Association between 21-gene-assay and detection of disseminated tumor cells in patients with early breast cancer: results from the IRMA trial.

PURPOSE: Disseminated tumor cells (DTCs) in the bone marrow (BM) are known to be of prognostic value for patients with early breast cancer (EBC). In addition to histopathological features, multigene expression assays, such as the commercially available 21-gene Breast Recurrence Score® assay, have been validated for evaluating prognosis and making decisions concerning adjuvant treatment in EBC. In a previous retrospective study from our group, the 21-gene assay was shown to be associated with DTC-detection. A secondary endpoint of the prospective IRMA trial was to evaluate the association between Recurrence Score® (RS) result and tumor cell dissemination in patients with EBC. METHODS: DTC-status and RS result were assessed in patients with ER-positive/HER2-negative EBC with 0-3 pathologic lymph nodes who underwent primary surgical treatment at the Department for Women's Health of Tuebingen University, Germany. RESULTS: Patients with a high RS result (≥ 26) were more frequently DTC-positive (22.6%) than patients with a low RS result (8.6%, p = 0.034). The odds for DTC-positivity increased with rising RS values (p = 0.047). CONCLUSION: We therefore confirm that a high genomic risk is associated with tumor cell dissemination into the BM. Further trials are needed to investigate whether therapeutic decisions could be further individualized by combining DTC-status and prognostic gene signature testing.

Electrosurgery and Other Technical Advancements in Minimally Invasive Gynecological Surgery - An Update.

Electrosurgery in gynecology has changed over the past few decades. The use of energy-based devices, especially in minimally invasive procedures, is extremely important for preparation, short reconvalescence and patient safety. Recently, there have been major advances in energy-based surgical devices that have further shortened OR time and increased patient safety. Although bipolar and monopolar electrosurgery is still very important, the introduction of high-frequency ultrasound in gynecologic surgery has improved cutting and coagulation by lowering thermal damage in the surrounding tissue. Furthermore, new technical inventions have fundamentally changed the treatment of specific diseases. The introduction of ablation in the therapy of uterine fibroids, for example, has made conventional myomectomy no longer necessary in some cases, as necrosis of fibroids can be induced by placing very small thermal probes into the fibroids. Robotic surgery will change the face of gynecological surgery in the near future, as the initial studies could show lower surgical morbidity and faster recovery of patients after robotic-assisted laparoscopy. In this article we provide a short overview of current technical advances, review possible indications as well as limitations, and take a look into the future of minimally invasive surgery in gynecology.

Association between breast cancer risk factors and molecular type in postmenopausal patients with hormone receptor-positive early breast cancer.

PURPOSE: Evidence shows that genetic and non-genetic risk factors for breast cancer (BC) differ relative to the molecular subtype. This analysis aimed to investigate associations between epidemiological risk factors and immunohistochemical subtypes in a cohort of postmenopausal, hormone receptor-positive BC patients. METHODS: The prospective, single-arm, multicenter phase IV PreFace study (Evaluation of Predictive Factors Regarding the Effectivity of Aromatase Inhibitor Therapy) included 3529 postmenopausal patients with hormone receptor-positive early BC. Data on their epidemiological risk factors were obtained from patients' diaries and their medical histories. Data on estrogen receptor, progesterone receptor, and HER2 receptor status were obtained from pathology reports. Patients with incomplete information were excluded. Data were analyzed using conditional inference regression analysis, analysis of variance, and the chi-squared test. RESULTS: In a cohort of 3392 patients, the strongest association with the molecular subtypes of BC was found for hormone replacement therapy (HRT) before diagnosis of early BC. The analysis showed that patients who took HRT at diagnosis had luminal A-like BC more often (83.7%) than those who had never taken HRT or had stopped taking it (75.5%). Luminal B-like BC and HER2-positive BC were diagnosed more often in women who had never taken HRT or had stopped taking it (13.3% and 11.2%, respectively) than in women who were taking HRT at diagnosis of BC (8.3% and 8.0%, respectively). CONCLUSIONS: This analysis shows an association between HRT and the distribution of molecular subtypes of BC. However, no associations between other factors (e.g., age at diagnosis, body mass index, smoking status, age at menopause, number of deliveries, age at first delivery, breastfeeding history, or family history) were noted.

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

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

HLA-G promotes myeloid-derived suppressor cell accumulation and suppressive activity during human pregnancy through engagement of the receptor ILT4.

Establishing and maintaining maternal-fetal tolerance is essential for a successful pregnancy; failure of immunological adaptation to pregnancy leads to severe complications such as abortion or preterm delivery. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that suppress T-cell responses, expand during pregnancy and thus may play a role in tolerance induction. Human leucocyte antigen G (HLA-G) is a major histocompatibility complex (MHC) I molecule with immune-modulatory properties, which is expressed during pregnancy. Here, we investigated the impact of HLA-G on MDSCs accumulation and activation in pregnant women. We demonstrate that granulocytic MDSCs (GR-MDSCs) express receptors for HLA-G, namely immunoglobulin-like transcript (ILT) 2 and 4, and that ILT4-expression by GR-MDSCs is regulated during pregnancy. Stimulation with soluble HLA-G (sHLA-G) increased suppressive activity of GR-MDSCs, induced MDSCs from peripheral blood mononuclear cells (PBMCs) and led to phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and induction of indoleamine-2,3-dioxygenase (IDO) in myeloid cells. Effects of sHLA-G on MDSC accumulation were mediated through ILT4. These results suggest an interaction between MDSCs and HLA-G in humans as a potential mechanism for maintaining maternal-fetal tolerance. Modulating MDSC function during pregnancy via HLA-G might provide new opportunities for a therapeutic manipulation of immunological pregnancy complications.

Ultrasound guided core needle biopsy prior to thermo ablative treatment of uterine tumors: first results.

PURPOSE: This study aimed at evaluating the diagnostic yield for core needle biopsies of uterine fibroids before laparoscopic radiofrequency volumetric thermal ablation (RFVTA) with the aim of sonographic imaging. This study was in the context of a randomized, prospective, single-center, longitudinal comparative study in which RFVTA and laparoscopic myomectomy for symptomatic uterine fibroids were compared. METHODS: All patients of the RFVTA-arm received a core needle biopsy under the guidance of an intraoperative laparoscopic ultrasound system. The Tissue samples were observed histologically. RESULTS: 24 patients were included and received in the median 3.17 biopsies (range 2-7). 45.8% of the fibroids were intramural. In 92% uterine leiomyoma was detected, in 4% a cell rich leiomyoma and in 4% a smooth muscle tumor with uncertain malignant potential (STUMP). There were no complications caused by core needle biopsy. CONCLUSIONS: Ultrasound guided core needle biopsy can be used to receive a histological result before treating uterine fibroids with thermo surgical methods like RFVTA.

Reliability of an e-PRO Tool of EORTC QLQ-C30 for Measurement of Health-Related Quality of Life in Patients With Breast Cancer: Prospective Randomized Trial.

BACKGROUND: Breast cancer represents the most common malignant disease in women worldwide. As currently systematic palliative treatment only has a limited effect on survival rates, the concept of health-related quality of life (HRQoL) is gaining more and more importance in the therapy setting of metastatic breast cancer. One of the major patient-reported outcomes (PROs) for measuring HRQoL in patients with breast cancer is provided by the European Organization for Research and Treatment of Cancer (EORTC). Currently, paper-based surveys still predominate, as only a few reliable and validated electronic-based questionnaires are available. Facing the possibilities associated with evolving digitalization in medicine, validation of electronic versions of well-established PRO is essential in order to contribute to comprehensive and holistic oncological care and to ensure high quality in cancer research. OBJECTIVE: The aim of this study was to analyze the reliability of a tablet-based measuring application for EORTC QLQ-C30 in German language in patients with adjuvant and (curative) metastatic breast cancer. METHODS: Paper- and tablet-based questionnaires were completed by a total of 106 female patients with adjuvant and metastatic breast cancer recruited as part of the e-PROCOM study. All patients were required to complete the electronic- (e-PRO) and paper-based versions of the HRQoL EORTC QLQ-C30 questionnaire. A frequency analysis was performed to determine descriptive sociodemographic characteristics. Both dimensions of reliability (parallel forms reliability [Wilcoxon test] and test of internal consistency [Spearman rho and agreement rates for single items, Pearson correlation and Kendall tau for each scale]) were analyzed. RESULTS: High correlations were shown for both dimensions of reliability (parallel forms reliability and internal consistency) in the patient's response behavior between paper- and electronic-based questionnaires. Regarding the test of parallel forms reliability, no significant differences were found in 27 of 30 single items and in 14 of 15 scales, whereas a statistically significant correlation in the test of consistency was found in all 30 single items and all 15 scales. CONCLUSIONS: The evaluated e-PRO version of the EORTC QLQ-C30 is reliable for patients with both adjuvant and metastatic breast cancer, showing a high correlation in almost all questions (and in many scales). Thus, we conclude that the validated paper-based PRO assessment and the e-PRO tool are equally valid. However, the reliability should also be analyzed in other prospective trials to ensure that usability is reliable in all patient groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT03132506; https://clinicaltrials.gov/ct2/show/NCT03132506 (Archived by WebCite at http://www.webcitation.org/6tRcgQuou).

Detection and prevalence of disseminated tumor cells from the bone marrow of early stage male breast cancer patients.

Male breast cancer (mBC) is a rare entity. As detection of disseminated tumor cells (DTCs) in the bone marrow of females with early stage breast cancer is a promising prognostic marker, we aimed to determine the prevalence and prognostic value of DTCs in mBC. Bone marrow aspirates were collected from male patients undergoing primary surgery for early stage breast cancer (T1-4, N0-2, M0) at Tuebingen University, Germany, between January 2001 and April 2015. DTCs were identified by immunocytochemistry (pancytokeratin antibody A45/B-B3) and cytomorphology. 24 patients with mBC were included into the analysis. DTCs were detected in four of these (17 %). There was no significant association between the DTC status and any other clinicopathological parameter. Also, no significant impact of the DTC status on DFS or OS could be observed. DTCs are detectable in patients with early stage mBC. The detection rate is comparable to that in women. No associations between DTCs and clinicopathological features or prognosis were observed, which is most likely due to the small sample size. The detection of DTCs in male patients with early stage breast cancer emphasizes the transmission of future clinical applications for DTCs from women to men.

Attrition in the First Three Therapy Lines in Patients with Advanced Breast Cancer in the German Real-World PRAEGNANT Registry.

Background With more effective therapies for patients with advanced breast cancer (aBC), therapy sequences are becoming increasingly important. However, some patients might drop out of the treatment sequence due to deterioration of their life status. Since little is known about attrition in the real-world setting, this study assessed attrition in the first three therapy lines using a real-world registry. Methods Patients with information available on the first three therapy lines were selected from the German PRAEGNANT registry (NCT02338167). Attrition was determined for each therapy line using competing risk analyses, with the start of the next therapy line or death as endpoints. Additionally, a simple attrition rate was calculated based on the proportion of patients who completed therapy but did not start the next therapy line. Results Competitive risk analyses were performed on 3988 1st line, 2651 2nd line and 1866 3rd line patients. The probabilities of not starting the next therapy line within 5 years after initiation of 1st, 2nd and 3rd line therapy were 30%, 24% and 24% respectively. Patients with HER2-positive disease had the highest risk for attrition, while patients with HRpos/HER2neg disease had the lowest risk. Attrition rates remained similar across molecular subgroups in the different therapy lines. Conclusion Attrition affects a large proportion of patients with aBC, which should be considered when planning novel therapy concepts that specifically address the sequencing of therapies. Taking attrition into account could help understand treatment effects resulting from sequential therapies and might help develop treatment strategies that specifically aim at maintaining quality of life.

Improved preoperative risk stratification in endometrial carcinoma patients: external validation of the ENDORISK Bayesian network model in a large population-based case series.

PURPOSE: Preoperative risk stratification of newly diagnosed endometrial carcinoma (EC) patients has been hindered by only moderate prediction performance for many years. Recently ENDORISK, a Bayesian network model, showed high predictive performance. It was the aim of this study to validate ENDORISK by applying the model to a population-based case series of EC patients. METHODS: ENDORISK was applied to a retrospective cohort of women surgically treated for EC from 2003 to 2013. Prediction accuracy for LNM as well as 5-year DSS was investigated. The model's overall performance was quantified by the Brier score, discriminative performance by area under the curve (AUC). RESULTS: A complete dataset was evaluable from 247 patients. 78.1% cases were endometrioid histotype. The majority of patients (n = 156;63.2%) had stage IA disease. Overall, positive lymph nodes were found in 20 (8.1%) patients. Using ENDORISK predicted probabilities, most (n = 156;63.2%) patients have been assigned to low or very low risk group with a false-negative rate of 0.6%. AUC for LNM prediction was 0.851 [95% confidence interval (CI) 0.761-0.941] with a Brier score of 0.06. For 5-year DSS the AUC was 0.698 (95% CI 0.595-0.800) as Brier score has been calculated 0.09. CONCLUSIONS: We were able to successfully validate ENDORISK for prediction of LNM and 5-year DSS. Next steps will now have to focus on ENDORISK performance in daily clinical practice. In addition, incorporating TCGA-derived molecular subtypes will be of key importance for future extended use. This study may support further promoting of data-based decision-making tools for personalized treatment of EC.

Recurrence Score® Result Impacts Treatment Decisions in Hormone Receptor-Positive, HER2-Negative Patients with Early Breast Cancer in a Real-World Setting-Results of the IRMA Trial.

BACKGROUND: Patients with hormone receptor-positive (HR+), HER2-negative (HER2-) early breast cancer (eBC) with a high risk of relapse often undergo adjuvant chemotherapy. However, only a few patients will gain benefit from chemotherapy. Since classical tumor characteristics (grade, tumor size, lymph node involvement, and Ki67) are of limited value to predict chemotherapy efficacy, multigene expression assays such as the Oncotype DX® test were developed to reduce over- and undertreatment. The IRMA trial analyzed the impact of Recurrence Score® (RS) assessment on adjuvant treatment recommendations. MATERIALS AND METHODS: The RS result was assessed in patients with HR+/HER2- unilateral eBC with 0-3 pathologic lymph nodes who underwent primary surgical treatment at the Department for Women's Health of Tuebingen University, Germany. Therapy recommendations without knowledge of the RS result were compared to therapy recommendations with awareness of the RS result. RESULTS: In total, 245 patients underwent RS assessment. Without knowledge of the RS result, 92/245 patients (37.6%) would have been advised to receive chemotherapy. After RS assessment, 56/245 patients (22.9%) were advised to undergo chemotherapy. Chemotherapy was waived in 47/92 patients (51.1%) that were initially recommended to receive it. Chemotherapy was added in 11/153 patients (7.2%) that were recommended to not receive it initially. SUMMARY: Using the RS result to guide adjuvant treatment decisions in HR+/HER2- breast cancer led to a substantial reduction of chemotherapy. In view of the results achieved in prospective studies, the RS result is among other risk-factors suitable for the individualization of adjuvant systemic therapy.

Feasibility of Adjuvant Treatment with Abemaciclib-Real-World Data from a Large German Breast Center.

Abemaciclib significantly improves invasive disease-free survival when combined with endocrine therapy in clinical high-risk patients with HR+/Her2- early breast cancer (eBC). The objective of the following study was to model how many patients with eBC would be available for adjuvant treatment with abemaciclib in a real-world setting. Patients that underwent complete surgical treatment for eBC between January 2018 and December 2020 in a large single-center university hospital in Germany were eligible. Descriptive statistics were used to describe the patient population that could benefit from abemaciclib according to the inclusion criteria of monarchE. Of 1474 patients with eBC, 1121 (76.1%) had a HR+/Her2- subtype. Of these, 217 (19.4%) fulfilled the monarchE inclusion criteria. Within patients that fulfilled the monarchE inclusion criteria, 48.9% received no adjuvant or neoadjuvant chemotherapy. Thus, in a real-world situation, fewer patients will be pretreated with chemotherapy than was the case in monarchE. Breast care units are facing a significant patient burden, since the 2-year abemaciclib therapy requires regular monitoring of toxicities. Specific care concepts to strengthen therapy adherence as well as further studies to deescalate adjuvant systemic treatment and individualize CDK 4/6 inhibitor therapy are therefore needed.

The Laminin Receptors Basal Cell Adhesion Molecule/Lutheran and Integrin α7ß1 on Human Hematopoietic Stem Cells.

In the adult organism, hematopoietic stem and progenitor cells (HSPC) reside in the bone marrow (BM) in specialized hematopoietic stem cell niches of which the extracellular matrix (ECM) is an integral component. Laminins (LM) are a family of heterotrimeric ECM molecules of which mainly family members containing an α4 or α5 chain are expressed in cells from BM niches and involved in HSPC homing and proliferation. Various integrin and non-integrin laminin receptors have been identified and characterized. Among these, the integrins α6ß1 and α3ß1 were reported to be strongly expressed on human and mouse HSPC. In the present study, we focus on two further specific laminin receptors, namely integrin α7ß1 and basal cell adhesion molecule/Lutheran (BCAM/Lu). Using RT-PCR analyses, immunofluorescence staining, immunoblotting and flow cytometry, we show that both are strongly expressed by human lineage-negative CD34 + HSPC. Treatment with function-blocking antibodies against BCAM/Lu neither inhibits the strong adhesive interaction of CD34 + HSPC with LM-511/LM-521 nor the LM-511/LM-521 mediated changes in CD34 + HSPC proliferation, but however, influences the cytokine-induced differentiation of HSPC in colony formation assays. In addition, stromal-derived factor (SDF) 1α-mediated transmigration of CD34 + HSPC through an endothelial cell layer was effectively diminished by BCAM/Lu antibodies, suggesting a direct involvement of BCAM/Lu in the migration process. This study indicates that both laminin receptors newly identified on human CD34 + HSPC should be taken into consideration in future studies.

Hematopoietic Stem and Progenitor Cell Expansion in Contact with Mesenchymal Stromal Cells in a Hanging Drop Model Uncovers Disadvantages of 3D Culture.

Efficient ex vivo expansion of hematopoietic stem cells with a concomitant preservation of stemness and self-renewal potential is still an unresolved ambition. Increased numbers of methods approaching this issue using three-dimensional (3D) cultures were reported. Here, we describe a simplified 3D hanging drop model for the coculture of cord blood-derived CD34(+) hematopoietic stem and progenitor cells (HSPCs) with bone marrow-derived mesenchymal stromal cells (MSCs). When seeded as a mixed cell suspension, MSCs segregated into tight spheroids. Despite the high expression of niche-specific extracellular matrix components by spheroid-forming MSCs, HSPCs did not migrate into the spheroids in the initial phase of coculture, indicating strong homotypic interactions of MSCs. After one week, however, HSPC attachment increased considerably, leading to spheroid collapse as demonstrated by electron microscopy and immunofluorescence staining. In terms of HSPC proliferation, the conventional 2D coculture system was superior to the hanging drop model. Furthermore, expansion of primitive hematopoietic progenitors was more favored in 2D than in 3D, as analyzed in colony-forming assays. Conclusively, our data demonstrate that MSCs, when arranged with a spread (monolayer) shape, exhibit better HSPC supportive qualities than spheroid-forming MSCs. Therefore, 3D systems are not necessarily superior to traditional 2D culture in this regard.

PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer.

Immune checkpoint inhibition represents a major recent breakthrough in the treatment of malignant diseases including breast cancer. Blocking the programmed death receptor-1 (PD-1) and its ligand, PD-L1, has shown impressive antitumor activity and may lead to durable long-term disease control, especially in the triple-negative subtypes of breast cancer (TNBC). Although immune checkpoint blockade is generally well tolerated, specific immune-related adverse events (irAEs) may occur. This review summarizes the clinical efficacy, perspectives, and future challenges of using PD-1/PD-L1-directed antibodies in the treatment of breast cancer.