The Clinical Relevance of the NATALEE Study: Application of the NATALEE Criteria to a Real-World Cohort from Two Large German Breast Cancer Centers.

The NATALEE study showed a significant benefit in invasive disease-free survival (iDFS) for patients with HR+/HER2- early breast cancer (eBC) at intermediate and high risk of recurrence who were treated with the CDK4/6 inhibitor Ribociclib in combination with endocrine therapy (ET). This retrospective study aims to apply the NATALEE inclusion criteria to a representative real-world cohort to estimate the proportion of HR+/HER2- breast cancer patients eligible for adjuvant Ribociclib therapy. Patients who underwent full surgical treatment for eBC between January 2018 and December 2020 at two large German university breast cancer centers (University of Ulm, University of Tuebingen) were included. Descriptive statistics were used to characterize the patient population eligible for Ribociclib treatment based on the NATALEE study's inclusion criteria. Out of 2384 enrolled patients, 1738 had HR+/HER2- eBC, of whom 43% (747/1738) met the NATALEE inclusion criteria. Of note, these patients were older, received less chemotherapy and presented with less advanced tumor stages compared to the NATALEE study cohort. Additionally, compared to the NATALEE study cohort, fewer patients had lymph node involvement (72.4% vs. 88.7%). Our analysis suggests that approximately 43% of all HR+/HER2- breast cancer patients will qualify for Ribociclib treatment. Given the numerous treatment options for patients with HR+/HER2- eBC, as well as the differences between the NATALEE cohort and patients in the real-world clinical setting, future analyses will be needed to determine which patients would benefit most from adjuvant CDK4/6 inhibitor treatment.

The cancer-associated meprin ß variant G32R provides an additional activation site and promotes cancer cell invasion.

The extracellular metalloprotease meprin ß is expressed as a homodimer and is primarily membrane bound. Meprin ß can be released from the cell surface by its known sheddases ADAM10 and ADAM17. Activation of pro-meprin ß at the cell surface prevents its shedding, thereby stabilizing its proteolytic activity at the plasma membrane. We show that a single amino acid exchange variant (G32R) of meprin ß, identified in endometrium cancer, is more active against a peptide substrate and the IL-6 receptor than wild-type meprin ß. We demonstrate that the change to an arginine residue at position 32 represents an additional activation site used by furin-like proteases in the Golgi, which consequently leads to reduced shedding by ADAM17. We investigated this meprin ß G32R variant to assess cell proliferation, invasion through a collagen IV matrix and outgrowth from tumor spheroids. We found that increased meprin ß G32R activity at the cell surface reduces cell proliferation, but increases cell invasion.

Three-dimensional model for improvement of endometriosis care (3D-E).

OBJECTIVE: Endometriosis affects approximately 10% of women of reproductive age and leads to significant morbidity and financial burden. Consequently, countries such as France and Germany are formulating strategies to combat endometriosis. In this study, we propose the implementation of our three-dimensional model (3D-E) to raise awareness about endometriosis and enhance timely diagnosis, treatment, and long-term care for affected patients. METHODS: Based on the adapted Six Sigma Principle and the modified recommendation of Sales et al. for implementing evidence-based findings into a clinical routine, we first conducted a comprehensive investigation to identify risk factors leading to diagnostic delay of endometriosis. After identifying improvable factors, the applicable options were selected due to defined criteria such as integrability in the clinical routine, cost-effectiveness, and evidence-based-principle. Finally, solutions feasible for health care providers were integrated and the 3D-E model was established. RESULTS: Some of the main risk factors contributing to diagnostic delays are symptoms acceptance and misinterpreted symptoms, especially if presenting to nongynecologists in cases of extragenital endometriosis with atypical presentation. Therefore, we tried to sensitize colleagues (first dimension) with a review paper in Germany's largest medical journal and started an elective for medical students (second dimension) at our university. In order to involve additional health care professionals in endometriosis care (third dimension), we are preparing the concept of the EndoNurse. CONCLUSION: The 3D-E model is a relatively low-cost, comprehensive, and worldwide adaptable approach for facilitating knowledge transfer, sensitizing health care providers, and improving endometriosis diagnostics and therapy for patients with endometriosis who are in the center of the model.

Curative Polyendocrine Therapy in a 21-year-Old Patient with Endometrial Carcinoma: Case Report and Review of the Literature.

INTRODUCTION: As the numbers of young patients diagnosed with early-stage endometrial carcinoma continue to rise, the question regarding fertility-preserving therapeutic options will increasingly gain significance in the future. CASE PRESENTATION: Here, we present the case of a 21-year-old patient diagnosed with symptomatic atypical endometrial hyperplasia. After 4 months of treatment with medroxyprogesterone acetate, a follow-up dilatation and curettage revealed early-stage, well-differentiated endometrioid endometrial carcinoma. Despite national guidelines recommending hysterectomy, the nulliparous patient expressed a desire to preserve her fertility. Subsequently, she underwent polyendocrine therapy with letrozole, everolimus, metformin, and Zoladex. Forty-three months after diagnosis, the patient successfully gave birth to a healthy child, and there have been no indications of recurrence thus far. DISCUSSION: This case suggests that triple endocrine therapy may be an option for selected patients with early endometrial cancer and a desire for fertility-sparing therapy.

Which Patients Do We Need to Test for BRCA1/2 Mutation? Feasibility of Adjuvant Olaparib Treatment in Early Breast Cancer-Real-World Data from Two Large German Breast Centers.

BACKGROUND: Approximately 6% of women with breast cancer carry pathogenic germline variants in predisposition genes such as BRCA1 and BRCA2. Depending on personal and family cancer history, it is therefore recommended to test for hereditary breast cancer. Moreover, as shown by the phase III OlympiA trial, olaparib significantly improves overall survival in patients with HER2 negative (HER2-) early breast cancer who (1) carry a BRCA1 or BRCA2 germline mutation (gBRCA1/2-positive), (2) have received (neo)adjuvant chemotherapy and (3) are at high clinical risk. The objective of the current analysis was to determine the number of patients with early HER2- breast cancer who are at high clinical risk, according to the inclusion criteria of OlympiA, and to estimate how many of these patients would meet the criteria for hereditary cancer testing in a real-world analysis. METHODS: All patients included in this retrospective analysis were treated for early breast cancer (eBC) at the Department of Gynecology and Obstetrics, Ulm University Hospital, Germany, and the Department of Women's Health at Tuebingen University Hospital, Germany, between January 2018 and December 2020. Patients were identified as high risk, in line with the clinicopathological determiners used in the OlympiA trial. The criteria of the German Consortium for Hereditary Breast and Ovarian Cancer were used to identify patients who qualify for hereditary cancer testing. RESULTS: Of 2384 eligible patients, 1738 patients (72.9%) showed a hormone receptor positive (HR+)/HER2- tumor biology, 345 patients (14.5%) displayed HER2+ breast cancer and 301 patients (12.6%) suffered from HR-/HER2- breast cancer (TNBC). Of 2039 HER2- breast cancer patients, 271 patients (13.3%) were at high clinical risk. This cohort encompassed 130 of the 1738 patients with HR+/HER2- breast cancer (7.5%) and 141 of 301 patients with TNBC (46.8%). A total of 121 of 271 patients (44.6%) with high clinical risk met the criteria for hereditary cancer testing (34 of 130 (26.2%) HR+/HER2- patients and 87 of 141 (61.7%) patients with TNBC). CONCLUSION: Approximately one in ten patients with HR+/HER2-, and half of the patients with TNBC, meet the high-risk criteria according to OlympiA. Half of these patients do not meet the criteria for hereditary cancer testing and should therefore be tested for the presence of gBRCA1/2 mutations, irrespective of their own or family cancer history. The overall number of patients with early breast cancer benefiting from olaparib needs to be investigated in future studies.

Extragenital Endometriosis in the Differential Diagnosis of Non- Gynecological Diseases.

BACKGROUND: Endometriosis is a chronic, benign disease that affects approximately 10% of women of childbearing age. Its characteristic clinical features are dysmenorrhea, dyschezia, dysuria, dyspareunia, and infertility. The manifestations of extragenital endometriosis (EE) are a diagnostic challenge, as this disease can mimic other diseases due to its unusual location with infiltration of various organs and corresponding symptoms. METHODS: This review is based on publications retrieved by a selective search of the literature on the commonest extragenital sites of endometriosis, including the relevant current guideline. RESULTS: Current evidence on the treatment of extragenital endometriosis consists largely of cohort studies and cross-sectional studies. The treatment is either surgical and/or conservative (e.g., hormonal therapy). Gastrointestinal endometriosis is the most common form of EE, affecting the rectum and sigmoid colon in nearly 90% of cases and typically presenting with dyschezia. Urogenital endometriosis is the second most common form of EE. It affects the bladder in more than 85% of cases and may present with dysuria, hematuria, or irritable bladder syndrome. The diaphragm is the most common site of thoracic endometri - osis, potentially presenting with period-associated shoulder pain or catamenial pneumothorax. Endometriosis affecting a nerve often presents with sciatica. In abdominal wall endometriosis, painful nodules arise in scars from prior abdominal surgery. CONCLUSION: There is, as yet, no causally directed treatment for chronic endometriosis. The treatment is decided upon individually in discussion with the patient, in consideration of risk factors and after assessment of the benefits and risks. Timely diagnosis is essential.