Physical activity levels are positively related to progression-free survival and reduced adverse events in advanced ER+ breast cancer.

BACKGROUND: Increased levels of physical activity are associated with a reduction of breast cancer mortality, especially in postmenopausal women with positive hormone receptor status. So far, previous observational case-control and cohort studies have focused on associations between overall leisure time physical activity and survival of women with breast cancer in general. METHODS: In this multicenter prospective cohort study, conducted in Germany between 30th August 2012 to 29th December 2017, we investigated general physical activity in a homogenous sample of n = 1440 postmenopausal women with advanced (inoperable locally advanced or metastatic), hormone receptor-positive breast cancer receiving the same therapy (everolimus and exemestane). Self-reported physical activity was assessed using the Godin Leisure Time Exercise Questionnaire (GLTEQ) before and every 3 months during treatment. Participants were then classified into "active" and "insufficiently active" to screen their activity behavior the week prior to medical treatment. In addition, changes in physical activity patterns were assessed. Adjusted Cox regression analyses were performed for the activity categories to determine hazard ratios (HR). Besides progression-free survival (PFS), adverse events (AEs), QoL, and fatigue were assessed every 3 months until study termination. RESULTS: Compared to "insufficiently active" patients, "active" individuals indicated a significantly longer PFS (HR: 0.84 [0.74; 0.984], p = .0295). No significant differences were observed for changes of physical activity behavior. Patients who reported to be "active" at baseline revealed significantly fewer AEs compared to "insufficiently" active patients. In detail, both severe and non-severe AEs occurred less frequently in the "active" patients group. In line with that, QoL and fatigue were better in physical "active" patients compared to their insufficient active counterparts at the last post-baseline assessment. Participants who remained or become active indicated less AEs, a higher QoL, and reduced fatigue levels. CONCLUSIONS: Physical activity behavior prior to medical treatment might have prognostic value in patients with advanced breast cancer in terms of extending the PFS. Moreover, physical activity before and during treatment may reduce treatment-related side effects and improve patients' QoL and fatigue. TRIAL REGISTRATION: EUPAS9462. Registered 30th October 2012 "retrospectively registered."

Efficacy and safety of everolimus plus exemestane in patients with hormone receptor-positive, HER-2-negative advanced breast cancer: Results from the open-label, multicentre, non-interventional BRAWO study.

BRAWO, a real-world study, assessed the efficacy, quality of life (QoL) and safety of EVE + EXE in postmenopausal women with HR+/HER2- advanced breast cancer (ABC) in routine clinical practice. Postmenopausal women with HR+/HER2-ABC with recurrence or progression after a NSAI were included. Primary Observation parameters included the evaluation of the effectiveness of EVE + EXE. A multivariate-analysis using Cox proportional hazard model was built to identify predictors of progression. Overall, 2100 patients were enrolled (August 2012-December 2017); 2074 were evaluable for efficacy and safety analyses. Majority of patients (60.6%) received EVE + EXE as first (28.7%) or second-line (31.9%) therapy. Visceral metastases were present in 54.1% patients. Median progression-free survival (mPFS) reported as 6.6 months (95%CI: 6.3-7.0). Multivariate-analysis in a subset of patients (n = 1837) found higher body mass index (BMI) and non-visceral metastases to be independent predictors of favorable PFS. Patients with a BMI of 20 to <25 had a mPFS of 6.0 (95%CI: 5.4-6.4) and those with a BMI ≥30 had mPFS of 8.5 (95%CI: 6.9-9.9). 41.2% patients achieved stable disease and 7.3% partial response. No major changes were observed QoL; 86.4% patients received stomatitis prophylaxis and 41.4% experienced EVE related AEs of stomatitis, mainly low grade. AEs occurred in 91.2% of patients, of which stomatitis (42.6%) and fatigue (19.8%) were most frequent. The BRAWO study provides real-world evidence of efficacy and safety of EVE + EXE in patients with HR+, HER2- ABC. A high BMI and the absence of visceral metastases were independent predictors of PFS in this cohort of patients.

Implementation of an Electronic Patient-Reported Outcome App for Health-Related Quality of Life in Breast Cancer Patients: Evaluation and Acceptability Analysis in a Two-Center Prospective Trial.

BACKGROUND: One in eight women is diagnosed with breast cancer in the course of their life. As systematic palliative treatment has only a limited effect on survival rates, the concept of health-related quality of life (HRQoL) was developed for measurement of patient-centered outcomes. Various studies have already demonstrated the reliability of paper-based patient-reported outcome (pPRO) and electronic patient-reported outcome (ePRO) surveys and that the 2 means of assessment are equally valid. OBJECTIVE: The aim of this study was to analyze the acceptance and evaluation of a tablet-based ePRO app for breast cancer patients and to examine its suitability, effort, and difficulty in the context of HRQoL and sociodemographic factors. METHODS: Overall, 106 women with adjuvant or advanced breast cancer were included in a 2-center study at 2 major university hospitals in Germany. Patients were asked to answer HRQoL and PRO questionnaires both on a tablet on-site using a specific eHealth assessment website and on paper. The suitability, effort, and difficulty of the app and self-reported technical skills were also assessed. Only the results of the electronically acquired data are presented here. The results of the reliability of the pPRO data have already been published elsewhere. RESULTS: Patients regarded the ePRO assessment as more suitable (80/106, 75.5%), less stressful (73/106, 68.9%), and less difficult (69/106, 65.1%) than pPRO. The majority of patients stated that ePRO assessment improves health care in hospitals (87/106, 82.1%). However, evaluation of ePROs depended on the level of education (P=.003) in the dimensions of effort and difficulty (regression analysis). The app was rated highly in all categories. HRQoL data and therapy setting did not show significant correlations with the app's evaluation parameters. CONCLUSIONS: The results indicate that ePRO surveys are feasible for measuring HRQoL in breast cancer patients and that those patients prefer ePRO assessment to pPRO assessment. It can also be seen that patients consider ePRO assessment to improve hospital health care. However, studies with larger numbers of patients are needed to develop apps that address the needs of patients with lower levels of education and technical skills.

Disseminated tumour cells from the bone marrow of early breast cancer patients: Results from an international pooled analysis.

PURPOSE: Presence of disseminated tumour cells (DTCs) in the bone marrow (BM) has been described as a surrogate of residual disease in patients with early breast cancer (EBC). PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) is a large international analysis of pooled data that aimed to assess the prognostic impact of DTCs in patients with EBC. EXPERIMENTAL DESIGN: Individual patient data were collected from 11 centres. Patients with EBC and available follow-up data in whom BM sampling was performed at the time of primary diagnosis before receiving any anticancer treatment were eligible. DTCs were identified by antibody staining against epithelial cytokeratins. Multivariate Cox regression was used to compare the survival of DTC-positive versus DTC-negative patients. RESULTS: In total, 10,307 patients were included. Of these, 2814 (27.3%) were DTC-positive. DTC detection was associated with higher tumour grade, larger tumour size, nodal positivity, oestrogen receptor and progesterone receptor negativity, and HER2 positivity (all p < 0.001). Multivariate analyses showed that DTC detection was an independent prognostic marker for overall survival, disease-free survival and distant disease-free survival with hazard ratios (HR) and 95% confidence intervals (CI) of 1.23 (95% CI: 1.06-1.43, p = 0.006), 1.30 (95% CI: 1.12-1.52, p < 0.001) and 1.30 (95% CI: 1.08-1.56, p = 0.006), respectively. There was no association between locoregional relapse-free survival and DTC detection (HR 1.21; 95% CI 0.68-2.16; p = 0.512). CONCLUSIONS: DTCs in the BM represent an independent prognostic marker in patients with EBC. The heterogeneous metastasis-initiating potential of DTCs is consistent with the concept of cancer dormancy.

CATCH: A Prospective Precision Oncology Trial in Metastatic Breast Cancer.

PURPOSE: CATCH (Comprehensive Assessment of clinical feaTures and biomarkers to identify patients with advanced or metastatic breast Cancer for marker driven trials in Humans) is a prospective precision oncology program that uses genomics and transcriptomics to guide therapeutic decisions in the clinical management of metastatic breast cancer. Herein, we report our single-center experience and results on the basis of the first 200 enrolled patients of an ongoing trial. METHODS: From June 2017 to March 2019, 200 patients who had either primary metastatic or progressive disease, with any number of previous treatment lines and at least one metastatic site accessible to biopsy, were enrolled. DNA and RNA from tumor tissue and corresponding blood-derived nontumor DNA were profiled using whole-genome and transcriptome sequencing. Identified actionable alterations were brought into clinical context in a multidisciplinary molecular tumor board (MTB) with the aim of prioritizing personalized treatment recommendations. RESULTS: Among the first 200 enrolled patients, 128 (64%) were discussed in the MTB, of which 64 (50%) were subsequently treated according to MTB recommendation. Of 53 evaluable patients, 21 (40%) achieved either stable disease (n = 13, 25%) or partial response (n = 8, 15%). Furthermore, 16 (30%) of those patients showed improvement in progression-free survival of at least 30% while on MTB-recommended treatment compared with the progression-free survival of the previous treatment line. CONCLUSION: The initial phase of this study demonstrates that precision oncology on the basis of whole-genome and RNA sequencing is feasible when applied in the clinical management of patients with metastatic breast cancer and provides clinical benefit to a substantial proportion of patients.

Surgeon's preference of subcutaneous tissue resection: most important factor for short-term complications in subcutaneous implant placement after mastectomy-results of a cohort study.

PURPOSE: Little is known about the reason of high short-term complication rates after the subcutaneous placement of breast implants or expanders after mastectomy without biological matrices or synthetic meshes. This study aims to evaluate complications and their risk factors to develop guidelines for decreasing complication rates. METHODS: We included all cases of mastectomy followed by subcutaneous implant or expander placement between 06/2017 and 05/2018 (n = 92). Mean follow-up time was 12 months. RESULTS: Explantation occurred in 15 cases (16.3%). The surgeon's preference for moderate vs. radical subcutaneous tissue resection had a significant influence on explantation rates (p = 0.026), impaired wound healing or infection (requiring surgery) (p = 0.029, p = 0.003 respectively) and major complications (p = 0.018). Multivariate analysis revealed significant influence on complication rates for radical subcutaneous tissue resection (p up to 0.003), higher implant volume (p up to 0.023), higher drain volume during the last 24 h (p = 0.049), higher resection weight (p = 0.035) and incision type (p = 0.011). CONCLUSION: Based on the significant risk factors we suggest the following guidelines to decrease complication rates: favoring thicker skin envelopes after surgical preparation, using smaller implants, removing drains based on a low output volume during the last 24 h and no use of periareolar incision with extension medial or lateral. We should consider ADMs for subcutaneous one-stage reconstructions. The individual surgeon's preference of subcutaneous tissue resection is of highest relevance for short-term complications-this has to be part of internal team discussions and should be considered in future trials for comparable results.

Evaluation of the anti-Thomsen-Friedenreich antibodies Nemod-TF1 and Nemod-TF2 as prognostic markers in breast cancer.

PURPOSE: The TF (Thomsen-Friedenreich, CD176, Galß1-3GalNAc) carbohydrate moiety is known as a specific oncofetal carbohydrate epitope present in fetal and neoplastic tissue as well as in stem cells. TF was demonstrated to mediate tumor-promoting features and to be highly immunogenic. The current study aimed to evaluate whether presence of the TF antigen is associated with clinico-pathological parameters and prognosis of early breast cancer (BC). METHODS: Primary BC tissue (n = 226) was stained for TF using two monoclonal anti-TF antibodies (Nemod-TF1, Nemod-TF2). Staining results were correlated to clinical data including survival. RESULTS: Nemod-TF1 staining was positively correlated to lymph node metastasis (p = 0.03) and the presence of tumor-associated MUC1 (TA-MUC1; p = 0.003). Further, the presence of the Nemod-TF1 epitope predicted worse prognosis in TA-MUC1 positive (overall survival: p = 0.026) as well as in triple negative (overall survival: p = 0.002; distant metastasis-free survival: p = 0.012) BC. CONCLUSIONS: The data presented here further support a role of TF in BC tumor biology. Whether anti-TF directed treatment approaches may gain clinical relevance in those cases determined as triple negative or TA-MUC1 positive remains to be determined.

Tumor-Specific Regulatory T Cells from the Bone Marrow Orchestrate Antitumor Immunity in Breast Cancer.

Endogenous antitumor effector T-cell responses and immune-suppressive regulatory T cells (Treg) critically influence the prognosis of patients with cancer, yet many of the mechanisms of how this occurs remain unresolved. On the basis of an analysis of the function, antigen specificity, and distribution of tumor antigen-reactive T cells and Tregs in patients with breast cancer and transgenic mouse tumor models, we showed that tumor-specific Tregs were selectively activated in the bone marrow (BM) and egressed into the peripheral blood. The BM was constantly depleted of tumor-specific Tregs and was instead a site of increased induction and activity of tumor-reactive effector/memory T cells. Treg egress from the BM was associated with activation-induced expression of peripheral homing receptors such as CCR2. Because breast cancer tissues express the CCR2 ligand CCL2, the activation and egress of tumor antigen-specific Tregs in the BM resulted in the accumulation of Tregs in breast tumor tissue. Such immune compartmentalization and redistribution of T-cell subpopulations between the BM and peripheral tissues were achieved by vaccination with adenoviral vector-encoded TRP-2 tumor antigen in a RET transgenic mouse model of spontaneous malignant melanoma. Thus, the BM simultaneously represented a source of tumor-infiltrating Tregs and a site for the induction of endogenous tumor-specific effector T-cell responses, suggesting that both antitumor immunity and local immune suppression are orchestrated in the BM.

IMpassion132 Phase III trial: atezolizumab and chemotherapy in early relapsing metastatic triple-negative breast cancer.

The PD-L1 inhibitor atezolizumab received US FDA accelerated approval as treatment for PD-L1-positive metastatic triple-negative breast cancer (TNBC). In IMpassion130, combining atezolizumab with first-line nab-paclitaxel for metastatic TNBC significantly improved progression-free survival and showed a clinically meaningful effect on overall survival in patients with PD-L1-positive tumors. The placebo-controlled randomized Phase III IMpassion132 (NCT03371017) trial is evaluating atezolizumab with first-line chemotherapy (capecitabine [mandatory in platinum-pretreated patients] or gemcitabine/carboplatin) for inoperable locally advanced/metastatic TNBC recurring ≤12 months after completing standard (neo)adjuvant anthracycline and taxane chemotherapy. Stratification factors are: visceral metastases, tumor immune cell PD-L1 status and selected chemotherapy. Patients are randomized to atezolizumab 1200 mg or placebo every 3 weeks with the chosen chemotherapy, continued until progression, unacceptable toxicity or withdrawal. The primary end point is overall survival.

Molecular Subtype Conversion between Primary and Metastatic Breast Cancer Corresponding to the Dynamics of Apoptotic and Intact Circulating Tumor Cells.

The presence of circulating tumor cells (CTCs), detected as a form of liquid biopsy is associated with poor survival in both early and metastatic breast cancer. Monitoring tumor biology based on intrinsic subtypes delivers treatment-relevant information on the heterogeneity or biomarker conversion between primary and metastatic tumors. This study aimed to correlate the change of the apoptotic and intact CTC counts with mRNA-assessed intrinsic subtype change. Thirty-four breast cancer patients with available triplets of primary tumors, distant metastasis biopsies and data on intact and apoptotic CTC dynamics were included in the analysis. The intrinsic subtype was determined per RT-qPCR quantification of the gene expression ESR1, PGR, ERBB2 and MKI67. Both luminal (p = 0.038) and triple negative (p = 0.035) patients showed a significant downregulation of apoptotic CTCs. Repeated biopsies of distant metastatic sites, as well as determining a potential shift of the intrinsic subtype, combined with data on intact and apoptotic CTC dynamics from liquid biopsies might help personalize systemic therapy and generate additional surrogate markers for successful systemic therapy.

Exam preparatory course for the 2nd part of the German medical examination in obstetrics and gynecology - a potential tool for the recruitment of new residents during the occupational decision process before the practical year?

BACKGROUND: The "Second Stage of the Physician Exam" at the end of the 5th year of medical school in Germany is the final step before the "Practical Year." An exam preparatory class can cover the complete content of Obstetrics and Gynecology (OB/GYN) in two days. We raise the question of whether such training might promote students' interest in the given specialty during occupational decision making and whether it could even be used by hospitals as a recruitment tool. This investigation is even more important in the context of fierce competition among young professionals at clinics and in different specialties. METHODS: We conducted a multimodal course evaluation for four exam preparatory courses (each of which lasted two days and involved 8.5 h of teaching), including pre- and post-course tests with 20 multiple-choice questions to quantify the level of skill gain. Additionally, a standardized evaluation of course satisfaction was performed, followed by a post-exam questionnaire that dealt with studying activities and individual professional objectives. RESULTS: Overall, n = 197 students took part in four identical courses. Among them, n = 121 completed the pre-/post-course tests, n = 170 completed the evaluation, and n = 110 completed the post-exam questionnaire. An average improvement from 13.9 to 17.2 correct answers was observed (max. 20; pre-/post-difference 95%-CI: [2.77; 3.86], t-test: p < 0.0001). By trend, the students noted that course participation positively influenced their later choice of specialty training (m = 3.63; scale 1 = "strongly disagree," 5 = "strongly agree"). CONCLUSIONS: In addition to self-studying, condensed classroom training is effective and reasonable and might also increase the attractivity of OB/GYN among students and have a positive effect on recruitment.

An Electronic Patient-Reported Outcome Tool for the FACT-B (Functional Assessment of Cancer Therapy-Breast) Questionnaire for Measuring the Health-Related Quality of Life in Patients With Breast Cancer: Reliability Study.

BACKGROUND: The most frequent malignant disease in women is breast cancer. In the metastatic setting, quality of life is the primary therapeutic goal, and systematic treatment has only a limited effect on survival rates; therefore, the concept of the health-related quality of life (HRQoL) and measurement of patient-reported outcomes (PROs) are gaining more and more importance in the therapy setting of diseases such as breast cancer. One of the frequently used questionnaires for measuring the HRQoL in patients with breast cancer is the Functional Assessment of Cancer Therapy-Breast (FACT-B). Currently, paper-based surveys still predominate, as only a few reliable and validated electronic-based questionnaires are available. ePRO tools for the FACT-B questionnaire with proven reliability are missing so far. OBJECTIVE: The aim of this study was to analyze the reliability of tablet-based measurement of FACT-B in the German language in adjuvant (curative) and metastatic breast cancer patients. METHODS: Paper- and tablet-based questionnaires were completed by a total of 106 female adjuvant and metastatic breast cancer patients. All patients were required to complete the electronically based (ePRO) and paper-based version of the FACT-B. A frequency analysis was performed to determine descriptive sociodemographic characteristics. Both dimensions of reliability (parallel forms reliability using Wilcoxon test and test of internal consistency using Spearman ρ) and agreement rates for single items, Kendall tau for each subscale, and total score were analyzed. RESULTS: High correlations were shown for both dimensions of reliability (parallel forms reliability and internal consistency) in the patients' response behavior between paper-based and electronically based questionnaires. Regarding the reliability test of parallel forms, no significant differences were found in 35 of 37 single items, while significant correlations in the test for consistency were found in all 37 single items, in all 5 sum individual item subscale scores, as well as in total FACT-B score. CONCLUSIONS: The ePRO version of the FACT-B questionnaire is reliable for patients with breast cancer in both adjuvant and metastatic settings, showing highly significant correlations with the paper-based version in almost all questions all subscales and the total score.

Implementation of a novel efficacy score to compare sealing and cutting devices in a porcine model.

BACKGROUND: In general surgery, minimally invasive laparoscopic procedures have been steadily increasing over the last decade. The application of advanced bipolar and ultrasonic energy devices for sealing and cutting of blood vessels plays a vital role in routine clinical procedures. The advantages of energy-based instruments are enhanced sealing capability combined with both fast sealing time and minimal thermal injury. The purpose of this study was to compare the safety and efficacy profiles of nine laparoscopic sealing and cutting devices in a porcine model, with a new scoring system. METHODS: Comparative studies in a porcine model were performed to assess vessel sealing, burst pressure, thermal spread, maximum heat, sealing/cooling time, and compression strength over the full jaw. Nine different devices from five manufacturers were tested in this study. The sealing and cutting devices (SCD) score has been developed to enable standardized comparisons of various devices. For this purpose, the most important parameters were identified through a consensus approach. RESULTS: All sealed vessels with different devices could withstand a median pressure of more than 300 mmHg (range 112-2046 mmHg). The time for the sealing procedure was 7.705 s (range 5.305-18.38 s) for the ultrasonic and 7.860 s (range 5.08-10.17 s) for the bipolar devices. The ultrasonic instruments reached a median temperature of 218.1 °C (range 81.3-349.75 °C) and the bipolar devices a temperature of 125.5 °C (range 94.1-133.35 °C). The tissue reached a median temperature of 61.9 (range 47.1-80.6 °C) after ultrasonic sealing and 76.7 °C (range 63.1-94.2 °C) after bipolar sealing. The median SCD score was 10.47 (range 7.16-13.72). CONCLUSION: All the instruments used seemed safe for use on the patient. The SCD score allows an indirect comparability of the instruments.

Parity improves anti-tumor immunity in breast cancer patients.

Compared to nulliparous women, parous women have an up to 50% lower lifetime risk of developing breast cancer. An endogenous mechanism to prevent the development of cancer is the destruction of tumor cells by T cells that recognize tumor-associated antigens (TAA). Since a number of TAA are also highly present in the breast and placenta of pregnant women, we investigated the induction and characteristics of spontaneous T cell responses against TAA during pregnancy. To this end, we collected peripheral blood from healthy nulliparous, primigravid and parous women, as well as from breast cancer patients. IFN-γ ELISpot assays were performed to measure the intensity and specificity of T cell responses against 11 different TAA. The impact of TAA-specific Treg cells on anti-TAA responses was assessed by performing the assay before and after depletion of CD4+CD25+ T cells. The antigenic specificities of these Treg cells were analyzed by the Treg specificity assay. Furthermore, we conducted flow cytometric analyses to determine the memory phenotype and cytokine secretion profile of TAA-specific T cells. Our results demonstrate that pregnancy induces functional and long-lived memory and effector T cells that react against multiple TAA. These persist for many decades in parous females, but are not found in age-matched females without children. We also detected TAA-specific Treg cells, which suppressed strong effector T cell responses after delivery. Nulliparous breast cancer patients displayed median TAA-specific effector T cell responses to be decreased threefold compared to parous patients, which could be restored in vitro after depletion of Treg cells.

Influence of Paclitaxel and Heparin on Vitality, Proliferation and Cytokine Production of Endometrial Cancer Cells.

BACKGROUND: Cancer patients have a higher risk for thromboembolic events compared to healthy individuals and are often treated with heparins. A beneficial effect of heparins on tumor patients above and beyond the classic anticoagulation effect has been reported, leading to an increased focus on the use of heparins in anticancer treatment. In recent years, it has become apparent that microenvironments greatly affect tumor development and can be a major source of tumor-promoting factors. Cytokines play an important role in tumor microenvironments, inducing carcinogenesis and influencing tumor progression by promoting angiogenesis, metastatic potential and immunosuppression. The possible interaction of heparins and cytokines could also have an effect on cancer cells. METHODS: This study investigated the effect of paclitaxel (PTX) combined with heparins on the vitality of endometrial cancer cells using viability and cytotoxicity assays. The study also examined whether treatment with paclitaxel and heparin influences cytokine secretion or expression. RESULTS: Heparin treatment did not influence cell viability, and no influence of heparins in combination with paclitaxel was seen for the evaluated cancer cell lines HEC-1-A, KLE, RL 95-2 and AN3-CA compared to untreated cells. Secretion of the cytokines CCL5, CCL2 and IL-6 increased after paclitaxel treatment in several endometrial cancer cell lines, but no general effect on cytokine secretion was detected after heparin treatment. A significant decrease in CCL5 expression was only detected in KLE cells following treatment with heparin and paclitaxel, and an increase in the expression of CCL5 in RL 95-2 cells. CONCLUSION: Further in-depth studies are needed to investigate the functions of cytokines CCL2, CCL5 and IL-6 in endometrial cancer cells treated with paclitaxel. Although no general effect on cytokine secretion was detected following heparin treatment, a selective modulatory impact could exist.

Tumor biomarker conversion between primary and metastatic breast cancer: mRNA assessment and its concordance with immunohistochemistry.

Biomarker changes between primary (PT) and metastatic tumor (MT) site may be significant in individualizing treatment strategies and can result from actual clonal evolution, biomarker conversion, or technical limitations of diagnostic tests. This study explored biomarker conversion during breast cancer (BC) progression in 67 patients with different tumor subtypes and metastatic sites via mRNA quantification and subsequently analyzed the concordance between real-time qPCR and immunohistochemistry (IHC). Immunostaining for estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 was performed on formalin-fixed, paraffin-embedded PT and MT tissue sections. RT-qPCR was performed using a multiplex RT-qPCR kit for ESR1, PGR, ERBB2, and MKI67 and the reference genes B2M and CALM2. Subsequent measurement of tumor biomarker mRNA expression to detect conversion revealed significant decreases in ESR1 and PGR mRNA and MKI67 upregulation (all p < 0.001) in MT compared to PT of all tumor subtypes and ERBB2 upregulation in MT from triple-negative PT patients (p = 0.023). Furthermore, ERBB2 mRNA was upregulated in MT brain biopsies, particularly those from triple-negative PTs (p = 0.023). High concordance between RT-qPCR and IHC was observed for ER/ESR1 (81%(κ 0.51) in PT and 84%(κ 0.34) in MT, PR/PGR (70%(κ 0.10) in PT and 78% (κ -0.32) in MT), and for HER2/ERBB2 (100% in PT and 89% in MT). Discordance between mRNA biomarker assessments of PT and MT resulting from receptor conversion calls for dynamic monitoring of BC tumor biomarkers. Overall, RT-qPCR assessment of BC target genes and their mRNA expression is highly concordant with IHC protein analysis in both primary and metastatic tumor.

Inter-rater reliability and double reading analysis of an automated three-dimensional breast ultrasound system: comparison of two independent examiners.

PURPOSE: Breast ultrasound could be a valuable tool complementary to mammography in breast cancer screening. Automated 3D breast ultrasound (ABUS) addresses challenges of hand-held ultrasound and could allow double reading analysis of ultrasound images. This trial assesses the inter-rater reliability and double reading analysis of an ABUS system. METHODS: To assess the reproducibility and diagnostic validity of the ABUS system, SomoV™, a blinded double reading analysis, was performed in 1019 patients (2038 breasts) by two examiners (examiner A/B) and compared to single reading results, as well as to the reference standard regarding its diagnostic validity. Cohen's kappa coefficients were calculated to measure the inter-rater reliability and agreement of the different diagnostic modalities. Patient comfort and time consumption for image acquisition and reading were analyzed descriptively as secondary objectives. RESULTS: Analysis of inter-rater reliability yielded agreement in 81.6% (κ = 0.37; p < 0.0001) showing fair agreement. Single reading analysis of SomoV™ exams (examiner A/examiner B) compared to reference standard showed good specificity (examiner A: 88.3%/examiner B: 84.5%), fair inter-rater agreement (examiner A: κ = 0.31/examiner B: κ = 0.31), and adequate sensitivity (examiner A: 53.1%/examiner B: 64.2%). Double reading analysis yielded good sensitivity and specificity (73.7 and 77.7%). Mammography (n = 1911) alone detected 160 of 176 carcinomas (sensitivity 90.1%). Adding SomoV™ to mammography would have detected 12 additional carcinomas, resulting in a higher sensitivity of 97.7%. CONCLUSION: SomoV™ is a promising technique with good sensitivity, high patient comfort, and fair inter-examiner reliability. It allows double reading analysis that, in combination with mammography, could increase detection rates in breast cancer screening.

PARP inhibition sensitizes endometrial cancer cells to paclitaxel-induced apoptosis.

PARP inhibitors are used in the treatment of gynecological malignancies and it has been demonstrated in preclinical studies that PARP inhibition sensitizes cancer cells to cytotoxic agents. In the present study, PARP expression was detected in different endometrial cancer cell lines by western blot analysis, and PARP activity was measured using an enzymatic assay. In addition, the endometrial cancer cell lines were treated with paclitaxel or carboplatin in combination with the PARP inhibitor PJ34 prior to a cell viability assay and apoptotic nuclei measurement. PARP protein was detected in all four cell lines examined, although its activity varied between the cell lines. Treatment with PJ34 in combination with paclitaxel decreased endometrial cancer cell viability compared with treatment with paclitaxel alone. These results indicate that the inhibition of PARP with PJ34 sensitizes endometrial cancer cells to cytotoxic treatment with paclitaxel.

Use of complementary and integrative medicine among German breast cancer patients: predictors and implications for patient care within the PRAEGNANT study network.

PURPOSE: The present study aims to analyze a cohort of advanced breast cancer patients in Germany to assess their interest in complementary and alternative medicine (CAM) and patient's use of most frequent CAM methods. PATIENTS AND METHODS: Based on the PREGNANT real-time breast cancer registry which is a multicenter study in Germany, questionnaires of 580 patients with advanced breast cancer were evaluated. The implemented questionnaire for CAM asked for general interest in CAM and for patient's use of different CAM methods at present and in the past. The interest and application of CAM were analyzed for association with patients' characteristics such as tumor, patient, and therapy characteristics. RESULTS: In total, 436 out of 580 (75%) patients claimed to be interested in CAM. Further, interest in CAM is significantly correlated with younger age and absence of metastasis at the time of diagnosis. Multivariate analysis confirmed the patient's age and distant disease status at the time of diagnosis as related to interest in CAM. A total of 56.4% of patients applied any CAM method in the past. Moreover, with increasing lines of therapies, the more frequent use of CAM was observed. Hereby, praying, vitamin supplements, and other food supplements were most frequently applied. CONCLUSION: Our data demonstrate high overall interest and frequent use of CAM in advanced breast cancer patients supporting a strong demand of breast cancer patients for complementary counseling and treatments additional to the established cancer therapies. It is indispensable to implement counseling and evidence-based complementary treatments into clinical routine of cancer centers and to adapt postgraduate medical education, respectively.

Impact of reproductive factors on breast cancer subtypes in postmenopausal women: a retrospective single-center study.

PURPOSE: Some reproductive factors are well-known general risk factors for breast cancer (BC). On the other hand, BC subtypes also have a high prognostic value. Correlations, however, that link these risk factors to the development of a particular one of the different BC subtypes are still poorly understood. The primary objective of our study was to assess the influence of different reproductive factors (duration of breastfeeding, parity, and age at first childbirth) on pathological BC subtypes. Secondarily, we correlated body mass index (BMI), age at primary diagnosis, and smoking behavior with tumor subclasses. PATIENTS AND METHODS: We performed a retrospective chart review of 1082 patients with BC who had been treated for postmenopausal BC at the Heidelberg University Hospital during the period 2009-2014. For statistical analysis, different types of correlation analysis as well as a logistic regression model were used. RESULTS: Relating to the primary objective, we found that patients with luminal-like BC had significantly fewer children than patients with triple-negative or HER2-positive subtype tumors (P = 0.027). Concerning the duration of breastfeeding, patients with a luminal A-like tumor had a significantly lower mean nursing period than patients with other subtypes (P = 0.012). Furthermore, patients who did breastfeed presented with a significantly lower number of hormone receptor-positive tumors (estrogen receptor-positive, P = 0.04; progesterone receptor-positive, P = 0.017) but the highest rate of HER2-overexpressing malignancies (P = 0.011). Moreover, late first childbirth was associated with the occurrence of luminal tumors (OR 0.952; P = 0.041). Regarding our secondary aim, higher BMI (P = 0.031) and higher age at primary diagnosis (P = 0.038) were both found to be significantly associated with luminal-like BC. CONCLUSION: The results suggest a correlation of the occurrence of luminal-like BC subtypes with low parity and short or no duration of breastfeeding. Prospective investigations are needed for further confirmation and to evaluate the molecular basis of our findings.