Matthias Rübner

Integration of Piezoceramic Modules into Die Castings - Procedure and Functionalities

The complete integration of piezoceramic sensor/actuator-modules into metal components using high pressure die casting is a promising approach for the fabrication of multifunctional structural elements with enhanced properties. A technique providing stabilization and protection of the module during the highly dynamic mould filling is presented. Demonstration parts are produced which are fully capable to detect vibrations. An approach to characterize this sensory functionality of the adaptronic system is presented.

Genetic variants in VEGF pathway genes in neoadjuvant breast cancer patients receiving bevacizumab: Results from the randomized phase III GeparQuinto study.

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression‐free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2‐negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre‐planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF‐A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49–3.75), 1.20 (95% CI, 0.88–1.64) and 0.61 (95% CI, 0.34–1.12). Notably, some SNPs in VEGF‐A exhibited a more pronounced effect in the triple‐negative subgroup. Several SNPs in VEGF‐A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.

Genetic variants in VEGF pathway genes in neoadjuvant breast cancer patients receiving bevacizumab

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression‐free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2‐negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre‐planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF‐A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49–3.75), 1.20 (95% CI, 0.88–1.64) and 0.61 (95% CI, 0.34–1.12). Notably, some SNPs in VEGF‐A exhibited a more pronounced effect in the triple‐negative subgroup. Several SNPs in VEGF‐A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.

Influence of the fabrication process on the functionality of piezoceramic patch transducers embedded in aluminum die castings

Piezoceramic patch transducers are integrated into aluminum components using high-pressure die casting. Expanded metal has proven suitable as a supporting structure for placing the patch transducers inside the die cavity and for stabilization during the injection of molten metal. However, difficulties arise when the transducers are positioned off the neutral axis within the wall of the casting. Numerical simulations of the die filling are performed to analyse the evolution of the integration process. The asymmetric infiltration of the supporting structure is identified as the major factor contributing to the formation of cracks and perforations inside the piezoceramic transducer. By means of measurements and numerical calculations of the electrical impedance of the transducer, a close relation is established between mechanical damage patterns observed in radiographs of the patch transducers and loss of performance.

Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer

Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503–10. ©2016 AACR.

Abstract S5-06: BRCA mutations, therapy response and prognosis in the neoadjuvant GeparQuinto study

Background: Mutations in BRCA1 and BRCA2 influence the molecular pathogenesis of breast cancer. However, little is known about the association between mutations, response to therapy, and prognosis. We therefore analysed these associations in triple negative breast cancer (TNBC) patients in the neoadjuvant GeparQuinto Study. Methods: The GeparQuinto study recruited 1956 patients with HER2 negative disease including a prespecified group of 671 TNBC patients with untreated breast cancer. Patients were randomized to receive four cycles EC (90/600 mg/m2; q3w) followed by four cycles docetaxel (100 mg/m2; q3w), with or without bevacizumab (15 mg/kg). Here we present the analysis for both randomization arms combined. Sufficient blood was available of 482 TNBC patients. BRCA1 and BRCA2 genotyping was successful in 469 patients with available germline DNA and was conducted by SureSelect custom capture and sequencing on HiSeq 2500. Mutation status was correlated with pathological complete response rates (pCR) and disease free survival (DFS). Results: A total of 74 (15.8%) mutations in BRCA1 (n=61) and BRCA2 (n=13) were detected after initial sequencing. A pCR (ypT0/ypN0) was observed in 50% (n=37) of mutation carriers but only 31.1% (n=123) of patients without mutations (p=0.002). Similar results were observed for pCR (pT0is/pN0) (52.7% vs. 36.5%; p=0.010). pCR (ypT0/ypN0) was predictive of disease free survival (DFS) in all patients (Hazard Ratio, HR=0.23; 95%CI: 0.15-0.37; p Conclusion: TNBC Patients with BRCA mutations showed a higher frequency of pCR than patients without BRCA mutations after treatment with epirubicin, cyclophosphamide and docetaxel (+/ bevacizumab), suggesting that BRCA mutations may influence pCR in response to treatment regimens that do not include platin chemotherapy. pCR as a surrogate marker for DFS was also confirmed in patients without BRCA mutations. In addition, the effect of pCR on prognosis seemed to be smaller among the mutation carriers, although the number of mutation carriers was too low to test for differences between mutation carriers and wildtype patients. The project has partly been funded within NIH-NIGMS U19 GM61388 and the Breast Cancer Research Foundation. Citation Format: Fasching PA, Loibl S, Eidtmann H, Tesch H, Untch M, Hilfrich J, Schem C, Rezai M, Gerber B, Costa SD, Blohmer JU, Fehm TN, Huober J, Liedtke C, Muller V, Nekljudova V, Weber K, Rack B, Rubner M, Wang L, Ingle JN, Weinshilboum RM, von Minckwitz G, Couch F. BRCA mutations, therapy response and prognosis in the neoadjuvant GeparQuinto study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-06.

Genetic risk factors for ovarian cancer and their role for endometriosis risk

OBJECTIVE Several genetic variants have been validated as risk factors for ovarian cancer. Endometriosis has also been described as a risk factor for ovarian cancer. Identifying genetic risk factors that are common to the two diseases might help improve our understanding of the molecular pathogenesis potentially linking the two conditions. METHODS In a hospital-based case-control analysis, 12 single nucleotide polymorphisms (SNPs), validated by the Ovarian Cancer Association Consortium (OCAC) and the Collaborative Oncological Gene-environment Study (COGS) project, were genotyped using TaqMan® OpenArray™ analysis. The cases consisted of patients with endometriosis, and the controls were healthy individuals without endometriosis. A total of 385 cases and 484 controls were analyzed. Odds ratios and P values were obtained using simple logistic regression models, as well as from multiple logistic regression models with adjustment for clinical predictors. RESULTS rs11651755 in HNF1B was found to be associated with endometriosis in this case-control study. The OR was 0.66 (95% CI, 0.51 to 0.84) and the P value after correction for multiple testing was 0.01. None of the other genotypes was associated with a risk for endometriosis. CONCLUSIONS As rs11651755 in HNF1B modified both the ovarian cancer risk and also the risk for endometriosis, HNF1B may be causally involved in the pathogenetic pathway leading from endometriosis to ovarian cancer.

Predicting Triple-Negative Breast Cancer Subtype Using Multiple Single Nucleotide Polymorphisms for Breast Cancer Risk and Several Variable Selection Methods

INTRODUCTION Studies of triple-negative breast cancer have recently been extending the inclusion criteria and incorporating additional molecular markers into the selection criteria, opening up scope for targeted therapies. The screening phases required for studies of this type are often prolonged, since the process of determining the molecular subtype and carrying out additional biomarker assessment is time-consuming. Parameters such as germline genotypes capable of predicting the molecular subtype before it becomes available from pathology might be helpful for treatment planning and optimizing the timing and cost of screening phases. This appears to be feasible, as rapid and low-cost genotyping methods are becoming increasingly available. The aim of this study was to identify single nucleotide polymorphisms (SNPs) for breast cancer risk capable of predicting triple negativity, in addition to clinical predictors, in breast cancer patients. METHODS This cross-sectional observational study included 1271 women with invasive breast cancer who were treated at a university hospital. A total of 76 validated breast cancer risk SNPs were successfully genotyped. Univariate associations between each SNP and triple negativity were explored using logistic regression analyses. Several variable selection and regression techniques were applied to identify a set of SNPs that together improve the prediction of triple negativity in addition to the clinical predictors of age at diagnosis and body mass index (BMI). The most accurate prediction method was determined by cross-validation. RESULTS The SNP rs10069690 (TERT, CLPTM1L) was the only significant SNP (corrected p = 0.02) after correction of p values for multiple testing in the univariate analyses. This SNP and three additional SNPs from the genes RAD51B, CCND1, and FGFR2 were selected for prediction of triple negativity. The addition of these SNPs to clinical predictors increased the cross-validated area under the curve (AUC) from 0.618 to 0.625. Age at diagnosis was the strongest predictor, stronger than any genetic characteristics. CONCLUSION Prediction of triple-negative breast cancer can be improved if SNPs associated with breast cancer risk are added to a prediction rule based on age at diagnosis and BMI. This finding could be used for prescreening purposes in complex molecular therapy studies for triple-negative breast cancer.

MicroRNA in diagnosis and therapy monitoring of early-stage triple-negative breast cancer

Breast cancer is a heterogeneous disease with distinct molecular subtypes including the aggressive subtype triple-negative breast cancer (TNBC). We compared blood-borne miRNA signatures of early-stage basal-like (cytokeratin-CK5-positive) TNBC patients to age-matched controls. The miRNAs of TNBC patients were assessed prior to and following platinum-based neoadjuvant chemotherapy (NCT). After an exploratory genome-wide study on 21 cases and 21 controls using microarrays, the identified signatures were verified independently in two laboratories on the same and a new cohort by RT-qPCR. We differentiated the blood of TNBC patients before NCT from controls with 84% sensitivity. The most significant miRNA for this diagnostic classification was miR-126-5p (two tailed t-test p-value of 1.4 × 10−5). Validation confirmed the microarray results for all tested miRNAs. Comparing cancer patients prior to and post NCT highlighted 321 significant miRNAs (among them miR-34a, p-value of 1.2 × 10−23). Our results also suggest that changes in miRNA expression during NCT may have predictive potential to predict pathological complete response (pCR). In conclusion we report that miRNA expression measured from blood facilitates early and minimally-invasive diagnosis of basal-like TNBC. We also demonstrate that NCT has a significant influence on miRNA expression. Finally, we show that blood-borne miRNA profiles monitored over time have potential to predict pCR.

BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the GeparQuinto Study

Purpose BRCA1/2 mutations are frequent in patients with triple-negative breast cancer (TNBC). These patients are often treated with primary systemic chemotherapy. The aim of this study was to analyze the effects of BRCA1/2 mutations on pathologic complete response (pCR) and disease-free survival (DFS) in a cohort of patients with TNBC treated with anthracycline and taxane-containing chemotherapy, with or without bevacizumab. Patients and Methods Germline DNA was sequenced to identify mutations in BRCA1 and BRCA2 in 493 patients with TNBC from the GeparQuinto study. The pCR rates were compared in patients with and without mutation, as well as in patients treated with and without bevacizumab. In addition, the influence of BRCA1/2 mutation status and pCR status on DFS was evaluated relative to treatment. Results BRCA1/2 mutations were detected in 18.3% of patients with TNBC. Overall, patients with mutations had a pCR rate of 50%, compared with 31.5% in patients without a mutation (odds ratio [OR], 2.17; 95% CI, 1.37 to 3.46; P = .001). The pCR rate among patients treated with bevacizumab was 61.5% for BRCA1/2 mutation carriers and 35.6% for those without mutations (OR, 2.90; 95% CI, 1.43 to 5.89; P = .004). pCR was a strong predictor of DFS for patients without BRCA1/2 mutations (hazard ratio, 0.18; 95% CI, 0.11 to 0.31) but not for patients with BRCA1/2 mutations (hazard ratio, 0.74; 95% CI, 0.32 to 1.69). Conclusion The addition of bevacizumab may increase the pCR after standard neoadjuvant chemotherapy for patients with TNBC with BRCA1/2 mutations. In patients treated with anthracycline and taxane-based chemotherapy (with or without bevacizumab), pCR was a weaker predictor of DFS for BRCA1/2 mutation carriers than for patients without mutations.