCP; 50–69 y)? (2) Which biological subtype has the highest rate of non-guideline-adherent-treatment (GL−) among oBCP? (3) Is a single GL− (i.e. radiotherapy/surgery/endocrine-therapy/chemotherapy) significantly associated with the survival outcome in each biological subgroup? Methods Between 1992 and 2008 the BRENDA (‘BRENDA’ = quality of BREast caNcer care unDer evidence-bAsed guidelines) study group recorded medical data of 17 participating certified breast cancer centers in Germany. We performed a retrospective multi-center database analysis of 5632 patient records. Guideline-adherent-treatment (GL+) of oBCP(n = 1918) was compared to GL+ of yBCP(n = 3714). Results OBCP were more likely to have hormone receptor positive (HR+) and HER2 neu negative (HER2−) breast cancer (77.5% vs 74.5%). The rate of GL− was significantly different (p The survival parameters for HR+/HER2− and TNBC were significantly worse in case of GL− regarding chemotherapy, and if applicable endocrine therapy. A similar association only existed in HR−/HER2+ tumors for GL− for radiotherapy and in HR+/HER2+ tumors for chemotherapy. Conclusions Beside the significantly different distribution of biological subtypes in the age groups there is an association between biological subtype, and GL+ influencing survival parameters in oBCP.

Because of substantial toxicities in older adults, chemotherapy is often omitted while the frequency of radiotherapy changes only minimally. In this study, we addressed the value of different assessments for predicting fatigue after radiotherapy in older breast cancer patients. We included 74 women with primary breast cancer over the age of 65 years treated with radiotherapy (26 % with additional chemotherapy). Assessments were conducted before adjuvant treatment and after radiotherapy. The assessments included the Vulnerable Elders Survey (VES-13), the Karnofsky Performance Status (KPS), the EORTC Quality of Life assessment (EORTC-QLQ-C30), a cancer-specific comprehensive geriatric assessment (cancer-specific CGA), and the Fried frailty score. Multiple linear regression analyses were used to assess correlations with the FACIT-fatigue scale. Patients were on average 71 years old (range, 65–86 years). Most tumors (n=62) were classified as intermediate risk according to the St. Gallen consensus. The cancer-specific CGA was best associated with fatigue (p

The question of how to improve healthcare quality and the need for patient empowerment and shared decision-making has been the subject of political and scientific debate for years. In addition to various quality initiatives, "top lists" summarizing selected recommendations to increase awareness of overuse, spread by means of public campaigns, has become popular on the international level - known as the "Choosing Wisely" initiative. However, the trustworthiness of "top lists", their impact on patient-relevant outcomes, their role in and integration into the context of the various pre-existing approaches to improve healthcare quality and the effects of neglecting under- and misuse are not clear. On the other hand, "top lists" may provide new opportunities to improve awareness and dissemination of carefully selected recommendations based on high-quality guidelines. Therefore, the Association of Scientific Medical Societies in Germany (AWMF) has established an ad hoc commission to design a system-specific initiative. The commission has the task to clarify goals, methods of development and concepts for implementation and evaluation, to address concerns and to build upon specific existing resources - e. g., the established quality management system for guidelines in Germany. The key goals defined by the commission include the systematization of the dialogue between healthcare practitioners and patients and the promotion of ethically founded decision-making as an answer to an increasing economic orientation of the healthcare system. To ensure the methodological quality of specific recommendations, the commission has developed a manual. To the best of our knowledge, this manual is the first detailed method paper aiming to guide developers of "Choosing Wisely" recommendations. More than 20 German medical scientific societies have already addressed the subject of "top lists".

Objectives To determine predictive/prognostic factors for patients with metastatic breast cancer (MBC) receiving first-line monochemotherapy using biomarker analysis and geriatric assessment (GA). Materials and Methods Karnofsky Performance Status (KPS) and GA as clinical parameters, and prognostic inflammatory and nutritional index (PINI), and Glasgow prognostic score (GPS) as biomarkers were analyzed for association with clinical outcome within the randomized phase III PEg-LIposomal Doxorubicin vs. CApecitabin iN MBC (PELICAN) trial of first-line pegylated liposomal doxorubicin (PLD) or capecitabine. Results Of 210 patients, 38% were > 65 years old. GA (n = 152) classified 74% as fit, 10% as compromised, and 16% as frail. Biomarkers showed no age dependency. In multivariate analysis (n = 70) KPS, GA, cumulative illness rating scale-geriatrics (CIRS-G), and GPS were significantly associated with time to progression, and KPS, CIRS-G, and instrumental activities of daily living (IADL) from GA, and PINI showed a significant correlation with overall survival. Conclusion GA evaluation was feasible. KPS significantly correlated with efficacy outcomes. Items of a GA and biomarkers of inflammation and nutrition may have prognostic significance in patients with MBC.

Objectives Inguinal lymphadenectomy in vulvar malignancies is associated with significant morbidity, especially in patients over 70years old. Under certain conditions, surgical guidelines recommend biopsy and evaluation of the sentinel node in early vulvar cancer. The purpose of our study is to evaluate ultrasonography as a predictor of inguinal lymph node involvement. Methods A retrospective study was performed with 60 patients who had vulvar malignancies (92% of which were squamous cell carcinomas) and who were treated at our hospital between 2002 and 2012. The patients ranged in age from 35 to 89years, with a median age of 76years. In total, 118 groin scans were retrospectively evaluated for sonographic evidence of lymph node involvement (i.e., absence of fatty hilum, irregular shape, cortical region diameter and vascularization pattern). The results were then compared with histopathologically confirmed lymph node status. Results Histopathologically confirmed lymph node status was available for 107 of the inguinal nodes examined by ultrasound, and lymph node metastases were found in 38 (35.5%) cases. The presence or absence of inguinal lymph node metastases was correctly identified by sonography in 92 (86.0%) of the scanned areas. Sensitivity was 76.3%, specificity was 91.3%, and positive and negative predictive values were 82.9% and 87.5%, respectively. Conclusions Ultrasonography of the inguinal lymph nodes showed a relatively high sensitivity and specificity for predicting inguinal tumor metastases. However, our results indicate that surgical lymph node staging is still needed to precisely determine inguinal lymph node status in vulvar cancer, especially because a missed lymph node-metastasis is often fatal.

Purpose Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use. Patients and Methods The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-β of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed. Results Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093). Conclusion Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.

Work–life balance is an upcoming issue for physicians. The working group “Family and Career” of the German Society for Gynecology and Obstetrics (DGGG) designed a survey to reflect the present work–life balance of female and male gynecologists in Germany. The 74-item, web-based survey “Profession–Family–Career” was sent to all members of the DGGG (n = 4,564). In total, there were 1,036 replies (23 %) from 75 % female gynecologists (n = 775) aged 38 ± 7 (mean ± standard deviation [SD]) years and 25 % male (n = 261) gynecologists aged 48 ± 11 years. Statistical analyses were performed using the mean and SD for descriptive analysis. Regression models were performed considering an effect of p ≤ 0.05 as statistically significant. 47 % women and 46 % men reported satisfaction with their current work–life balance independent of gender (p gender = 0.15). 70 % women and 75 % men answered that work life and private life were equally important to them (p gender = 0.12). While 39 % women versus 11 % men worked part-time (p gender 0.05). At least 37 % women and men neglected both their partner and their children very often due to their work. Female physicians often described their work situation similar to male physicians, although important differences regarding total work time, overtime work and appreciation by supervisors were reported. Work life affected private life of women and men in a similar way.

The pathogenic impact of tumor-infiltrating B cells is unresolved at present, however, some studies suggest that they may have immune regulatory potential. Here, we report that the microenvironment of various solid tumors includes B cells that express granzyme B (GrB, GZMB), where these B cells can be found adjacent to interleukin (IL)-21–secreting regulatory T cells (Treg) that contribute to immune tolerance of tumor antigens. Because Tregs and plasmacytoid dendritic cells are known to modulate T-effector cells by a GrB-dependent mechanism, we hypothesized that a similar process may operate to modulate regulatory B cells (Breg). IL-21 induced outgrowth of B cells expressing high levels of GrB, which thereby limited T-cell proliferation by a GrB-dependent degradation of the T-cell receptor ζ-chain. Mechanistic investigations into how IL-21 induced GrB expression in B cells to confer Breg function revealed a CD19+CD38+CD1d+IgM+CD147+ expression signature, along with expression of additional key regulatory molecules including IL-10, CD25, and indoleamine-2,3-dioxygenase. Notably, induction of GrB by IL-21 integrated signals mediated by surface immunoglobulin M (B-cell receptor) and Toll-like receptors, each of which were enhanced with expression of the B-cell marker CD5. Our findings show for the first time that IL-21 induces GrB+ human Bregs. They also establish the existence of human B cells with a regulatory phenotype in solid tumor infiltrates, where they may contribute to the suppression of antitumor immune responses. Together, these findings may stimulate novel diagnostic and cell therapeutic approaches to better manage human cancer as well as autoimmune and graft-versus-host pathologies. Cancer Res; 73(8); 2468–79. ©2013 AACR.

Background The Z0011-study, a landmark randomised controlled trial (RCT) challenged the benefits of complete axillary lymph node dissection (ALND) compared with sentinel lymph node dissection only (SLND) in breast cancer patients with positive sentinel nodes. The study, however, has been criticised for lack of power and low applicability. The aim of this review was to systematically assess the evidence on the comparative benefits and harms of ALND versus SLND for sentinel node positive breast cancer patients. Methods We systematically searched PubMed, Embase, the Cochrane Library, and reference lists of pertinent review articles from January 2006 to August 2011. We dually reviewed the literature and rated the risk of bias of each study. For effectiveness, we included RCTs and observational studies of at least 1year follow-up. In addition, we considered studies conducted in sentinel node-negative women to assess the risk of harms. If data were sufficient, we conducted random effects meta-analysis of outcomes of interest. Results Meta-analysis of three studies with 50,120 patients indicated similar 5-year survival and regional recurrence rates between patients treated with ALND or SLND, although prognostic tumour characteristics varied among the 3 study-populations. Results from 6 studies on more than 11,500 patients reported a higher risk for harms for ALND than SLND. Long-term evidence on pertinent health outcomes is missing. Conclusion The available evidence indicates that for some women with early invasive breast cancer SLND appears to be a justifiable alternative to ALND. Surgeons need to discuss advantages and disadvantages of both approaches with their patients.

Purpose Visceral metastasis of breast cancer (BC) is an alarming development and correlates with poor median overall survival. The purpose of this retrospective study is to examine the risk factors for developing visceral metastasis by considering tumor biology and patient characteristics. Methods Using the BRENDA database, the risk factors such as histological and intrinsic subtypes of BC, age at primary diagnosis, grading, nodal status, tumor size and year of primary diagnosis were examined in univariate and multivariate analysis. Categorical variables were compared by using χ2 tests. Furthermore, multivariate Cox proportional hazards regression models, Kaplan–Meier product-limit method and log-rank test were applied. The results of two tree-building algorithms, “exhausted CHAID” (Chi-squared Automatic Interaction Detector) and CART (Classification and Regression Trees) were verified with further multivariate analysis, radial basis function networks (RBF-net), feedforward multilayer perceptron networks (MLP) and logistic regression. Results In a patient collective of 886 metastasized patients, 56.9% had developed visceral metastases and 27.1% visceral-only metastases. The different histological and intrinsic subtypes of BC and the grading correlate significantly with the visceral-only metastasis behavior, whereas the age at primary diagnosis, the nodal status, the tumor size and the year of the primary diagnosis had no influence. Patients with ductal/other BC, LuminalB/HER2, TNBC, HER2 overexpressing subtype and grade 3 had an increased risk for the development of visceral-only metastasis. Conclusions Intrinsic and histological subtypes as well as the grading of BC affected significantly the visceral metastasis behavior.

In the treatment of breast cancer, decisions on adjuvant treatment reflect individual patient characteristics like age and comorbidity. This study assessed the association between adherence to guidelines for adjuvant treatment and survival while taking into account age at diagnosis and comorbidities. We collected the Charlson comorbidity index at baseline for 2179 women treated for primary breast cancer from 1992 to 2008 who participated in a German retrospective multicenter cohort study. We assessed subsequent adjuvant therapy guideline adherence and survival in relation to baseline comorbidities. Guidelines for adjuvant chemotherapy and radiotherapy were more often violated in patients with higher Charlson score. Patients with higher Charlson scores received chemotherapy and radiotherapy less often and had higher rates of mastectomy. Irrespective of comorbidity (Charlson score 0, 1-2, ≥3), patients with 100% guideline-adherent adjuvant treatment showed better overall and disease-free survival (DFS) compared to patients with guideline violations (GVs). Controlling for age, comorbidity and tumor characteristics, the hazard ratio for at least one GV was 1.65 (95% confidence interval [CI]: 1.33-2.07) for overall survival and 1.84 (95% CI: 1.53-2.22) for DFS. Guideline-adherent treatment was significantly less frequent in comorbid patients, although guideline adherence was strongly associated with improved survival, irrespective of severity, and number of comorbid diseases.

Background Mammography and ultrasound are the gold standard imaging techniques for preoperative assessment and for monitoring the efficacy of neoadjuvant chemotherapy in breast cancer. Maximum accuracy in predicting pathological tumor size non-invasively is critical for individualized therapy and surgical planning. We therefore aimed to assess the accuracy of tumor size measurement by ultrasound and mammography in a multicentered health services research study. Methods We retrospectively analyzed data from 6543 patients with unifocal, unilateral primary breast cancer. The maximum tumor diameter was measured by ultrasound and/or mammographic imaging. All measurements were compared to final tumor diameter determined by postoperative histopathological examination. We compared the precision of each imaging method across different patient subgroups as well as the method-specific accuracy in each patient subgroup. Results Overall, the correlation with histology was 0.61 for mammography and 0.60 for ultrasound. Both correlations were higher in pT2 cancers than in pT1 and pT3. Ultrasound as well as mammography revealed a significantly higher correlation with histology in invasive ductal compared to lobular cancers (p

Background The development of metastases is a negative prognostic parameter for the clinical outcome of breast cancer. Bone constitutes the first site of distant metastases for many affected women. The purpose of this retrospective multicentre study was to evaluate if and how different variables such as primary tumour stage, biological and histological subtype, age at primary diagnosis, tumour size, the number of affected lymph nodes as well as grading influence the development of bone-only metastases. Methods This retrospective German multicentre study is based on the BRENDA collective and included 9625 patients with primary breast cancer recruited from 1992 to 2008. In this analysis, we investigated a subgroup of 226 patients with bone-only metastases. Association between bone-only relapse and clinico-pathological risk factors was assessed in multivariate models using the tree-building algorithms “exhausted CHAID (Chi-square Automatic Interaction Detectors)” and CART(Classification and Regression Tree), as well as radial basis function networks (RBF-net), feedforward multilayer perceptron networks (MLP) and logistic regression. Results Multivariate analysis demonstrated that breast cancer subtypes have the strongest influence on the development of bone-only metastases (χ2 = 28). 29.9 % of patients with luminal A or luminal B (ABC-patients) and 11.4 % with triple negative BC (TNBC) or HER2-overexpressing tumours had bone-only metastases (p