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Background Breast cancer tumors are known to be highly heterogeneous and differences in their metabolic phenotypes, especially at protein level, are less well-understood. Profiling of metabolism-related proteins harbors the potential to establish new patient stratification regimes and biomarkers promoting individualized therapy. In our study, we aimed to examine the relationship between metabolism-associated protein expression profiles and clinicopathological characteristics in a large cohort of breast cancer patients. Methods Breast cancer specimens from 801 consecutive patients, diagnosed between 2009 and 2011, were investigated using reverse phase protein arrays (RPPA). Patients were treated in accordance with national guidelines in five certified German breast centers. To obtain quantitative expression data, 37 antibodies detecting proteins relevant to cancer metabolism, were applied. Hierarchical cluster analysis and individual target characterization were performed. Clustering results and individual protein expression patterns were associated with clinical data. The Kaplan-Meier method was used to estimate survival functions. Univariate and multivariate Cox regression models were applied to assess the impact of protein expression and other clinicopathological features on survival. Results We identified three metabolic clusters of breast cancer, which do not reflect the receptor-defined subtypes, but are significantly correlated with overall survival (OS, p  ≤ 0.03) and recurrence-free survival (RFS, p  ≤ 0.01). Furthermore, univariate and multivariate analysis of individual protein expression profiles demonstrated the central role of serine hydroxymethyltransferase 2 (SHMT2) and amino acid transporter ASCT2 (SLC1A5) as independent prognostic factors in breast cancer patients. High SHMT2 protein expression was significantly correlated with poor OS (hazard ratio (HR) = 1.53, 95% confidence interval (CI) = 1.10–2.12, p  ≤ 0.01) and RFS (HR = 1.54, 95% CI = 1.16–2.04, p  ≤ 0.01). High protein expression of ASCT2 was significantly correlated with poor RFS (HR = 1.31, 95% CI = 1.01–1.71, p  ≤ 0.05). Conclusions Our data confirm the heterogeneity of breast tumors at a functional proteomic level and dissects the relationship between metabolism-related proteins, pathological features and patient survival. These observations highlight the importance of SHMT2 and ASCT2 as valuable individual prognostic markers and potential targets for personalized breast cancer therapy. Trial registration ClinicalTrials.gov, NCT01592825 . Registered on 3 May 2012.

Background Today, more than 70% of patients with primary node-negative breast cancer are cured by local therapy alone. Many patients receive overtreatment by adjuvant chemotherapy due to inadequate risk assessment. So far, few clinical trials have prospectively evaluated tumor biology based prognostic factors. Risk assessment by a biological algorithm including invasion factors urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) will assess up to 35-55% of node-negative patients as low-risk and thus avoid chemotherapy. In contrast, a clinical-pathological algorithm will only classify 20-40% of patients as low-risk. High-risk node-negative patients should receive chemotherapy. Anthracycline-based regimens are accepted as a standard, the additional benefit of taxanes remains an open question. Methods/Design The international NNBC3 (\"Node Negative Breast Cancer 3-Europe\") trial compares biological risk assessment (UP) using invasion factors uPA/PAI-1 with a clinical-pathological algorithm (CP). In this trial, the type of risk assessment (CP or UP) was chosen upfront by each center for its patients. Fresh frozen tissue was obtained to determine uPA/PAI-1 using an enzyme-linked immunosorbent assay (ELISA). Patients assessed as high-risk were stratified by human epidermal growth factor receptor 2 (HER2) status and then randomised to receive anthracycline-containing chemotherapy 5-Fluorouracil (F)/Epirubicin (E)/Cyclophosphymide (C) or an anthracycline-taxane sequence (FE 100 C*6 versus FE 100 C*3 followed by Docetaxel 100 *3). Discussion In this trial, 4,149 node-negative patients with operable breast cancer from 153 centers in Germany and France were included since 2002. Measurement of uPA/PAI-1 by ELISA was performed with standardised central quality assurance for 2,497 patients (60%) from 56 \"UP\"-centers. The NNBC 3-Europe trial showed that inclusion of patients into a clinical phase III trial is feasible based on biological testing of fresh frozen tumor material. In addition, 2,661 patients were classified as high-risk and thus received chemotherapy. As adjuvant chemotherapy, 1,334 high-risk patients received FE 100 C-Docetaxel 100 , and 1,327 received French FE 100 C. No unexpected toxicities were observed. Chemotherapy efficacy and comparison of UP with CP will be evaluated after longer follow-up. Trial Registration clinical Trials.gov NCT01222052 .

Tumour-infiltrating lymphocytes (TILs) are considered to have prognostic and predictive value for patients with early breast cancer. We examined 1166 breast cancer patients from a prospective, multicentre cohort (Prognostic Assessment in Routine Application (PiA), n = 1270, NCT 01592825) following recommendations from the International TILs Working Group. TIL quantification was performed using predefined groups and as a continuous variable in 10% increments. The primary objective was the distribution of TILs in different breast cancer types. The second objective was the association with the recurrence-free interval (RFI) and overall survival (OS). Stromal infiltration with more than 60% TILs appeared in 2% of hormone receptor (HR)-positive and HER2-negative tumours, in 9.8% of HER2-positive tumours (any HR) and 19.4% of triple-negative breast cancers (TNBCs). Each 10% increment was associated with an improvement in the prognosis in HER2-positive samples (RFI, hazard ratio 0.773, 95% CI 0.587–1.017; OS, hazard ratio 0.700, 95% CI 0.523–0.937). When defining exploratory cut-offs for TILs, the use of a 30% threshold for the HR-positive and HER2-negative group, a 20% threshold for the HER2 group and a 60% threshold for the TNBC group appeared to be the most suitable. TILs bore prognostic value, especially in HER2-positive breast cancer. For clinical use, additional research on the components of immune infiltration might be reasonable.

Purpose Phosphatidylinositide-3-kinase (PI3K) regulates proliferation and apoptosis; somatic PIK3CA -mutations may activate these processes. Aim of this study was to determine the prevalence of PIK3CA -mutations in a cohort of early stage breast cancer patients and the association to the course of disease. Patients and methods From an unselected cohort of 1270 breast cancer patients (PiA, Prognostic Assessment in routine application, NCT 01592825) 1123 tumours were tested for the three PIK3CA hotspot-mutations H1047R, E545K, and E542K by qPCR. Primary objectives were the prevalence of somatic PIK3CA -mutations and their association to tumour characteristics. Secondary objective was the association of PIK3CA -mutations to recurrence-free interval (RFI) and overall survival. Results PIK3CA -mutation rate was 26.7% (300 of 1123). PIK3CA -mutations were significantly more frequent in steroid hormone-receptor (SHR)-positive HER2-negative (31.4%), and G1 and G2 tumours (32.8%). Overall, we did not observe a significant association of PIK3CA-mutations to RFI. In SHR-positive BCs with PIK3CA-mutations, a strong trend for impaired  RFI was observed (adjusted HR 1.64, 95% CI 0.958–2.807), whilst in SHR-negative BCs PIK3CA -mutations were insignificantly associated with improved RFI (adjusted HR 0.49; 95% CI 0.152–1.597). Of note, we observed a significantly detrimental prognostic impact of PIK3CA -mutations on RFI in SHR-positive, HER2-negative BCs if only aromatase inhibitors were administered as adjuvant therapy (adjusted HR 4.44, 95% CI 1.385–13.920), whilst no impact was observed in tamoxifen treated patients. Conclusion This cohort study speficies the overall mutation rate of PIK3CA in early breast cancer. The impact of PIK3CA-mutations on RFI and OS was heterogeneous. Our results suggest that estrogen deprivation failes to be active in case of PIK3CA-mutation.

Purpose Systemic therapy plays a major part in the cure of patients with early breast cancer (eBC). However, personalized treatment concepts are required to avoid potentially harmful overtreatment. Biomarkers are pivotal for individualized therapy. The Notch signalling pathway is widely considered as a suitable prognostic or predictive marker in eBC. This study aimed primarily at assessing the relationship between NOTCH1 mRNA expression levels and histopathological features of breast cancer tumors, as well as clinical characteristics of the correspondent eBC patients. As a secondary aim, we investigated the prognostic and predictive value of NOTCH1 by assessing possible associations between NOTCH1 mRNA expression and recurrence-free interval (RFI) and overall survival after five years of observation. Patients and methods The relative NOTCH1 mRNA expression was determined in 414 tumour samples, using quantitative PCR in a prospective, multicenter cohort ( P rognostic Assessment i n Routine A pplication (PiA), 2009–2011, NCT01592825) of 1,270 female eBC patients. Results High NOTCH1 mRNA expression was detected in one-third of the tumours and was associated with negative hormone receptor status and high uPA/PAI-1 status. In addition, high NOTCH1 mRNA expression was found to be associated with more RFI related events (adjusted hazard ratio 2.1, 95% CI 1.077–4.118). Patients who received adjuvant chemotherapy and had high NOTCH1 mRNA expression in the tumour ( n  = 86) were three times more likely to have an RFI event (adjusted hazard ratio 3.1, 95% CI 1.321–7.245, p  = 0.009). Conclusion In this cohort, NOTCH1 mRNA expression had a prognostic and predictive impact. Tumours with high NOTCH1 mRNA expression may be less sensitive to cytotoxic treatment and downregulation of the Notch signalling pathway (e.g. by γ-secretase inhibitors) may be valuable for eBC therapy as an individualised treatment option.

Das Leben in der modernen Welt ist eng mit der Exposition gegenüber Umweltfaktoren verknüpft, die auf physikalische oder chemische Weise das Risiko einer Krebserkrankung erhöhen. Das gilt auch für Brustkrebs und die weiblichen Genitalkarzinome. Von besonderem Interesse sind Chemikalien, die, ohne selber Hormone zu sein, hormonelle Regulationsprozesse beeinflussen. Sie werden als „endokrine Disruptoren“ oder „hormonell aktive Agentien“ bezeichnet. Ihre hormonartigen Wirkungen treiben die Proliferationsprozesse östrogenresponsiver Zellen. Damit wirken diese Substanzen als Promotoren initiierter Krebszellen. Wenn diese Substanzen zu bestimmten, besonders vulnerablen Phasen der Individualentwicklung einwirken, zum Beispiel in der Fetalentwicklung oder in der peripuberalen Ausprägung der sekundären Geschlechtsmerkmale, können diese Entwicklungsprozesse in pathologischer Weise geprimed werden. So werden zu sehr viel späteren Zeiten Krebserkrankungen ausgelöst oder begünstigt. Selbst eine generationenübergreifende Kanzerogenese ist beschrieben worden. Chemikalien mit eindeutiger karzinogener Wirkung, wie die polyzyklischen aromatischen Kohlenwasserstoffe, die beispielsweise Teer- und Teerprodukte kontaminieren, wirken lokal und systemisch karzinogen und begünstigen damit die Entstehung von Brust- und Genitalkarzinomen. Unter den physikalischen karzinogenen Faktoren sind extrem niederfrequente Magnetwechselfelder („extremely low-frequency electromagnetic field“, ELF – EMF) und Licht in der Nacht zu beachten. Abschließend werden Rauchen und Alkohol Konsum in ihrer Beziehung zu Brust- und Genitalkarzinomen diskutiert.

Introduction/BackgroundGenomic breast cancer gene mutation (BRCAm) increases the risk for hereditary breast and/or ovarian cancer (HBOC). However, BRCAm and other homologous recombination deficiencies (HRD) also render eminent sensitivity of ovarian cancer (OC) to poly-(ADPribose)-polymerase inhibitors (PARPi). Therefore, international guidelines recommend biomarker testing to assess familial risk (blood) and to tailor individual treatment (tumour and/or blood). Real-world management of patients with primary advanced, high-grade, epithelial OC is currently being evaluated by the prospective, non-interventional study SCOUT-1 (NOGGO ov54, NCT04830709).Methodology750 patients with completed surgery (if applicable), eligible for platinum-based chemotherapy, tested for BRCA1/2m (solitary or within HRD-test) and provided written informed consent, are planned to be enrolled in SCOUT-1 and followed for up to 7 years. Interim analyses (IA) were defined at 175, 250 and 375 enrolled patients followed for at least 6 months. Here we present details on biomarker testing based on data from 1stIA; only descriptive statistical methods were applied.ResultsOut of 175 patients considered for 1stIA (data cut-off: April 20th, 2023), 159 qualified for the Full Analysis Set (FAS). Burden for HBOC was assessed for 76.7% (N=122 patients); of these 40.2% (N=49) showed increased risk (risk score ≥ 3, DKG checklist). BRCA-test-results (blood and/or tumour) were available for 152 patients (95.6%) and BRCAm was detected in 24.3% (N=37) of the patients tested (30 with BRCA1m; 6 with BRCA2m; 1 with BRCA1&2m). Genomic BRCAm was detected in 26 patients; 16 (61.5%) of those showed an increased risk for HBOC at assessment of family history. Of all tumours tested (N=62), 45.2% (N=28) were HRD positive.ConclusionThe incidence of BRCAm and HRD observed at the time of the 1stIA is consistent with previously published data. Significant number of patients with genomic BRCAm had no increased risk according to HBOC assessment. Number of patients tested for HRD remains low.DisclosuresThis study is funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Introduction/BackgroundLow-grade serous carcinomas (LGSC) are associated with better prognoses compared to their high-grade serous (HGSC) counterparts. Nevertheless, we are confronted with a challenging treatment, since the median age upon diagnosis is younger, standard platinum-based chemotherapy is less effective and, most importantly, it has still not been as well studied as HGSC. The purpose of this ongoing study was to examine patients’ perception and assessment regarding their disease and therapy as well as the level of information among women with LGSC and borderline ovarian tumors (BOT).MethodologyA questionnaire was developed based on the experiences of previous EXPRESSION-trials and provided to patients with LGSC and BOT. The hardcopy-version was converted into an online database and statistically analyzed via SPSS-Software.ResultsFrom March 2019, 321 patients with LGSC and BOT from eighteen German clinics and gynecological practices participated in the survey, 90 (28%) with LGSC and 231 (72%) with BOT. While nearly all patients (97.8% LGSC; 94.3% BOT) had primary surgery, 58% of LGSC patients received adjuvant chemotherapy. Patients indicated the attending physician as the main source of information (81% LGSC; 85% BOT). The majority were pleased with the explanation about their illness and therapy. Significantly more BOT-patients were not aware of their tumor stage during initial diagnosis (31.4% LGSC vs 64.5% BOT, p= <0.0001). 47.8% of LGSC-patients did not know the difference between LGSC and HGSC and 73.9% were not offered a hormone replacement therapy. BOT-patients estimate the aggressiveness (31.2% BOT vs. 52.2% LGSC) and the risk of recurrence (28.2% BOT vs. 44% LGSC) of their disease lower than LGSC-patients.ConclusionThis study underlines the high need for more detailed explanation in this specific patient group with a greater focus on the underlying tumor biology and the corresponding course of disease and prognosis.

BackgroundThere is limited information about the impact of radical surgery including pelvic and para-aortic lymphadenectomy and subsequent platinum-based chemotherapy on sexuality in patients with advanced ovarian cancer.ObjectiveTo evaluate the impact of radical surgery including pelvic and para-aortic lymphadenectomy and subsequent platinum-based chemotherapy on sexuality in patients with advanced ovarian cancer as a sub-protocol of the prospectively randomized LION trial.MethodsThe Sexual Activity Questionnaire was applied to assess sexual function according to its sub-scales activity, pleasure, and discomfort. The 'orgasm' sub-scale from the Female Sexual Function Index was also added. The questionnaire was administered in combination with the EORTC QLQ-C30 questionnaire at baseline prior surgery, after 6, 12, and 24 months. The primary endpoint was changes in sexual function.ResultsOverall, 495 patients received the questionnaires. 254 (51%) responded at baseline. Of these, 55 (22%) patients were sexually active, 182 (72%) were sexually inactive, and for 17 (7%) patients' data were not available. There was a total of 55/495 (11%) patients at 6 months, 139 (28%) patients at 12 months, and 81 (16%) patients at 24 months. Median age was 60.5 years (range 21.4–75.8). At baseline, sexually active responders were significantly younger (median age 51.5 years,) than sexually inactive responders (median age 61.8 years) and tended to have a better performance status. Discomfort evaluated as dryness of the vagina and pain during sexual intercourse was significantly worse at 12 months than at baseline (p<0.001); however, the surgical variable, lymphadenectomy, did not have any impact on this. The orgasm sub-scale showed diverging results with a deterioration from baseline to 12 months in the lymphadenectomy group compared with the no-lymphadenectomy group (p=0.02).ConclusionThe majority of patients were sexually inactive; however, in those who were sexually active, pain during intercourse was worse at 12 months. In addition, the orgasm sub-scale demonstrated worse results in patients who underwent complete lymphadenectomy. The study suggests that surgery in the retroperitoneal space may influence sexual function.