Implementation and Evaluation of a Breast Cancer Disease Model Using Real-World Claims Data in Germany from 2010 to 2020.

Breast cancer is the leading cause of cancer-related mortality among women in Germany and worldwide. This retrospective claims data analysis utilizing data from AOK Baden-Wuerttemberg, a major statutory German health insurance provider, aimed to construct and assess a real-world data breast cancer disease model. The study included 27,869 female breast cancer patients and 55,738 age-matched controls, analyzing data from 2010 to 2020. Three distinct breast cancer stages were analyzed: Stage A (early breast cancer without lymph node involvement), Stage B (early breast cancer with lymph node involvement), and Stage C (primary distant metastatic breast cancer). Tumor subtypes were estimated based on the prescription of antihormonal or HER2-targeted therapy. The study established that 77.9% of patients had HR+ breast cancer and 9.8% HER2+; HR+/HER2- was the most common subtype (70.9%). Overall survival (OS) analysis demonstrated significantly lower survival rates for stages B and C than for controls, with 5-year OS rates ranging from 79.3% for stage B to 35.4% for stage C. OS rates were further stratified by tumor subtype and stage, revealing varying prognoses. Distant recurrence-free survival (DRFS) analysis showed higher recurrence rates in stage B than in stage A, with HR-/HER2- displaying the worst DRFS. This study, the first to model breast cancer subtypes, stages, and outcomes using German claims data, provides valuable insights into real-world breast cancer epidemiology and demonstrates that this breast cancer disease model has the potential to be representative of treatment outcomes.

Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome.

Ligands of the natural killer group 2D (NKG2DL) family are expressed on malignant cells and are usually absent from healthy tissues. Recognition of NKG2DLs such as MICA/B and ULBP1-3 by the activating immunoreceptor NKG2D, expressed by NK and cytotoxic T cells, stimulates anti-tumor immunity in breast cancer. Upregulation of membrane-bound NKG2DLs in breast cancer has been demonstrated by immunohistochemistry. Tumor cells release NKG2DLs via proteolytic cleavage as soluble (s)NKG2DLs, which allows for effective immune escape and is associated with poor prognosis. In this study, we collected serum from 140 breast cancer (BC) and 20 ductal carcinoma in situ (DCIS) patients at the time of initial diagnosis and 20 healthy volunteers (HVs). Serum levels of sNKG2DLs were quantified through the use of ELISA and correlated with clinical data. The analyzed sNKG2DLs were low to absent in HVs and significantly higher in BC patients. For some of the ligands analyzed, higher sNKG2DLs serum levels were associated with the classification of malignant tumor (TNM) stage and grading. Low sMICA serum levels were associated with significantly longer progression-free (PFS) and overall survival (OS). In conclusion, we provide the first insights into sNKG2DLs in BC patients and suggest their potential role in tumor immune escape in breast cancer. Furthermore, our observations suggest that serum sMICA levels may serve as a prognostic parameter in the patients analyzed in this study.

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.

Image-guided metabolomics and transcriptomics reveal tumour heterogeneity in luminal A and B human breast cancer beyond glucose tracer uptake.

BACKGROUND: Breast cancer is a metabolically heterogeneous disease, and although the concept of heterogeneous cancer metabolism is known, its precise role in human breast cancer is yet to be fully elucidated. METHODS: We investigated in an explorative approach a cohort of 42 primary mamma carcinoma patients with positron emission tomography/magnetic resonance imaging (PET/MR) prior to surgery, followed by histopathology and molecular diagnosis. From a subset of patients, which showed high metabolic heterogeneity based on tracer uptake and pathology classification, tumour centre and periphery specimen tissue samples were further investigated by a targeted breast cancer gene expression panel and quantitative metabolomics by nuclear magnetic resonance (NMR) spectroscopy. All data were analysed in a combinatory approach. RESULTS: [18 F]FDG (2-deoxy-2-[fluorine-18]fluoro-d-glucose) tracer uptake confirmed dominance of glucose metabolism in the breast tumour centre, with lower levels in the periphery. Additionally, we observed differences in lipid and proliferation related genes between luminal A and B subtypes in the centre and periphery. Tumour periphery showed elevated acetate levels and enrichment in lipid metabolic pathways genes especially in luminal B. Furthermore, serine was increased in the periphery and higher expression of thymidylate synthase (TYMS) indicated one-carbon metabolism increased in tumour periphery. The overall metabolic activity based on [18 F]FDG uptake of luminal B subtype was higher than that of luminal A and the difference between the periphery and centre increased with tumour grade. CONCLUSION: Our analysis indicates variations in metabolism among different breast cancer subtypes and sampling locations which details the heterogeneity of the breast tumours. Correlation analysis of [18 F]FDG tracer uptake, transcriptome and tumour metabolites like acetate and serine facilitate the search for new candidates for metabolic tracers and permit distinguishing luminal A and B. This knowledge may help to differentiate subtypes preclinically or to provide patients guide for neoadjuvant therapy and optimised surgical protocols based on individual tumour metabolism.

Efficacy of Lapatinib in Patients with HER2-Negative Metastatic Breast Cancer and HER2-Positive Circulating Tumor Cells-The DETECT III Clinical Trial.

BACKGROUND: The phenotypes of tumor cells change during disease progression, but invasive rebiopsies of metastatic lesions are not always feasible. Here we aimed to determine whether initially HER2-negative metastatic breast cancer (MBC) patients with HER2-positive circulating tumor cells (CTCs) benefit from a HER2-targeted therapy. METHODS: The open-label, interventional randomized phase III clinical trial (EudraCT Number 2010-024238-46, CliniclTrials.gov Identifier: NCT01619111) recruited from March 2012 until September 2019 with a follow-up duration of 19.5 months. It was a multicenter clinical trial with 94 participating German study centers. A total of 2137 patients with HER2-negative MBC were screened for HER2-positive CTCs with a final modified intention-to-treat population of 101 patients. Eligible patients were randomized to standard therapy with or without lapatinib. Primary study endpoints included CTC clearance (no CTCs at the end of treatment) and secondary endpoints were progression-free survival, overall survival (OS), and safety. RESULTS: In both treatment arms CTC clearance at first follow-up visit-although not being significantly different for both arms at any time point-was significantly associated with improved OS (42.4 vs 14.1 months; P = 0.002). Patients treated additionally with lapatinib had a significantly improved OS over patients receiving standard treatment (20.5 vs 9.1 months, P = 0.009). CONCLUSIONS: DETECT III is the first clinical study indicating that phenotyping of CTCs might have clinical utility for stratification of MBC cancer patients to HER2-targeting therapies. The OS benefit could be related to lapatinib, but further studies are required to prove this clinical observation. ClinicalTrials.gov Registration Number: NCT01619111.

Efficacy, safety, and prognosis prediction in patients treated with ribociclib in combination with letrozole: Final results of phase 3b RIBECCA study in hormone receptor positive, human epidermal growth factor receptor-2 negative, locally advanced or metastatic breast cancer.

BACKGROUND: In MONALEESA-2, addition of ribociclib to letrozole resulted in significantly longer progression-free survival (PFS) in postmenopausal women with HR+HER2- advanced breast cancer (ABC). RIBociclib for the treatment of advanCed breast CAncer (RIBECCA) study investigated ribociclib plus letrozole in a patient population reflecting routine clinical practice. PATIENTS AND METHODS: In this multicenter, open-label, single-arm, phase 3b study, patients with HR+HER2- ABC not amenable to curative therapy and ECOG performance status ≤ 2 received ribociclib plus letrozole (cohort A: postmenopausal women and men in first-line; cohort B: pre-/perimenopausal women in first-line [B1], patients pretreated for advanced disease [B2]). The primary endpoint was clinical benefit rate (CBR) by week 24; secondary endpoints included overall response rate (ORR), PFS, overall survival (OS), and safety. Association of patient and tumor characteristics with PFS was analyzed by multivariable Cox regression analysis. RESULTS: Overall, 487 patients were evaluable for efficacy, 502 for safety. By week 24, CBR was 60.8 % (95 % CI, 56.3-65.1), ORR was 19.3 % (95 % CI, 15.9-23.1). Median PFS was 21.8 months (95 % CI, 13.9-25.3) in first-line postmenopausal patients and 11.0 months (95 % CI, 8.2-16.4) in premenopausal and pretreated patients. Median OS was not reached. Higher baseline ECOG performance status, higher histological grade, and negative progesterone receptor status showed an unfavorable effect on PFS. Most common adverse events were neutropenia (50.0 %), nausea (42.0 %), and fatigue (39.2 %). CONCLUSION: In this broad population of patients with HR+HER2- ABC, efficacy and safety results of ribociclib plus letrozole were similar to those observed in pivotal trials.

Characteristics, Treatment Patterns and Survival of International Federation of Gynecology and Obstetrics Stage IV Epithelial Ovarian Cancer-A Population-Based Study.

BACKGROUND: The aim of the present study was to describe an unselected population of patients with diagnosis of FIGO stage IV OC. METHODS: Data from 1183 patients were available for analysis. RESULTS: The majority of patients (962/1183, 81.3%) received cancer-directed treatment. The median follow-up time was 3.8 years, and the median overall survival duration was 1.9 years. Notably, patients >80 years had a low overall survival rate (HR of age >80 years vs. ≤50 years was 3.81, 95%-CI [2.76, 5.27], p < 0.0001). The survival rate was best in patients with HGSOC (p < 0.0001). The highest overall survival rate was observed in patients in the group with surgical intervention followed by systemic treatment, with an unadjusted HR of 0.72, 95%-CI [0.59, 0.86], p = 0.007 vs. systemic treatment only. After adjustment for age and histology, survival differences between treatment schemes were smaller (HR 0.81, 95%-CI [0.66, 1.00], p = 0.12). CONCLUSIONS: In this cohort of patients with FIGO stage IV OC, more than 80% of the patients received cancer-directed treatment. Age and high-grade serous histology were determinants for survival. The highest overall survival rate was observed in patients who underwent surgery followed by systemic treatment.

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.

Update Breast Cancer 2023 Part 1 - Early Stage Breast Cancer.

With abemaciclib (monarchE study) and olaparib (OlympiA study) gaining approval in the adjuvant treatment setting, a significant change in the standard of care for patients with early stage breast cancer has been established for some time now. Accordingly, some diverse developments are slowly being transferred from the metastatic to the adjuvant treatment setting. Recently, there have also been positive reports of the NATALEE study. Other clinical studies are currently investigating substances that are already established in the metastatic setting. These include, for example, the DESTINY Breast05 study with trastuzumab deruxtecan and the SASCIA study with sacituzumab govitecan. In this review paper, we summarize and place in context the latest developments over the past months.

Update Breast Cancer 2023 Part 2 - Advanced-Stage Breast Cancer.

In recent years, a number of new therapies have led to advances in the treatment of patients with advanced breast carcinoma. These substances are mainly CDK4/6 inhibitors and other substances that can overcome endocrine resistance, oral selective estrogen receptor degraders, antibody drug conjugates (ADCs), and PARP inhibitors. This review summarizes and evaluates the latest study results that have been published in recent months. This includes the overall survival data of the Destiny-Breast03 study, the first analysis of the CAPItello-291 study, the comparison of CDK4/6 inhibitor treatment with chemotherapy in the first line of therapy (RIGHT Choice study), the first analysis of the Destiny-Breast02 study in the treatment setting after T-DM1 treatment, and the first analysis of the Serena-2 study. Most of these studies have the potential to significantly change the therapeutic landscape for patients with advanced breast carcinoma and show that the continued rapid development of new therapies is always producing new results.

AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2023.

The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) presents the 2023 update of the evidence-based recommendations for the diagnosis and treatment of patients with locally advanced and metastatic breast cancer (mBC).

Arbeitsgemeinschaft Gynäkologische Onkologie Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2023.

Background: Each year the interdisciplinary Arbeitsgemeinschaft Gynäkologische Onkologie (AGO), German Gynecological Oncology Group Breast Committee on Diagnosis and Treatment of Breast Cancer provides updated state-of-the-art recommendations for early and metastatic breast cancer. Summary: The updated evidence-based treatment recommendation for early and metastatic breast cancer has been released in March 2023. Key Messages: This paper concisely captures the updated recommendations for early breast cancer chapter by chapter.

Microfluidic Isolation of Disseminated Tumor Cells from the Bone Marrow of Breast Cancer Patients.

Disseminated tumor cells (DTCs) in the bone marrow (BM) of breast cancer (BC) patients are putative precursors of metastatic disease, and their presence is associated with an adverse clinical outcome. To achieve the personalization of therapy on a clinical routine level, the characterization of DTCs and in vitro drug testing on DTCs are of great interest. Therefore, biobanking methods, as well as novel approaches to DTC isolation, need to be developed. In this study, we established a protocol for the biobanking of BM samples and evaluated a microfluidic-based separation system (Parsortix®) for the enrichment of cryopreserved DTCs. We were able to successfully isolate viable DTCs after the prior cryopreservation of BM samples. We calculated a significant increase of up to 90-fold in harvested DTCs with the proposed method compared to the current standard techniques, opening up new analysis possibilities for DTCs. Our advanced method further presents options for 3D DTC cultures, enabling the individualized testing of targeted therapies for BC patients. In conclusion, we present a novel approach for DTC enrichment, with possibilities for future clinical implications.

[Therapiesteuerung in der Hämatologie und Onkologie].

Die diesjährige Frühjahrstagung der DGHO (Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e. V.) stand unter der Überschrift «Herausforderungen in der Onkologie - personalisierte Therapiesteuerung¼. Über drei Themenkomplexe hinweg wurden aktuelle Möglichkeiten und Perspektiven der Therapiesteuerung in der Onkologie hinsichtlich «Methoden¼, gelungenen «Beispielen¼ sowie der «Umsetzung in der Versorgung¼ diskutiert.

Targeting NKG2DL with Bispecific NKG2D-CD16 and NKG2D-CD3 Fusion Proteins on Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with a poor response rate to conventional systemic treatment and high relapse rates. Members of the natural killer group 2D ligand (NKG2DL) family are expressed on cancer cells but are typically absent from healthy tissues; thus, they are promising tumor antigens for novel immunotherapeutic approaches. We developed bispecific fusion proteins (BFPs) consisting of the NKG2D receptor domain targeting multiple NKG2DLs, fused to either anti-CD3 (NKG2D-CD3) or anti-CD16 (NKG2D-CD16) Fab fragments. First, we characterized the expression of the NKG2DLs (MICA, MICB, ULBP1-4) on TNBC cell lines and observed the highest surface expression for MICA and ULBP2. Targeting TNBC cells with NKG2D-CD3/CD16 efficiently activated both NK and T cells, leading to their degranulation and cytokine release and lysis of TNBC cells. Furthermore, PBMCs from TNBC patients currently undergoing chemotherapy showed significantly higher NK and T cell activation and tumor cell lysis when stimulated with NKG2D-CD3/CD16. In conclusions, BFPs activate and direct the NK and T cells of healthy and TNBC patients against TNBC cells, leading to efficient eradication of tumor cells. Therefore, NKG2D-based NK and T cell engagers could be a valuable addition to the treatment options for TNBC patients.

Update Breast Cancer 2023 Part 3 - Expert Opinions of Early Stage Breast Cancer Therapies.

The St. Gallen (SG) International Breast Cancer Conference is held every two years, previously in St. Gallen and now in Vienna. This year (2023) marks the eighteenth edition of this conference, which focuses on the treatment of patients with early-stage breast carcinoma. A panel discussion will be held at the end of this four-day event, during which a panel of experts will give their opinions on current controversial issues relating to the treatment of early-stage breast cancer patients. To this end, questions are generally formulated in such a way that clinically realistic cases are presented - often including poignant hypothetical modifications. This review reports on the outcome of these discussions and summarises the data associated with individual questions raised.

Breast cancer patient-derived microtumors resemble tumor heterogeneity and enable protein-based stratification and functional validation of individualized drug treatment.

Despite tremendous progress in deciphering breast cancer at the genomic level, the pronounced intra- and intertumoral heterogeneity remains a major obstacle to the advancement of novel and more effective treatment approaches. Frequent treatment failure and the development of treatment resistance highlight the need for patient-derived tumor models that reflect the individual tumors of breast cancer patients and allow a comprehensive analyses and parallel functional validation of individualized and therapeutically targetable vulnerabilities in protein signal transduction pathways. Here, we introduce the generation and application of breast cancer patient-derived 3D microtumors (BC-PDMs). Residual fresh tumor tissue specimens were collected from n = 102 patients diagnosed with breast cancer and subjected to BC-PDM isolation. BC-PDMs retained histopathological characteristics, and extracellular matrix (ECM) components together with key protein signaling pathway signatures of the corresponding primary tumor tissue. Accordingly, BC-PDMs reflect the inter- and intratumoral heterogeneity of breast cancer and its key signal transduction properties. DigiWest®-based protein expression profiling of identified treatment responder and non-responder BC-PDMs enabled the identification of potential resistance and sensitivity markers of individual drug treatments, including markers previously associated with treatment response and yet undescribed proteins. The combination of individualized drug testing with comprehensive protein profiling analyses of BC-PDMs may provide a valuable complement for personalized treatment stratification and response prediction for breast cancer.

Tumor-Free Resection Margin Distance in the Surgical Treatment of Node-Negative Squamous Cell Cancer of the Vulva Has No Impact on Survival: Analysis of a Large Patient Cohort in a Tertiary Care Center.

BACKGROUND: The aim of this study was to evaluate the impact of pathological tumor-free margin distance on survival in SCC patients treated with surgery alone. METHODS: This retrospective study included 128 patients with node-negative disease that received no adjuvant treatment. Disease-free and overall survival were analyzed according to pathological tumor-free margin distance. RESULTS: The patients were subclassified into three resection margin category groups: "1 to 3 mm" (n = 42), ">3 to 8 mm" (n = 47) or ">8 mm" (n = 39). Thirty-nine of the 128 patients (30.5%) developed recurrent disease. Median follow-up for disease-free survival (DFS) was 6.49 years (95% CI 5.16 years; 7.62 years), and median follow-up for overall survival (OS) was 6.29 years (95% CI 5.45 years; 7.33 years). The 5-year DFS rate was 0.70 (95% CI: 0.62-0.79), and the 5-year OS rate was 0.79 (95% CI: 0.71-0.87). Regarding the survival outcome, there were no independent significant differences in either disease-free survival (DFS) (p = 0.300) or overall survival (p = 1.000) among patients within the three tumor-free resection margin categories. Multivariate analyses did not show any statistically significant association between tumor-free resection margin distance and recurrent disease or death, either when analyzed as a categorical variable or when analyzed as a continuous variable. CONCLUSION: The present study did not show a significant impact of pathological tumor-free resection margin distance following surgery in patients with node-negative SCC of the vulva (that did not receive adjuvant treatment) on disease-free and overall survival.