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Background/aim: The loss of breast cancer cell differentiation during metastatic progression leads to a down-regulation of class 1 human leukocyte antigen (HLA) expression, which in turn hinders cytotoxic T lymphocytes from effectively preventing tumor cell proliferation. Consequently, one would expect that decreased HLA expression would correlate with decreased 5-year survival. However, estrogen receptor alpha (ESR1) is known to be positively associated with overall survival. The study aimed to determine the expression levels of HLA-A, HLA-B/C, and ESR1 and to assess their influence on distant disease-free survival (DDFS)., Materials and Methods: This retrospective subgroup analysis of the initial prospective, single-center, double-blind cohort study included a total of 34 patients who underwent a new treatment line for metastatic breast cancer (MBC). The MBC cells were examined using RT-qPCR., Results: The acquired data and the subsequent survival and ROC analyses indicated a positive association of reduced expression of HLA-A and HLA-B/C with DDFS. A statistically significant association of ESR1 with DDFS could not be shown., Conclusion: A potential positive association between reduced expression of HLA-A and HLA-B/C and DDFS is observed. This contrasts with the generally observed association between HLA expression loss and poor prognosis, as reported in previous protein-based studies. In metastatic settings, reduced expression of particular HLA subsets, measured at the mRNA level, might have a protective effect against disease progression., (Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Cell lines derived from circulating tumor cells (CTCs) in the blood provide important biological information on cancer metastasis. CTC-ITB-01 is a CTC cell line derived from a patient with metastatic estrogen receptor-alpha (ER-alpha) positive breast cancer two months before the death of the patient. After a LC-MC/MS based proteomics analysis of CTC-ITB-01, we found extraordinary high levels of the poorly characterized protein SUSD2 (sushi domain-containing protein 2) in CTC-ITB-01. Expression of SUSD2 on subsets of CTCs was validated on clinical blood samples of patients with metastatic breast cancer. SUSD2-positive CTCs could be captured specifically by a MACS-based approach. We overexpressed SUSD2 in the poorly-metastatic cell line MCF-7. This resulted in upregulation of ER-alpha, the tumor progression protein GRP78 (78-kDa glucose-regulated protein) and downregulation of the tumor suppressor protein PDCD4 (programmed cell death protein 4). We observed downregulation of SUSD2 and PDCD4 after hypoxia and simulation of re-oxygenation in the blood in MCF-7 and MDA-MB-468, while in CTC-ITB-01 SUSD2 levels remained unchanged, and only PDCD4 was downregulated under hypoxia. In conclusion, we show, for the first time, that SUSD2 is expressed in CTCs and appears to affect key proteins in tumor progression and survival., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Purpose: Toxicity to systemic cancer treatment represents a major anxiety for patients and a challenge to treatment plans. We aimed to develop machine learning algorithms for the upfront prediction of an individual's risk of experiencing treatment-relevant toxicity during the course of treatment., Methods: Clinical records were retrieved from a single-center, consecutive cohort of patients who underwent neoadjuvant treatment for early breast cancer. We developed and validated machine learning algorithms to predict grade 3 or 4 toxicity (anemia, neutropenia, deviation of liver enzymes, nephrotoxicity, thrombopenia, electrolyte disturbance, or neuropathy). We used 10-fold cross-validation to develop two algorithms (logistic regression with elastic net penalty [GLM] and support vector machines [SVMs]). Algorithm predictions were compared with documented toxicity events and diagnostic performance was evaluated via area under the curve (AUROC)., Results: A total of 590 patients were identified, 432 in the development set and 158 in the validation set. The median age was 51 years, and 55.8% (329 of 590) experienced grade 3 or 4 toxicity. The performance improved significantly when adding referenced treatment information (referenced regimen, referenced summation dose intensity product) in addition to patient and tumor variables: GLM AUROC 0.59 versus 0.75, P = .02; SVM AUROC 0.64 versus 0.75, P = .01., Conclusion: The individual risk of treatment-relevant toxicity can be predicted using machine learning algorithms. We demonstrate a promising way to improve efficacy and facilitate proactive toxicity management of systemic cancer treatment.

Introduction: Significant progress has been made in the targeted therapy of metastatic breast cancer (mBC) in recent years. In this context, new biomarkers enable personalized therapy management and individualized therapy monitoring. Therefore, the systemic treatment is based increasingly on the biological characteristics of the tumor disease. Given the challenges of obtaining fresh tumor tissue through biopsies, the significance of liquid biopsies for assessing circulating tumor cells (CTCs) or circulating tumor DNA is of growing importance for the detection of prognostic and predictive biomarkers. Multiple studies have shown that the number of CTCs decreases under therapy, especially under anti-HER2-targeted therapy, and that the expression of the HER2 status on CTCs could play a role in predicting therapy response and therapeutic monitoring. The aim of this study was to analyze the HER2 status of CTCs in mBC patients before and after 3 months of systemic therapy to evaluate changes in the number of HER2-positive CTCs. The study focuses on HER2-low, which plays an increasingly important role in clinical practice due to new developments of HER2 targeting antibody-drug conjugates. In this context, temporal and spatial heterogeneity of the disease represent a major diagnostic challenge., Methods: A total of 324 patients with complete immunohistochemistry of biopsied metastases were divided into five groups: HER2 negative (-)/hormone receptor (HR) negative (-), HER2 -/HR positive (+), HER2 +/HR±, HER2-low/HR+, and HER2-low/HR-. Before and after 3 months of a new therapeutic line for mBC, CTCs were enumerated and analyzed for HER2 expression using the CellSearch® system. Overall survival of all subgroups was calculated., Results: The analyses revealed a discrepancy between the HER2 status of CTCs and corresponding tumor tissues in 98 patients (30.2%). The number of CTCs in general and the number of HER2+ CTCs decreased during systemic treatment, mainly in HER2+ tumors, but also in the other subgroups., Conclusions: Discrepancy in the HER2 status of the metastases and of CTCs was observed in approximately one-third of patients. Measuring HER2 on CTCs could potentially offer a means to longitudinally monitor HER2 status during therapy and simultaneously address challenges such as tumor heterogeneity. Therefore, the predictive value of HER2 on CTCs should be further investigated in clinical trials., (© 2024 S. Karger AG, Basel.)

Background: The risk of breast cancer patients for long-term side effects of therapy such as neurotoxicity and cardiotoxicity as well as late effects regarding comorbidities varies from individual to individual. Personalised follow-up care concepts that are tailored to individual needs and the risk of recurrences, side effects and late effects are lacking in routine care in Germany., Methods: We describe the methodology of BETTER-CARE, a parallel-arm cluster-randomised controlled trial conducted at 15 intervention and 15 control centres, aiming to recruit 1140 patients, and the results of the pilot phase. The needs- and risk-adapted complex intervention, based on existing development frameworks, includes a multidisciplinary network and digital platforms for symptom and need documentation and just-in-time adaptive interventions. The control group comprises usual care according to clinical guidelines. The primary outcome is health-related quality of life (EORTC QLQ-C30 global health), and secondary outcomes include treatment adherence., Results: The 2-month pilot phase comprising 16 patients in one intervention and one control pilot centre demonstrated the feasibility of the BETTER-CARE approach., Discussion: BETTER-CARE is a feasible intervention and study concept, investigating individualised needs- and risk-adapted breast cancer follow-up care in Germany. If successful, the approach could be implemented in German routine care., Trial Registration: German Clinical Trial Register DRKS00028840. Registered on April 2022., Competing Interests: Declarations Ethics approval and consent to participate The study was approved in April 2022 by the central ethics committee in Würzburg (registry number 12/22-sc). All centres have obtained approval by the local ethics committees before recruitment. Written informed consent was obtained from all subjects before study participation. Consent for publication Not applicable. Competing interests The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AH, JW, IF, AB, TMD, PG, KiH, LH, KH, HM, VR, AS, CV declare that they or a family member have not had any economic or personal ties in the last 3 years. HB reports research grants from the Federal Joint Committee (G-BA) within the Innovationfond, during the conduct of the study; royalties or licenses from HelloBetter, consulting fees from Roche, speaker honoraria as a member of the digital agenda BPtK and for E-Mental-Health Lectures DRV-BW, SAMA, Medical Centre Göppingen, and Participation on a Data Safety Monitoring Board for IMMERSE EU-Project. EB reports Honoraria for a workshop at “6. Hamburger Tag der Psychoonkologie ´Krebs und Innovation´ “. SYB reports research grants from the Federal Joint Committee (G-BA) within the Innovationfond, during the conduct of the study; Advisory board honoraria and speaker fees received from Medtronic, Sanofi, Köhler, AstraZeneca, Lilly, MSD, Hologic, Roche. JeS reports speaker honoraria received from AstraZeneca, Clovis Oncology, Dajichi Sanko, GILEDA, GSK, Lilly, Novartis Pharma GmbH, Pfizer, SEAGEN; support for attending meetings and/or travel received from Dajichi Sanko, GILEDA, Lilly. MW reports research grants from the Federal Joint Committee (G-BA) within the Innovationfond, during the conduct of the study; personal fees, non-financial support, speaker fees, consultancy honoraria or grants received from Novartis, Pfizer, Roche, Celgene, Daiichi Sankyo, AstraZeneca. RP reports research grants from the Federal Joint Committee (G-BA) within the Innovationfond, during the conduct of the study. AW reports research grants from the Federal Joint Committee (G-BA) within the Innovationfond, during the conduct of the study; consulting fees received from AstraZeneca, Celgene, Eisai, Lilly, Novartis, Pfizer, Roche, MSD, Pierre Fabre, Clovis, Organon, Seagen, Exact Sciences, Gilead, Dajichi Sanko; speaker honoraria received from Aurikamed and Onkowissen; support for attending meetings and/or travel received from Pfizer, Dajichi Sanko, Seagan; leadership or fiduciary role in AGO, S3-Guideline Breast Cancer, German Society of Breast Cancer, BGGF. PUH reports research grants from the Federal Joint Committee (G-BA) within the Innovationfond, during the conduct of the study; research grants from the German Ministry of Research and Education, Federal Joint Committee (G-BA), European Union, German Parkinson Society, University Hospital Würzburg, German Heart Foundation, German Research Foundation, Bavarian State, German Cancer Aid, Charité – Universitätsmedizin Berlin (within Mondafis; supported by an unrestricted research grant to the Charité from Bayer), University Göttingen (within FIND-AF randomised; supported by an unrestricted research grant to the University Göttingen from Boehringer-Ingelheim), University Hospital Heidelberg (within RASUNOA-prime; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer-Ingelheim, Daiichi Sankyo), outside the submitted work., (© 2024. The Author(s).)

Background: Early identification of quality of life (QoL) loss and side effects is a key challenge in breast cancer therapy. Digital tools can be helpful components of therapeutic support. Enable, a smartphone app, was used in a multicenter, prospective randomized controlled trial in 3 breast cancer centers. The app simultaneously serves as a therapy companion (eg, by displaying appointments), a tool for documenting QoL (eg, by enabling data collection for QoL questionnaires), and documentation of patient-reported side effects. The need for digital tools is continually rising. However, evidence of the effects of long-term use of mobile health (mHealth) apps in aftercare for patients with breast cancer is limited. Therefore, evaluating the usability and understanding the user experience of this mHealth app could potentially contribute valuable insights in this field., Objective: A usability study was conducted to explore how patients with breast cancer receiving neoadjuvant, adjuvant, or palliative outpatient treatment rated their engagement with the app , the user experience, and the benefits of using the app., Methods: A mixed methods approach was chosen to combine subjective and objective measures, including an eye-tracking procedure, a standardized usability questionnaire (mHealth App Usability Questionnaire), and semistructured interviews. Participants were surveyed twice during the study period. Interviews were transcribed verbatim and analyzed using thematic analysis. Analysis of the eye-tracking data was carried out using the tracker-integrated software. Descriptive analysis was conducted for the quantitative data., Results: The mHealth App Usability Questionnaire results (n=105) indicated good overall usability for 2 different time points (4 wk: mean 89.15, SD 9.65; 20 wk: mean 85.57, SD 12.88). The qualitative analysis of the eye-tracking recordings (n=10) and interviews (n=16) showed that users found the Enable app easy to use. The design of the app, information about therapies and side effects, and usefulness of the app as a therapy companion were rated positively. Additionally, participants contributed requests for additional app features and suggestions for improving the content and usability of the app. Relevant themes included optimization of the appointment feature, updating the app's content regularly, and self-administration. In contrast to the app's current passive method of operation, participants expressed a desire for more active engagement through messaging, alarms, or emails., Conclusions: The results of this study demonstrate the good usability of the Enable app as well as the potential for further development. We concluded from patients' feedback and requests that mHealth apps could benefit from giving patients a more active role (eg, being able to actively document side effects as they occur). Additionally, regular updates of app content could further contribute to encouraging continued use of mHealth apps. Our findings may also assist other researchers in tailoring their mHealth apps to the actual needs of patients undergoing breast cancer therapy., (©Carolin Anders, Preetha Moorthy, Laura Svensson, Julia Müller, Oliver Heinze, Petra Knaup, Markus Wallwiener, Thomas M Deutsch, Thao-Vy Le, Lina Weinert. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 05.03.2024.)

Background: The proliferation marker Ki-67 is a major pathological feature for the description of the state of disease in breast cancer. It helps to define the molecular subtype and to stratify between therapy regimens in early breast cancer and helps to assess the therapy response. Circulating tumor cells (CTCs) are a negative prognostic biomarker for progression free (PFS) and overall survival (OS) in patients with metastatic breast cancer. Therefore, the CTC count is often described as surrogate for the tumor burden. Both, decrease of Ki-67 and CTC count are considered as evidence for therapy response. The presented work analyzed the correlation between the Ki-67 indices of metastatic tissue biopsies and CTC counts in biopsy time-adjacent peripheral blood samples., Patients and Methods: Blood samples from 70 metastatic breast cancer patients were obtained before the start of a new line of systemic therapy. CTCs were enumerated using CellSearch® (Menarini Silicon Biosystems, Bologna, Italy) whereas intact CTCs (iCTCs) and non-intact or apoptotic CTCs (aCTCs) were distinguished using morphologic criteria. The proportion of cells expressing Ki-67 was evaluated using immunohistochemistry on biopsies of metastases obtained concurrently with CTC sampling before the start of a new line of systemic therapy., Results: 65.7% of patients had a Ki-67 index of > 25%. 28.6% of patients had ≥ 5, 47.1% ≥ 1 iCTCs. 37.1% had ≥ 5, 51.4% ≥ 1 aCTCs. No correlation was shown between Ki-67 index and iCTC and aCTC count (r = 0.05 resp. r = 0.05, Spearman's correlation index). High CTC-counts did not coincide with high Ki-67 index. High Ki-67, ≥ 5 iCTCs and aCTCs are associated with poor progression free (PFS) and overall survival (OS)., Conclusion: CTCs and Ki-67 are independent prognostic markers in metastatic breast cancer. High Ki-67 in metastatic tumor tissue is not correlated to high iCTC or aCTC counts in peripheral blood., (© 2023. The Author(s).)

Purpose: Today, the decision to treat patients with chemotherapy for early breast cancer (EBC) is made based on the patient's individual risk stratification and tumor biology. In cases with chemotherapy indication, the neoadjuvant application (NACT) is the preferred option in comparison with primary surgery and adjuvant chemotherapy (ACT). Age remains a relevant factor in the decision-making process. The aim of the present study was to illustrate the impact of age on the use of systemic therapy in clinical routine., Methods: The study separately analyzed chemotherapy use among six age cohorts of EBC patients who had been treated at 104 German breast units between January 2008 and December 2017., Results: In total, 124,084 patients were included, 46,279 (37.3%) of whom had received chemotherapy. For 44,765 of these cases, detailed information on treatment was available. Within this cohort, chemotherapy was administered as NACT to 14,783 patients (33.0%) and as ACT to 29,982 (67.0%) patients. Due to the higher prevalence of unfavorable tumor subtypes, younger patients had a higher rate of chemotherapy (≤ 29y: 74.2%; 30-39y: 71.3%) and a higher proportion of NACT administration ( ≤ 29y: 66.9%; 30-39y: 56.0%) in comparison with elderly patients, who had lower rates for overall chemotherapy (60-69y: 37.5%; ≥ 70y: 17.6%) and NACT (60-69y: 25.5%; ≥ 70y: 22.8%). Pathologic complete response was higher in younger than in older patients (≤ 29y: 30.4% vs. ≥ 70y: 16.7%), especially for HER2- subtypes., Conclusion: The data from the nationwide German cohort reveal relevant age-dependent discrepancies concerning the use of chemotherapy for EBC., (© 2023. The Author(s).)

Background: Assessments of health-related quality of life (HRQoL) play an important role in transition to palliative care for women with metastatic breast cancer. We developed machine learning (ML) algorithms to analyse longitudinal HRQoL data and identify patients who may benefit from palliative care due to disease progression., Methods: We recruited patients from two institutions and administered the EuroQoL Visual Analog Scale (EQ-VAS) via an online platform over a 6-month period. We trained a regularised regression algorithm using 10-fold cross-validation to determine if a patient was at high or low risk of disease progression based on changes in the EQ-VAS scores using data of one institution and validated the performance on data of the other institution. Progression-free survival (PFS) was the end-point. We conducted Kaplan-Meier and Cox regression analysis adjusted for clinical risk factors., Results: Of 179 patients, 98 (54.7%) had progressive disease after a median follow-up of 14weeks. Using EQ-VAS scores collected at weeks 1-6 to predict disease progression at week 12, in the validation set (n = 63), PFS was significantly lower in the intelligent EQ-VAS high-risk versus low-risk group: median PFS 7 versus 10weeks, log-rank P < 0.038). Intelligent EQ-VAS had the strongest association with PFS (adjusted hazard ratio 2.69, 95% confidence interval 1.17-6.18, P = 0.02)., Conclusion: ML algorithms can analyse changes in longitudinal HRQoL data to identify patients with disease progression earlier than standard follow-up methods. Intelligent EQ-VAS scores were identified as independent prognostic factor. Future studies may validate these results to remotely monitor patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In cancer metastasis, single circulating tumor cells (CTCs) in the blood and disseminated tumor cells (DTCs) in the bone marrow mediate cancer metastasis. Because suitable biomarker proteins are lacking, CTCs and DTCs with mesenchymal attributes are difficult to isolate from the bulk of normal blood cells. To establish a procedure allowing the isolation of such cells, we analyzed the cell line BC-M1 established from DTCs in the bone marrow of a breast cancer patient by stable isotope labeling by amino acids in cell culture (SILAC) and mass spectrometry. We found high levels of the transmembrane protein CUB domain-containing protein 1 (CDCP1) in breast cancer cell lines with mesenchymal attributes. Peripheral blood mononuclear cells were virtually negative for CDCP1. Confirmation in vivo by CellSearch revealed CDCP1-positive CTCs in 8 of 30 analyzed breast cancer patients. Only EpCam-positive CTCs were enriched by CellSearch. Using the extracellular domain of CDCP1, we established a magnetic-activated cell sorting (MACS) approach enabling also the enrichment of EpCam-negative CTCs. Thus, our approach is particularly suited for the isolation of mesenchymal CTCs with downregulated epithelial cancer that occur, for example, in triple-negative breast cancer patients who are prone to therapy failure.

Background/aim: Loss of differentiation of breast cancer cells in association with a down-regulated class I human leukocyte antigen (HLA) expression can lead to proliferation unhampered by cytotoxic T lymphocytes, which has been proven to be of prognostic relevance. The objective of this study was to determine the levels of HLA-A and HLA-B/C expression in metastatic breast cancer (MBC) cells and their usefulness for predicting 5-year survival., Materials and Methods: This prospective double-blinded cohort study analyzed patients starting a new line of therapy for MBC. RT-qPCR was used to determine the levels of HLA-A and B/C expression in MBC cells and the mRNA-based tumor intrinsic subtype. Two receiver operating characteristic curves (ROC) were constructed in order to determine whether HLA-A and HLA-B/C expression levels can be used for predicting 5-year survival. Youden J points, and sensitivity and specificity optimized cut-off points were determined for both ROC curves., Results: We enrolled 34 patients. The ROC curve for HLA-B/C had the highest AUC compared to HLA-A (0.55 vs. 0.42). High levels of HLA-A and HLA-B/C expression (40-ΔΔCT of 33.5 and 31.9, respectively) were highly specific (reaching 87.5% for HLA-A and even 100% specificity for HLA-B/C) yet insensitive for five-year survival in our study., Conclusion: High expression of certain class I HLA molecule subtypes by MBCs, in particular high HLA-A or B/C expression by MBC cells seems very specific in predicting the 5-year survival. We determined cut-off values for these HLA molecule clusters with high specificity, which might help identify patients with a favorable prognosis as prognosticators of a 5-year overall survival if their sensitivity is improved in larger prospective cohorts., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Circulating miRNAs can provide valid prognostic and predictive information for breast cancer diagnosis and subsequent management. They may comprise quintessential biomarkers that can be obtained minimally invasively from liquid biopsy in metastatic breast cancer patients. Therefore, they would be clinically crucial for monitoring therapy response, with the goal of detecting early relapse. This study investigated miRNA expression in patients with early and/or late relapse, and the predictive value for assessing overall (OS) and progression-free survival (PFS)., Methods: Forty-seven patients with metastatic breast cancer from the University Women's Hospital Heidelberg were enrolled in this study. Expression of miR-200a, miR-200b, miR-200c, miR-141, and miR-429 was analyzed by RT-qPCR before a new line of systemic therapy and after the first cycle of a respective therapy. Tumor response was assessed every 3 months using the RECIST criteria. Statistical analysis focused on the relation of miR-200s expression and early vs. late cancer relapse in relation to systemic treatment. The association of miRNAs with PFS and OS was investigated., Results: Before starting a new line of systemic therapy, miR-429 (p = 0.024) expression was significantly higher in patients with early relapse (PFS ≤ 4 months) than in patients with late relapse (PFS > 4 months). After one cycle of systemic therapy, miR-200a (p = 0.039), miR-200b (p = 0.003), miR-141 (p = 0.017), and miR-429 (p = 0.010) expression was higher in early than in late progressive cancer. In addition, 4 out of 5 miR-200 family members (miR-200a, miR-200b, miR-141, and miR-429) predicted PFS (p = 0.048, p = 0.008, p = 0.026, and p = 0.016, respectively). Patients with heightened miRNA levels showed a significant reduction in OS and PFS., Conclusion: Circulating miR-200s were differentially expressed among patients with late and/or early relapse. 4 of 5 members of the miR-200 family predicted significantly early relapse after systemic treatment. Our results encourage the use of circulating miR-200s as valuable prognostic biomarkers during metastatic breast cancer therapy., (© 2022. The Author(s).)

The extracellular circulating microRNA (miR)-200 regulates epithelial-mesenchymal transition and, thus, plays an essential role in the metastatic cascade and has shown itself to be a promising prognostic and predictive biomarker in metastatic breast cancer (MBC). Expression levels of the plasma miR-200 family were analyzed in relationship to systemic treatment, circulating tumor cells (CTC) count, progression-free survival (PFS), and overall survival (OS). Expression of miR-200a, miR-200b, miR-200c, miR-141, and miR-429, and CTC status (CTC-positive ≥ 5 CTC/7.5 mL) was assessed in 47 patients at baseline (BL), after the first completed cycle of a new line of systemic therapy (1C), and upon the progression of disease (PD). MiR-200a, miR-200b, and miR-141 expression was reduced at 1C compared to BL. Upon PD, all miR-200s were upregulated compared to 1C. At all timepoints, the levels of miR-200s were elevated in CTC-positive versus CTC-negative patients. Further, heightened miR-200s expression and positive CTC status were associated with poorer OS at BL and 1C. In MBC patients, circulating miR-200 family members decreased after one cycle of a new line of systemic therapy, were elevated during PD, and were indicative of CTC status. Notably, increased levels of miR-200s and elevated CTC count correlated with poorer OS and PFS. As such, both are promising biomarkers for optimizing the clinical management of MBC.

Background: One in eight women is diagnosed with breast cancer in the course of their life. As systematic palliative treatment has only a limited effect on survival rates, the concept of health-related quality of life (HRQoL) was developed for measurement of patient-centered outcomes. Various studies have already demonstrated the reliability of paper-based patient-reported outcome (pPRO) and electronic patient-reported outcome (ePRO) surveys and that the 2 means of assessment are equally valid., Objective: The aim of this study was to analyze the acceptance and evaluation of a tablet-based ePRO app for breast cancer patients and to examine its suitability, effort, and difficulty in the context of HRQoL and sociodemographic factors., Methods: Overall, 106 women with adjuvant or advanced breast cancer were included in a 2-center study at 2 major university hospitals in Germany. Patients were asked to answer HRQoL and PRO questionnaires both on a tablet on-site using a specific eHealth assessment website and on paper. The suitability, effort, and difficulty of the app and self-reported technical skills were also assessed. Only the results of the electronically acquired data are presented here. The results of the reliability of the pPRO data have already been published elsewhere., Results: Patients regarded the ePRO assessment as more suitable (80/106, 75.5%), less stressful (73/106, 68.9%), and less difficult (69/106, 65.1%) than pPRO. The majority of patients stated that ePRO assessment improves health care in hospitals (87/106, 82.1%). However, evaluation of ePROs depended on the level of education (P=.003) in the dimensions of effort and difficulty (regression analysis). The app was rated highly in all categories. HRQoL data and therapy setting did not show significant correlations with the app's evaluation parameters., Conclusions: The results indicate that ePRO surveys are feasible for measuring HRQoL in breast cancer patients and that those patients prefer ePRO assessment to pPRO assessment. It can also be seen that patients consider ePRO assessment to improve hospital health care. However, studies with larger numbers of patients are needed to develop apps that address the needs of patients with lower levels of education and technical skills., (©Joachim Graf, Nina Sickenberger, Katharina Brusniak, Lina Maria Matthies, Thomas M Deutsch, Elisabeth Simoes, Claudia Plappert, Lucia Keilmann, Andreas Hartkopf, Christina Barbara Walter, Markus Hahn, Tobias Engler, Stephanie Wallwiener, Florian Schuetz, Peter A Fasching, Andreas Schneeweiss, Sara Yvonne Brucker, Markus Wallwiener. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 08.02.2022.)

Background: Health-related quality of life (HRQoL) is used to evaluate the treatment of metastatic breast cancer. In a long-term therapy setting, HRQoL can be used as an important benchmark for treatment success. With the help of digital apps, HRQoL monitoring can be extended to more remote areas and be administered on a more frequent basis., Objective: This study aims to evaluate 3 common HRQoL questionnaires in metastasized breast cancer in terms of TTD in a digital, web-based setting. We further aim to examine the development of the HRQoL in different systemic treatment groups in each of these evaluation instruments., Methods: A total of 192 patients with metastatic breast cancer were analyzed in this bicentric prospective online cohort study at two German university hospitals. Patients completed questionnaires on HRQoL (EuroQol Visual Analog Scale [EQ-VAS], EuroQol 5 Dimension 5 Level [EQ-5D-5L], European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 item [EORTC QLQ-C30]) via an online platform over a 6-month period. Treatment schedules and medical history were retrieved from medical records. Unadjusted Cox regression analysis on treatment-related factors was performed. We conducted subgroup analyses in regard to TTD events between different treatments., Results: The EQ-VAS showed a higher rate of deterioration after 8 weeks (84/179, 46.9%) than the EQ-5D-5L (47/163, 28.8%) and EORTC QLQ-C30 (65/176, 36.9%). Unadjusted Cox regression revealed significant connections between known metastases in the liver (P=.03, HR 1.64, 95% CI 1.06-2.52) and pleura (P=.04, HR 0.42, 95% CI 0.18-0.96) in the EQ-VAS. Significant relations between EQ-VAS events and single EQ-5D-5L items and the EQ-5D-5L summary score were demonstrated. All treatment groups significantly differed from the CDK4/6 inhibition subgroup in the EQ-VAS., Conclusions: Compared to the EQ-5D-5L and QLQ-C30, the EQ-VAS showed a higher rate of deterioration after 8 weeks. Significant connections to certain metastatic locations were only detected in the EQ-VAS. The EQ-VAS is capable of reflecting the distinctive HRQoL profiles of different systemic treatments as well as the different aspects of HRQoL presented in the EQ-5D-5L. TTD with the EQ-VAS is an adequate mean of examining longitudinal development of HRQoL among breast cancer patients., (©Katharina Brusniak, Manuel Feisst, Linda Sebesteny, Andreas Hartkopf, Joachim Graf, Tobias Engler, Andreas Schneeweiss, Markus Wallwiener, Thomas Maximilian Deutsch. Originally published in JMIR Cancer (https://cancer.jmir.org), 12.10.2021.)

Background: Over the past decade, chemotherapy has been used more selectively in early breast cancer (EBC) due to better risk stratification. Neoadjuvant chemotherapy (NACT) has evolved to the primary treatment option. The type and size of hospitals is known to have a substantial influence on the kinds of treatment they provide, and therefore on patient outcomes (e.g. rates for pathological complete response, pCR), but it is not yet known how this has affected delivery of chemotherapy for EBC in Germany., Methods: This study analyzed chemotherapy use and pCR rates after NACT for EBC patients treated at 104 German institutions 2008-2017. Institutions were separated into associated hospital type (university hospital; teaching hospital; community hospital) and annual caseload (≤100; 101-250; >250 cases/year)., Results: Overall, 124,084 patients were included, of whom 11.6% were treated at university hospitals, 63.1% at teaching hospitals, and 25.3% at community hospitals. In total, 46,274 (37.3%) received chemotherapy, of whom 44,765 had information available about systemic treatment and surgery. From 2008 to 2017, chemotherapy use declined from 48.3% to 36.4% for university hospitals, from 40.7% to 30.3% for teaching hospitals, and from 42.4% to 33.7% for community hospitals. Furthermore, the proportion of NACT increased the most in university hospitals (from 32.0% to 68.1%); whereas, the rate of pCR (defined as ypT0 ypN0) increased irrespective of institutional type. Analyses regarding annual caseload did not show any differences., Conclusions: The results from this large, nationwide cohort reflect a more selective use of chemotherapy in Germany, irrespective of institutional type or case load., Competing Interests: Declaration of competing interest Fabian Riedel declares that he has no conflict of interest. Ann Sophie Hoffmann declares that she has no conflict of interest. Mareike Moderow declares that she has no conflict of interest. Manuel Feisst declares that he has no conflict of interest. Sabine Heublein declares that she has no conflict of interest. Thomas Maximilian Deutsch declares that he has no conflict of interest. Benedikt Schäfgen declares that he has no conflict of interest. Michael Golatta declares that he has no conflict of interest. Christoph Domschke declares that he has no conflict of interest. Markus Wallwiener declares that he has no conflict of interest. Jörg Heil declares that that he has no conflict of interest. André Hennigs declares that he has no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The influence of music on the performance of surgical procedures such as laparoscopy is controversial and methodologically difficult to quantify. Here, outcome measurements using laparoscopic box training tools under standardized conditions might offer a feasible approach. To date, the effect of music exposure at different sound pressure levels (SPL) on outcome has not been evaluated systematically for laparoscopic novices., Methods: Between May 2017 and October 2018, n = 87 students (49 males, 38 females) from Heidelberg University Medical School performed three different laparoscopy exercises using the "Luebecker Toolbox" that were repeated twice under standardized conditions. Time was recorded for each run. All students were randomly assigned to four groups exposed to the same music compilation but at different SPLs (50-80 dB), an acoustically shielded (earplug) group, or a control group (no intervention)., Results: Best absolute performance was shown under exposure to 70 dB in all three exercises (a, b, c) with mean performance time of 121, 142, and 115 s (p < 0.05 for a and c). For the control group mean performance times were 157, 144, and 150 s, respectively. In the earplug group, no significant difference in performance was found compared to the control group (p > 0.05) except for exercise (a) (p = 0.011)., Conclusion: Music exposure seems to have beneficial effects on training performance. In comparison to the control group, significantly better results were reached at 70 dB SPL, while exposure to lower (50 or 60 dB) or higher (80 dB) SPL as well as under acoustic shielding did not influence performance.

Neoadjuvant chemotherapy (NACT) in early breast cancer (EBC) enables in vivo sensitivity testing and less radical surgery as compared to primary surgery and adjuvant chemotherapy (ACT). The aim of our study is to illustrate trends of systemic treatment of EBC. The study analyzed chemotherapy usage and time trends for patients with EBC treated at 104 German breast units between January 2008 and December 2017. The data were obtained through a quality-controlled benchmarking process. Altogether, 124 084 patients were included, of whom 46 279 (37.3%) received chemotherapy. For 44 765 of these cases, detailed information on systemic treatment and surgery were available. Overall use of chemotherapy declined from 42.0% in 2008 to 32.0% in 2017. During that same time, the proportion of NACT increased from 20.0% to 57.7%, irrespective of tumor subtype. The pathological complete response (pCR) rate (defined as ypT0 ypN0) at surgery after NACT increased from 15.0% to 34.2%. The results from this large cohort from the clinical routine reflect the refined indications for chemotherapy in EBC., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Pregnant women are increasingly using mobile apps to access health information during the antenatal period. Therefore, digital health solutions can potentially be used as monitoring instruments during pregnancy. However, a main factor of success is high user engagement., Objective: The aim of this study was to analyze engagement and factors influencing compliance in a longitudinal study targeting pregnant women using a digital health app with self-tracking., Methods: Digitally collected data concerning demographics, medical history, technical aspects, and mental health from 585 pregnant women were analyzed. Patients filling out ≥80% of items at every study visit were considered to be highly compliant. Factors associated with high compliance were identified using logistic regression. The effect of a change in mental and physical well-being on compliance was assessed using a one-sample t test., Results: Only 25% of patients could be considered compliant. Overall, 63% left at least one visit blank. Influential variables for higher engagement included higher education, higher income, private health insurance, nonsmoking, and German origin. There was no relationship between a change in the number of physical complaints or depressive symptoms and study dropout., Conclusions: Maintaining high engagement with digital monitoring devices over a long time remains challenging. As cultural and socioeconomic background factors had the strongest influence, more effort needs to be directed toward understanding the needs of patients from different demographic backgrounds to ensure high-quality care for all patients. More studies need to report on compliance to disclose potential demographic bias., (©Katharina Brusniak, Hannah Maria Arndt, Manuel Feisst, Kathrin Haßdenteufel, Lina Maria Matthies, Thomas Maximilian Deutsch, Hannes Hudalla, Harald Abele, Markus Wallwiener, Stephanie Wallwiener. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 14.10.2020.)

Purpose: Several prognostic indexes for overall survival (OS) after radiotherapy of brain metastases in breast cancer patients exist but are mainly validated for whole-brain radiotherapy or not specifically for breast cancer patients. To date, no such index provides information beyond mere OS. Methods: We retrospectively analyzed 95 breast cancer patients treated with stereotactic radiosurgery for 203 brain metastases. The Kaplan-Meier method with log-rank test was used to assess OS, local control (LC), distant cranial control (DCC), and extracranial control (EC). Cox regression was applied to detect prognostic outcome factors. A point scoring system was designed to stratify patients based on outcome. Nine established prognostic indexes were analyzed using the concordance index (c-index). Results: Two out of nine analyzed prognostic indexes for OS showed a significant c-index, the breast graded prognostic assessment (bGPA; 0.631; 95% CI, 0.514-0.748; p = 0.037) and the modified bGPA (mod-bGPA; 0.662; 95% CI, 0.547-0.777; p = 0.010). Significant results from multivariate analysis (Karnofsky Performance Score, Her2/neu receptor status, extracranial control) were used to generate a new point system: the breast cancer stereotactic radiotherapy score (bSRS), which discriminated three significantly different prognostic groups, for LC, DCC, EC, and OS, respectively. However, the c-index was only significant for OS (0.689; 95% CI, 0.577-0.802; p = 0.003). Conclusions: The new bSRS score was superior to the bGPA and mod-bGPA scores for prognosis of OS. The bSRS is easy to use and the first tool, which might also provide outcome assessment beyond mere OS. Future studies need to validate these findings., (Copyright © 2020 Weykamp, El Shafie, König, Seidensaal, Forster, Arians, Regnery, Hoegen, Deutsch, Schneeweiss, Debus and Hörner-Rieber.)

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., (©Maren Goetz, Claudia Schiele, Mitho Müller, Lina M Matthies, Thomas M Deutsch, Claudio Spano, Johanna Graf, Stephan Zipfel, Armin Bauer, Sara Y Brucker, Markus Wallwiener, Stephanie Wallwiener. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 11.08.2020.)

Background: The estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) statuses are frequently discordant between the primary tumor and metastatic lesions in metastatic breast cancer. This can have important therapeutic implications., Patients and Methods: In all, 541 patients with available receptor statuses from both primary tumor and metastatic lesion treated at Heidelberg and Tuebingen University Hospitals between 1982 and 2018 were included., Results: Statistically significant discordance rates of 14% and 32% were found for ER and PR. HER2 status was statistically insignificantly discordant in 15% of patients. Gain in HER2 positivity was associated with an improved overall survival, whereas loss of HR positivity was associated with worse overall survival. Antiendocrine treatment differed in 20% of cases before and after biopsy and HER2-directed treatment in 14% of cases., Conclusions: Receptor statuses are discordant between primary tumor and metastasis in a considerable fraction of patients with metastatic breast cancer. Next to a highly presumed predictive value with respect to efficacy of endocrine and HER2-targeted therapy, discordance seems to provide prognostically relevant information. Where feasible, metastatic lesions should be biopsied in accordance with current guidelines.

Purpose: As an independent, negative-prognostic biomarker for progression-free survival (PFS) and overall survival (OS), circulating tumor cells (CTCs) constitute a promising component for developing a liquid biopsy for patients with metastatic breast cancer (MBC). The effects of HER2-targeted therapy such as trastuzumab, pertuzumab, T-DM1, and lapatinib on CTC status and longitudinal enumeration were assessed in this trial., Methods: CTC status of 264 patients with MBC was analyzed prior to and after 4 weeks of a new line of palliative systemic therapy. CTCs were assessed using CellSearch®. Three groups were compared: patients with HER2-positive MBC receiving ongoing HER2-targeted therapy (n = 28), patients with de novo HER2-positive MBC and no HER2-targeted therapy in the last 12 months prior to enrollment and start of HER2-targeted therapy (n = 15), and patients with HER2-nonamplified disease and no HER2-targeted therapy (n = 212)., Results: Positive CTC status (≥ 5 CTC/7.5 ml blood) at enrollment was observed in the 3 groups for 17.9, 46.7, and 46.2% (p = 0.02) of patients, respectively. At least one CTC/7.5 ml was seen in 28.6, 53.3, and 67.0% (p < 0.001) of these patients. Furthermore, 3.6, 40.0, and 3.3% (p < 0.001) of the patients had at least one HER2-positive CTC. After 4 weeks of therapy 7.1, 0.0, and 31.1% (p = 0.001) of patients had still a positive CTC status (≥ 5 CTC/7.5 ml blood). At least one CTC/7.5 ml was still observed in 25.0, 20.0, and 50.5% (p = 0.004) of the patients. Furthermore, 7.1, 0.0, and 1.9% (p = 0.187) had at least one HER2-positive CTC. After 3 months of therapy, 35.7, 20.0, and 28.3% (p = 0.536) showed disease progression., Conclusions: HER2-targeted therapy seems to reduce the overall CTC count in patients with MBC. This should be taken into account when CTC status is used as an indicator for aggressive or indolent metastatic tumor disease.

Purpose/Objective: Oligometastatic disease (OMD) and oligoprogressive disease (OPD) describe tumor states with a limited metastasization. In contrast to other disease states, treatment of OMD or OPD has not yet become common for breast cancer. We sought to understand the outcomes and toxicities of this treatment paradigm. Material/Methods: We retrospectively analyzed female breast cancer patients with OMD (≤3 metastases) or OPD (1 progressive lesion) who received stereotactic body radiotherapy (SBRT) for their respective extracranial metastatic lesions between 01/2002 and 07/2019. Survival analysis was performed using the Kaplan-Meier method with log-rank test being used for evaluation of significance. Cox regression was used to detect prognostic outcome factors. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE v. 5.0). Results: Forty-six patients (70% OMD; 30% OPD) with 58 lesions met criteria for inclusion. The majority of treatments (34 out of 58; 58.6%) were delivered from 2017 to 2018. Treatment sites were bone, liver, lung [ n = 19 (33%) for each site], and adrenal gland [ n = 1 (1%)]. Median biologically effective dose (BED at α/β = 10) was 81.6 Gy (range: 45-112.5 Gy) and median planning target volume was 36.60 mL (range: 3.76-311.00 mL). At 2 years, local control (LC) was 89%, distant control (DC) was 44%, progression free survival (PFS) was 17% and overall survival (OS) was 62%. Multivariate analysis identified the diagnosis of a solitary metastasis as an independent prognostic factor for superior DC (HR = 0.186, CI [0.055; 0.626], p = 0.007) and PFS (HR = 0.363, CI [0.152; 0.863], p = 0.022). OS was independently inferior for patients treated at a higher age (HR = 5.788, CI [1.077; 31.119] p = 0.041). Nine (15.5%) grade I° and one (1.7%) grade II° toxicities were recorded, with no grade III° or higher toxicities. Conclusion: Extracranial SBRT in breast cancer patients with OMD or OPD was well-tolerated with excellent LC. SBRT should especially be offered to younger OMD and OPD breast cancer patients with only one metastasis. The increase in utilization since 2017 points toward a growing acceptance of SBRT for OMD and OPD in breast cancer., (Copyright © 2020 Weykamp, König, Seidensaal, Forster, Hoegen, Akbaba, Mende, Welte, Deutsch, Schneeweiss, Debus and Hörner-Rieber.)

Breast cancers (BC) can mutate, allowing metastatic tumors (MT) to sometimes differ to primary tumors (PT) in gene expression. Despite contemporary metastatic breast cancer (MBC) therapy, subtype conversion seems prognostically disadvantageous. We strived to determine the influence of mRNA-assessed intrinsic subtype stability comparing PT and MT biopsies and circulating tumor cell (CTC)-based liquid biopsies on progression free survival (PFS) and overall survival (OS). Additional analyzed prognostic factors were PT subtype, MT subtype and hormone receptor loss. Kaplan-Meier curves and the log rank tests were used to compare PFSs and OSs. The proportions of luminal B and triple negative subtype MTs were increased compared to those observed in PTs. Fifteen patients were found to have tumors that underwent intrinsic subtype conversion and their OS was significantly decreased ( p = 0.038). No such difference was observed when it comes to PFS. The majority of these tumors switched to a more aggressive intrinsic subtype. No significant differences in PFSs or OSs were observed between subtype converters with triple negative PTs compared to those with luminal subtype PTs. The same is true of subtype stable patients. Total CTC, iCTC and aCTC counts decreased with therapy, but there were no significant differences between subtype converters and subtype stable patients. Our data confirm a poorer overall survival of the intrinsic subtype converters and emphasize the importance of acquiring biopsies and re-biopsies of all available metastatic lesions alongside with CTC-based liquid biopsies for earlier recognition of patients with poorer prognosis and in need of altered individualized therapy regimens.

Detection of circulating tumor cells (CTC) can distinguish between aggressive and indolent metastatic disease in breast cancer patients and is thus considered an independent, negative prognostic factor. A clear decline in CTCs is observed in patients who respond to systemic therapy. Nevertheless, CTCs can decrease in patients experiencing disease progression during systemic therapy, too. This study aims to determine the differences between CTC decline in patients responding to therapy and those in whom disease is progressing. Therefore, CTC values were compared at the start and after one cycle of a new line of systemic therapy. In all, 108 initially CTC-positive patients (with ≥5 intact CTCs in 7.5 mL blood) were enrolled in this study and intact and apoptotic CTCs were measured via the CellSearch ® system. A cut-off analysis was performed using Youden's J statistics to differentiate between CTC change in the two groups. Here, 64 (59.3%) patients showed stable disease or partial response vs. 44 (40.7%) presenting disease progression. Median overall survival was 23 (range: 4-92) vs. 7 (2-43) months ( p < 0.001). Median intact CTC count at enrollment was 15.0 (5-2760) vs. 30.5 (5-200000) cells ( p = 0.39) and 2.5 (0-420) vs. 8.5 (0-15000) cells after one cycle of systemic therapy ( p = 0.001). Median apoptotic CTC count at enrollment was 10.5 (0-1500) vs. 9 (0-800) cells ( p = 0.475) and 1 (0-200) vs. 3 (0-250) cells after one cycle of systemic therapy ( p = 0.01). A 50% reduction in baseline apoptotic CTC count represents the optimal cut-off to differentiate between therapy response and disease progression. An apoptotic CTC reduction of ≤10% is 74% specific for early disease progression.

Circulating tumor cell (CTC) detection is a prognostic factor in the metastatic breast cancer (MBC) setting. Discrepancies in primary (PT) and metastatic tumor (MT) genetic profiles are also of prognostic importance. Our study aimed to compare the CTC statuses and prognoses between those with subtype stable MBCs and MBCs with specific biomarker conversions. The study enrolled 261 MBC patients, treated at the National Center for Tumor Diseases, Heidelberg, Germany in a five-year period. All underwent PT and MT biopsies and subsequent CTC enumeration before the initiation of systemic therapy. ER and HER2 statuses of the PTs and MTs were determined and progression free survivals (PFSs) and overall survivals (OSs) were recorded. We compared CTC statuses, CTC counts, PFSs and OSs between subgroups of patients with different receptor change patterns. Patients who had tumors that converted to triple negative MTs had the shortest median OSs, while HER2 expression was not associated with a shorter median OS. No significant differences in PFSs and OSs have been demonstrated by Kaplan-Meier curve comparisons in any of the subgroup analyses. CTC counts were similar in all subgroups. CTCs were comparably less frequently detected in patients with a stable HER2 expression. Similar proportions of CTC positives were observed in all other subtype change pattern subgroups, barring the aforementioned HER2 stable subgroup. The detection of CTCs was of no appreciable prognostic value in different receptor change pattern subgroups in our cohort.

The presence of circulating tumor cells (CTCs), detected as a form of liquid biopsy is associated with poor survival in both early and metastatic breast cancer. Monitoring tumor biology based on intrinsic subtypes delivers treatment-relevant information on the heterogeneity or biomarker conversion between primary and metastatic tumors. This study aimed to correlate the change of the apoptotic and intact CTC counts with mRNA-assessed intrinsic subtype change. Thirty-four breast cancer patients with available triplets of primary tumors, distant metastasis biopsies and data on intact and apoptotic CTC dynamics were included in the analysis. The intrinsic subtype was determined per RT-qPCR quantification of the gene expression ESR1, PGR, ERBB2 and MKI67. Both luminal ( p = 0.038) and triple negative ( p = 0.035) patients showed a significant downregulation of apoptotic CTCs. Repeated biopsies of distant metastatic sites, as well as determining a potential shift of the intrinsic subtype, combined with data on intact and apoptotic CTC dynamics from liquid biopsies might help personalize systemic therapy and generate additional surrogate markers for successful systemic therapy.

Purpose: Serial longitudinal enumeration of circulating tumor cells (CTCs) has shown its prognostic value on progression-free survival and overall survival (OS) in patients with stage IV breast cancer. This study prospectively evaluated the role of CTCs as a prognostic marker during further progression of metastatic breast cancer (MBC)., Methods: Among 476 MBC patients recruited between 2010 and 2015, the 103 patients with a known CTC status at baseline (CTC BL ) and within 4 weeks of tumor progression (CTC PD ) were included. Progressive disease (PD) was defined according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Using the CellSearch method, < 5 and ≥ 5 CTCs per 7.5 ml blood were determined as negative and positive, respectively. A shift in CTC status from baseline to progression ([Formula: see text] to [Formula: see text] and vice versa) was considered as alternating Kinetics BL-PD ., Results: Median follow-up was 29.9 [21.2, 40.0] months. CTC PD positivity (37%, n = 38) was associated with a significantly shorter OS than CTC PD negativity (8.0 [5.1, 10.9] vs 22.6 [15.3, 39.8] months; P < 0.001). Alternating Kinetics BL-PD was observed in 24% of the patients. This significantly changed the OS prediction of [Formula: see text] patients ([Formula: see text] vs [Formula: see text], 11.4 [9.7, not available (NA)] vs. 7.6 [4.4, 11.5] months; P = 0.044) and [Formula: see text] patients ([Formula: see text] vs. [Formula: see text], 8.4 [4.0, NA] vs. 22.6 [18.9, NA] months, respectively; P < 0.001). Prediction of survival was significantly improved (P = 0.002) by adding CTC PD status to clinicopathological characteristics and CTC BL status., Conclusions: CTC status upon further disease progression is a prognostic factor that could significantly improve well-established models. Thus, it represents a potential additional instrument supporting treatment decision.

Biomarker changes between primary (PT) and metastatic tumor (MT) site may be significant in individualizing treatment strategies and can result from actual clonal evolution, biomarker conversion, or technical limitations of diagnostic tests. This study explored biomarker conversion during breast cancer (BC) progression in 67 patients with different tumor subtypes and metastatic sites via mRNA quantification and subsequently analyzed the concordance between real-time qPCR and immunohistochemistry (IHC). Immunostaining for estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 was performed on formalin-fixed, paraffin-embedded PT and MT tissue sections. RT-qPCR was performed using a multiplex RT-qPCR kit for ESR1 , PGR , ERBB2 , and MKI67 and the reference genes B2M and CALM2 . Subsequent measurement of tumor biomarker mRNA expression to detect conversion revealed significant decreases in ESR1 and PGR mRNA and MKI67 upregulation (all p < 0.001) in MT compared to PT of all tumor subtypes and ERBB2 upregulation in MT from triple-negative PT patients ( p = 0.023). Furthermore, ERBB2 mRNA was upregulated in MT brain biopsies, particularly those from triple-negative PTs ( p = 0.023). High concordance between RT-qPCR and IHC was observed for ER/ ESR1 (81%(κ 0.51) in PT and 84%(κ 0.34) in MT, PR/ PGR (70%(κ 0.10) in PT and 78% (κ -0.32) in MT), and for HER2/ ERBB2 (100% in PT and 89% in MT). Discordance between mRNA biomarker assessments of PT and MT resulting from receptor conversion calls for dynamic monitoring of BC tumor biomarkers. Overall, RT-qPCR assessment of BC target genes and their mRNA expression is highly concordant with IHC protein analysis in both primary and metastatic tumor., Competing Interests: CONFLICTS OF INTEREST RMW is the founder and an employee of STRATIFYER Molecular Pathology GmbH and participated in developing the RT-qPCR system. All other authors declare that they have no competing interests.

Purpose: While intact circulating tumor cells (iCTC) have independent negative prognostic impact on patients with metastatic breast cancer (MBC), the prognostic relevance of apoptotic CTC (aCTC) has not been validated in larger patient cohorts. This study assessed aCTC and iCTC statuses at baseline (CTC BL ) and CTC kinetics (CTC KIN ) as changes from CTC BL to one completed treatment cycle for their utility in predicting response, progression-free survival (PFS), and overall survival (OS) in MBC., Methods: Status of iCTC and aCTC was prospectively assessed in 442 patients using the CellSearch™ system. Different cutoffs were analyzed both for iCTC and aCTC (≥5, ≥10, ≥25 and ≥50 CTC/7.5 ml). CTC KIN were characterized by ≥25 % changes in CTC counts., Results: Numbers of iCTC and aCTC at baseline correlated strongly (r = 0.7). For iCTC BL positive patients, additional detection of aCTC BL had a significant prognostic impact on OS (aCTC BL positive 10.3 vs. aCTC BL negative 16.4 months, p = 0.012). Worst prognosis for OS was observed in patients with ≥50 iCTC/7.5 ml and simultaneously detected aCTC. Determination of aCTC KIN showed stronger discriminating power than iCTC KIN , with higher PFS and OS for the group with decreasing CTCs (PFS 7.7 vs. 6.1; OS 22.2 vs. 16.4)., Conclusions: Intact and aCTC are predictive of outcome in MBC. Apoptotic CTC counts ≥ 5/7.5 ml in conjunction with iCTC at baseline have an independent unfavorable prognostic impact on OS. Decreasing aCTC KIN at ≥ 5/7.5 ml in serial enumeration is associated with favorable outcome. Therefore, separate enumeration of iCTC and aCTC is useful in tailoring systemic treatment.