Heregulin (HRG) assessment for clinical trial eligibility testing in a molecular registry (PRAEGNANT) in Germany.

BACKGROUND: Eligibility criteria are a critical part of clinical trials, as they define the patient population under investigation. Besides certain patient characteristics, clinical trials often include biomarker testing for eligibility. However, patient-identification mostly relies on the trial site itself and is often a time-consuming procedure, which could result in missing out on potentially eligible patients. Pre-selection of those patients using a registry could facilitate the process of eligibility testing and increase the number of identified patients. One aim with the PRAEGNANT registry (NCT02338167) is to identify patients for therapies based on clinical and molecular data. Here, we report eligibility testing for the SHERBOC trial using the German PRAEGNANT registry. METHODS: Heregulin (HRG) has been reported to identify patients with better responses to therapy with the anti-HER3 monoclonal antibody seribantumab (MM-121). The SHERBOC trial investigated adding seribantumab (MM-121) to standard therapy in patients with advanced HER2-negative, hormone receptor-positive (HR-positive) breast cancer and HRG overexpression. The PRAEGNANT registry was used for identification and tumor testing, helping to link potential HRG positive patients to the trial. Patients enrolled in PRAEGNANT have invasive and metastatic or locally advanced, inoperable breast cancer. Patients eligible for SHERBOC were identified by using the registry. Study aims were to describe the HRG positivity rate, screening procedures, and patient characteristics associated with inclusion and exclusion criteria. RESULTS: Among 2769 unselected advanced breast cancer patients, 650 were HER2-negative, HR-positive and currently receiving first- or second-line treatment, thus potentially eligible for SHERBOC at the end of current treatment; 125 patients also met further clinical eligibility criteria (e.g. menopausal status, ECOG). In the first/second treatment lines, patients selected for SHERBOC based on further eligibility criteria had a more favorable prognosis than those not selected. HRG status was tested in 38 patients, 14 of whom (36.8%) proved to be HRG-positive. CONCLUSION: Using a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials. TRIAL REGISTRATION: Clinicaltrials, NCT02338167 , Registered 14 January 2015 - retrospectively registered.

Cost effectiveness of bilateral risk-reducing mastectomy and salpingo-oophorectomy.

BACKGROUND: Growing demand for risk-reducing surgery in individuals with inherited susceptibility to cancer leads to the question whether these procedures are cost effective for the executing hospitals. This study compared the clinical costs for bilateral risk-reducing mastectomy (BRRM) with and without different types of reconstruction, risk-reducing salpingo-oophorectomy (RRSO), and their combinations with corresponding reimbursements in the statutory health-care system in Germany. PATIENTS AND METHODS: Real total costs of care for BRRM with and without reconstruction, RRSO, and their combinations were calculated as the sum of all personnel and technical costs. These costs calculated in a German University hospital were compared with the sum of all reimbursements in the German DRG-based health-care system. RESULTS: While sole RRSO, BRRM without reconstruction, and BRRM with secondary DIEP (deep inferior epigastric perforator)-reconstruction still result in a small benefit, we even found shortfalls for the hospital with all other prophylactic operations under consideration. The calculated deficits were especially high for BRRM with implant-based breast reconstruction and for combined operations when the risk reduction is achieved with a minimum of separate operations. CONCLUSIONS: Risk-reducing surgery in BRCA-mutation carriers is frequently not cost-covering for the executing hospitals in the German health-care system. Thus, appropriate concepts are required to ensure a nationwide care.

Filtration based assessment of CTCs and CellSearch® based assessment are both powerful predictors of prognosis for metastatic breast cancer patients.

BACKGROUND: The assessment of circulating tumor cells (CTCs) has been shown to enable monitoring of treatment response and early detection of metastatic breast cancer (MBC) recurrence. The aim of this study was to compare a well-established CTC detection method based on immunomagnetic isolation with a new, filtration-based platform. METHODS: In this prospective study, two 7.5 ml blood draws were obtained from 60 MBC patients and CTC enumeration was assessed using both the CellSearch® and the newly developed filtration-based platform. We analyzed the correlation of CTC-positivity between both methods and their ability to predict prognosis. Overall survival (OS) was calculated and Kaplan-Meier curves were estimated with thresholds of ≥1 and ≥5 detected CTCs. RESULTS: The CTC positivity rate of the CellSearch® system was 56.7% and of the filtration-based platform 66.7%. There was a high correlation of CTC enumeration obtained with both methods. The OS for patients without detected CTCs, regardless of the method used, was significantly higher compared to patients with one or more CTCs (p < 0.001). The median OS of patients with no CTCs vs. ≥ 1 CTC assessed by CellSearch® was 1.83 years (95% CI: 1.63-2.02) vs. 0.74 years (95% CI: 0.51-1.52). If CTCs were detected by the filtration-based method the median OS times were 1.88 years (95% CI: 1.74-2.03) vs. 0.59 years (95% CI: 0.38-0.80). CONCLUSIONS: The newly established EpCAM independently filtration-based system is a suitable method to determine CTC counts for MBC patients. Our study confirms CTCs as being strong predictors of prognosis in our population of MBC patients.

Cost-effectiveness of risk-reducing surgeries in preventing hereditary breast and ovarian cancer.

OBJECTIVES: Risk-reducing surgeries are a feasible option for mitigating the risk in individuals with inherited susceptibility to cancer, but are the procedures cost-effective in the current health-care system in Germany? This study compared the health-care costs for bilateral risk-reducing mastectomy (BRRM) and risk-reducing (bilateral) salpingo-oophorectomy (RRSO) with cancer treatment costs that could potentially be prevented. PATIENTS AND METHODS: The analysis is based on interdisciplinary consultations with individuals with a high familial risk for breast and ovarian cancer at the University Breast Center for Franconia (Germany) between 2009 and 2013 (370 consultations; 44 patients with BRCA1 mutations and 26 with BRCA2 mutations). Health-care costs for risk-reducing surgeries in BRCA mutation carriers were calculated as reimbursements in the German diagnosis-related groups (DRG) hospital pricing system. These costs for the health-care system were compared with the potential cancer treatment costs that could possibly be prevented by risk-reducing surgeries. RESULTS: Long-term health-care costs can be reduced by risk-reducing surgeries after genetic testing in BRCA mutation carriers. The health-care system in Germany would have saved € 136,295 if BRRM had been performed and € 791,653 if RRSO had been performed before the development of cancer in only 50% of the 70 mutation carriers seen in our center. Moreover, in patients with combined RRSO and BRRM (without breast reconstruction), one further life-year for a 40-year-old BRCA mutation carrier would cost € 2,183. CONCLUSION: Intensive care, including risk-reducing surgeries in BRCA mutation carriers, is cost-effective from the point of view of the health-care system in Germany.

Subjective assessment of ovarian masses using pattern recognition: the impact of experience on diagnostic performance and interobserver variability.

PURPOSE: To compare diagnostic performance and interobserver variability in a group of 36 examiners, with four different levels of experience. METHODS: Nine junior trainees, eight level I senior trainees, 11 level II senior gynecologists, and eight level III expert sonologists classified 105 ultrasound images of adnexal masses into three subgroups of ovarian lesions (malignancies, functional cysts, and dermoid cysts). RESULTS: The level III sonologists obtained the best diagnostic results together with the lowest interobserver variability (κ = 0.70, SD = 0.04). They achieved significantly better results in comparison with the junior trainees and also the senior trainees (κ = 0.51, SD = 0.12, p < 0.001; and κ = 0.51, SD = 0.09, p < 0.001). Differences between level III sonologists and the group of level II observers did not reach statistical significance (κ = 0.65, SD = 0.09, p = 0.70). There were no significant differences between senior and junior trainees (p = 1.0) and both groups achieved a significantly poorer diagnostic performance in comparison with the level II observers (p < 0.01 and p < 0.01). For all observers, the largest differences were seen for classifying malignancies, the best results for classifying functional cysts, and the poorest for evaluating dermoid cysts. CONCLUSIONS: Diagnostic performance of pattern recognition significantly improves with an increasing level of experience, emphasizing the importance of standardized ultrasound training programs with supervision by experts.

Radiation dose considerations by intra-individual Monte Carlo simulations in dual source spiral coronary computed tomography angiography with electrocardiogram-triggered tube current modulation and adaptive pitch.

OBJECTIVES: To evaluate radiation dose levels in patients undergoing spiral coronary computed tomography angiography (CTA) on a dual-source system in clinical routine. METHODS: Coronary CTA was performed for 56 patients with electrocardiogram-triggered tube current modulation (TCM) and heart-rate (HR) dependent pitch adaptation. Individual Monte Carlo (MC) simulations were performed for dose assessment. Retrospective simulations with constant tube current (CTC) served as reference. Lung tissue was segmented and used for organ and effective dose (ED) calculation. RESULTS: Estimates for mean relative ED was 7.1 ± 2.1 mSv/100 mAs for TCM and 12.5 ± 5.3 mSv/100 mAs for CTC (P < 0.001). Relative dose reduction at low HR (≤60 bpm) was highest (49 ± 5%) compared to intermediate (60-70 bpm, 33 ± 12%) and high HR (>70 bpm, 29 ± 12%). However lowest ED is achieved at high HR (5.2 ± 1.5 mSv/100 mAs), compared with intermediate (6.7 ± 1.6 mSv/100 mAs) and low (8.3 ± 2.1 mSv/100 mAs) HR when automated pitch adaptation is applied. CONCLUSIONS: Radiation dose savings up to 52% are achievable by TCM at low and regular HR. However lowest ED is attained at high HR by pitch adaptation despite inferior radiation dose reduction by TCM. KEY POINTS: • Monte Carlo simulations allow for individual radiation dose calculations. • ECG-triggered tube current modulation (TCM) can effectively reduce radiation dose. • Slow and regular heart rates allow for highest dose reductions by TCM. • Adaptive pitch accounts for lowest radiation dose at high heart rates. • Women receive higher effective dose than men undergoing spiral coronary CT-angiography.

Assessment of breast cancer tumour size using six different methods.

OBJECTIVES: Tumour size estimates using mammography (MG), conventional ultrasound (US), compound imaging (CI) and real-time elastography (RTE) were compared with histopathological specimen sizes. METHODS: The largest diameters of 97 malignant breast lesions were measured. Two US and CI measurements were made: US1/CI1 (hypoechoic nucleus only) and US2/CI2 (hypoechoic nucleus plus hyperechoic halo). Measurements were compared with histopathological tumour sizes using linear regression and Bland-Altman plots. RESULTS: Size prediction was best with ultrasound (US/CI/RTE: R (2) 0.31-0.36); mammography was poorer (R(2) = 0.19). The most accurate method was US2, while US1 and CI1 were poorest. Bland-Altman plots showed better size estimation with US2, CI2 and RTE, with low variation, while mammography showed greatest variability. Smaller tumours were better assessed than larger ones. CI2 and US2 performed best for ductal tumours and RTE for lobular cancers. Tumour size prediction accuracy did not correlate significantly with breast density, but on MG tumours were more difficult to detect in high-density tissue. CONCLUSIONS: The size of ductal tumours is best predicted with US2 and CI2, while for lobular cancers RTE is best. Hyperechoic tumour surroundings should be included in US and CI measurements and RTE used as an additional technique in the clinical staging process.

Exercise effects on bone mineral density, falls, coronary risk factors, and health care costs in older women: the randomized controlled senior fitness and prevention (SEFIP) study.

BACKGROUND: Physical exercise affects many risk factors and diseases and therefore can play a vital role in general disease prevention and treatment of elderly individuals and may reduce costs. We sought to determine whether a single exercise program affects fracture risk (bone mineral density [BMD] and falls), coronary heart disease (CHD) risk factors, and health care costs in community-dwelling elderly women. METHODS: We conducted a randomized, single-blinded, controlled trial from May 1, 2005, through July 31, 2008, recruiting women 65 years or older who were living independently in the area of Erlangen-Nuremberg, Germany. In all, 246 women were randomly assigned to an 18-month exercise program (exercise group) or a wellness program (control group). The exercise group (n = 123) performed a multipurpose exercise program with special emphasis on exercise intensity; the controls (n = 123) focused on well-being with a low-intensity, low-frequency program. The main outcome measures were BMD, the number of falls, the Framingham-based 10-year CHD risk, and direct health care costs. RESULTS: For the 227 women who completed the 18-month study, significant exercise effects were observed for BMD of the lumbar spine (mean [95% confidence interval (CI)] percentage of change in BMD [baseline to follow-up] for the exercise group: 1.77% [1.26% to 2.28%] vs controls: 0.33% [-0.24% to 0.91%]; P < .001), femoral neck (exercise group: 1.01% [0.37% to 1.65%] vs controls: -1.05% [-1.70% to -0.40%]; P < .001), and fall rate per person during 18 months (exercise group: 1.00 [0.76 to 1.24] vs controls: 1.66 [1.33 to 1.99]; P = .002). The 10-year CHD risk was significantly affected in both subgroups (absolute change for the exercise group: -1.96% [95% CI, -2.69% to -1.23%] vs controls: -1.15% [-1.69% to -0.62%]; P = .22), with no significant difference between the groups. The direct health care costs per participant during the 18-month intervention showed nonsignificant differences between the groups (exercise group: 2255 euros[95% CI, 1791 euros-2718 euros] vs controls: 2780 euros [2187 euros-3372 euros]; P = .20). CONCLUSION: Compared with a general wellness program, our 18-month exercise program significantly improved BMD and fall risk, but not predicted CHD risk, in elderly women. This benefit occurred at no increase in direct costs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00267839.

Assessment of multiple ordinal endpoints.

Ranking multivariate ordinal data and applying a non-parametric test is an analytical approach commonly employed to compare treatments. We study three types of ranking and demonstrate how to combine them. The ranking methods rest upon partial orders of the multidimensional measurements or upon the sum of ranks. Since their usage is simple as regards statistical assumptions and technical realization, they are also adapted for health professionals without deep statistical knowledge. Our goal is discussing differences between the approaches and disclosing possible statistical consequences of their usage.