[Register and cohort studies : Overview of the most important data sources at the German Rheumatism Research Center]. / Register- und Kohortenstudien : Eine Übersicht über die wichtigsten Datenquellen am Deutschen Rheuma-Forschungszentrum.

Over the past 28 years the German Rheumatism Research Center in Berlin has initiated various epidemiological studies in which data on patients with inflammatory rheumatic diseases are collected nationwide and multicentric. The spectrum ranges from rheumatoid arthritis and spondylarthritis to connective tissue diseases and rheumatic diseases in childhood. Based on the respective scientific question, studies of different types were established. The German National Databases for adults and children annually collect cross-sectional data to map the care of patients. In two inception cohorts, adults with early arthritis and patients with juvenile idiopathic arthritis are investigated from disease onset. The long-term observational cohorts/registries RABBIT, RABBIT-SpA and JuMBO focus on the long-term efficacy and safety of biologic drugs and other targeted treatments. Rhekiss investigates women with inflammatory rheumatic diseases when trying to become pregnant, during pregnancy and postpartum. This article highlights each of these observational studies with its characteristics as well as national and international collaborations.

[Perspectives for rheumatological health services research at the German Rheumatism Research Center]. / Perspektiven für die rheumatologische Versorgungsforschung am Deutschen Rheuma-Forschungszentrum.

This review article summarizes the current projects and perspectives of rheumatological healthcare research in the program area epidemiology of the German Rheumatism Research Center. Health services research is conducted with the help of various data sources. In addition to the classical rheumatological disease registers, health insurance data and population-related cohorts are increasingly being used for analyses. From data collection and monitoring to analysis algorithms, digital applications will change the healthcare research over the coming years. Collaborative analyses with national and international cooperation partners, including biomarkers, complete the research fields in the program area epidemiology. The digitalization of research projects is a central component that will further change health services research in the coming decade.

[RABBIT-SpA: a new disease register for axial spondyloarthritis and psoriatic arthritis]. / RABBIT-SpA: ein neues Krankheitsregister für axiale Spondyloarthritis und Psoriasisarthritis.

BACKGROUND: The treatment of axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) has changed enormously in recent years due to market authorization of a number of new biologicals with different modes of action and the increasing use of biosimilars. Real-world data on long-term safety and efficacy under routine daily conditions is not yet sufficient. Therefore, the German Rheumatism Research Center has initiated a new cohort study covering axSpA and PsA. OBJECTIVE: Presentation of initial results from the new register RABBIT-SpA, which was started in May 2017. MATERIAL AND METHODS: This is a prospective longitudinal cohort study with a similar study design to the German biologics register RABBIT. Patients can be included at the start of a new treatment either in the so-called index drug group or in the comparison group (conventional systemic treatment, including non-steroidal anti-inflammatory drugs, NSAID). Follow-up per patient should be at least 5 years and preferably 10 years. The RABBIT-SpA uses a web-based documentation system. RESULTS: Up to mid-December 2018 a total of 514 axSpA patients had been documented in RABBIT-SpA, 410 with an index drug and 104 with conventional treatment. There are differences between these treatment groups, e. g. in the duration of the disease and in parameters of disease activity. It is also noticeable that in axSpA patients, approximately 5 years lie between the onset of the symptoms and confirmation of the diagnosis. Of the 355 PsA patients, 265 were included with an index drug and 90 with conventional treatment. Of the PsA patients 86% have a dominant peripheral manifestation. The average number of pressure tender joints is 8 and the average number of swollen joints is 4. CONCLUSION: The online register RABBIT-SpA is well-received by the participating rheumatological institutions. The electronic recording of patient data can be carried out in a reasonable time. Participation in the RABBIT-SpA is open to new rheumatological institutions at any time.

Metastatic breast cancer: are we treating the same patients as in the past?

BACKGROUND: Early detection and improved (neo)-adjuvant treatment has extended survival of breast cancer over the last decades. It remains controversial whether a survival benefit is achieved once metastases have occurred. This study investigates survival trends in metastatic breast cancer (MBC) looking at the distribution of prognostic factors and the time period of the diagnosis of the primary and metastatic disease. PATIENTS AND METHODS: In this retrospective study, 1635 patients, diagnosed with MBC and treated at three German cancer centers, were included. For the survival analysis, patients were grouped into three time periods [1980-1994 (a), 1995-1999 (b) and 2000-2009 (c)], which were chosen according to the availability of new antineoplastic drugs for the treatment of MBC. Additionally, patients were divided into three risk groups using the simultaneously published prognostic score. RESULTS: The analysis of overall survival according to the date of primary diagnosis demonstrated a significant decline compared with the reference (a): (a versus b) hazard ratio (HR) = 1.37; P < 0.001; (a versus c) HR = 2.45; P < 0.001. Considering the time of first occurrence of metastasis, survival remains unchanged over the three periods (a versus b): HR = 0.94 P = 0.436; (a versus c): HR = 0.95; P = 0.435. However, a significant shift towards more unfavorable risk factors was seen. CONCLUSIONS: Although survival in MBC remains unchanged over time, patients developing metastatic disease have a more aggressive disease that is presumably compensated by more effective treatment. This alteration of tumor biology in MBC may be explained by a negative selection of patients with adverse risk profiles due to the advantages of the adjuvant therapy.

An internally and externally validated prognostic score for metastatic breast cancer: analysis of 2269 patients.

BACKGROUND: The prognosis of metastatic breast cancer (MBC) is extremely heterogeneous. Although patients with MBC will uniformly die to their disease, survival may range from a few months to several years. This underscores the importance of defining prognostic factors to develop risk-adopted treatment strategies. Our aim has been to use simple measures to judge a patient's prognosis when metastatic disease is diagnosed. PATIENTS AND METHODS: We retrospectively analyzed 2269 patients from four clinical cancer registries. The prognostic score was calculated from the regression coefficients found in the Cox regression analysis. Based on the score, patients were classified into high-, intermediate-, and low-risk groups. Bootstrapping and time-dependent receiver operating characteristic curves were used for internal validation. Two independent datasets were used for external validation. RESULTS: Metastatic-free interval, localization of metastases, and hormone receptor status were identified as significant prognostic factors in the multivariate analysis. The three prognostic groups showed highly significant differences regarding overall survival from the time of metastasis [intermediate compared with low risk: hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.36-2.27, P < 0.001; high compared with low risk: HR 3.54, 95% CI 2.81-4.45, P < 0.001). The median overall survival in these three groups were 61, 38, and 22 months, respectively. The external validation showed congruent results. CONCLUSIONS: We developed a prognostic score, based on routine parameters easily accessible in daily clinical care. Although major progress has been made, the optimal therapeutic management of the individual patient is still unknown. Besides elaborative molecular classification of tumors, simple clinical measures such as our model may be helpful to further individualize optimal breast cancer care.

A comparison of international breast cancer guidelines - do the national guidelines differ in treatment recommendations?

AIM OF THE STUDY: Clinical practice guidelines (CPG) are an appropriate method to optimise routine clinical care. Numerous CPGs for the diagnosis and treatment of breast cancer have been developed by national health institutions or medical societies. While a comparison of methodological criteria has been undertaken before, it is unknown whether these CPGs differ in their actual treatment recommendations. METHODS: We included national breast cancer CPGs from the USA, Canada, Australia, the UK, and Germany that satisfy internationally recognised methodological criteria and are in widespread use in daily clinical care. Treatment recommendations for adjuvant invasive breast cancer including surgery, radiation, endocrine therapy, chemotherapy and anti-HER2-therapy were compared. RESULTS: Recommendations for endocrine therapy show discordances regarding optimal usage of ovarian function suppression for premenopausal patients and aromatase inhibitors for postmenopausal patients. However, most other treatment recommendations exhibit a large degree of congruency. This reflects the fact that they rest on the same evidence base, and that many national guidelines are adopted from other guidelines so that well accepted guidelines are cited within other guidelines. CONCLUDING STATEMENT: Considering that the development of guidelines is a very expensive and resource-intensive task the question arises whether the development of national guidelines in numerous countries is worth the effort since the recommendations differ only marginally.

Endocrine therapy in obese patients with primary breast cancer: another piece of evidence in an unfinished puzzle.

Obesity, defined as a body mass index (BMI) ≥30 is an independent risk factor in breast cancer and is correlated with shorter survival and enhanced recurrence rates. The present subgroup analysis of the German BRENDA-cohort aimed to investigate the correlation between BMI, recurrence-free survival (RFS) and adjuvant endocrine therapy. In this subgroup analysis, 4,636 patients were retrospectively examined using multivariate analyses. Overall 3,759 (81.1%) patients had a BMI <30 (non-obese) and 877 (18.9%) a BMI ≥30 (obese). In the group of all 3,896 (84.0%) patients with hormone-receptor-positive (HR+) breast carcinomas a significant reduction in RFS was demonstrated for those who were obese (P = 0.002; HR = 1.45 (95% CI: 1.15-1.83)), also after adjustment for Nottingham Prognostic Index (NPI) (P = 0.028; HR = 1.30 (95% CI: 1.03-1.65)). In hormone-receptor-negative (HR-) patients BMI had no influence on RFS (P = 0.380; HR = 1.20 (95% CI: 0.80-1.81)). Considering menopausal status, a significantly shorter RFS was seen in postmenopausal obese than in non-obese patients (P < 0.001; HR = 1.61 (95% CI: 1.24-2.09)), whereas the premenopausal patient group only showed a trend towards a shorter RFS (P = 0.202; HR = 1.44 (95% CI: 0.82-2.53)). The group of HR+ postmenopausal patients with normal or intermediate weight showed a non-significant statistical trend towards a survival benefit for aromatase inhibitors (AI) compared to tamoxifen (RFS: P = 0.486; HR = 1.29 (95% CI: 0.63-2.62), while obese patients tended to benefit more from tamoxifen (RFS: P = 0.289; HR = 0.65 (95% CI: 0.29-1.45)). In accordance with recently published results we demonstrated a negative effect of a high BMI on outcome in primary breast cancer. Furthermore the efficacy of AI seems dependent on BMI in contrast to tamoxifen. Prospective studies to optimise the therapy of obese breast cancer patients are urgently needed.

High estrogen receptor expression in early breast cancer: chemotherapy needed to improve RFS?

One of the most controversial questions in early breast cancer treatment is the need of chemotherapy in patients with estrogen receptor positive disease. Therefore, we analyzed a group of patients with high estrogen receptor (ER) expression to scrutinize the role of chemotherapy in this situation. To gauge the effect of chemotherapy on recurrence free survival (RFS) three treatment modalities were compared: endocrine treatment only, chemoendocrine treatment, and chemotherapy. 3,971 breast cancer patients whose treatment modalities as well as ER level were known, were included in this retrospective analysis. Their level of ER expression was documented as immunoreactive score (IRS). A high ER group was defined as ER IRS ≥ 9; primary endpoint was RFS. RFS was associated with ER, with the best outcome for strong and the worst result for negative expression. Adjusted to Nottingham prognostic index (NPI), RFS did not differ between the treatment cohorts of endocrine treatment and chemoendocrine treatment (P = 0.828) in the high ER group. Patients with chemotherapy alone fared significantly worse (P = 0.003). Even in high risk patients (according to NPI) the chemoendocrine and the endocrine treatment only groups did not differ significantly (HR = 1.15; 95% CI (0.56-2.34), P = 0.709). Omission of endocrine treatment led to significantly worse outcome (P = 0.013). In conclusion, RFS was significantly longer in patients with high ER expression than with weak or no ER expression. In the high expression group, there was no significant difference in RFS between endocrine treatment only and chemoendocrine therapy-even in high risk patients, for whom chemoendocrine treatment is routinely indicated. It seems insufficient for high ER patients to only consider tumor size, nodal status, and grading in order to decide which patient will benefit from adding chemotherapy to endocrine treatment.

A phase I/II study of bortezomib and capecitabine in patients with metastatic breast cancer previously treated with taxanes and/or anthracyclines.

BACKGROUND: Proteasome inhibitors are a novel class of compounds entering clinical trials as a method to increase tumour sensitivity to standard chemotherapy. This phase I/II trial was carried out to evaluate the combination of capecitabine and the proteasome inhibitor bortezomib in anthracycline and/or taxane-pretreated patients with metastatic breast cancer. PATIENTS AND METHODS: A total of 35 patients were treated with bortezomib (1.0-1.3 mg/m(2) on days 1, 4, 8 and 11) and capecitabine (1500-2500 mg/m(2) on days 1-14) in 3-week intervals for up to eight cycles. RESULTS: The maximum tolerated doses (MTDs) were bortezomib 1.3 mg/m(2) and capecitabine 2500 mg/m(2). The treatment was generally well tolerated and associated with toxic effects that were consistent with the known side-effects of the individual agents. The intent-to-treat overall response rate was 15% and an additional 27% of patients had stable disease (SD). In the 20 patients treated at the MTD, the response rate was 15% and 40% had SD. Median time to progression and overall survival were 3.5 months [95% confidence interval (CI) 1.9-4.4] and 7.5 months (95% CI 5.6-14.6), respectively. Median duration of response was 4.4 months. CONCLUSION: The combination of bortezomib and capecitabine is well tolerated and has moderate antitumour activity in heavily pretreated patients.