Publications by authors named "Sara Y Brucker"

179 Publications

Mendelian randomisation study of smoking exposure in relation to breast cancer risk.

Br J Cancer 2021 Aug 2. Epub 2021 Aug 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.

Methods: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.

Results: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.

Conclusion: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
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http://dx.doi.org/10.1038/s41416-021-01432-8DOI Listing
August 2021

Prognostic effect of low-level HER2 expression in patients with clinically negative HER2 status.

Eur J Cancer 2021 Sep 23;155:1-12. Epub 2021 Jul 23.

Department of Gynecology and Obstetrics, Marienhospital Bottrop, Bottrop, Germany.

Purpose: Assessment of HER2 overexpression using immunohistochemistry (IHC) and/or in situ hybridisation (ISH) for the detection of HER2 amplifications is standard to identify patients for established HER2-directed treatments. Patients with lower HER2 expression levels have recently also become candidates for novel therapies targeting HER2. This study aimed to assess tumour and patient characteristics and prognosis in patients with advanced breast cancer (aBC), relative to low HER2 expression levels.

Methods: PRAEGNANT is a prospective aBC registry (NCT02338167), focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis includes patients with conventionally HER2-negative aBC. Clinical outcome was compared in the groups with no (IHC score 0) or with low HER2 expression (IHC 1+, or IHC 2+/ISH negative).

Results: Low HER2 expression levels in triple-negative aBC patients did not influence progression-free survival. Overall survival appeared poorer in patients with IHC 2+ compared with patients with no HER2 expression in the unadjusted analysis (hazard ratio 2.24, 95% confidence interval 0.1.12-4.47). However, this effect was not maintained in the adjusted analysis. In HER2-negative, hormone receptor-positive patients, low HER2 expression appeared to have no effect on prognosis, neither progression-free survival nor overall survival.

Conclusions: We could not demonstrate that HER2 expression at a low level and assessed in clinical routine can differentiate patients into prognostic groups. However, the prevalence of patients with a low expression makes this population interesting for clinical trials with potentially active treatments using HER2 as a target.
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http://dx.doi.org/10.1016/j.ejca.2021.06.033DOI Listing
September 2021

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

Eur J Cancer 2021 Sep 12;154:128-137. Epub 2021 Jul 12.

Department of Women's Health, University of Tuebingen, Tuebingen, Germany.

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.
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http://dx.doi.org/10.1016/j.ejca.2021.06.028DOI Listing
September 2021

Treatment of Patients with Early Breast Cancer: Evidence, Controversies, Consensus: German Expert Opinions on the 17th International St. Gallen Consensus Conference.

Geburtshilfe Frauenheilkd 2021 Jun 19;81(6):637-653. Epub 2021 May 19.

Universitätsklinik und Poliklinik für Gynäkologie, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany.

This year's 17th St. Gallen (SG) Consensus Conference on the Treatment of Patients with Early Breast Cancer (SG-BCC) with the title "Customizing local and systemic therapies for women with early breast cancer" focused on the challenge of targeting the treatment of early breast cancer more specifically to the individual disease situation of each patient. As in previous years, a German working group of leading breast cancer experts discussed the results of the international SG-BCC 2021 in the context of the German guideline. It is helpful to compare the SG recommendations with the recently updated treatment recommendations of the Breast Commission of the German Working Group on Gynaecological Oncology (Arbeitsgemeinschaft Gynäkologische Onkologie e. V., AGO) and the S3 guideline because the SG-BCC panel comprised experts from different countries, which is why country-specific aspects can be incorporated into the SG recommendations. The German treatment recommendations of the AGO and the S3 guideline are based on current evidence. Nevertheless, any therapeutic decision must always undergo a risk-benefit analysis for the specific situation and to be discussed with the patient.
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http://dx.doi.org/10.1055/a-1483-2782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216767PMC
June 2021

Prognosis of Patients With Early Breast Cancer Receiving 5 Years vs 2 Years of Adjuvant Bisphosphonate Treatment: A Phase 3 Randomized Clinical Trial.

JAMA Oncol 2021 Aug;7(8):1149-1157

Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany.

Importance: Bisphosphonate treatment in patients with early breast cancer has become part of care, but the optimal treatment duration is still unclear.

Objective: To compare 2 vs 5 years of zoledronate treatment following adjuvant chemotherapy in patients with early breast cancer.

Design, Setting, And Participants: The SUCCESS A phase 3 multicenter randomized open-label clinical trial with a 2 × 2 factorial design enrolled 3754 patients from September 21, 2005, to March 12, 2007 (last patient out, May 7, 2014). Final data analysis was conducted from September 2019 to October 2020. In 250 German study centers, patients were eligible for participation in the SUCCESS A trial if they had either node-positive or high-risk node-negative (defined as at least 1 of the following: tumor size ≥ pT2, histologic grade 3, negative hormone receptor status, or age ≤35 years) primary invasive breast cancer.

Interventions: Patients were first randomized to adjuvant chemotherapy with 3 cycles of fluorouracil, epirubicin, and cyclophosphamide followed by 3 cycles of docetaxel with or without gemcitabine (not presented in this report). After chemotherapy, patients underwent a second randomization of 5 years of zoledronate treatment (4 mg intravenously every 3 months for 2 years, followed by 4 mg intravenously every 6 months for 3 years) vs 2 years of zoledronate treatment (4 mg intravenously every 3 months for 2 years).

Main Outcomes And Measures: The primary end point of the study was disease-free survival; secondary end points were overall survival, distant disease-free survival, and the incidence of skeletal-related adverse events. Survival times were measured from 2 years after the start of zoledronate treatment (landmark analysis).

Results: Overall, data on 2987 patients were available for analysis; median age was 53 (range, 21-86) years. Disease-free survival, overall survival, and distant disease-free survival did not differ significantly between the 2 treatment arms (5 vs 2 years) as shown by adjusted multivariable Cox proportional hazards regression models (disease-free survival: hazard ratio [HR], 0.97; 95% CI, 0.75-1.25; P = .81; overall survival: HR, 0.98; 95% CI, 0.67-1.42; P = .90; distant disease-free survival: HR, 0.87; 95% CI, 0.65-1.18; P = .38). Adverse events were observed more often in the 5-year (46.2%) vs 2-year (27.2%) zoledronate treatment arm, which was particularly true for the skeletal-related events bone pain (5 years, 8.3% vs 2 years, 3.7%) and arthralgia (5 years, 5.1% vs 2 years, 3.1%).

Conclusions And Relevance: The results of this phase 3 randomized clinical trial indicate that extending the zoledronate treatment beyond 2 years does not improve the prognosis of high-risk patients with early breast cancer receiving chemotherapy, suggesting that the currently recommended bisphosphonate treatment duration of 3 to 5 years could be reduced.

Trial Registration: ClinicalTrials.gov Identifier: NCT02181101.
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http://dx.doi.org/10.1001/jamaoncol.2021.1854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227465PMC
August 2021

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

Am J Hum Genet 2021 07 18;108(7):1190-1203. Epub 2021 Jun 18.

Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10).
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http://dx.doi.org/10.1016/j.ajhg.2021.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322933PMC
July 2021

Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature.

Int J Environ Res Public Health 2021 05 25;18(11). Epub 2021 May 25.

Department of Women's Health, Tübingen University Hospital, Calwerstr. 7, 72076 Tübingen, Germany.

The risk of gonadal germ cell tumors is increased over the lifetime of patients with XY-disorders of sex development (XY-DSD). The aim of this study was to evaluate clinical features and histopathological outcome after gonadectomy in patients with XY-DSD to assess the risk of malignant transformation to gonadal germ cell tumors. Thirty-five women treated for XY-DSD at our hospital between 2003 and 2020 were enrolled in this study. Twenty-seven (77%) underwent prophylactic gonadectomy, 10 (29%) at our department and 17 (48%) at external hospitals. Eight (23%) patients didn't receive gonadectomy. Of the patients who underwent a surgical procedure at our hospital, two patients were diagnosed with a unilateral seminoma, one patient with a bilateral and one patient with a unilateral Sertoli cell adenoma. According to these findings, preventive gonadectomy in patients with XY-DSD should be taken into consideration. Guidelines concerning the necessity of gonadectomy to avoid malignant transformation are still lacking. The risk of malignant germ cell tumors from rudimentary gonads has not been investigated sufficiently to date, as it is mostly based on case series due to the rarity of the condition. In our study we retrospectively analyzed patients who partly underwent bilateral gonadectomy, aiming to fill this gap. Concerning the ideal point of time for gonadectomy, further studies with a higher number of patients are needed.
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http://dx.doi.org/10.3390/ijerph18115648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197511PMC
May 2021

Challenges and Opportunities for Real-World Evidence in Metastatic Luminal Breast Cancer.

Breast Care (Basel) 2021 Apr 16;16(2):108-114. Epub 2021 Mar 16.

Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany.

Background: The therapeutic armamentarium for patients with metastatic breast cancer is becoming more and more specific. Recommendations from clinical trials are not available for all treatment situations and patient subgroups, and it is therefore important to collect real-world data.

Summary: To develop recommendations for up-to-date treatments and participation in clinical trials for patients with metastatic breast cancer, the Prospective Academic Translational Research PRAEGNANT Network was established to optimize the quality of oncological care in the advanced therapeutic setting. The main aim of PRAEGNANT is to systematically record medical care for patients with metastatic breast cancer in the real-life setting, including the outcome and side effects of different treatment strategies, to monitor quality-of-life changes during therapy, to identify patients eligible for participation in clinical studies, and to allow targeted therapies based on the molecular structures of breast carcinomas.

Key Messages: This article describes the PRAEGNANT network and sheds light on the question of whether the various end points from clinical trials can be transferred to the real-world treatment situation.
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http://dx.doi.org/10.1159/000515701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114055PMC
April 2021

Long Term Findings Concerning the Mental and Physical Condition, Quality of Life and Sexuality after Laparoscopically Assisted Creation of a Neovagina (Modified Vecchietti Technique) in Young MRKHS (Mayer-Rokitansky-Küster-Hauser-Syndrome) Patients.

J Clin Med 2021 Mar 18;10(6). Epub 2021 Mar 18.

Department of Women's Health, Women's University Hospital, Calwerstr. 7, 72076 Tübingen, Germany.

The Mayer-Rokitansky-Küster-Hauser-syndrome (MRKHS) is characterized by a congenital uterine and vaginal aplasia. A large body of literature reports that a diagnosis of MRKHS has a variety of psychological effects on patients and doubts about female identity. The aim of the underlying study was to detect the patient-reported physical and mental health and sexual function before and after laparoscopically assisted creation of a neovagina. 160 women with MRKHS who underwent this type of surgery between September 2009 and December 2015 were invited to complete the questionnaires. Packages consisting of six questionnaires were handed out before surgery, six and 12 months after surgery. Data from 82 patients could be included in the study. Patients had a mean age of 19.9 years at inclusion in the study. We detected an impairment of the health-related mental quality of life. There was no higher risk for psychological disorders. MRKHS patients show similar self-acceptance and normal body image compared to the general population. The sexual function is limited before surgery and normalizes after surgery. Useful factors for coping with the disease are an interdisciplinary approach in diagnostics and treatment, psychosocial adaptation as well as a supportive social environment.
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http://dx.doi.org/10.3390/jcm10061269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003280PMC
March 2021

Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta-analysis.

Cancer 2021 Jul 1;127(14):2409-2422. Epub 2021 Apr 1.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Endometrial cancers (ECs) with somatic mutations in DNA polymerase epsilon (POLE) are characterized by unfavorable pathological features, which prompt adjuvant treatment. Paradoxically, women with POLE-mutated EC have outstanding clinical outcomes, and this raises concerns of overtreatment. The authors investigated whether favorable outcomes were independent of treatment.

Methods: A PubMed search for POLE and endometrial was restricted to articles published between March 1, 2012, and March 1, 2018, that provided individual patient data (IPD), adjuvant treatment, and survival. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) reporting guidelines for IPD, the authors used univariate and multivariate one-stage meta-analyses with mixed effects Cox models (random effects for study cohorts) to infer the associations of treatment, traditional prognostic factors, and outcome, which was defined as the time from first diagnosis to any adverse event (progression/recurrence or death from EC).

Results: Three hundred fifty-nine women with POLE-mutated EC were identified; 294 (82%) had pathogenic mutations. Worse outcomes were demonstrated in patients with nonpathogenic POLE mutations (hazard ratio, 3.42; 95% confidence interval, 1.47-7.58; log-rank P < .01). Except for stage (P < .01), traditional prognosticators were not associated with progression/recurrence or death from disease. Adverse events were rare (11 progressions/recurrences and 3 disease-specific deaths). Salvage rates in patients who experienced recurrence were high and sustained, with 8 of 11 alive without evidence of disease (range, 5.5-14.2 years). Adjuvant treatment was not associated with outcome.

Conclusions: Clinical outcomes for ECs with pathogenic POLE mutations are not associated with most traditional risk parameters, and patients do not appear to benefit from adjuvant therapy. The observed low rates of recurrence/progression and the high and sustained salvage rates raise the possibility of safely de-escalating treatment for these patients.

Lay Summary: Ten percent of all endometrial cancers have mutations in the DNA repair gene DNA polymerase epsilon (POLE). Women who have endometrial cancers with true POLE mutations experience almost no recurrences or deaths from their cancer even when their tumors appear to have very unfavorable characteristics. Additional therapy (radiation and chemotherapy) does not appear to improve outcomes for women with POLE-mutated endometrial cancer, and this supports the move to less therapy and less associated toxicity. Diligent classification of endometrial cancers by molecular features provides valuable information to inform prognosis and to direct treatment/no treatment.
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http://dx.doi.org/10.1002/cncr.33516DOI Listing
July 2021

Mutations in and Other Panel Genes in Patients With Metastatic Breast Cancer -Association With Patient and Disease Characteristics and Effect on Prognosis.

J Clin Oncol 2021 May 29;39(15):1619-1630. Epub 2021 Mar 29.

Department of Gynecology and Obstetrics, Carl Gustav Carus Faculty of Medicine and University Hospital, Technical University of Dresden, Dresden, Germany.

Purpose: Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome.

Patients And Methods: Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed.

Results: Germline mutations in 12 established BC predisposition genes (including and ) were detected in 271 (10.4%) patients. A mutation in or was seen in 129 patients (5.0%). mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% 6.6%, < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC.

Conclusion: Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.
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http://dx.doi.org/10.1200/JCO.20.01200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274805PMC
May 2021

Laparoscopic Peritoneal Wash Cytology-Derived Primary Human Mesothelial Cells for In Vitro Cell Culture and Simulation of Human Peritoneum.

Biomedicines 2021 Feb 10;9(2). Epub 2021 Feb 10.

Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany.

Peritoneal mucosa of mesothelial cells line the abdominal cavity, surround intestinal organs and the female reproductive organs and are responsible for immunological integrity, organ functionality and regeneration. Peritoneal diseases range from inflammation, adhesions, endometriosis, and cancer. Efficient technologies to isolate and cultivate healthy patient-derived mesothelial cells with maximal purity enable the generation of capable 2D and 3D as well as in vivo-like microfluidic cell culture models to investigate pathomechanisms and treatment strategies. Here, we describe a new and easily reproducible technique for the isolation and culture of primary human mesothelial cells from laparoscopic peritoneal wash cytology. We established a protocol containing multiple washing and centrifugation steps, followed by cell culture at the highest purity and over multiple passages. Isolated peritoneal mesothelial cells were characterized in detail, utilizing brightfield and immunofluorescence microscopy, flow cytometry as well as Raman microspectroscopy and multivariate data analysis. Thereby, cytokeratin expression enabled specific discrimination from primary peritoneal human fibroblasts. Raman microspectroscopy and imaging were used to study morphology and biochemical properties of primary mesothelial cell culture compared to cryo-fixed and cryo-sectioned peritoneal tissue.
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http://dx.doi.org/10.3390/biomedicines9020176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916778PMC
February 2021

Peritoneal Adhesions and their Prevention - Current Trends.

Surg Technol Int 2021 May;38:221-233

Department for Women's Health, University Hospital Tübingen, Tübingen, Germany.

The development of adhesions after gynecologic surgery is a severe problem with ramifications that go beyond the medical complications patients suffer (which most often include pain, obstruction and infertility), since they also impose a huge financial burden on the health care system and increase the workload of surgeons and all personnel involved in surgical follow-up care. Surgical techniques to avoid adhesion formation have not proven to be sufficient and pharmaceutical approaches for their prevention are even less effective, which means that the use of adhesion prevention devices is essential for achieving decent prophylaxis. This review explores the wide range of adhesion prevention products currently available on the market. Particular emphasis is put on prospective randomized controlled clinical trials that include second-look interventions, as these offer the most solid evidence of efficacy. We focused on adhesion scores, which are the most common way to quantify adhesion formation. This enables a direct comparison of the efficacies of different devices. While the greatest amount of data are available for oxidized regenerated cellulose, the outcomes with this adhesion barrier are mediocre and several studies have shown little efficacy. The best results have been achieved using adhesion barriers based on either modified starch, i.e., 4DryField® PH (PlantTec Medical GmbH, Lüneburg, Germany), or expanded polytetrafluoroethylene, i.e., GoreTex (W.L. Gore & Associates, Inc., Medical Products Division, Flagstaff, AZ), albeit the latter, as a non-resorbable barrier, has a huge disadvantage of having to be surgically removed again. Therefore, 4DryField® PH currently appears to be a promising approach and further studies are recommended.
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May 2021

Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium.

Cancer Epidemiol Biomarkers Prev 2021 04 26;30(4):623-642. Epub 2021 Jan 26.

Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.

Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.

Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype ( > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.

Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.

Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026532PMC
April 2021

Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome.

Am J Hum Genet 2021 02;108(2):337-345

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.
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http://dx.doi.org/10.1016/j.ajhg.2020.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896104PMC
February 2021

The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium.

Front Cell Dev Biol 2020 21;8:556543. Epub 2020 Oct 21.

Research Institute of Women's Health, Eberhard-Karls University, Tübingen, Germany.

The serum- and glucocorticoid-inducible kinase 1 (SGK1) is subject to genetic up-regulation by diverse stimulators including glucocorticoids, mineralocorticoids, dehydration, ischemia, radiation and hyperosmotic shock. To become active, the expressed kinase requires phosphorylation, which is accomplished by PI3K/PDK1 and mTOR dependent signaling. SGK1 enhances the expression/activity of various transport proteins including Na/K-ATPase as well as ion-, glucose-, and amino acid- carriers in the plasma membrane. SGK1 can further up-regulate diverse ion channels, such as Na-, Ca-, K- and Cl channels. SGK1 regulates expression/activity of a wide variety of transcription factors (such as FKHRL1/Foxo3a, β-catenin, NFκB and p53). SGK1 thus contributes to the regulation of transport, glycolysis, angiogenesis, cell survival, immune regulation, cell migration, tissue fibrosis and tissue calcification. In this review we summarized the current findings that SGK1 plays a crucial function in the regulation of endometrial function. Specifically, it plays a dual role in the regulation of endometrial receptivity necessary for implantation and, subsequently in pregnancy maintenance. Furthermore, fetal programming of blood pressure regulation requires maternal SGK1. Underlying mechanisms are, however, still ill-defined and there is a substantial need for additional information to fully understand the role of SGK1 in the orchestration of embryo implantation, embryo survival and fetal programming.
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http://dx.doi.org/10.3389/fcell.2020.556543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609842PMC
October 2020

Unmet Supportive Care Needs Among Women With Breast and Gynecological Cancer: Relevance of Attachment Anxiety and Psychological Distress.

Front Psychol 2020 21;11:558190. Epub 2020 Oct 21.

Department of Psychosomatic Medicine and Psychotherapy, LVR University Hospital, Essen, University of Duisburg-Essen, Essen, Germany.

Objective: Attachment anxiety and avoidance are known risk factors for the development of unmet needs and poor well-being among patients with chronic diseases. Few studies have addressed this in individuals with cancer. We aimed to explore the relationship between supportive care needs, attachment styles and distress in women with breast and gynecological cancer.

Methods: Using a cross-sectional paper-pencil ( = 157) and online survey ( = 614), a total of 771 patients with breast or gynecological cancer completed a set of validated questionnaires. From September 2013 to January 2014, consecutive inpatients and outpatients of the university hospital Tuebingen were included in the study. Further, participants were recruited through social media, patient internet platforms, self-help group leaders and patient networks. We used the Supportive Care Needs Survey (SCNS-SF-34) with the need dimensions: health system, patient care, psychological, physical, and sexual needs, as well as the Experiences in Close Relationships-Revised Questionnaire, and the Distress Thermometer. A multiple linear regression model was used to analyze the influence of attachment styles (anxiety and avoidance) on the SCNS-SF-34 dimensions. A moderation analysis was used to explore the influence of the interaction between attachment anxiety and distress for all SCNS-SF-34 dimensions.

Results: Attachment anxiety was a significant determinant and led to higher unmet supportive care needs in all dimensions, whereas attachment avoidance was not significant. Distress did moderate the relationship between attachment anxiety and psychological and health system needs and led to a higher unmet needs development. For the other SCNS-SF-34 dimensions, distress was not confirmed as a moderator.

Conclusion: Our findings highlight attachment anxiety as a risk factor for the development of unmet supportive care needs and potentially impaired psychological adjustment to cancer. Further studies are needed to elucidate the interactions between attachment styles, distress and supportive care needs among cancer patients.
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http://dx.doi.org/10.3389/fpsyg.2020.558190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609386PMC
October 2020

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

BMC Cancer 2020 Nov 11;20(1):1091. Epub 2020 Nov 11.

Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Background: Eligibility criteria are a critical part of clinical trials, as they define the patient population under investigation. Besides certain patient characteristics, clinical trials often include biomarker testing for eligibility. However, patient-identification mostly relies on the trial site itself and is often a time-consuming procedure, which could result in missing out on potentially eligible patients. Pre-selection of those patients using a registry could facilitate the process of eligibility testing and increase the number of identified patients. One aim with the PRAEGNANT registry (NCT02338167) is to identify patients for therapies based on clinical and molecular data. Here, we report eligibility testing for the SHERBOC trial using the German PRAEGNANT registry.

Methods: Heregulin (HRG) has been reported to identify patients with better responses to therapy with the anti-HER3 monoclonal antibody seribantumab (MM-121). The SHERBOC trial investigated adding seribantumab (MM-121) to standard therapy in patients with advanced HER2-negative, hormone receptor-positive (HR-positive) breast cancer and HRG overexpression. The PRAEGNANT registry was used for identification and tumor testing, helping to link potential HRG positive patients to the trial. Patients enrolled in PRAEGNANT have invasive and metastatic or locally advanced, inoperable breast cancer. Patients eligible for SHERBOC were identified by using the registry. Study aims were to describe the HRG positivity rate, screening procedures, and patient characteristics associated with inclusion and exclusion criteria.

Results: Among 2769 unselected advanced breast cancer patients, 650 were HER2-negative, HR-positive and currently receiving first- or second-line treatment, thus potentially eligible for SHERBOC at the end of current treatment; 125 patients also met further clinical eligibility criteria (e.g. menopausal status, ECOG). In the first/second treatment lines, patients selected for SHERBOC based on further eligibility criteria had a more favorable prognosis than those not selected. HRG status was tested in 38 patients, 14 of whom (36.8%) proved to be HRG-positive.

Conclusion: Using a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials.

Trial Registration: Clinicaltrials, NCT02338167 , Registered 14 January 2015 - retrospectively registered.
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http://dx.doi.org/10.1186/s12885-020-07546-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656772PMC
November 2020

Treatment Landscape and Prognosis After Treatment with Trastuzumab Emtansine.

Geburtshilfe Frauenheilkd 2020 Nov 6;80(11):1134-1142. Epub 2020 Nov 6.

Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany.

Pertuzumab and T-DM1 are two efficient anti-HER2 treatments for patients with HER2-positive advanced breast cancer. While pertuzumab is usually given in first-line treatment and T-DM1 in second-line treatment, standard therapy options seem to be exhausted up to now after the treatment of patients with these two therapy options. Therefore, it is important to have data that describes the therapy situation and prognosis after T-DM1 treatment. The PRAEGNANT metastatic breast cancer registry (NCT02338167) is a prospective registry for breast cancer patients with a focus on molecular biomarkers. Patients of all therapy lines with any kind of treatment are eligible. Collected data comprises therapies, adverse events, quality of life and other patient reported outcomes. Here we report on the patient characteristics and descriptive prognostic data for HER2-positive patients who have completed a treatment with T-DM1. Therapy patterns after T-DM1 and progression-free survival are reported as well as overall survival. A total of 85 patients were identified for the study who were prospectively observed during therapy after the termination of T-DM1. The main reason for T-DM1 termination was progress. Following T-DM1, lapatinib, trastuzumab and chemotherapy were the main therapy choices. Median progression-free survival was 4.8 months (95% CI: 3.2 - 6.3) and median overall survival was 18.4 months (95% CI: 15.5 - 21.3). Therapy options after T-DM1 in a real-world setting seem to exhibit a relevant clinical efficacy, supporting the concept of continuous anti-HER2 treatments in the advanced therapy setting for breast cancer patients. Novel therapies are needed to improve the rather short median progression-free survival.
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http://dx.doi.org/10.1055/a-1286-2917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647719PMC
November 2020

Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer-results from the randomized phase III SUCCESS-A trial.

Breast Cancer Res 2020 10 23;22(1):111. Epub 2020 Oct 23.

Department of Gynecology and Obstetrics, Ulm University Hospital, Prittwitzstrasse 43, 89075, Ulm, Germany.

Background: When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients.

Methods: A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety.

Results: No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively.

Conclusion: Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting.

Trial Registration: Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.
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http://dx.doi.org/10.1186/s13058-020-01348-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583247PMC
October 2020

Progression-Free Survival and Overall Survival in Patients with Advanced HER2-Positive Breast Cancer Treated with Trastuzumab Emtansine (T-DM1) after Previous Treatment with Pertuzumab.

Cancers (Basel) 2020 Oct 17;12(10). Epub 2020 Oct 17.

Department of Gynecology and Obstetrics, Düsseldorf University Hospital, 40225 Düsseldorf, Germany.

The approval of trastuzumab emtansine (T-DM1) was conducted without pertuzumab as previous therapy. Efficacy data on T-DM1 following pertuzumab treatment are therefore limited. This study explores this issue in a real-world setting. Within the prospective PRAEGNANT (Prospective Academic Translational Research Network for the Optimization of the Oncological Health Care Quality in the Advanced Setting) metastatic breast cancer registry (NCT02338167), patients in all therapy lines receiving any kind of treatment were eligible for inclusion. This report describes patient characteristics and progression-free survival (PFS) in human epidermal growth factor receptor 2 (HER2)-positive patients receiving T-DM1 after pertuzumab treatment. Seventy-six patients were identified, 39 of whom received T-DM1 as second-line therapy, 25 as third-line, and 12 as fourth-line therapy or higher. Pertuzumab was mostly administered as a first-line treatment ( = 61; 80.3%). The median PFS in all patients was 3.5 months (95% CI: 2.8-7.8); in second-line treatment, 7.7 months (95% CI: 2.8-11.0); in third-line, 3.4 months (95% CI: 2.3-not reached (NR)); and in fourth-line therapy or higher, 2.7 months (95% CI: 1.2-NR). T-DM1 was mainly administered second-line after pertuzumab, but also in more heavily pretreated patients. The PFS in higher therapy lines appears to be shorter than in second-line.
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http://dx.doi.org/10.3390/cancers12103021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603111PMC
October 2020

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Am J Hum Genet 2020 11 5;107(5):837-848. Epub 2020 Oct 5.

Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong; Hong Kong Sanatorium and Hospital, Department of Pathology, Happy Valley, Hong Kong.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS was quantified using Cox regression analyses. We assessed PRS interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10 percentile and 20.5% at the 90 percentile of PRS. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675034PMC
November 2020

Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers.

Cancers (Basel) 2020 Sep 29;12(10). Epub 2020 Sep 29.

Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, 72076 Tuebingen, Germany.

The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways in human cancers. A gain of function mutation in mainly leads to the constitutive activation of the MAPK pathway, while the activation of the PI3K/Akt pathway occurs either through the loss of PTEN or a gain of function mutation of the catalytic subunit alpha of PI3K (). In this study, we investigated the underlying signaling pathway involved in YB-1 phosphorylation at serine 102 (S102) in -mutated triple-negative breast cancer (TNBC) MDA-MB-231 cells versus / mutated TNBC MDA-MB-453 cells. Our data demonstrate that S102 phosphorylation of YB-1 in -mutated cells is mainly dependent on the MAPK/ERK pathway, while in /-mutated cells, YB-1 S102 phosphorylation is entirely dependent on the PI3K/Akt pathway. Independent of the individual dominant pathway regulating YB-1 phosphorylation, dual targeting of MEK and PI3K efficiently inhibited YB-1 phosphorylation and blocked cell proliferation. This represents functional crosstalk between the two pathways. Our data obtained from the experiments, applying pharmacological inhibitors and genetic approaches, shows that YB-1 is a key player in cell proliferation, clonogenic activity, and tumor growth of TNBC cells through the MAPK and PI3K pathways. Therefore, dual inhibition of these two pathways or single targeting of YB-1 may be an effective strategy to treat TNBC.
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http://dx.doi.org/10.3390/cancers12102795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601769PMC
September 2020

DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs).

Sci Rep 2020 09 30;10(1):16131. Epub 2020 Sep 30.

Institute of Medical Genetics and Applied Genomics, Tübingen University, Calwerstraße 7, 72076, Tübingen, Germany.

The proper communication between gut and brain is pivotal for the maintenance of health and, dysregulation of the gut-brain axis can lead to several clinical disorders. In Parkinson's disease (PD) 85% of all patients experienced constipation many years before showing any signs of motor phenotypes. For differential diagnosis and preventive treatment, there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperone protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 influences the risk of PD remains incompletely understood. In the present study, we provide evidence that DJ-1 is implicated in shaping the gut microbiome including; their metabolite production, inflammation and innate immune cells (ILCs) development. We revealed that deficiency of DJ-1 leads to a significant increase in two specific genera/species, namely Alistipes and Rikenella. In DJ-1 knock-out (DJ-1) mice the production of fecal calprotectin and MCP-1 inflammatory proteins were elevated. Fecal and serum metabolic profile showed that malonate which influences the immune system was significantly more abundant in DJ-1 mice. DJ-1 appeared also to be involved in ILCs development. Further, inflammatory genes related to PD were augmented in the midbrain of DJ-1 mice. Our data suggest that metabolites and inflammation produced in the gut could be used as biomarkers for PD detection. Perhaps, these metabolites and inflammatory mediators could be involved in triggering inflammation resulting in PD pathology.
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http://dx.doi.org/10.1038/s41598-020-72903-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528091PMC
September 2020

Endocrine-Resistant Breast Cancer: Mechanisms and Treatment.

Breast Care (Basel) 2020 Aug 29;15(4):347-354. Epub 2020 Jul 29.

Department of Women's Health, University of Tübingen, Tübingen, Germany.

Background: Endocrine treatment is one of the most effective therapies for estrogen receptor-positive breast cancer. However, most tumors will develop resistance to endocrine therapy as the cancer progresses. This review focuses on the mechanisms and markers of endocrine-resistant breast cancer. In addition, current and future strategies to overcome endocrine resistance are discussed.

Summary: Several molecular mechanisms of endocrine resistance have been identified, including alterations in the ESR1 gene or in the PIK3CA/mTOR pathway. Meanwhile, CDK4/6, mTOR, and PI3K inhibition have shown to improve the efficacy of endocrine treatment and new promising approaches are being developed.

Key Message: Overcoming primary or acquired resistance to endocrine treatment remains a major challenge. Since the molecular mechanisms of endocrine resistance are manifold, optimal combination and sequencing strategies will have to be developed in the future.
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http://dx.doi.org/10.1159/000508675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490658PMC
August 2020

Initial experience with CDK4/6 inhibitor-based therapies compared to antihormone monotherapies in routine clinical use in patients with hormone receptor positive, HER2 negative breast cancer - Data from the PRAEGNANT research network for the first 2 years of drug availability in Germany.

Breast 2020 Dec 29;54:88-95. Epub 2020 Aug 29.

Department of Gynecology and Obstetrics, Breast Center, and CCC Munich, Munich University Hospital, Germany.

Purpose: Treatment with CDK4/6 inhibitors and endocrine therapy (CDK4/6i + ET) is a standard for patients with advanced hormone receptor-positive, HER2-negative (HR + HER2-) breast cancer (BC). However, real-world data on the implementation of therapy usage, efficacy, and toxicity have not yet been reported.

Methods: The PRAEGNANT registry was used to identify advanced HR + HER2- BC patients (n = 1136). The use of chemotherapy, ET, everolimus + ET, and CDK4/6i + ET was analyzed for first-line, second-line, and third-line therapy. Progression-free survival (PFS) and overall survival (OS) were also compared between patients treated with CDK4/6i + ET and ET monotherapy. Also toxicity was assessed.

Results: CDK4/6i + ET use increased from 38.5% to 62.7% in the first 2 years after CDK4/6i treatment became available (November 2016). Chemotherapy and ET monotherapy use decreased from 2015 to 2018 from 42.2% to 27.2% and from 53% to 9.5%, respectively. In this early analysis no statistically significant differences were found comparing CDK4/6i + ET and ET monotherapy patients with regard to PFS and OS. Leukopenia was was seen in 11.3% of patients under CDK4/6i + ET and 0.5% under ET monotherapy.

Conclusions: In clinical practice, CDK4/6i + ET has been rapidly implemented. A group of patients with a more unfavorable prognosis was possibly treated in the real-world setting than in the reported randomized clinical trials. The available data suggest that longer follow-up times and a larger sample size are required in order to identify differences in survival outcomes. Studies should be supported that investigate whether chemotherapy can be avoided or delayed in this patient population by using CDK4/6i + ET.
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http://dx.doi.org/10.1016/j.breast.2020.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509062PMC
December 2020

Annexin A7 Regulates Endometrial Receptivity.

Front Cell Dev Biol 2020 14;8:770. Epub 2020 Aug 14.

Department of Physiology, Eberhard Karls University of Tübingen, Tübingen, Germany.

A limited window of receptivity is a prerequisite of reproductive success. Indispensable receptivity genes include cyclooxygenase 2 (COX2), an enzyme accomplishing formation of prostaglandin E (PGE). A powerful regulator of PGE formation is Annexin A7 (). The present study thus explored whether ANXA7 impacts on implantation and fertility. Here we show that is expressed in endometrial tissue and increases upon decidual transformation of human endometrial stromal cells (HESCs) in a time-dependent manner. Silencing ANXA7 significantly decreased the expression of and , canonical decidual marker genes, but enhances COX2 and PGE levels. Genetic knockout of in mice significantly increases the number of implantation sites and litter sizes. Further, analysis of human endometrial biopsies showed that transcript and protein levels are decreased during the midluteal window of implantation in women suffering from recurrent pregnancy loss (RPL) when compared to subfertile patients. Taken together, the data indicate that ANXA7 has a conserved role in regulating endometrial receptivity and implantation.
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http://dx.doi.org/10.3389/fcell.2020.00770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456953PMC
August 2020

Effects of a Brief Electronic Mindfulness-Based Intervention on Relieving Prenatal Depression and Anxiety in Hospitalized High-Risk Pregnant Women: Exploratory Pilot Study.

J Med Internet Res 2020 08 11;22(8):e17593. Epub 2020 Aug 11.

Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.

Background: Peripartum depression and anxiety disorders are highly prevalent and are correlated with adverse maternal and neonatal outcomes. Antenatal care in Germany does not yet include structured screening and effective low-threshold treatment options for women facing peripartum depression and anxiety disorders. Mindfulness-based interventions (MBIs) are increasingly becoming a focus of interest for the management of such patients. Studies have shown a decrease in pregnancy-related stress and anxiety in expectant mothers following mindfulness programs.

Objective: The aim of this study was to explore the clinical effectiveness of a 1-week electronic course of mindfulness on prenatal depression and anxiety in hospitalized, high-risk pregnant women. We hypothesized that participating in a 1-week electronic MBI (eMBI) could alleviate symptoms of depression and anxiety during the hospital stay.

Methods: A prospective pilot study with an explorative study design was conducted from January to May 2019 in a sample of 68 women hospitalized due to high-risk pregnancies. After enrolling into the study, the participants were given access to an eMBI app on how to deal with stress, anxiety, and symptoms of depression. Psychometric parameters were assessed via electronic questionnaires comprising the Edinburgh Postnatal Depression Scale (EPDS), State-Trait Anxiety Inventory (STAI-S), and abridged version of the Pregnancy-Related Anxiety Questionnaire (PRAQ-R).

Results: We observed a high prevalence of peripartum depression and anxiety among hospitalized high-risk pregnant women: 39% (26/67) of the study participants in the first assessment and 41% (16/39) of the participants in the second assessment achieved EPDS scores above the cutoff value for minor/major depression. The number of participants with anxiety levels above the cutoff value (66% [45/68] of the participants in the first assessment and 67% [26/39] of the participants in the second assessment) was significantly more than that of the participants with anxiety levels below the cutoff value, as measured with the STAI-S. After completing the 1-week electronic course on mindfulness, the participants showed a significant reduction in the mean state anxiety levels (P<.03). Regarding pregnancy-related anxiety, participants who completed more than 50% of the 1-week course showed lower scores in PRAQ-R in the second assessment (P<.05). No significant changes in the EPDS scores were found after completing the intervention.

Conclusions: Peripartum anxiety and depression represent a relevant health issue in hospitalized pregnant patients. Short-term eMBIs could have the potential to reduce anxiety levels and pregnancy-related anxiety. However, we observed that compliance to eMBI seems to be related to lower symptoms of pregnancy-related stress among high-risk patients. eMBIs represent accessible mental health resources at reduced costs and can be adapted for hospitalized patients during pregnancy.
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http://dx.doi.org/10.2196/17593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448174PMC
August 2020
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