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Background: Although adequate physical activity has been shown to be beneficial in early breast cancer, evidence in metastatic breast cancer is sparse and contradictory, which could be related to distinct effects of physical activity on the different molecular cancer subtypes. Therefore, we here evaluated the effect of physical activity on progression-free and overall survival (PFS, OS) in metastatic breast cancer, specifically looking at molecular subtypes., Methods: International Physical Activity Questionnaire (IPAQ) questionnaires, filled out by patients enrolled in the prospective PRAEGNANT registry (NCT02338167; n = 1,270) were used to calculate metabolic equivalent task (MET) minutes, which were subsequently categorized into low (n = 138), moderate (n = 995) or high IPAQ categories (n = 137). Cox regression analyses were used to evaluate the impact of IPAQ categories and its interaction with molecular subtypes on PFS and OS., Results: Patient and tumor characteristics were equally distributed across IPAQ categories. HER2pos, HRpos and TNBC were present in 23.1%, 65.7% and 11.2% of patients, respectively. IPAQ scores did not have an impact on PFS and OS in addition to established prognostic factors, either overall or in particular molecular subtypes (PFS: p = 0.33 and OS: p = 0.08, likelihood ratio test). Exploratory analyses showed higher overall survival rates for high IPAQ categories compared to low/moderate IPAQ categories in luminal B-like breast cancer., Conclusions: Self-reported physical activity using the IPAQ questionnaire did not significantly affect PFS or OS in patients suffering from metastatic breast cancer. Nevertheless, some hypothesis-generating differences between molecular subtypes could be observed, which may be interesting to evaluate further., (© 2024. The Author(s).)

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., (© 2024 UICC.)

Purpose: To summarize the radiotherapy-relevant statements of the 18th St. Gallen Breast Cancer Consensus Conference and interpret the findings in light of German guideline recommendations., Methods: Statements and voting results from the 18th St. Gallen International Breast Cancer Consensus Conference were collected and analyzed according to their relevance for the radiation oncology community. The voting results were discussed in two hybrid meetings among the authors of this manuscript on March 18 and 19, 2023, in light of the German S3 guideline and the 2023 version of the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) guidelines., Results and Conclusion: There was a high level of agreement between the radiotherapy-related statements of the 18th St. Gallen International Breast Cancer Consensus Conference and the German S3 and AGO guidelines. Discrepancies include the impact of number of lymph node metastases for the indication for postmastectomy radiotherapy., (© 2024. The Author(s).)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Peter A. Fasching reports personal fees from Novartis, grants from Biontech, grants and personal fees from Pfizer, personal fees from Daiichi-Sankyo, personal fees from Astra Zeneca, personal fees from Eisai, personal fees from Merck Sharp & Dohme, grants from Cepheid, personal fees from Lilly, personal fees from Pierre Fabre, personal fees from SeaGen, personal fees from Roche, personal fees from Hexal, personal fees from Agendia, personal fees from Sanofi Aventis, personal fees from Gilead, during the conduct of the study. Thomas Decker reports being on advisory board with Novartis, Lilly. Andreas Hartkopf reports consulting fees from Novartis, Pfizer, Lilly, MSD, AstraZeneca, Roche, Seattle Genetics, ExactSiences; honoraria from Novartis, Pfizer, Lilly, MSD, AstraZeneca, Roche; travel expenses from Roche, Pfizer, AstraZeneca; grants or contracts from ExactSiences; writing Support from Novartis. Arnd Nusch has no conflict of interest to disclose. Bernhard J. Heinrich has received documentation fees from Novartis. Christian M. Kurbacher received grants or contracts from Astra Zeneca, BMS, Eli Lilly, Immunomedics, MSD, Novartis, Pfizer, Riemser, Roche, Seattle Genetics; consulting fees from Amgen, Eli Lilly, Novartis, Pfizer, Riemser, Roche, GSK, Servier; honoraria from Amgen, Astra Zeneca, Clovis Oncology, Eli Lilly, MSD, Novartis, Pfizer, Roche, GSK; support for attending meetings and/or travel from Amgen, AstraZeneca, Immunomedics, Pfizer, TEVA Oncology; has been on advisory board with Amgen, Astra Zeneca, Eli Lilly, MSD, Novartis, Pfizer, Onkotrakt, PharmaMar, Riemser, Roche, GSK; has been on board of directors (unpaid) in Berufsverband niedergelassener gynäkologischer Onkologen in Deutschland e. V.(BNGO). Roswitha Fuchs has no conflict of interest to disclose. Hans Tesch has received consulting fees from Pierre Fabre, Pfizer Pharma, Mundipharma, ClinSol, Novartis, Lilly, Grünenthal, Vifor, AstraZeneca, Mylan, Amgen; honoraria from Vifor, Novartis, AstraZeneca, ClinSol, MundiPharma, Lilly, Amgen; travel expenses from Pierre Fabre, Pfizer, Mundipharma, ClinSol, Novartis, Lilly, Grünenthal, Vifor, AstraZeneca, Mylan, Amgen; has been on advisory board with Novartis, BMS, Molecular Health GmbH, AstraZeneca, Pfizer, Roche, Grünenthal, Mylan; has been in leadership or fiduciary role in Arbeitskreis KlinischeStudien e.V., ASCO, BNHO, DGHO, DKG, ESMO, Deutsche Ges. für Senologie. Petra Krabisch has no conflict of interest to disclose. Jens Huober reports research funding from Celgene, Novartis, Hexal; honoraria from Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene, Eisai, Abbvie; consulting/advisory relationship with Lilly, Novartis, Roche, Pfizer, Hexal, AstraZeneca, MSD, Celgene, Abbvie; travel expenses from Roche, Pfizer, Novartis, Celgene, Daiichi. Sherko Kuemmel reports receiving consulting fees from Lilly, pfm medical, Somatex, MSD; honoraria from Roche, Genomic Health, Novartis, Amgen, Celgene, Daiichi Sankyo, AstraZeneca, Pfizer; travel expenses from Roche, Daiichi Sankyo, Lilly, Sonoscape; advisory board with Roche, Daiichi Sankyo, Lilly, MSD, AstraZeneca, Pfizer; leadership of fiduciary role in WSG (Co Director), AGO, NOGGOe.V, AGimed. Sara Y. Brucker reports receiving honoraria from Storz, Pfizer, Roche, Novartis, MSD, AstraZeneca; travel expenses from Storz, Pfizer, Roche, Novartis, MSD, AstraZeneca; advisory board with Storz, Pfizer, Roche, Novartis, MSD, AstraZeneca. Wolfgang Janni received grants or contracts from Novartis; consulting fees from Novartis; honoraria from Novartis; payment for expert testimony from Novartis; travel expenses from Novartis. Andreas Schneeweiss received writing support from Roche; grants or contracts from Celgene, Roche, AbbVie; consulting fees from Celgene, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly; payment for expert testimony from Roche, AstraZeneca; travel expenses from Celgene, Roche, Pfizer. Martin Schuler reports receiving consultant fees from AstraZeneca, Boehringer Ingelheim, BMS, GSK, Janssen, Novartis, Roche, Takeda; honoraria from Amgen, Boehringer Ingelheim, BMS, Janssen, MSD, Novartis; research funding to institution from AstraZeneca, BMS. Tanja Fehm received honoraria from Roche, Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, MSD, TEVA; travel expenses from Daiichi Sankyo, Roche; was on advisory board with Daiichi Sankyo, Roche, Pfizer., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Oral cancer medications offer advantages but also pose challenges for therapy management and adherence. An eHealth-based platform such as CANKADO can help to support therapy management by probing the patient's quality of life (QoL) continuously throughout the course of treatment., Material and Methods: AGO-B WSG PreCycle (NCT03220178) is a multicenter, randomized phase IV intergroup trial evaluating the impact of eHealth-based Patient-Reported Outcome (ePRO) assessment on QoL in patients with hormone receptor-positive (HR + )/HER2-negative (HER2-) advanced breast cancer treated with palbociclib and endocrine therapy. Patients were randomized (2:1) to CANKADO-active arm (supported by CANKADO PRO-React) or CANKADO-inform arm (drug intake documentation only) This exploratory analysis reports the impact of CANKADO PRO-React on safety. Time to first serious adverse event (SAE) was estimated taking competing risks into account., Results: While distributions of adverse events (AEs) were similar by arm overall, patients in the CANKADO-active arm had a favorable hazard ratio of 0.67 (95%CI 0.46-0.97; p = 0.04) for time to first SAE and were significantly less likely overall to suffer an SAE than patients in the inform arm. At 24 months, 22.9% [17.9%-27.8%] of patients in CANKADO-active had suffered an SAE vs. 30.3% [22.6%-38.0%] in CANKADO-inform. AE-related dose reductions affected approximately 20% of patients (CANKADO-active: 18.2%, CANKADO-inform: 21.1%)., Conclusion: Exploratory safety analysis of PreCycle demonstrates for the first time in a randomized prospective trial that interactive autonomous eHealth-based support has a substantial favorable impact on the risk of SAEs and mitigates their severity for patients with advanced HR+/HER2- breast cancer on oral tumor therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [NH reported support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from palleos healthcare; consulting fees from Gilead, Pfizer, Sanofi, Sandoz, Roche, Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, EPG Communication, Lilly, MSD, Pierre Fabre, Roche, Seagen, Viatris, Daiichi Sankyo, Gilead, MEDSCAPE, Novartis, Pfizer, Sanofi, Springer, Zuelligpharma; and co-director position at WSG – West German Study Group. REK reported consulting fees to an immediate family member from Roche/Genentech, Novartis, BMS, Pfizer, Lilly, Sandoz, Daiichi Sankyo, Agendia, AstraZeneca, Merck Sharp & Dohne, Ondonate Therapeutics, Sattle Genetics, and palleos healthcare; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events to an immediate family member from Roche, Novartis, BMS, Amgen, Pfizer, Genomic Health, and NanoString Technologies. TS reported stock or stock options from CANKADO GmbH; other financial or non-financial interests from CANKADO GmbH. RW reported consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events as well as support for attending meetings and/or travel from Agendia, Aristo, BMS, Daiichi Sankyo, Exact Sciences, Glaxo Smith Kline, Lilly, MSD, Mylan, Novartis, Paxman, Pfizer, PINK, Sandoz/Hexal, Riemser, Seattle Genetics/Seagen, Tesaro Bio, Veracyte, Amgen, AstraZeneca, Clovis Oncology, Eisai, Gilead, Hexal, Medstrom Medical, Mundipharma, Nanostring, Ondonate, palleos healthcare, Perre Fabre, PumyBiotechnology, Roche, Sanofi Genzyme, Stemline, Teva, Viatris; other financial or non-financial interests from FOMF, Pomme Med, MCI, Aurikamed, medconcept and Breast Center, Department of Obstetrics and Gynecology and Comprehensive Center (CCC) Munich, LMU University Hospital, Munich Germany. DL reported consulting fees from AstraZeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; honoraria from Astra Zeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; payment for expert testimony from AstraZeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; support for attending meetings and/or travel from AstraZeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; Board or Advisory Board from AstraZeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Deutsche Stiftung für junge Erwachsene mit Krebs. OH reported consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events as well as support for attending meetings and/or travel, and participation on a Data Safety Monitoring Board or Advisory Board from Roche, MSD, Gilead, Novartis, Lilly, Pfizer, AstraZeneca, Daiichi Sankyo, Seagen, Amgen, Eisai; from Roche, MSD, Gilead, Novartis, Lilly, Pfizer, AstraZeneca, Daiichi Sankyo, Seagen, Amgen, Eisai. TDecker reported personal fees from Adboards, Novartis and iOMEDICO. MR reported consulting fees from Roche, Daiichi Sankyo, Somatex; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, AstraZeneca, Novartis, Daiichi Sankyo, Gilead, Somatex, Pfizer, Lilly; support for attending meetings and/or travel from Novartis, Pfizer, Gilead and Astra Zeneca. PS reported honoraria from Abbvie, Amgen, AstraZeneca, BMS, MSD Oncology, Pfizer, Merck Serono, Roche, Novartis; consulting or advisory role from Abbvie, Amgen, AstraZeneca, BMS; speakers' bureau from Abbvie, Amgen, AstraZeneca, BMS, Roche, Pfizer; research funding from Abbvie, BMS, Novartis, Roche; travel, accommodations, expenses from Abbvie, AstraZeneca; other from Abbvie, Amgen, BMS, Eisai, Incyte, Ipsen, Gilead Sciences, AstraZeneca, Janssen Oncology, Lilly Medical, Merck Serono, MSD Oncology, Pfizer, Roche, Novartis, Takeda. OG reported consulting fees from Daiichi Sankyo, BMS, Genomic Health/Exact Sciences, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Pierre Fabre, Gilead, Molecular Health; honoraria from Genomic Health/Exact Sciences, Eisai, Roche, BMS, Pfizer, Novartis, NanoString Technologies, Agendia, AstraZeneca; travel support from Roche, Daiichi Sankyo, all outside of the submitted work; co-director position at West German Study Group (WSG). PAF reported personal fees for advisory board from Agendia, AstraZeneca, Daiichi Sankyo, Eisai, Hexal, Lilly, Merck, Sharp&Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi Aventis, Seagen; personal fees for invited speaker from AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, Merck, Sharp&Dohme, Novartis, Seagen; personal fees for medical writing support from Roche; non-financial support to the Institution from BioNTech, Cepheid; non-financial interests: member for Arbeitsgemeinschaft für Gynäkologische Onkologie, ASCO, Deutsche Gesellschaft für Senologie, Translational Research in Oncology. MS reported grants or contracts paid to the Institution from from AstraZeneca, BioNTech, Eisai, German Breast Group, Genentech, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche; consulting fees from AstraZeneca, BioNTech, Eisai, Daiichi Sankyo, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Novartis, Pfizer, Roche, Seagen; support for attending meetings and/or travel from Pfizer, Roche; patents planned, issued or pending EP 2951317 B1, EP 2390370 B1; participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche and Seagen. All other authors have declared no conflicts of interest.]., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Efficacy and quality of life (QoL) are key criteria for therapy selection in metastatic breast cancer (MBC). In hormone receptor positive (HR +) human epidermal growth factor receptor 2 negative (HER2 -) MBC, addition of targeted oral agents such as everolimus or a cycline-dependent kinase 4/6 (CDK 4/6) inhibitor (e.g., palbociclib, ribociclib, abemaciclib) to endocrine therapy substantially prolongs progression-free survival and in the case of a CDK 4/6i also overall survival. However, the prerequisite is adherence to therapy over the entire course of treatment. However, particularly with new oral drugs, adherence presents a challenge to disease management. In this context, factors influencing adherence include maintaining patients' satisfaction and early detection/management of side effects. New strategies for continuous support of oncological patients are needed. An eHealth-based platform can help to support therapy management and physician-patient interaction., Methods: PreCycle is a multicenter, randomized, phase IV trial in HR + HER2 - MBC. All patients (n = 960) receive the CDK 4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. PreCycle evaluates and compares the time to deterioration (TTD) of QoL in patients supported by eHealth systems with substantially different functionality: CANKADO active vs. inform. CANKADO active is the fully functional CANKADO-based eHealth treatment support system. CANKADO inform is a CANKADO-based eHealth service with a personal login, documentation of daily drug intake, but no further functions. To evaluate QoL, the FACT-B questionnaire is completed at every visit. As little is known about relationships between behavior (e.g., adherence), genetic background, and drug efficacy, the trial includes both patient-reported outcome and biomarker screening for discovery of forecast models for adherence, symptoms, QoL, progression free survival (PFS), and overall survival (OS)., Discussion: The primary objective of PreCycle is to test the hypothesis of superiority for time to deterioration (TTD) in terms of DQoL = "Deterioration of quality of life" (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in patients merely receiving eHealth-based information (CANKADO inform). EudraCT Number: 2016-004191-22., (© 2023. The Author(s).)

Importance: Trastuzumab has been the standard of care for the treatment of patients with ERBB2-positive breast cancer; however, cardiac events have been reported. This long-term follow-up study provides clinical evidence supporting the similarity of a trastuzumab biosimilar (SB3) to reference trastuzumab (TRZ)., Objective: To compare cardiac safety and efficacy between SB3 and TRZ for patients with ERBB2-positive early or locally advanced breast cancer after up to 6 years of follow-up., Design, Setting, and Participants: This prespecified secondary analysis of a randomized clinical trial, conducted from April 2016 to January 2021, included patients with ERBB2-positive early or locally advanced breast cancer from a multicenter double-blind, parallel-group, equivalence phase 3 randomized clinical trial of SB3 vs TRZ with concomitant neoadjuvant chemotherapy who completed neoadjuvant and adjuvant treatment., Interventions: In the original trial, patients were randomized to either SB3 or TRZ with concomitant neoadjuvant chemotherapy for 8 cycles (4 cycles of docetaxel followed by 4 cycles of fluorouracil, epirubicin, and cyclophosphamide). After surgery, patients continued SB3 or TRZ monotherapy for 10 cycles of adjuvant treatment per previous treatment allocation. Following neoadjuvant and adjuvant treatment, patients were monitored for up to 5 years., Main Outcomes and Measures: The primary outcomes were the incidence of symptomatic congestive heart failure and asymptomatic, significant decrease in left ventricular ejection fraction (LVEF). The secondary outcomes were event-free survival (EFS) and overall survival (OS)., Results: A total of 538 female patients were included (median age, 51 years [range, 22-65 years]). Baseline characteristics were comparable between the SB3 and TRZ groups. Cardiac safety was monitored for 367 patients (SB3, n = 186; TRZ, n = 181). Median follow-up was 68 months (range, 8.5-78.1 months). Asymptomatic, clinically significant LVEF decreases were rarely reported (SB3, 1 patient [0.4%]; TRZ, 2 [0.7%]). No patient experienced symptomatic cardiac failure or death due to a cardiovascular event. Survival was evaluated for the 367 patients in the cardiac safety cohort and an additional 171 patients enrolled after a protocol amendment (538 patients [SB3, n = 267; TRZ, n = 271]). No difference was observed in EFS or OS between treatment groups (EFS: hazard ratio [HR], 0.84; 95% CI, 0.58-1.20; P = .34; OS: HR, 0.61; 95% CI, 0.36-1.05; P = .07). Five-year EFS rates were 79.8% (95% CI, 74.8%-84.9%) in the SB3 group and 75.0% (95% CI, 69.7%-80.3%) in the TRZ group, and OS rates were 92.5% (95% CI, 89.2%-95.7%) in the SB3 group and 85.4% (95% CI, 81.0%-89.7%) in the TRZ group., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, SB3 demonstrated cardiac safety and survival comparable to those of TRZ after up to 6 years of follow-up in patients with ERBB2-positive early or locally advanced breast cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT02771795.

Purpose of Review: Hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer does respond to chemotherapy but can be addressed with a better therapeutic index by using biologically modified endocrine therapy. The most pronounced recent successes were reached by antibody drug conjugates (ADCs)., Recent Findings: In early HR+/HER2- disease, adjuvant treatment escalations have taken place for high-risk patients using abemaciclib for the HR+ BRCA- subset and olaparib for HR+ BRCA+ patients. In metastatic spread, among all CDK (cyclin-dependent kinase) 4/6 inhibitors used for first-line therapy, only ribociclib improved overall survival in pre and postmenopausal patients. Palbociclib failed to demonstrate overall survival benefits. New options come up with oral selective oestrogen receptor degraders (SERDs) such as elacestrant, which will replace fulvestrant and is clinically important in combination therapies. ADCs, together with new patient categories such as HER2low or HER3+, enlarge the treatment portfolio and challenge the need of supportive care. The antitrophoblast antigen 2 (TROP2) ADC sacituzumab govitecan improves overall survival in heavily pretreated HR+/HER2- patients by 3.2 months. The best improvement of overall survival was shown bý trastuzumab deruxtecan in less pretreated HER2low (HER2 1+ or HER2 2+/no gene amplification) patients with a gained life span of 6 months., Summary: Real-world data on the sequence of different ADCs with similar payloads are needed to establish best possible treatment algorithms. All these new agents will find their place after CDK4/6 inhibitor-based endocrine combination therapy., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The PRAEGNANT study is a registry study for metastatic breast cancer patients, focusing on biomarker detection. Recently, within this study, genetic alterations in 37 breast cancer predisposition genes were analyzed and genetic findings were detected for 396 participants. The aim of this project was to return genetic results to the physicians and to analyze actions taken (e.g., disclosure of results to patients, validation of results, clinical impact, and impact on the patient's quality of life) using a questionnaire., Methods: 235 questionnaires were sent out to the study centers, with each questionnaire representing one patient with a genetic finding. The questionnaire consisted of twelve questions in the German language, referring to the disclosure of results, validation of test results, and their impact on treatment decisions and on the patient's quality of life., Results: 135 (57.5%) questionnaires were completed. Of these, 46 (34.1%) stated that results were returned to the patients. In 80.0% (N = 36) of cases where results were returned, the patient had not been aware of the finding previously. For 27 patients (64.3%), genetic findings had not been validated beforehand. All validation procedures (N = 15) were covered by the patients' health insurance. For 11 (25.0%) patients, physicians reported that the research results influenced current or future decision-making on treatment, and for 37.8% (N = 17) the results influenced whether family members will be genetically tested., Conclusion: This study provides novel insights into the return of research results and into clinical and personal benefits of disclosure of genetic findings within a German registry., (© 2022. The Author(s).)

Background: Patients with de novo metastatic breast cancer (dnMBC) may have different clinical and pathological characteristics. In studies concerned with first-line metastatic patients, the proportion of these patients without secondary resistance mechanisms may have a large influence ont the study results. The aim of this study was to identify patient and tumor characteristics that are associated with dnMBC vs. recurrent MBC (rMBC)., Methods: This is a retrospective analysis of data prospectively collected in the PRAEGNANT metastatic breast cancer registry (NCT02338167). Firs line treated patients were eligible. Patient and tumor characteristics were compared with common disease and tumor characteristics relative to de novo metastatic status, as well as early and late recurrences after primary disease without metastases., Results: Among the 947 patients identified, 355 were included with de novo metastatic disease (37.5%). Older age and HER2-positive disease were significantly associated with a higher frequency of dnMBC. Patients younger than 50, 50-69, or 70 years or older had dnMBC frequencies of 22.7%, 44.0%, and 57.6%, respectively. HER2-positive patients had dnMBC at initial presentation in 49.1% of cases, in comparison with 21.9%, 35.5%, and 37.6% in patients with triple-negative, luminal A-like and luminal B-like breast cancer, respectively., Conclusion: Age and breast cancer subtype are associated with the frequency of first-line MBC patients. Inclusion criteria concerning age or breast cancer subtype can influence the frequency of these patients in a selected patient population and can therefore modify the number of patients with secondary resistance to specific therapies in clinical trials., Competing Interests: Conflict of interest statement V.M. has received speaker honoraria from Amgen, Astra Zeneca, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro and Nektar. A.D.H. has received honoraria from Teva, GenomicHealth, Lilly, AstraZeneca, Novartis, Pfizer, Pierre Fabre, SeaGen and Roche. P.A.F. received honoraria from Novartis, Pfizer, Roche, Amgen, Celgene, Daiichi-Sankyo, AstraZeneca, Merck-Sharp & Dohme, Eisai, Puma and Teva; his institution conducts research with funding from Novartis and Biontech. H.-C.K. has received honoraria from Carl Zeiss meditec, Theraclion, Novartis, Amgen, AstraZeneca, Pfizer, GSK, SurgVision, Onkowissen and Genomic Health/Exact Sciences, travel support from Tesaro and Daiichi Sankyo and holds stock of Theraclion and Phaon scientific. H.T. has received honoraria from Novartis, Roche, Celgene, TEVA, and Pfizer, and travel support from Roche, Celgene, and Pfizer. J.E. has received consulting fees from AstraZeneca, Daiichi Sankyo, Pfizer, Novartis, Lilly, Pierre Fabre, Roche, Tesaro; contracted research from Daiichi Sankyo, Pfizer, Lilly, Novartis, Seattle Genetics, AstraZeneca, Roche, and Odonate; and travel support from Astra Zeneca, Daiichi Sankyo, Celgene, Pfizer, Novartis, Lilly, and Tesaro. D.L. has received honoraria from Novartis, Pfizer, Amgen, Eli Lilly, Teva, Loreal, GSK, MSD, Roche, Astra Zeneca. M.W. received grants from Astra Zeneca, grants from Celgene, grants from Roche, grants from MSD and grants from Novartis during the conduct of the study. E.B. has received honoraria from Novartis, Pfizer, Amgen, Daiichi-Sankyo, and onkowissen.de. P.W. has received honoraria for scientific talks or grants from Amgen, Novartis, MSD, Pfizer, PharmaMar, Teva, Eisai, Clovis and Tesaro. C.H. has received honoraria from Roche Pharma, Pfizer, Astra Zeneca, Novartis, and Onkovis. C.M.K. received honoraria from Amgen, Astra Zeneca, Eli Lilly, MSD Sharp & Dohme, Novartis, Pfizer, Onkotrakt, PharmaMar, Riemser, Roche, Tesaro, Hilotherm, NewCo, research grants from Astra Zeneca, BMS, Immunomedics, MSD Sharp&Dohme (Merck), NewCo, Novartis, Pfizer, PharmaMar, Reimser, Roche, Seattle Genetics and travel support from Amgen, Astra Zeneca, Hexal, Immunomedics, PharmaMar, Pfizer, Tesaro, TEVA Oncology. R.W. has received honoraria from Amgen, Astra Zeneca, Celgene, Daiichi-Sankyo, Esai, Exact Science, Nanostring, GSK, Hexal, Lilly, MSD, Mundipharma, Novartis, Odonate, Pfizer, Pierre Fabre, Riemser, Roche, Sandoz, Seattle Genetics, Tesaro Bio, Teva, and Viatris. M.U. has received honoraria from Abbvie, Amgen, Astra Zeneca, BMS, Celgene, Daiichi-Sankyo, Eisai, Lilly Deutschland, Lilly Int., MSD Merck, Mundipharma, Myriad Genetics, Odonate, Pfizer, PUMA Biotechnology, Roche Pharma, Sanofi Aventis Deutschland, TEVA Pharmaceuticals Ind Ltd, Novartis, Pierre Fabre, Clovis Oncology, and Seattle Genetics. W.J. has received honoraria and research grants from Sanofi-Aventis, Novartis, Lilly, Pfizer, Roche, Chugai, Astra Zeneca, MSD, and Daiichi-Sankyo. F.A.T. has received honoraria from Hexal, Novartis, Tesaro and travel expenses from GSK. M.P.L. has received honoraria from Lilly, Pfizer, Roche, MSD, Hexal, Novartis, AstraZeneca, Eisai, Exact Sciences, Pierre-Fabre, PharmaMar and medac for advisory boards, lectures, and travel support. S.Y.B. has received honoraria from Roche Pharma, Novartis, Pfizer, MSD, Teva, Astra Zeneca. T.N.F. has received honoraria from Novartis, Roche, Pfizer, TEVA, Diachii Sankyo, Astra Zeneca and MSD. All remaining others (A.H., P.H., L.H., M.W.B, S.U., J.M., L.A.W., D.W., L.L.M.) have declared that they do not have any conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6i) have significantly improved clinical outcomes in patients with advanced hormone receptor-positive (HR+) breast cancer and have demonstrated favourable antitumour immune responses in preclinical studies., Methods: Here, we investigated peripheral immune responses to ribociclib in patients with metastatic HR+ breast cancer as a preplanned exploratory subanalysis of the RIBECCA trial (NCT03096847). Peripheral blood mononuclear cells were subjected to immune cell profiling, gene expression analysis of immune-related signatures, and deep T cell receptor profiling before treatment started and after 12 weeks of treatment with ribociclib., Results: Gene expression analysis revealed an upregulation of signatures associated with an activated adaptive immune system and a decrease in immunosuppressive cytokine signalling during treatment with ribociclib. Profiling of peripheral immune cell subpopulations showed a decrease in Treg cell frequencies, which was associated with treatment response. Furthermore, induction of CD4+ naive T cells could be seen, whereas effector and memory T cell populations remained largely unchanged. Correspondingly, T cell repertoire diversity remained mostly unchanged during treatment, although an increase in clonality could be observed in single patients., Conclusions: We show that treatment with ribociclib has significant effects on the peripheral innate and adaptive immune response in patients with HR+ breast cancer. Our data suggest that these effects lead to an activation of an already existing immune response rather than a de novo induction and make a strong case for future combination strategies of CDK4/6i with immunotherapies to enhance the adaptive immune response in HR+ breast cancer., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SB, TD, PF, TF, WJ, SK, AS, MS and DL are members of the RIBECCA trial consortium and received speaker and advisory board honoraria from Novartis for work related to the RIBECCA study. CAP received speaker honoraria from Novartis for work unrelated to this manuscript. UK received speaker and advisory board honoraria from Novartis for work unrelated to this manuscript. The other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Assessment of HER2 overexpression using immunohistochemistry (IHC) and/or in situ hybridisation (ISH) for the detection of HER2 amplifications is standard to identify patients for established HER2-directed treatments. Patients with lower HER2 expression levels have recently also become candidates for novel therapies targeting HER2. This study aimed to assess tumour and patient characteristics and prognosis in patients with advanced breast cancer (aBC), relative to low HER2 expression levels., Methods: PRAEGNANT is a prospective aBC registry (NCT02338167), focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis includes patients with conventionally HER2-negative aBC. Clinical outcome was compared in the groups with no (IHC score 0) or with low HER2 expression (IHC 1+, or IHC 2+/ISH negative)., Results: Low HER2 expression levels in triple-negative aBC patients did not influence progression-free survival. Overall survival appeared poorer in patients with IHC 2+ compared with patients with no HER2 expression in the unadjusted analysis (hazard ratio 2.24, 95% confidence interval 0.1.12-4.47). However, this effect was not maintained in the adjusted analysis. In HER2-negative, hormone receptor-positive patients, low HER2 expression appeared to have no effect on prognosis, neither progression-free survival nor overall survival., Conclusions: We could not demonstrate that HER2 expression at a low level and assessed in clinical routine can differentiate patients into prognostic groups. However, the prevalence of patients with a low expression makes this population interesting for clinical trials with potentially active treatments using HER2 as a target., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.D.H. has received honoraria from Teva, GenomicHealth, Celgene, AstraZeneca, Novartis, Pfizer and Roche; J.E. has received honoraria from AstraZeneca, Daiichi-Sankyo, Eisai, Lilly, Novartis, Pierre Fabre, Roche and Pfizer; M.P.L. has received honoraria from Pfizer, Lilly, Roche, MSD, Hexal, Novartis, AstraZeneca, Eisai, medac and Exact Sciences for advisory boards, lectures and travel support; B.V. has received honoraria from Novartis; F.A.T. has received honoraria from Hexal, Novartis, Tesaro and travel expenses from GSK; F.O. received speaker and consultancy honoraria from Amgen, AstraZeneca, Bayer, BMS, Boehringer, Celgene, Cellex, Chugai, Gilead, Hexal, Ipsen, Janssen-Cilag, Merck, MSD, Novartis, Riemser, Roche, Tesaro and Teva; P.H. received honoraria, unrestricted educational grants and research funding from Amgen, AstraZeneca, Eli Lilly, MSD, Novartis, Pfizer and Roche; H.T. has received honoraria from Novartis, Roche, Celgene, TEVA and Pfizer, and travel support from Roche, Celgene and Pfizer; J.E. has received honoraria from AstraZeneca, Daiichi-Sankyo, Eisai, Lilly, Novartis, Pierre Fabre, Roche and Pfizer; D.L. has received honoraria from Amgen, Eli Lilly, Pfizer, Roche, MSD, Hexal, Novartis, AstraZeneca, TEVA, Celgene, Eisai, and Loreal. M.W. has received speaker honoraria from AstraZeneca, Celgene and Novartis; V.M. has received speaker honoraria from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro and Nektar; E.B. has received honoraria from Novartis, Pfizer, Amgen, Daiichi-Sankyo and onkowissen.de; C.H. has received honoraria from Roche Pharma, Pfizer, AstraZeneca, Novartis and Onkovis; C.M.K. received honoraria from Amgen, Axios, Roche, Teva, Novartis, MSD Sharp & Dohme, Mundipharma, NewCo, Pfizer, Riemser and ZytoService, research grants from Amgen, Axios, Novartis, MSD Sharp & Dohme, NewCo, Pfizer and ZytoService, and travel support from Amgen, Paxman Inc., PharmaMar and Pfizer; R.W. has received honoraria from Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Esai, Exact Science, Nanostring, GSK, Hexal, Lilly, MSD, Mundipharma, Novartis, Odonate, Pfizer, Pierre Fabre, Riemser, Roche, Sandoz, Seattle Genetics, Tesaro Bio, Teva and Viatris; C.T. has received honoraria from Roche, Daiichi-Sankyo and AstraZeneca; M.U. has received honoraria from Abbvie, Amgen, AstraZeneca, BMS, Celgene, Daiichi-Sankyo, Eisai, Lilly Deutschland, Lilly Int., MSD Merck, Mundipharma, Myriad Genetics, Odonate, Pfizer, PUMA Biotechnology, Roche Pharma, Sanofi Aventis Deutschland, TEVA Pharmaceuticals Ind Ltd, Novartis, Pierre Fabre, Clovis Oncology and Seattle Genetics; P.A.F. received honoraria from Novartis, Pfizer, Roche, Amgen, Celgene, Daiichi-Sankyo, AstraZeneca, Merck-Sharp & Dohme, Eisai, Puma and Teva, his institution conducts research with funding from Novartis and Biontech; W.J. has received honoraria and research grants from Sanofi-Aventis, Novartis, Lilly, Pfizer, Roche, Chugai, AstraZeneca, MSD and Daiichi-Sankyo; T.N.F. has received honoraria from Novartis, Roche, Pfizer, TEVA, Diachii Sankyo, AstraZeneca and MSD; S.Y.B. has received honoraria from Roche Pharma, Novartis, Pfizer, MSD, Teva and AstraZeneca. A.S. has received honoraria from Roche, AstraZeneca, Aurikamed GmbH, Celgene, ClinSol Research GmbH, Connectmedica Sp.Z o.o., Deutsche Gesellschaft für Senologie GmbH, if-kongress management gmbh, I-MED Institute GmbH, Lilly Deutschland GmbH, Medicultus GmbH, med publico GmbH, MSD Sharp & Dohme GmbH, onkowissen.de GmbH, Pfizer GmbH, Schattauer Verlag GmbH, Promedicis GmbH, Tesaro Bio Germany GmbH and W. Zuckschwerdt Verlag GmbH; H.-C.K. has received honoraria from Carl Zeiss Meditec, Theraclion, Novartis, Amgen, AstraZeneca, Pfizer, GSK, SurgVision, Onkowissen and Genomic Health/Exact Sciences, travel support from Tesaro and Daiichi-Sankyo and holds stock of Theraclion and Phaon scientific. All remaining others (A.H., L.H., L.A.W., M.W.B., P.W., D.W.) have declared that they do not have any conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Neratinib is approved in the European Union for extended adjuvant treatment of human epidermal growth factor receptor 2-positive/hormone receptor-positive (copositive) early breast cancer ≤1 year of completion of prior trastuzumab-based therapy. Here, we report analyses of the hormone receptor-positive subgroup (N = 1631) from the ExteNET trial performed for the German health technology assessment (HTA)., Results: With 2 years of median follow-up, HTA analyses revealed a significant advantage in disease-free survival (DFS) for neratinib vs. placebo (absolute/relative risk reduction: 4.1/48.2%; hazard ratio [HR] [95% confidence interval {CI}]: 0.45 [0.29; 0.69]; p = 0.0002), consistent with distant DFS (absolute/relative risk reduction: 3.1/46.3%; HR [95% CI]: 0.52 [0.32; 0.84]; p = 0.0082). The 5-year follow-up confirmed this outcome.Quality of life analyses did not show clinically relevant differences over all time points. Only at month 1, the Functional Assessment of Cancer Therapy - General total score revealed a statistically relevant difference to the disadvantage of neratinib classified as clinically relevant. The tolerability profile of neratinib was dominated by gastrointestinal events, mainly diarrhoea (all grades: 94.4%; grade III: 39.4%; no systematic antidiarrhoeal prophylaxis), nausea (all grades/grade III: 43.9/1.6%), vomiting (26.6/3.2%), abdominal pain (23.8/1.9%), fatigue (28.1/1.9%) and rash (14.3/0.4%). No cumulative or irreversible toxicities were observed. As shown in the CONTROL study and instituted via a risk management plan, diarrhoea management can reduce frequency, cumulative duration and severity of diarrhoea., Conclusion: Extended adjuvant neratinib provides a clinically relevant benefit with further incremental reduction of relapse risk in the curative setting. Accordingly, the German HTA authority has granted an added benefit for this new treatment option., Competing Interests: Conflict of interest statement D.L. received consulting fees from Pierre Fabre, AstraZeneca, Novartis, Eli Lilly, Pfizer, Celgene, L'Oreal, Teva, Tesaro and Amgen as well as fees for non-CME services (e.g. speakers' bureaus) from Pierre Fabre, AstraZeneca, Novartis, Eli Lilly, Pfizer, Celgene, L'Oreal, Teva, Tesaro and Amgen. H.T. received consulting fees from Pierre Fabre, Pfizer Pharma GmbH, Mundipharma, ClinSol, Novartis, Lilly, Grünenthal, Vifor, AstraZeneca and Mylan. M.S. received honoraria for the speaker or consultancy role from AMGEN, AstraZeneca, Eisai, Lilly, Myelo Therapeutics, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche and Seattle Genetics. He received research funding from AstraZeneca, BioNTech, Eisai, Genentech, German Breast Group, Myelo Therapeutics, Novartis, Palleos, Pantarhei Bioscience, Pierre Fabre and Roche. He received travel reimbursement from Pfizer and Roche. A.D.H. received consulting fees from Roche, Novartis, Teva, Pfizer, AstraZeneca, Eisai, Hexal, Genomic Health, Lilly, MSD and Pierre Fabre as well as fees for non-CME services (e.g. speakers' bureaus) from Roche, Novartis, Teva, Pfizer, AstraZeneca, Lilly and MSD. N.H. received consulting fees from Pierre Fabre and Roche. S.S. is an employee at AMS Advanced Medical Services GmbH, München, Germany; A.R., L.G. and C.R. are employees at Pierre Fabre Pharma GmbH, Freiburg, Germany, and R.V. is an employee at Pierre Fabre Médicament, Boulogne-Billancourt, France., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome., Patients and Methods: Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed., Results: Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2 ) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC., Conclusion: Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies., Competing Interests: Peter A. FaschingHonoraria: Roche, Novartis, Pfizer, ClinSol GmbH, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, AstraZeneca, Hexal, Lilly, Cepheid, BionTech, Pierre FabreConsulting or Advisory Role: Amgen, Teva, Celgene, Novartis, Pfizer, Roche, Puma Biotechnology, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, AstraZeneca, Hexal, Myelo Therapeutics GmbH, MacrogenicsResearch Funding: Novartis, BioNTech AG, Cepheid Eric C. PolleyResearch Funding: GRAIL Hans TeschHonoraria: Novartis, Roche Pharma AG, Pfizer, Amgen GmbH, AstraZeneca, Vifor Pharma, Lilly, Eisai, MSD Oncology, Grünethal, Bristol Myers Squibb, Mundipharma, ClinSol GmbHTravel, Accommodations, Expenses: Roche Pharma AG, Pfizer, Novartis, Amgen, AstraZeneca, Vifor Pharma, Lilly, Eisai Europe, MSD Oncology Johannes EttlHonoraria: Pfizer, Novartis, Lilly, Roche, Teva, AstraZeneca, Tesaro, Celgene, Pierre FabreConsulting or Advisory Role: Pfizer, Novartis, Lilly, Tesaro, Roche, Pierre Fabre, Daiichi SankyoSpeakers' Bureau: Pfizer, Roche, Lilly, Teva, Celgene, AstraZenecaResearch Funding: LillyTravel, Accommodations, Expenses: Pfizer, Teva, Celgene, Lilly, NovartisOther Relationship: Tesaro Friedrich OverkampHonoraria: Amgen, AstraZeneca, Bayer, Beiersdorf, Bristol Myers Squibb, Boehringer, Chugai, Celgene, Eisai, Gilead, Hexal, Ipsen, Janssen, Merck, Merck Sharp & Dohme, Novartis, Novonordisc, Riemser, Servier, ShireConsulting or Advisory Role: Amgen, Bristol Myers Squibb, Boehringer, Celgene, Clovis, Eusapharma, Hexal, Oncopeptides, Pfizer, Takeda Michael P. LuxHonoraria: Novartis, Pfizer, Lilly, AstraZeneca, Hexal, Eisai, Roche Pharma AG, Genomic Health, MSD OncologyConsulting or Advisory Role: Roche Pharma AG, Lilly, Pfizer, Novartis, AstraZeneca, Grünenthal Group, Genomic Health, Eisai, MSD Oncology, Pierre FabreSpeakers' Bureau: Roche Pharma AG, Novartis, Pfizer, Lilly, AstraZeneca, MSD Oncology, Eisai Germany, Exact SciencesResearch Funding: Discovering Hands, MSD Oncology, German Breast Group, Roche, PRAEGNANT Network, Grünenthal Group, SamantreeTravel, Accommodations, Expenses: Pfizer, Roche Pharma AGOther Relationship: MedacUncompensated Relationships: Pfizer, AstraZeneca Diana LüftnerHonoraria: AstraZeneca, Amgen, GlaxoSmithKline, Lilly, Pfizer, Novartis, L'Oreal, Teva Innovation Canada, SanofiResearch Funding: NovartisTravel, Accommodations, Expenses: Sanofi, Pfizer, Novartis Markus WallwienerHonoraria: Novartis, Pfizer, Roche, AstraZeneca, CelgeneConsulting or Advisory Role: Novartis, Roche, Pfizer, AstraZenecaResearch Funding: Novartis, Pfizer, AstraZeneca Volkmar MüllerHonoraria: AstraZeneca, Amgen, Daiichi Sankyo, Eisai, Pfizer, Novartis, Roche, Teva, Tesaro, MSD Oncology, Pierre Fabre, Nektar, Genomic Health, Lilly, Seattle GeneticsConsulting or Advisory Role: Hexal, Roche, Amgen, Daiichi Sankyo, Nektar, Eisai, Lilly, Seattle GeneticsResearch Funding: Novartis, Seattle Genetics, Roche/GenentechTravel, Accommodations, Expenses: Roche, Pfizer, Daiichi Sankyo Erik BellevilleConsulting or Advisory Role: Novartis, HexalResearch Funding: Novartis, Hexal, Merrimack, AstraZeneca, PfizerTravel, Accommodations, Expenses: Onkowissen Michael UntchHonoraria: AstraZeneca, Art tempi, Bristol Myers Squibb, Celgene, Daiji Sankyo, Roche Pharma AG, Pfizer, Mundipharma, MSD Oncology, Pierre Fabre, Sanofi, Seattle Genetics, AgendiaConsulting or Advisory Role: Amgen, Abbvie, Celgene, Lilly, Mundipharma, Novartis, MSD Oncology, Pfizer, Roche Pharma AG, Agendia, Pierre Fabre, Seattle Genetics Hans-Christian KolbergStock and Other Ownership Interests: Theraclion, Phaon ScientificHonoraria: AstraZeneca, Amgen, Theraclion, Carl Zeiss Meditec, Novartis, Pfizer, Roche, Genomic Health, SurgVision, Theramex, MSD Oncology, OnkowissenConsulting or Advisory Role: SurgVision, AmgenTravel, Accommodations, Expenses: Carl Zeiss Meditec, Novartis, Pfizer, Amgen, Roche, LIV Pharma, Tesaro, Daiichi Sankyo, Genomic Health Arndt HartmannHonoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, Boehringer Ingelheim, Abbvie, Janssen-Cilag, IpsenConsulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Cepheid, Qiagen, Janssen-Cilag, AstraZeneca, Ipsen, NanoString Technologies, Illumina, 3DHISTECH, DiaceuticsResearch Funding: Cepheid, BioNTech AG, Roche, Janssen-Cilag, NanoString Technologies, AstraZenecaExpert Testimony: NanoString Technologies Wolfgang JanniHonoraria: Novartis, Roche, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo Europe GmbH, MSD OncologyConsulting or Advisory Role: Menarini Silicon Biosystems, Novartis, Roche, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, Seattle GeneticsResearch Funding: Janssen Diagnostics, Menarini Silicon Biosystems, Novartis, Roche, Pfizer, Lilly, Amgen Pauline WimbergerHonoraria: AstraZeneca, MSD Oncology, Teva, Eisai, Novartis/Pfizer, Roche Pharma AG, Amgen, PfizerConsulting or Advisory Role: Amgen, AstraZeneca, MSD Oncology, Novartis, Roche Pharma AG, Tesaro, PharmaMarTravel, Accommodations, Expenses: Roche Pharma AG Florin-Andrei TaranHonoraria: Tesaro, NovartisConsulting or Advisory Role: GlaxoSmithKline, Roche, NovartisTravel, Accommodations, Expenses: GlaxoSmithKline Tanja N. FehmConsulting or Advisory Role: Roche, Novartis, Amgen, Pfizer, AstraZeneca, Daiichi Sankyo, MSD OncologyTravel, Accommodations, Expenses: Roche Diethelm WallwienerConsulting or Advisory Role: ConsalResearch Funding: Roche Pharma AG, Pfizer, Novartis Pharmaceuticals UK Ltd, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo/Lilly, Sanofi, GlaxoSmithKline, Merck Sharp & Dohme Sara Y. BruckerConsulting or Advisory Role: Roche, Novartis, Pfizer, Teva, Merck Sharp & Dohme, OlympusResearch Funding: Novartis, Roche, Pfizer, Genomic HealthTravel, Accommodations, Expenses: Novartis, Roche, Pfizer, Olympus, Teva, Merck Sharp & Dohme Andreas SchneeweissHonoraria: Roche Pharma AG, Celgene, AstraZeneca, Pfizer, Novartis, MSD Oncology, Lilly, TesaroResearch Funding: Roche Pharma AG, Celgene, Abbvie, Molecular PartnersExpert Testimony: Roche, AstraZenecaTravel, Accommodations, Expenses: Roche, Celgene Andreas D. HartkopfHonoraria: Roche, Novartis, Lilly, AstraZeneca, Merck Sharp & Dohme, Seagen, Daiichi Sankyo, GlaxoSmithKline, Genomic Health, Agendia, Pfizer, Amgen Fergus J. CouchConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: Ambry Genetics, QiagenResearch Funding: GRAILTravel, Accommodations, Expenses: GRAIL, QiagenOther Relationship: Ambry GeneticsNo other potential conflicts of interest were reported.

Purpose: Treatment with CDK4/6 inhibitors and endocrine therapy (CDK4/6i + ET) is a standard for patients with advanced hormone receptor-positive, HER2-negative (HR + HER2-) breast cancer (BC). However, real-world data on the implementation of therapy usage, efficacy, and toxicity have not yet been reported., Methods: The PRAEGNANT registry was used to identify advanced HR + HER2- BC patients (n = 1136). The use of chemotherapy, ET, everolimus + ET, and CDK4/6i + ET was analyzed for first-line, second-line, and third-line therapy. Progression-free survival (PFS) and overall survival (OS) were also compared between patients treated with CDK4/6i + ET and ET monotherapy. Also toxicity was assessed., Results: CDK4/6i + ET use increased from 38.5% to 62.7% in the first 2 years after CDK4/6i treatment became available (November 2016). Chemotherapy and ET monotherapy use decreased from 2015 to 2018 from 42.2% to 27.2% and from 53% to 9.5%, respectively. In this early analysis no statistically significant differences were found comparing CDK4/6i + ET and ET monotherapy patients with regard to PFS and OS. Leukopenia was was seen in 11.3% of patients under CDK4/6i + ET and 0.5% under ET monotherapy., Conclusions: In clinical practice, CDK4/6i + ET has been rapidly implemented. A group of patients with a more unfavorable prognosis was possibly treated in the real-world setting than in the reported randomized clinical trials. The available data suggest that longer follow-up times and a larger sample size are required in order to identify differences in survival outcomes. Studies should be supported that investigate whether chemotherapy can be avoided or delayed in this patient population by using CDK4/6i + ET., Competing Interests: Declaration of competing interest A.S. received honoraria from Roche, AstraZeneca, Aurikamed GmbH, Celgene, ClinSol Research GmbH, Connectmedica Sp.Z o.o., Deutsche Gesellschaft für Senologie GmbH, if-kongress management gmbh, I-MED Institute GmbH, Lilly Deutschland GmbH, Medicultus GmbH, med publico GmbH, MSD Sharp & Dohme GmbH, onkowissen.de GmbH, Pfizer GmbH, Schattauer Verlag GmbH, Promedicis GmbH, Tesaro Bio Germany GmbH, W. Zuckschwerdt Verlag GmbH. J.E. received honoraria from AstraZeneca, Celgene, Novartis, Lilly, Pfizer, Pierre Fabre, Roche and TEVA and travel support from Celgene, Pfizer, TEVA, and Pierre Fabre. D.L. received honoraria from Amgen, AstraZeneca, Celgene, Lilly, Loreal, MSD, Novartis, Pfizer, Tesaro, Teva. M.W.B reports support from Novartis, Merck Sharp & Dohme, AstraZeneca, Roche, Amgen, Eisai, paid to his institution. E.B. received honoraria from Novartis, Celgene, Riemser, Pfizer, Hexal, Amgen, onkowissen.de for consulting, clinical research management or medical education activities. P.A.F. received honoraria from Novartis, Pfizer, Roche, Amgen, Celgene, Daiichi-Sankyo, AstraZeneca, Merck-Sharp & Dohme, Eisai, Puma and Teva. His institution conducts research with funding from Novartis and Biontech. T.N.F. reports personal fees from Roche, personal fees from Novartis, personal fees from Pfizer, personal fees from Daichii Sankyo, personal fees from Lilly, personal fees from MSD, outside the submitted work. P.H. received honoraria, unrestricted educational grants and research funding from Amgen, AstraZeneca, Eli Lilly, MSD, Novartis, Pfizer, and Roche. A.D.H. received honoraria from Teva, GenomicHealth, Celgene, AstraZeneca, Novartis, Pfizer, and Roche. C.H. received honoraria from Amgen, Celgene, Oncovis, Roche, and Pfizer. J.H. received honoraria from Astra Zeneca, MSD, Lilly, travel grants from Novartis and research grants from Novartis, Celgene. E.R. reports personal fees from Roche, Pfizer, Amgen, Novartis, Tesaro, Astra Zeneca, Celgene, Pierre Fabre and Riemer, non-financial support from Olympus GmbH, personal fees from Riemser, outside the submitted work. W.J. received research grants and honoroaria from Novartis, Pfizer, Amgen, Chugai, Roche, Genomic-Health, AstraZeneca, Lilly. H.-C.K. received honoraria from Carl Zeiss meditec, TEVA, Theraclion, Novartis, Amgen, AstraZeneca, Pfizer, Janssen-Cilag, GSK, LIV Pharma, and Genomic Health. C.M.K. received honoraria from Amgen, Axios, Roche, Teva, Novartis, MSD Sharp & Dohme, Mundipharma, NewCo, Pfizer, Riemser, and ZytoService, research grants from Amgen, Axios, Novartis, MSD Sharp & Dohme, NewCo, Pfizer, and ZytoService, and travel support from Amgen, Paxman Inc., PharmaMar, and Pfizer. M.P.L. has participated on advisory boards for AstraZeneca, MSD, Novartis, Pfizer, Eisai, Genomic Health, Tesaro and Roche and has received honoraria for lectures from MSD, Lilly, Roche, Novartis, Pfizer, Genomic Health, AstraZeneca, medac and Eisai. V.M. received speaker honoraria from Amgen, Astra Zeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, Novartis, Roche, Teva, Janssen-Cilag and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro and Nektar. N.N. received consultancy honoraria from Janssen-Cilag and travel support from Novartis. F.O. received speaker and consultancy honoraria from Amgen, AstraZeneca, Bayer, BMS, Boehringer, Celgene, Cellex, Chugai, Gilead, Hexal, Ipsen, Janssen-Cilag, Merck, MSD, Novartis, Riemser, Roche, Tesaro, Teva. H.T. received honoraria from Novartis, Roche, Celgene, TEVA, and Pfizer and travel support. F.-A. T. received honoraria from Astra Zeneca, Genomic Health and Novartis. C.T. received honoraria from Amgen, Astra-Zeneca, Celgene, Novartis, Pfizer, and Roche. M.U. reports support paid to his institution from Abbvie, Amgen GmbH München, Astra Zeneca, BMS, Celgene GmbH München, Daiji Sankyo, Eisai GmbH München, Janssen Cilag, Johnsen&Johnsen, Lilly Deutschland, Lilly Int., MSD Merck, Mundipharma, Myriad Genetics GmbH Zürich, Odonate, Pfizer GmbH Berlin, PUMA Biotechnology, Riemser, Roche Pharma AG, Grenzach Wyhlen, Sanofi Aventis Deutschland GmbH, Sividon Diagnostics Köln, TEVA Pharmaceuticals Ind. Ltd. und. Berlin(.)P.W. received honoraria from Amgen, AstraZeneca, Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar, Roche, TEVA, Eisai Clovis and Tesaro. She participated in advisory boards of Amgen, AstraZeneca, Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar, Roche, TEVA, Eisai Clovis and Tesaro. Her institution received research grants from Amgen, AstraZeneca, MSD, Novartis, Pfizer, Pharmamar, Clovis and Tesaro. R.W. received honoraria from Agendia, Amgen, Astra Zeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Daiichi-Sankyo, Esai, Genomic Health, Glaxo Smith Kline, Lilly, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva. M.W. received speaker honoraria from AstraZeneca, Celgene, and Novartis. S.Y.B. reports personal fees from Novartis and Pfizer, both outside the submitted work. All remaining authors (J.S., E.K., M.G., L.H., B.V., D.W.) have declared that they do not have any conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

SB3 is a biosimilar of trastuzumab that has been approved for use in the treatment of human epidermal growth factor 2-positive breast cancer and human epidermal growth factor 2-positive gastric cancer. Antibody-dependent cellular cytotoxicity is one of several critical quality attributes of trastuzumab. Data from the development of SB3 support the hypothesis of a relationship between antibody-dependent cellular cytotoxicity activity and clinical outcomes in terms of the response rate and long-term survival. Current analytic methods utilizing advanced technology allow the detection of small changes in other quality attributes that influence antibody-dependent cellular cytotoxicity, such as glycosylation and FcγRIIIa binding. Use of such methods to monitor batch-to-batch consistency enables production of trastuzumab biosimilars with consistent quality. Trastuzumab biosimilars such as SB3 therefore have the potential to increase accessibility to trastuzumab-based therapy without compromising efficacy or safety.

Background: We assessed long-term cardiac safety and efficacy in patients with human epidermal growth factor receptor 2-positive early breast cancer treated with a trastuzumab biosimilar (SB3) or its reference product, trastuzumab (TRZ), in a phase 3 study., Methods: Patients who completed the phase 3 study could be enrolled in this extension study. The outcomes included the incidence of symptomatic congestive heart failure (CHF), asymptomatic significant left ventricular ejection fraction (LVEF) decrease, incidence of other cardiac events, event-free survival (EFS), and overall survival. In post hoc analysis, the Cox proportional hazards regression model was used to assess factors associated with EFS., Results: A total of 367 patients were enrolled in the study (SB3, n = 186; TRZ, n = 181). The median follow-up duration from the main study enrolment was 40.8 and 40.5 months for SB3 and TRZ, respectively. During the two-year follow-up after adjuvant therapy, incidence of asymptomatic significant LVEF decrease was rare (SB3, n = 1; TRZ, n = 2), with all patients recovering with LVEF ≥ 50%, and no cases of symptomatic CHF or other cardiac events were reported. At 3 years, the EFS was 91.9% with SB3 and 85.2% with TRZ. The number of patients with events was 17 (9.1%) with SB3 and 31 (17.1%) with TRZ [hazard ratio: 0.47, 95% confidence interval: 0.26-0.87]. Antibody-dependent cell-mediated cytotoxicity (ADCC) activity and the breast pathologic complete response rate were the factors associated with EFS., Conclusion: Cardiotoxicity was rare in this extension study. EFS was higher with SB3 versus TRZ, with post hoc analysis suggesting that a downward drift in ADCC activity was a contributing factor., Clinical Trial Registration Numbers: NCT02771795 (EudraCT 2015-005663-17)., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Clinical trials investigating therapies for metastatic breast cancer (mBC) generally use progression-free survival (PFS) as primary endpoint, which is not accepted as patient-relevant outcome within the German benefit assessment. Hence a validation of PFS as surrogate endpoint for overall survival (OS) is needed, e.g., in the indication of HR+, HER2-negative mBC., Methods: A systematic search was conducted. RCT were included if at least one study arm investigated fulvestrant, letrozole, tamoxifen, exemestane, or anastrozole. Additionally, hazard ratios reported for OS/PFS including confidence interval or standard error were mandatory. Pearson correlation coefficient was calculated to estimate the relation of surrogate endpoint PFS and patient-relevant outcome OS as well as the surrogate threshold effect (STE) which is used to determine thresholds for the estimate of the surrogate endpoint., Results: 16 studies with 5324 patients in total were included in the analyses. The correlation between hazard ratios of PFS and OS was statistically significant (r = 0.72, 95% CI 0.35-0.90) representing a positive linear relationship. STE analysis was applied. The meta-regression model revealed a STE for HR PFS of 0.60 and sensitivity analyses underlined robustness of the results., Conclusions: Based on the derived STE, it is possible to draw conclusions on a significant effect in OS for a hypothetical trial demonstrating an upper confidence limit of HR PFS  < 0.60 in PFS. However, only final OS results are able to confirm if a clinical relevant difference in survival time can be achieved.

In BOLERO-2, adding everolimus to exemestane resulted in a twofold increase in median progression-free survival (PFS) vs exemestane in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (aBC) after progression on a non-steroidal aromatase inhibitor (NSAI). Here, we report on the open-label, single-arm, phase IIIB 4EVER trial (NCT01626222). This trial evaluated the clinical effectiveness of everolimus plus exemestane in postmenopausal women with HR+, HER2- aBC who had progressed on or after an NSAI, but with no restrictions on the time of progression after NSAI, prior chemotherapy for advanced disease or previous exemestane. The primary endpoint was overall response rate (ORR; i.e. the percentage of patients with a best overall response of complete or partial response per RECIST 1.1) within the first 24 weeks of treatment. Secondary endpoints included PFS, overall survival, safety and health-related quality of life. Between June 2012 and November 2013, 299 patients were enrolled at 82 German centers: 281 patients were evaluable for efficacy and 299 for safety. The ORR was 8.9% (95% confidence interval [CI]: 5.8-12.9%). Median PFS was 5.6 months (95% CI: 5.4-6.0 months). The most frequent grade 3/4 adverse events were stomatitis (8.4%), general physical health deterioration (6.7%), dyspnea (4.7%) and anemia (4.3%). The ORR in 4EVER was lower than in BOLERO-2, likely due to inclusion of patients with more advanced disease and extensive pretreatment. These data confirm the clinical benefits and known safety profile of everolimus plus exemestane in postmenopausal women with HR+, HER2- aBC., (© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose of Review: Over the last decades the time which is needed to translate a preclinical finding or idea in the clinic has reduced continuously. Especially but not only for breast cancer the number of tested drugs and targeted pathways have increased immensely. In addition, the introduction of immune-oncological treatments has further advanced the possibilities for future treatments. This review focuses on recent developments in the prevention and treatment of breast cancer including results from major clinical trials and recent conferences., Recent Findings: Many pathways involved in the progression or treatment of breast cancer have been also identified in the cause and pathogenesis of breast cancer. Therefore, breast cancer risk can be described in much more detail, possibly leading to new prevention strategies. In breast cancer treatment the introduction of PARP inhibitors has begun. Recent trials will lead to a better understanding whether PI3K inhibitors can be developed for application in the clinic and first large randomized trials show the superiority of anti PD-1/PD-L1 treatments., Summary: Treatment strategies which were developed over the last decade are moving rapidly into the clinical use. The understanding of treatment targets and involved side effects will be important for the safe implementation of these treatments into routine practice.

Purpose: Neoadjuvant combination treatment with chemotherapy (CTX), trastuzumab (TZM), and pertuzumab (PTZ) has been shown to result in higher pathological complete response rates (pCR) in comparison with treatment with chemotherapy and trastuzumab (CTX/TZM). This analysis was aimed at real-world validation of these results from prospective randomized trials., Methods: In a retrospective analysis conducted in the PRAEGNANT network, patients were eligible for inclusion if they had either received neoadjuvant therapy with CTX/TZM or chemotherapy, trastuzumab, and pertuzumab (CTX/TZM/PTZ) and subsequently underwent surgery for their primary breast cancer. The effect of the two neoadjuvant regimens on pCR in addition to commonly applicable predictors of pCR was analyzed in 300 patients from three study sites, using logistic regression analyses with treatment arm, age, clinical tumor stage, grading, and hormone receptor status as predictors., Results: pCR with complete disappearance of all tumor cells was seen in 30.2% (n = 58) of patients treated with CTX/TZM and in 52.8% (n = 57) of those treated with CTX/TZM/PTZ. CTX/TZM/PTZ was positively associated with pCR (adjusted odds ratio 2.44; 95% CI 1.49-4.02). Mastectomy rates were not influenced by the therapy., Conclusions: The results of clinical trials were confirmed in this dataset of patients who were treated outside of clinical trials in everyday routine work. pCR rates can be improved by 20% with pertuzumab in routine clinical use.

Purpose: This study describes comprehensive data from a breast cancer registry concerning the use of endocrine treatment (ET) and chemotherapy in the first, second and higher therapy lines in hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC)., Methods: The PRAEGNANT study is a real-time registry for patients with MBC. Therapies were categorized into the following categories: chemotherapy, aromatase inhibitor (AI), tamoxifen, fulvestrant, or everolimus plus ET and reported for first, second and third line or higher therapy use. Also treatment sequences for the first, second and third therapy line were analyzed., Results: This analysis includes 958 patients with HR positive, HER2 negative MBC. 42.7% were treated with a chemotherapy in the first therapy line compared to 45.9% receiving an ET. A total of 25.9% were treated with everolimus plus anti-hormone therapy in any therapy line. 34.1% were treated with fulvestrant as single agent therapy. Analyzing therapy sequences, the administration of three different chemotherapies in a row was the most frequently used pattern., Conclusions: This analysis shows that across all three first therapy lines chemotherapy is a dominant therapy for HR positive, HER2 negative MBC patients. Education about the efficacy of ET might help to increase its use and decrease the possible burden of chemotherapy related toxicities., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Improvements in the survival of patients with breast cancer, together with a better understanding of the pathology of the disease, have led to the emergence of bone health as a key aspect of patient management. Patients with breast cancer are typically at risk of skeletal complications throughout their disease course. The receptor activator of nuclear factor κ B ligand (RANKL) inhibitor denosumab and bisphosphonates (e.g. zoledronic acid) are approved in Europe for the prevention of skeletal-related events (pathologic fracture, radiation or surgery to bone, and spinal cord compression) in adults with bone metastases secondary to solid tumours. These agents are also approved at lower doses for the treatment of patients with postmenopausal osteoporosis, a population largely overlapping with those in the early stages of breast cancer, and those with cancer treatment-induced bone loss, which is caused primarily by aromatase inhibitors. In this review, we consider the evidence supporting the use of therapeutic agents to protect bone health throughout the course of breast cancer. Timing of treatment initiation, dose and treatment duration may prove to be barriers to the optimization of the practical use of these agents in the management of patients with breast cancer. Furthermore, with longer survival times, patients may expect to receive long-term treatment with denosumab or bisphosphonates, therefore consideration must be given to safety. Thus, we aim to summarize the recommendations for the use of these agents in management of patients with breast cancer in Europe. We also discuss the recent evidence for their potential antineoplastic effects., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: Improved progression-free survival is considered as treatment goal for patients with metastatic breast cancer (MBC) since it is assumed to delay or prevent deterioration of quality of life. Aim of our analysis was to examine the influence of disease progression on health-related quality of life (HRQoL)., Materials and Methods: The PRAEGNANT study comprises a real-life registry for patients with MBC. HRQoL was assessed with the EORTC-QLQ-C30 Version 3.0 questionnaire at study entry and every 3 months thereafter. The primary endpoint was minimally important deterioration (MID) in global HRQoL score by ≥ five points between baseline and any follow-up assessment. A logistic regression model was built with MID (yes/no) at a follow-up timepoint as outcome variable and several covariates as predictors., Results: In total, 329 patients were included in this analysis, with disease progression in 63 patients. Concerning the primary study aim, progression status predicted MID of global HRQoL status in addition to the other covariates. The adjusted odds ratio for the effect of progression status on MID was 2.22 (95% CI: 1.04 - 4.73). Comparisons of mean differences of QoL domains/scales yielded no differences., Conclusions: We provide evidence that disease progression in patients with metastatic breast cancer in a real-world registry has a significant negative impact on HRQoL as measured by MID of HRQoL. This study emphasizes the relevance of avoiding progression and prolonging PFS to maintain QoL., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: The present study aims to analyze a cohort of advanced breast cancer patients in Germany to assess their interest in complementary and alternative medicine (CAM) and patient's use of most frequent CAM methods., Patients and Methods: Based on the PREGNANT real-time breast cancer registry which is a multicenter study in Germany, questionnaires of 580 patients with advanced breast cancer were evaluated. The implemented questionnaire for CAM asked for general interest in CAM and for patient's use of different CAM methods at present and in the past. The interest and application of CAM were analyzed for association with patients' characteristics such as tumor, patient, and therapy characteristics., Results: In total, 436 out of 580 (75%) patients claimed to be interested in CAM. Further, interest in CAM is significantly correlated with younger age and absence of metastasis at the time of diagnosis. Multivariate analysis confirmed the patient's age and distant disease status at the time of diagnosis as related to interest in CAM. A total of 56.4% of patients applied any CAM method in the past. Moreover, with increasing lines of therapies, the more frequent use of CAM was observed. Hereby, praying, vitamin supplements, and other food supplements were most frequently applied., Conclusion: Our data demonstrate high overall interest and frequent use of CAM in advanced breast cancer patients supporting a strong demand of breast cancer patients for complementary counseling and treatments additional to the established cancer therapies. It is indispensable to implement counseling and evidence-based complementary treatments into clinical routine of cancer centers and to adapt postgraduate medical education, respectively.

Purpose: The aim of this study is to provide an overview of the potential barriers to uptake of bone-targeted agents for the prevention of skeletal-related events (SREs) in patients with breast cancer and bone metastases., Methods: A top-line literature review was conducted to identify trends in and barriers to initiating bone-targeted therapy in patients with metastatic breast cancer., Results: The majority of patients with bone metastases that are secondary to breast cancer clearly benefit from treatment with a bone-targeted agent such as the RANK ligand inhibitor denosumab or the bisphosphonate zoledronic acid, because both delay the onset of SREs. Evidence suggests, however, that these agents are not being used in these patients as per European guideline recommendations., Conclusions: Adoption of a number of behavioral changes may help to overcome barriers to earlier initiation of treatment with bone-targeted agents in these patients. This includes raising awareness of the guidelines that are available for bone-targeted therapies, providing physician and patient education on the appropriate use of these agents, and highlighting to physicians the importance of early treatment and regular monitoring for adverse events. Earlier initiation of treatment should help to reduce the risk of SREs and thus lessen the burden that these debilitating skeletal complications place on patients and healthcare systems.

As breast cancer is a diverse disease, clinical trials are becoming increasingly diversified and are consequently being conducted in very small subgroups of patients, making study recruitment increasingly difficult. The aim of this study was to assess the use of data from a remote data entry system that serves a large national registry for metastatic breast cancer. The PRAEGNANT network is a real-time registry with an integrated biomaterials bank that was designed as a scientific study and as a means of identifying patients who are eligible for clinical trials, based on clinical and molecular information. Here, we report on the automated use of the clinical data documented to identify patients for a clinical trial (EMBRACA) for patients with metastatic breast cancer. The patients' charts were assessed by two independent physicians involved in the clinical trial and also by a computer program that tested patients for eligibility using a structured query language script. In all, 326 patients from two study sites in the PRAEGNANT network were included in the analysis. Using expert assessment, 120 of the 326 patients (37 %) appeared to be eligible for inclusion in the EMBRACA study; with the computer algorithm assessment, a total of 129 appeared to be eligible. The sensitivity of the computer algorithm was 0.87 and its specificity was 0.88. Using computer-based identification of patients for clinical trials appears feasible. With the instrument's high specificity, its application in a large cohort of patients appears to be feasible, and the workload for reassessing the patients is limited.

The surface receptor CUB domain-containing protein 1 (CDCP1) is highly expressed in several adenocarcinomas and speculated to participate in anchorage-independent cell survival and cell motility. Tyrosine kinase phosphorylation seems to be crucial for intracellular signaling of CDCP1. Lapatinib, a tyrosine kinase inhibitor (TKI), is approved for treatment of HER-2/neu overexpressing metastatic breast cancer and functions by preventing autophosphorylation following HER-2/neu receptor activation. This study aimed to investigate the effect of CDCP1 expression on anchorage-independent growth and cell motility of breast cancer cells. Moreover, studies were performed to examine if lapatinib provided any beneficial effect on HER-2/neu((+)/-)/CDCP1(+) breast cancer cell lines. In our studies, we affirmed that CDCP1 prevents cells from undergoing apoptosis when cultured in the absence of cell-substratum anchorage and that migratory and invasive properties of these cells were decreased when CDCP1 was down-regulated. However, only HER-2/neu(+), but not HER-2/neu((+)/-) cells showed decreased proliferation and invasion and an enhanced level of apoptosis towards loss of anchorage when treated with lapatinib. Therefore, we conclude that CDCP1 might be involved in regulating adhesion and motility of breast cancer cells but that lapatinib has no effect on tyrosine kinases regulating CDCP1. Nonetheless, other TKIs might offer therapeutic approaches for CDCP1-targeted breast cancer therapy and should be studied considering this aspect., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background/aim: The aim of the present study was to investigate the effects of conventional and dose-dense chemotherapy on serum levels of soluble adhesion molecules sICAM-1 and sVCAM-1 in node-positive patients with breast cancer., Patients and Methods: sICAM-1 and sVCAM-1 were measured in the blood serum of 147 patients with breast cancer and with 1 to 3 affected lymph nodes prior to and after conventional or dose-dense chemotherapy within a randomized phase III study (NOGGO trial)., Results: The increase in sICAM-1 (p<0.0001) and sVCAM-1 (p<0.001) levels after chemotherapy was statistically significant within the entire sample and the dose-dense study arm. sVCAM-1 levels were not altered by conventional chemotherapy, but were markedly and significantly increased after the dose-dense regimen. Higher sICAM-1 concentrations were found in postmenopausal patients, and the difference was significant before, but not after treatment. There was no significant correlation with other prognostic criteria., Conclusion: Both sVCAM-1 and sICAM-1 levels changed significantly after adjuvant chemotherapy, the effect being more marked under the dose-dense regimen. The possible prognostic relevance of adhesion molecule concentration and the effect of different modes of chemotherapy remains to be determined.

Introduction: In sequence to our first survey in 2004 on antihormonal therapy with aromatase inhibitors (AIs), we conducted a second survey on the prescription practice in 2005., Material and Methods: We distributed the anonymous questionnaires amongst the participants of the 2005 congresses of the German Society of Senology and German Society of Haematology and Oncology., Results: The surveys were mostly completed by gynaecologists (46%) and medical oncologists (46%). According to the responses given, over 31,000 breast cancer patients were treated in these institutions in 2004, over 18,000 of whom received AIs. 37/30% of doctors prescribed AIs for national/private health insurance patients depending on the known risks of tamoxifen treatment (> 50% of cases). Whilst only 6/10% of doctors prescribed AIs for more than 50% of patients with either national/private health insurance in 2004, this figure reached 49% in 2005, independent of the type of medical insurance. Assuming unrestricted approval, 68/65% of doctors would treat over 50% of their patients with an AI., Conclusion: The rate of treatment with AIs has increased dramatically. The previous gold standard, tamoxifen, was by and large replaced by AIs in 2004/2005. We may assume that almost all receptor- positive breast cancer patients will receive an AI in the course of their adjuvant therapy in the very near future.

Background: The goal of the present study was to investigate the changes in concentration of the important lymph-angiogenesis factors vascular endothelium-derived growth factor (VEGF) and VEGF-D under adjuvant chemotherapy., Materials and Methods: The blood plasma of a total of 142 patients with breast carcinoma and with 1 to 3 affected lymph nodes was investigated, using the quantitative sandwich enzyme immunoassay technique, prior to and following chemotherapy, within the framework of a randomized phase III study: the patients received either conventional or dose-intensified chemotherapy., Results: In general, there was a significant reduction in VEGF levels after chemotherapy only in patients with large tumors (T3) (p = 0.043). There was also an almost significant reduction in patients with an overexpression of c-erbB-2 (Dako Score +3, p = 0.052). In contrast, the clearest reduction in VEGF-D occurred in patients with a positive hormone receptor status (p = 0.04) or in patients with a low expression of c-erbB-2 (Dako Score +1, p = 0.05). A significant effect of chemotherapy on VEGF-D was determined only in patients who had a baseline level that was above the normal (conventionel treatment p = 0.005; dose-intensified treatment p = 0.004)., Conclusion: Both VEGF and VEGF-D levels changed after chemotherapy, depending on the patient and tumor characteristics. With respect to changes in the plasma levels of VEGF and VEGF-D, there were no significant differences between dose-intensified and conventional chemotherapy.

Introduction: The prescription practice of adjuvant therapy with aromatase inhibitors (AI) in Germany is not known, also considering that approval is still limited or awaited. We conducted a survey among breast specialists of the German Society of Senology., Method: A standardized questionnaire and the latest abstracts of the 3 trials were sent out to 1,223 members, responses were anonymized. All questions were to be answered with respect to the patients' national health insurance (NHS) or private health insurance (PHS) status., Results: Questionnaire were predominantly completed by gynecologists (82.4%). In all, >16,000 breast cancer patients had been treated in 2003. A total of 69.4% of physicians initiated adjuvant AI in up to 25% of NHS patients, 5.6% treated >50% of patients. However, 10.3% of physicians treated >50% of their PHS patients with an AI. Under the hypothesis of an unrestricted label for AI, 44.5% of physicians would treat >50% patients. The switch to an AI after 2-3 years of tamoxifen was chosen in 22% for NHS patients and in 36% of PHS patients. Continuing an AI after 5 years of tamoxifen was favored. in 26% of NHS and 35% of PHS patients., Conclusion: Tamoxifen as the previous gold standard is being replaced by AI; a dramatic change in treatment pattern is expected with less restricted approval.

Elevated levels of the extracellular domain of HER-2/neu in serum (sHER-2/neu) have been shown to be of prognostic importance. In this phase II study with weekly paclitaxel in metastatic breast cancer, we investigated the predictive quality of this serum oncoprotein by correlating the outcome of therapy to sHER-2/neu levels. Paclitaxel (90 mg/m2 weekly x6, q9w) was administered to 35 patients with complete outcome assessment and biochemical follow-up. sHER-2/neu was measured using standardized enzyme-linked immunoassays. We found that 62.9% (22/35) of the patients had elevated levels (> or = 15 ng/ml) of sHER-2/neu. The overall response rate (RR) to weekly paclitaxel was 40.0% (14/35). There was no difference in RR between sHER-2/neu-positive patients (40.9%) and sHER-2/neu-negative patients (38.5%; p = 0.4). The progression-free interval was longer for sHER-2/neu-negative patients (53.2 weeks) in comparison to sHER-2/neu-positive patients (31.2 weeks; p = 0.098). Responses were significantly more durable in sHER-2/neu-negative patients (65.2 weeks) than in the sHER-2/neu-positive subgroup (25.7 weeks; p = 0.042). Introducing hypothetical cut-offs into the sHER-2/neu-positive subset, we found that in patients with a sHER-2/neu level of greater than 22 ng/ml, the progression-free survival decreased significantly with increasing sHER-2/neu levels (p < or = 0.022). Considering the high impact of progression-free survival and duration of response as outcome parameters, the sHER-2/neu status is a predictive indicator for benefit from paclitaxel chemotherapy.

The clinical role of HER-2/neu, a 185 kD epithelial transmembranous protein, has evolved after the approval of the anti-HER-2/neu targeted monoclonal antibody trastuzumab (Herceptin) for the therapy of metastatic breast cancer. The extracellular domain of HER-2/neu undergoes proteolytic cleavage from the full-length protein by metalloproteases, and is shed into the blood as a circulating antigen. While HER-2/neu gene amplification and/or protein overexpression are detected in approximately 25% of primary breast cancers, serum HER-2/neu levels are elevated beyond the upper limit of normal in 50 to 60% of stage IV breast cancer patients. HER-2/neu in serum can be detected by enzyme immunoassays (manual and automated versions). It has been shown to have prognostic and predictive information in breast cancer patients. Monitoring for recurrence by serum HER-2/neu reaches a high sensitivity for HER-2/neu positive tumors. Longitudinal follow-up of patients during any kind of systemic therapy allows for monitoring of the therapeutic success. When utilized in these applications, serum HER-2/neu testing is complementary to HER-2/neu tissue results and to the determination of classical tumor markers such as CA 15-3, CA 27.29 and CEA, which are not targeted by specific forms of systemic therapy.

Purpose: The objective of this study was to evaluate the efficacy and tolerability of leuprorelin acetate in adjuvant treatment in comparison to standard chemotherapy with CMF in premenopausal, estrogen-receptor-positive or unknown, node-positive patients with early breast cancer., Patients and Methods: The patients were randomly assigned to receive either 2 years of hormone ablation with leuprorelin acetate 11.25 mg as a subcutaneous injection every three months or six courses of CMF (cyclophosphamide 500 mg/m2, methotrexate 40 mg/m2, fluorouracil 600 mg/m2, days 1 and 8, q 4 weeks). The primary study end-point was recurrence-free survival (RFS) after 2 years. Secondary end-points included overall survival, adverse events and hormonal suppression., Results: Between 1995 and 1999, a total of 589 patients with breast cancer were randomized to treatment with leuprorelin acetate or CMF. The data of 227 patients were available for this first interim analysis. One hundred and ten and 117 patients were assigned to leuprorelin acetate and chemotherapy, respectively. Both treatment arms were well balanced for baseline characteristics. So far, no difference between the groups has emerged with respect to recurrence-free or overall survivaL Suppression of serum estradiol levels and menstruation was less marked in the CMF-group compared to the leuprorelin arm. The most common adverse events were low-grade hot flushes, weight gain and increased sweating in the leuprorelin-treated patients and alopecia, nausea and vomiting in the CMF-group., Conclusion: According to these preliminary results, ovarian suppression with leuprorelin acetate was as effective as standard chemotherapy for premenopausal women with hormone-sensitive, node-positive early breast cancer.

Breast cancer remains a leading cause of cancer death in women despite widespread screening, in part because screening mammography has high rates of false-negative results and because many women decline to have routine mammograms. The development of sensitive and specific assays for breast tumor markers would improve detection and facilitate screening, diagnosis, therapeutic monitoring and surveillance for recurrence. Nuclear matrix proteins (NMPs) are promising candidates for tumor markers because they are involved in malignant transformation. Therefore, they may be useful for screening and early diagnosis of small tumors. Proteomic analysis was used to demonstrate that a 28.3 kD serum protein, designated NMP66, can distinguish malignant disease from benign conditions and normal controls. NMP66 is now being evaluated as a potential biomarker for early breast cancer detection in large-scale clinical trials.