Background: In node-negative breast cancer (NNBC), a high risk of recurrence is determined by clinico-pathological or tumor-biological assessment. Taxanes may improve adjuvant chemotherapy. Methods: NNBC 3-Europe, the first randomized phase-3 trial in node-negative breast cancer (BC) with tumor-biological risk assessment, recruited 4146 node-negative breast cancer patients from 2002 to 2009 in 153 centers. Risk assessment was performed by clinico-pathological factors (43%) or biomarkers (uPA/PAI-1, urokinase-type plasminogen activator/its inhibitor PAI-1). High-risk patients received six courses 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), cyclophosphamide (500 mg/m2) (FEC), or three courses FEC followed by three courses docetaxel 100 mg/m2 (FEC-Doc). Primary endpoint was disease-free survival (DFS). Results: In the intent-to-treat population, 1286 patients had received FEC-Doc, and 1255 received FEC. Median follow-up was 45 months. Tumor characteristics were equally distributed; 90.6% of tested tumors had high uPA/PAI-1-concentrations. Planned courses were given in 84.4% (FEC-Doc) and 91.5% (FEC). Five-year-DFS was 93.2% (95% C.I. 91.1–94.8) with FEC-Doc and 93.7% (91.7–95.3) with FEC. Five-year-overall survival was 97.0% (95.4–98.0) for FEC-Doc and 96.6% % (94.9–97.8) for FEC. Conclusions: With adequate adjuvant chemotherapy, even high-risk node-negative breast cancer patients have an excellent prognosis. Docetaxel did not further reduce the rate of early recurrences and led to significantly more treatment discontinuations.

Published classifiers for prediction of pCR (a), study centers that contributed to the EXPRESSION trial (b), baseline characteristics of patients in the EXPRESSION trial (c), publicly available breast cancer datasets (d), comparison of patients who achieved versus not achieved a pCR (e), association of clinicopathologic parameters with pCR (f)

Classifier performance in the subgroup of ER+/HER2-patients

AbstractPurpose: Expression-based classifiers to predict pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) are not routinely used in the clinic. We aimed to build and validate a classifier for pCR after NACT. Patients and Methods: We performed a prospective multicenter study (EXPRESSION) including 114 patients treated with anthracycline/taxane-based NACT. Pretreatment core needle biopsies from 91 patients were used for gene expression analysis and classifier construction, followed by validation in five external cohorts (n = 619). Results: A 20-gene classifier established in the EXPRESSION cohort using a Youden index–based cut-off point predicted pCR in the validation cohorts with an accuracy, AUC, negative predictive value (NPV), positive predictive value, sensitivity, and specificity of 0.811, 0.768, 0.829, 0.587, 0.216, and 0.962, respectively. Alternatively, aiming for a high NPV by defining the cut-off point for classification based on the complete responder with the lowest predicted probability of pCR in the EXPRESSION cohort led to an NPV of 0.960 upon external validation. With this extreme-low cut-off point, a recommendation to not treat with anthracycline/taxane-based NACT would be possible for 121 of 619 unselected patients (19.5%) and 112 of 322 patients with luminal breast cancer (34.8%). The analysis of the molecular subtypes showed that the identification of patients who do not achieve a pCR by the 20-gene classifier was particularly relevant in luminal breast cancer. Conclusions: The novel 20-gene classifier reliably identifies patients who do not achieve a pCR in about one third of luminal breast cancers in both the EXPRESSION and combined validation cohorts.

Background: Immune checkpoint blockade is increasingly discussed in breast cancer. We examined the prognostic significance of the immune checkpoint receptors cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) in node-negative breast cancer. Methods: Microarray based gene-expression data for CTLA-4 (221331_x_at) and PD-1 (207634_at) were analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n=824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of CTLA-4 as well as PD-1 for metastasis-free survival (MFS) was examined in the whole cohort and in different molecular subtypes: luminal (ER + /HER2 - ), basal-like (ER - /HER2 - ) and HER2 + . Independent prognostic relevance was analysed using multivariate Cox regression. Results: Higher RNA expression of CTLA-4 was related to better MFS in a meta-analysis of the whole cohort (HR 0.58, 95% CI 0.38-0.88, P=0.0102). Prognostic significance was most pronounced in the HER2 + positive molecular subtype (HR 0.23, 95% CI 0.08-0.65, P=0.0062) as compared to luminal (HR 0.68, 95% CI 0.39-1.18, P=0.1744) and basal-like (HR 0.53, 95% CI 0.25-1.15), P=0.1087) carcinomas of the breast. PD-1 RNA expression, however, was not associated with outcome in the whole cohort of patients (HR 0.88, 95% CI 0.32-2.43, P=0.1853). A trend for improved survival was noticed in basal-like breast cancer (HR 0.40, 95% CI 0.15-1.08, P=0.0701). Neither luminal (HR 0.81, 95% CI 0.28-2.36, P=0.2122) nor HER2 + (HR 0.85, 95% CI 0.27-2.68, P=0.7759) patients showed an association of PD-1 with MFS. CTLA-4 showed independent prognostic significance (HR 0.393, 95% CI 0.224-0.688, P=0.001) in multivariate analysis. In addition to CTLA-4, only histological grade of differentiation (HR 2.335, 95% CI 1.490-3.660, P Conclusions: The immune checkpoint receptor CTLA-4 has independent prognostic significance in node-negative breast cancer. Higher expression of CTLA-4 is associated with improved outcome. The prognostic impact of CTLA-4 differs between molecular subtypes and is most pronounced in HER2 + breast cancer. Citation Format: Schmidt M, van de Sandt L, Heimes A-S, Battista M, Lebrecht A, Almstedt K, Hoffmann G, Rahnenfuhrer J, Hengstler JG. Prognostic significance of immune checkpoint receptors in node-negative breast cancer. [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 P2-08-07.

The aim of our study was to investigate 2D and 3D ultrasound assessment of pelvic floor muscle contractility as an objective non-invasive diagnostic tool in urogynecologic patients.

Bei ca. 10% aller Patienten, die sich einer kontrollierten FSH-Stimulation mit anschließender intrazytoplasmatischer Spermieninjektion (ICSI) unterziehen, liegt die Befruchtungsrate bei unter 30%. Dies minimiert die Erfolgschancen derjenigen Patienten um ein Vielfaches. Seit 2011 wird der Calcium-Ionophor Calcimycin (A23187) als ready-to-use-Präparat zur Behandlung derartig gravierender Befruchtungsversager angeboten. Kann durch die erhöhte Befruchtungsrate aufgrund des Einsatzes eines Calcium-Ionophors die Schwangerschaftsrate verbessert werden? Untersucht wurden die Fertilisations- und Schwangerschaftsrate von Patientinnen, die sich einer ICSI-Behandlung unterzogen. Dabei wurden die Behandlungen mit und ohne Aktivierung mittels Calcium-Ionophor (A23187) verglichen.

Abstract Background: Immune checkpoint blockade is increasingly discussed in breast cancer. We examined the prognostic significance of the immune checkpoint receptors cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) in node-negative breast cancer. Methods: Microarray based gene-expression data for CTLA-4 (221331_x_at) and PD-1 (207634_at) were analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n=824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of CTLA-4 as well as PD-1 for metastasis-free survival (MFS) was examined in the whole cohort and in different molecular subtypes: luminal (ER+/HER2-), basal-like (ER-/HER2-) and HER2+. Independent prognostic relevance was analysed using multivariate Cox regression. Results: Higher RNA expression of CTLA-4 was related to better MFS in a meta-analysis of the whole cohort (HR 0.58, 95% CI 0.38-0.88, P=0.0102). Prognostic significance was most pronounced in the HER2+ positive molecular subtype (HR 0.23, 95% CI 0.08-0.65, P=0.0062) as compared to luminal (HR 0.68, 95% CI 0.39-1.18, P=0.1744) and basal-like (HR 0.53, 95% CI 0.25-1.15), P=0.1087) carcinomas of the breast. PD-1 RNA expression, however, was not associated with outcome in the whole cohort of patients (HR 0.88, 95% CI 0.32-2.43, P=0.1853). A trend for improved survival was noticed in basal-like breast cancer (HR 0.40, 95% CI 0.15-1.08, P=0.0701). Neither luminal (HR 0.81, 95% CI 0.28-2.36, P=0.2122) nor HER2+ (HR 0.85, 95% CI 0.27-2.68, P=0.7759) patients showed an association of PD-1 with MFS. CTLA-4 showed independent prognostic significance (HR 0.393, 95% CI 0.224-0.688, P=0.001) in multivariate analysis. In addition to CTLA-4, only histological grade of differentiation (HR 2.335, 95% CI 1.490-3.660, P<0.0001) and tumor size (HR 1.924, 95% CI 1.260-2.937, P=0.002), but neither PD-1 nor age nor HER2 status nor hormone receptor status retained an independent prognostic association with MFS. Conclusions: The immune checkpoint receptor CTLA-4 has independent prognostic significance in node-negative breast cancer. Higher expression of CTLA-4 is associated with improved outcome. The prognostic impact of CTLA-4 differs between molecular subtypes and is most pronounced in HER2+ breast cancer. Citation Format: Schmidt M, van de Sandt L, Heimes A-S, Battista M, Lebrecht A, Almstedt K, Hoffmann G, Rahnenführer J, Hengstler JG. Prognostic significance of immune checkpoint receptors in node-negative breast cancer. [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 P2-08-07.

The tyrosine kinase c-met alters signaling cascades such as the BRAF-MAPK and PI3K-PKB pathways. These alterations are involved in the carcinogenesis of type I but not type II ovarian cancer (OC). Therefore, the present study investigated the patterns of c-met expression in a cohort of consecutive patients with OC. c-met expression was determined by immunohistochemical analysis. Differences in c-met overexpression among subgroups of established clinicopathological features, including age, histological subtype, tumor stage, histological grading, post-operative tumor burden and completeness of chemotherapy, were determined by χ2 test. Cox regression analyses were performed to determine the prognostic effect of c-met. Survival rates were estimated using the Kaplan-Meier method. A total of 106 patients were enrolled into the study. c-met was overexpressed in 20.8% of the entire cohort; 35.7% of patients with type I OC and 8.6% of patients with type II OC showed overexpression (P=0.001). However, c-met overexpression was not associated with any other established clinicopathological features (all P-values >0.05). Univariate Cox regression analysis showed that overexpression of c-met was associated neither with progression-free survival (PFS) nor with disease-specific survival (DSS) (P=0.835 and P=0.414, respectively). Kaplan-Meier plots also failed to demonstrate an effect of c-met on the 5-year PFS and DSS rates (P=0.938 and P=0.412, respectively). These findings support the hypotheses that the overexpression of c-met is associated with type I but not type II OC, and that overexpression of c-met does not affect the prognosis of OC.

Die Qualität der Operation und der Indikationsstellung zur BET zeigt sich in der Lokalrezidivrate, die gemäß der Leitlinien unter 5% liegen sollte. Die neuere OP-Technik des Areolarrandschnittes zeigt kosmetisch deutlich bessere Ergebnisse und damit eine höhere Patientenzufriedenheit als die herkömmliche Schnittführung direkt über dem Tumor. Es gibt bisher allerdings nur wenige Untersuchungen, die das Risiko eines Lokalrezidivs bei beiden Techniken analysieren.

Background: Interferons are crucial for adaptive immunity and play an important role as central coordinators of tumor-immune system interactions. We examined the subtype specific prognostic significance of an interferon (IFN) metagene in node-negative breast cancer. Methods: Using microarray based gene-expression data, we identified co-regulated genes related to biological processes. After hierarchical clustering, we defined an interferon (IFN) metagene which was composed of 36 interferon-stimulated genes. The subtype specific prognostic role of the IFN metagene was analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n=824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of the IFN metagene for metastasis-free survival (MFS) was examined in different molecular subtypes: luminal A (ER+/HER2-/aurora kinase A [AURKA]low, luminal B (ER+/HER2-/AURKAhigh), basal-like (ER-/HER2-), and HER2+. Results: Prognostic significance of the IFN metagene was restricted to the HER2+ positive molecular subtype (HR 0.50, 95% CI 0.28-0.88, P=0.0056). Prognostic effects were not seen in luminal A (HR 1.00, 95% CI 0.65-1.53, P=0.8819), luminal B (HR 1.00, 95% CI 0.76-1.32, P=0.9770) or basal-like (HR 0.87, 95% CI 0.66-1.15, P=0.3282) carcinomas of the breast. Conclusions: The prognostic significance of the interferon metagene in node-negative breast cancer is subtype specific and confined to the HER2+ molecular subtype. A higher expression of the IFN metagene is associated with improved outcome in HER2+ breast cancer. Citation Format: Marcus Schmidt, Leonie van de Sandt, Karolina Edlund, Isabel Sicking, Marco Battista, Anne-Sophie Heimes, Antje Lebrecht, Gerald Hoffmann, Mathias Gehrmann, Jorg Rahnenfuhrer, Jan G Hengstler. Prognostic significance of the interferon metagene in node-negative breast cancer depends on the molecular subtype [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-20.

PURPOSE:The available literature on the treatment options for recurrent or metastatic endometrial cancer (EC) is full of controversies. Therefore, we explore the results of the AGO pattern of care studies from the years 2013, 2009 and 2006.METHODS:A questionnaire was developed and sent to all 682 German gynecological departments in 2013 (775 in 2009, 500 in 2006, respectively). The results of the questionnaires were compared with each other using Fisher's exact test.RESULTS:Responses were available in 40.0 % in 2013, 33.3 % in 2009 and 35.8 % in 2006. In 2013 the most preferred endocrine drug was progestin (79.8 %), followed by tamoxifen (42.8 %), aromatase inhibitor (19.8 %), fulvestrant (16.3 %) and a combination (3.9 %) (p < 0.001). 65.3, 59.8, 51.7 and 38.2 % of the participants used platinum, taxane, a combination of cytostatic drugs, anthracycline in metastatic EC, respectively (p = 0.215). 96.2, 92.7, 49.8 and 60.9 % of the participants performed an operation, radiotherapy, endocrine therapy and chemotherapy in 2013 because of a local recurrence, respectively (p < 0.001). Compared to 2009 and 2006 these rates remained stable (no p value <0.05). Because of a distant metastasis 50.4, 64.2, 78.5 and 90.8 % of the participants performed an operation, radiotherapy, endocrine therapy and chemotherapy in 2013, respectively (p < 0.001). Compared to 2009 and 2006 more participants performed an operation or radiotherapy and less an endocrine treatment.CONCLUSIONS:Whereas progestin was the favorite drug, the participants of this study did not prefer a specific cytostatic drug for metastatic EC in 2013. This might have reflected the available literature, which did not provide a real standard of care.

Postoperative Schmerzen sind ein verbreitetes Problem nach Latissimus-dorsi-Lappenplastiken zur Brustrekonstruktion. Eine orale Analgesie ist häufig nicht ausreichend wirksam. PCA-Pumpen oder thorakale Periduralkatheter sind oft mit unangenehmen Nebenwirkungen bzw. höherem Aufwand kombiniert. Wir berichten über die ersten Erfahrungen mit einer kontinuierlichen Wundinfiltration von 0,2% Ropivacain über ein Wundkathetersystem.

Introduction: Defects of the levator ani muscle complex could represent a pathophysiological link between vaginal birth trauma and urogynecological symptoms many years later. The aim of our study was to determine the prevalence of levator ani muscle defects using 3D or 4D ultrasound and palpation in urogynecological patients. Material and Methods: Urogynecological patients were retrospectively investigated using 3D or 4D ultrasound. Clinical examination consisted of palpation and 3D or 4D imaging of the levator ani muscle. Results: A total of 319 women were included in the analysis. Mean age was 64.9 years, average parity was 2.1. Stress incontinence was present in 50.8 %, overactive bladder symptoms in 69.3 % and pelvic organ prolapse in 42.3 % of patients. A levator ani defect was found on ultrasound in 76 patients (23.8 %) and on palpation in 64 women (20.0 %). In the group of patients with pelvic organ prolapse, levator ani defects were found in 32.6 % of patients using ultrasound and in 26.7 % of patients using palpation. The odds ratio (OR) for levator ani defects in women with pelvic organ prolapse was 2.3 (95 % CI [CI: confidence interval]: 1.36-3.88], p = 0.002). Conclusion: In a cohort of urogynecological patients seen at a tertiary urogynecological unit, the prevalence of levator ani defects was significantly higher in women with pelvic organ prolapse compared to women with stress incontinence or urge symptoms.

Purpose In 2013, 2009 and 2006, the Arbeitsgemeinschaft Gynäkologische Onkologie evaluated the therapeutic approaches for endometrial carcinoma and the adherence to their guideline in Germany. Here, the adjuvant treatment decisions were presented. Methods A questionnaire was developed and sent to all 682 German gynecological departments in 2013 (775 in 2009 and 500 in 2006, respectively). The results of the questionnaires were compared with the recommendations of the guideline and with each other using Fisher’s exact test. Results Responses were available in 40.0 % in 2013, 33.3 % in 2009 and 35.8 % in 2006. Participants recommended external beam radiotherapy (EBRT) in 13 out of 16 requested stages and vaginal brachytherapy (VBT) in only 10 out of 16 requested stages as suggested by the guideline. Comparing the results of 2013 with 2009, less participants used EBRT and VBT in 7 out of 16 and in 6 out of 16 requested stages, respectively. Conversely, more participants offered adjuvant chemotherapy (CT) in 2013 (90.4 %) compared to 61.9 % in 2009 ( p < 0.001) and 48.8 % in 2006 ( p < 0.001), respectively. However, the stage-adjusted recommendations of CT were not in line with the guideline in 11 out of 15 requested stages. In total, 77.3 % of the participants use a multiple drug schedule with a platinum and a taxane compound. Conclusions The results suggest non-adherence to the guideline concerning the stage-adjusted use of VBT and CT in endometrial carcinoma. These findings emphasize great uncertainties and the need of more clarifying trials. Furthermore, a shift from radiotherapy toward CT is observable.

Einleitung/Zielsetzung: Die „Focal Adhesion Kinase“ (FAK) gehört der Gruppe zytoplasmatischer Tyrosinkinasen an und spielt eine wichtige Rolle in der Signaltransduktion. Unsere Arbeitsgruppe untersuchte die prognostische Bedeutung der „Focal Adhesion Kinase“ (FAK) in den verschiedenen Subtypen des nodal-negativen Mammakarzinoms.

552 Background: Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase playing an important role as a key mediator for signal transduction. We examined the subtype specific prognostic significance of FAK in node-negative breast cancer. Methods: Using microarray based gene-expression data, we analysed the prognostic significance of FAK (208820_at). The subtype specific prognostic role of FAK was analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n = 824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of FAK for metastasis-free survival (MFS) was examined in the whole cohort of patients as well as in different molecular subtypes: luminal A (ER+/HER2-/aurora kinase A [AURKA]low, luminal B (ER+/HER2-/AURKAhigh), basal-like (ER-/HER2-), and HER2+. Results: Prognostic significance of FAK was seen in the whole cohort of patients (HR 1.48, 95% CI 1.16-1.87, P = 0.001). Considering the different molecular subtypes, the prognostic effect was most pronounced in luminal B carcinomas (HR 1.67, 95% CI 1.07-2.62, P = 0.0233). FAK expression was neither significantly associated with MFS in luminal A (HR 1.69, 95% CI 0.96-2.98, P = 0.0692), basal-like (HR 0.98, 95% CI 0.64-1.50, P = 0.9400) nor HER2+ (HR 1.63, 95% CI 0.49-5.46, P = 0.8512) carcinomas of the breast. Conclusions: A higher expression of FAK was associated with worse MFS in node-negative breast cancer. The prognostic significance was confined to luminal B carcinomas.

In etwa 10% liegt dem palpablen Knoten der weiblichen Brust ein Karzinom zu Grunde. Die übrigen Fälle lassen sich durch ein breites Spektrum benigner Befunde erklären. Diese differentialdiagnostische Abklärung erfolgt in Abhängigkeit des Alters und des Brustkrebsrisikos der Betroffenen. Neben der Anamnese, der körperlichen und sonografischen Untersuchung werden häufig eine Mammografie und stanzbioptische Abklärung angestrengt. Gelegentlich ist eine operative histologische Sicherung angezeigt.