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ZusammenfassungÜber viele Jahrzehnte war die komplette Ausräumung der axillären Lymphknoten im Sinne einer Axilladissektion ein Standardverfahren in der Therapie des Mammakarzinom. Die Zielsetzung lag in der Bestimmung des histologischen Nodalstatus für die Festlegung der adjuvanten Therapie sowie in der Sicherung der lokoregionären Tumorkontrolle. Neben der Diskussion zur Optimierung der Therapiestrategien in der systemischen Behandlung und in der Strahlentherapie fokussieren aktuelle Diskussionen insbesondere auch auf die Verbesserung der chirurgischen Maßnahmen beim Mammakarzinom. Unter Berücksichtigung der zunehmenden Bedeutung der neoadjuvanten Chemotherapie erfährt die operative Behandlung des Mammakarzinoms sowohl im Bereich der Brust als auch im Bereich der Achselhöhle einen Wandel. Basierend auf der derzeitigen Datenlage wird die SLNE vor einer neoadjuvanten Chemotherapie grundsätzlich nicht empfohlen. Demgegenüber wird die operative axilläre Intervention – von der SLNE über die TAD bis zur ALND – nach der neoadjuvanten Chemotherapie als Vorgehen der Wahl zum axillären Staging angesehen. Zur Verringerung der Falsch-negativ-Rate des operativen Stagings der Axilla bei pN+CNB vor NACT und ycN0 nach NACT sind Targeted axillary Dissection (TAD), die Entfernung von > 2 SLNs (SLNE, kein ungezieltes axilläres Sampling), die Immunhistochemie zur Detektion von isolierten Tumorzellen oder Mikrometastasen und die Markierung von positiven Lymphknoten vor NACT als Standard anzusehen. In dem aktuellen Update zur operativen axillären Intervention wird auf die Bedeutung von isolierten Tumorzellen und Mikrometastasen nach neoadjuvanter Chemotherapie und die klinischen Konsequenzen einer mittels SLNE und TAD diagnostizierten Low Volume residual Disease eingegangen und ein Überblick bez. der diesjährigen AGO-Empfehlungen zum operativen Management der Axilla im Rahmen der Primäroperation und im Zusammenhang mit der neoadjuvanten Chemotherapie gegeben.

Background The GAIN-2 trial was designed to identify a superior intense dose-dense (idd) strategy for high-risk patients with early breast cancer. Here, we report an interim analysis, at which the predefined futility boundary was crossed. Patients and methods GAIN-2 was an open-label, randomised, multicentre phase III trial. Two thousand eight hundred and eighty seven patients were randomised 1:1 between three courses each of idd epirubicin (E) 150 mg/m2, nab-paclitaxel (nP) 330 mg/m2 and cyclophosphamide (C) 2000 mg/m2 (iddEnPC) versus four cycles of leucocyte nadir-based tailored and dose-dense EC (dtEC) followed by four cycles of tailored and dose-dense docetaxel (dtD) (dtEC-dtD). Results The duration of median follow-up was 45.8 (range 0.0–88.3) months. Trial objectives included invasive disease-free survival (iDFS) as the primary end-point. A total of 593 patients received the treatment as neoadjuvant chemotherapy. At the time of futility interim analysis, 414 events for iDFS were reported. Overall, there was no difference in iDFS between iddEnPC and dtEC-dtD with 4-year iDFS rates of 84.3% (95% confidence interval (CI) 82.0–86.4%). Among all predefined subgroups, hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-), lobular cancer and ≤50 years subgroups predicted for better iDFS in the dtEC-dtD arm. Overall, 88.1% of patients completed all treatment in both arms. Haematological toxicity grade 3/4 and grade 3/4 non-haematological adverse events were significantly higher with iddEnPC (iddEnPC 50.8% vs dtEC-dtD 45.1%, P = 0.002), especially arthralgia and peripheral sensory neuropathy. Two treatment-related deaths occurred during dtEC-dtD, corresponding to a low mortality rate of 0.07%. Conclusions iDFS is equal in both regimens, but tailoring dose-dense chemotherapy improved outcomes in HR+/HER2-, lobular cancer and patients ≤50 years.

Breast cancer; Cancer Càncer de mama; Càncer Cáncer de mama; Cáncer The METRIC study (NCT#0199733) explored a novel antibody–drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1–14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine. Funding provided by Celldex Therapeutics, Inc.

BRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities.Patients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed. Primary objective was the rate of neutropenia grade (G)III-IV in cycle 1 (C1). Secondary objectives included effects on overall and other haematological toxicities GIII-IV in C1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were explored.Two hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence intervals [CI]: 0.87-1.82, P = 0.226) nor for other haematological toxicities GIII-IV (OR: 0.91, 95% CI: 0.64-1.31, P = 0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p 0.001). No difference was seen under cyclophosphamide or platinum-containing chemotherapies.gBRCA1/2m was not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further research.

Purpose To prospectively compare HRQoL effects of two modern adjuvant chemotherapy breast cancer treatment regimens at six time-points up to 16 months after random assignment. Methods The open-label, randomized, Phase 3 “Panther trial” was conducted between February 2007 and September 2011. 760 women, aged 65 years and younger, after surgery for non-metastatic node-positive or high-risk node-negative breast cancer were randomized 1:1 to the experimental group (four cycles of tailored and dose-dense adjuvant epirubicin and cyclophosphamide/2 weeks followed by four cycles of tailored dose-dense docetaxel/2 weeks) or standard group (three cycles of fluorouracil and epirubicin-cyclophosphamide/3 weeks followed by three cycles of docetaxel/3 weeks). HRQoL was assessed at all Swedish centres using EORTC QLQ-C30 and EORTC QLQ-BR23 at six points during 16 months before randomization. Results Response rates to questionnaires were highest at baseline 728/780 (93%) and lowest 16 months after randomization, 557/750 (74%). HRQoL declined during treatment in both groups. At the end of treatment, the experimental group reported statistically significantly lower HRQoL (P Conclusions Negative HRQoL impact of the dose-dense and tailored strategy appears to be prominent during treatment, but HRQoL recover once treatment ends. Trial Registration clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.

Background: BRCA1/2 genes play a central role in DNA repair. Therefore, pts harboring gBRCA1/2m treated with chemotherapy might be at higher risk of acute hematological toxicities due to the lower level of functional BRCA1/2 protein potentially resulting in more toxicity. Published results are discordant, further data are needed. Methods: Pts with early TNBC and known gBRCA1/2m treated with anthracycline-taxane based NACT in the GeparQuinto (n=487), GeparSixto (n=291) and GeparOcto (n=393) studies were included. Primary G-CSF prophylaxis was foreseen only for the iddETC arm in GeparOcto. Primary objective was the rate of neutropenia grade (G)3-4 after cycle 1; secondary objectives were the rate of other hematological toxicities G3-4 and the overall toxicity rate after cycle 1 as well as hematological toxicities in gBRCA1/2 pts during the taxane part of chemotherapy. Results: 209/1171 evaluated pts (17.8%) had a gBRCA1/2m (177 gBRCA1m, 33 gBRCA2m). Median age was 48yrs [21-78]. The rate of neutropenia G3-4 after cycle 1 in gBRCA1/2 wildtype (wt) pts was 35.7% vs 37.4% in gBRCA1/2m (p=0.683), 35.9% in gBRCA1m (p=1.000), 44.8% in gBRCA2m (p=0.330). gBRCA1/2 mutational status did not predict neutropenia G3-4 at univariate (OR=1.08, 95%CI 0.78-1.48 p=0.658) or multivariate analysis adjusted for age, BMI and treatment (OR=1.26, 95%CI 0.87-1.82 p=0.226). The overall rate and the rates of other hematological toxicities are shown in the table. gBRCA1/2 mutational status did also not predict for any other hematological toxicities G3-4 (univariate OR=0.94, 95%CI 0.64-1.40 p=0.773; multivariate OR=0.94, 95%CI 0.62-1.43 p=0.779). gBRCA1/2 mutational status predicted for hematological toxicities G3-4 under taxane treatment (univariate OR=1.94, 95%CI 1.35-2.77 p During taxane treatment, the overall rate of hematological toxicities G3-4 in wt pts was 43.1% (n=270) vs 59.5% (n=91) in gBRCA1/2m, p Conclusions: Overall, gBRCA1/2 mutation is not associated with a significantly higher risk of severe hematological toxicities. Under taxane therapy, pts with gBRCA1/2 demonstrate a higher rate of hematological toxicities G3-4, especially neutropenia, compared to wildtype pts, and should therefore be carefully monitored. Hematological toxicities after cycle 1wildtypegBRCA1/2mp-valuegBRCA1mp-valuegBRCA2mp-valueN%N%N%N%neutropenia G3-432635.77437.40.6836135.91.0001344.80.330febrile neutropenia171.831.41.00010.60.33726.10.130leucopenia G3-424425.83818.20.0212815.80.0041030.30.548anemia G3-420.200.01.00000.01.00000.01.000thrombopenia G3-4111.210.50.70510.60.70400.01.000any hematological toxicities G1-477782.617081.70.76314180.10.4533090.90.344any hematological toxicities G3-442846.38843.60.5337241.90.3171651.60.587 Citation Format: Jenny Furlanetto, Volker Möbus, Andreas Schneeweiss, Kerstin Rhiem, Hans Tesch, Jens-Uwe Blohmer, Kristina Lübbe, Michael Untch, Christoph Salat, Jens Huober, Peter Klare, Rita Schmutzler, Fergus J Couch, Bianca Lederer, Bernd Gerber, Dirk-Michael Zahm, Ingo Bauerfeind, Valentina Nekljudova, Claus Hanusch, Christian Jackisch, Theresa Link, Sibylle Loibl, Peter A Fasching. Germline (g)BRCA1/2 mutations (m) and hematological toxicities in patients (pts) with triple negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NACT) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-03.

Background: Despite the large number of patients with early breast cancer (EBC) that have been treated with capecitabine in randomized trials no individual patient data meta-analysis has yet been conducted. So far only two literature-based meta-analyses have been published including only five neoadjuvant studies and two adjuvant trials, respectively. Whereas the first did not report an improvement in response to neoadjuvant therapy, the latter found an improvement in disease-free survival (DFS) in the capecitabine arm. Methods: In order to select trials the following criteria were used at www.clinicaltrials.gov: Use of capecitabine in EBC as adjuvant or neoadjuvant therapy; randomized; N>100 patients; recruitment completed and outcomes available. This yielded the following trials: GeparTrio, GeparQuattro, GAIN, ICE, ICE II, FinXX, Alliance/CALGB 49907, Roche / US Oncology 01062, NSABP-B40, ABCSG-24, CREATE-X, GEICAM 2003/10, GEICAM 2003/11_CIBOMA 2004/01. Data were available for all these trials and 15,457 patients were included in this individual patient data based meta-analysis. The primary objective was to examine the effect of capecitabine on disease-free survival (DFS). Secondary objectives were to examine effects on distant DFS (DDFS), overall survival (OS), pathological complete response (for neoadjuvant studies) and whether there was an interaction of occurrence of capecitabine-specific toxicity (mucositis, diarrhea, hand-foot syndrome) and treatment effect. Bi- and multivariable frailty-based Cox proportional hazards models including log-normal distributed random effects of study were used to report hazard ratios with 95% CI between the groups of patients treated with or without capecitabine for DFS, DDFS and OS. Results: Individual data from 15,457 patients was collected. Of these 7,980 received capecitabine during the course of their treatment and 7,477 patients were treated in the control arms. Median age at diagnosis was 54 years in both groups. Most patients were diagnosed with stage 2 tumors (55.9%) and the majority presented with nodal involvement (74.0%). Estrogen and progesterone receptor positivity was observed in 66.0% and 56.9%, respectively, and 15.1% of patients were diagnosed as HER2-positive. 2,816 patients (18.2%) received neoadjuvant treatment and 12,641 (81.8%) an adjuvant chemotherapy regimen. Cox regression analyses of all included patients revealed that the addition of capecitabine did not alter DFS significantly compared to treatment without capecitabine (HR 0.952; 95% CI 0.895-1.012; p-value 0.115). There was also no effect on DFS if studies were selected in which capecitabine was given instead of another drug (HR 1.035; 95% CI 0.945-1.134; p=0.455). However, capecitabine in addition to systemic treatment lead to a small but significant improvement of DFS (HR 0.888; 95% CI 0.817-0.965; p=0.005). Results concerning other endpoints will be presented at the meeting. Conclusion: Capecitabine did not alter DFS in this meta-analysis of 15,457 patients with early breast cancer from 12 prospective randomized trials, but as addition to systemic treatment DFS was improved. Subgroup analyses are needed for final interpretation and will be presented at the meeting. Citation Format: Marion van Mackelenbergh, Fenja Seither, Volker Möbus, Joyce O'Shaugnessy, Miguel Martin, Heikki Joenssuu, Michael Untch, Ulrike Nitz, Juan J Miralles, Masakazu Toi, Harry D Bear, Hymann Muss, Toralf Reimer, Valentina Nekljudova, Sibylle Loibl. Effects of capecitabine as part of neo-/adjuvant chemotherapy. A meta-analysis of individual patient data from 12 randomized trials including 15,457 patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-07.

Estrogen receptor-positive breast cancer is a highly prevalent but heterogeneous disease among women. Advanced molecular stratification is required to enable individually most efficient treatments based on relevant prognostic and predictive biomarkers. First objective of our study was the hypothesis-driven discovery of biomarkers involved in tumor progression upon xenotransplantation of Luminal breast cancer into humanized mice. The second objective was the marker validation and correlation with the clinical outcome of Luminal breast cancer disease within the GeparTrio trial. An elevated mdm2 gene copy number was associated with enhanced tumor growth and lung metastasis in humanized tumor mice. The viability, proliferation and migration capacity of inherently mdm2 positive breast cancer cells in vitro were significantly reduced upon mdm2 knockdown or anti-mdm2 targeting. An mdm2 gain significantly correlated with a worse DFS and OS of Luminal breast cancer patients, albeit it was also associated with an enhanced preoperative pathological response rate. We provide evidence for an enhanced Luminal breast cancer stratification based on mdm2. Moreover, mdm2 can potentially be utilized as a therapeutic target in the Luminal subtype.

Despite the large number of patients with early breast cancer (EBC) who have been treated with capecitabine in randomised trials, no individual patient data meta-analysis has been conducted. The primary objective was to examine the effect of capecitabine on disease-free survival (DFS), and the secondary objectives were to analyse distant DFS (DDFS), overall survival (OS), pathological complete response (for neoadjuvant studies) and the interaction between capecitabine-related toxicity and treatment effect.www.gov and www.pubmed.ncbi.nlm.nih.gov were searched using the following criteria: use of capecitabine for EBC as adjuvant or neoadjuvant therapy; multicentre randomised trial with100 patients; recruitment completed, and outcomes available. Required data were available for 13 trials.Individual data from 15,993 patients were collected. Cox regression analyses of all included patients revealed that the addition of capecitabine did not alter DFS significantly compared with treatment without capecitabine (hazard ratio [HR] 0.952; 95% CI 0.895-1.012; P value = 0.115). There was also no effect on DFS in the subset of studies where capecitabine was given instead of another drug (HR 1.035; 95% CI 0.945-1.134; P = 0.455). However, capecitabine administered in addition to the standard systemic treatment improved DFS (HR 0.888; 95% CI 0.817-0.965; P = 0.005). An OS improvement was observed in the entire cohort (HR 0.892; 95% CI 0.824-0.965, P = 0.005) and in the subset of capecitabine addition (HR 0.837; 95% CI 0.751, 0.933, P = 0.001). Subgroup analyses revealed that triple-negative breast cancer (TNBC) patients benefitted from treatment with capecitabine overall and in addition to other systemic treatments in terms of DFS and OS.Capecitabine was able to improve DFS and OS in patients with TNBC and in all patients with EBC when administered in addition to systemic treatment.

Background GeparOcto demonstrated that pathological complete response (pCR) of intense dose-dense epirubicin, paclitaxel and cyclophosphamide (iddEPC) was comparable to weekly paclitaxel/non-pegylated liposomal doxorubicin (plus carboplatin (PM(Cb) in triple-negative breast cancer [TNBC]) in high-risk early breast cancer (BC). Here, we report time-to-event secondary end-points. Patients and methods Patients were randomised to receive 18 weeks of E (150 mg/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w or weekly P (80 mg/m2) plus M (20 mg/m2) plus, in TNBC, Cb (AUC 1.5). Patients with human epidermal growth factor receptor 2-positive (HER2+)BC received trastuzumab (6[loading dose 8]mg/kg q3w) and pertuzumab (420[840]mg q3w) with P and C cycles. Results 945 patients started treatment (iddEPC n = 470; PM(Cb) n = 475). After a median follow-up of 47.0 (range 1.6-61.5) months, 162 (75 in iddEPC; 87 in PM(Cb)) invasive disease-free survival (iDFS) events and 79 (41 in iddEPC; 38 in PM(Cb)) deaths were reported. No significant difference was observed in 4-year iDFS (81.9% iddEPC versus 79.7% PM(Cb), HR = 1.16 [95%CI 0.85-1.59], log-rank p = 0.334) or 4-year overall survival (OS) (90.3% iddEPC versus 90.6% PM(Cb), HR = 0.90 [95%CI 0.58-1.40], log-rank p = 0.637) overall and in HER2+ and TNBC subgroups. HR+/HER2- BC patients, however, had significantly better 4-year iDFS (77.9% iddEPC versus 62.5% PM, HR = 2.11 [95%CI 1.08-4.10], log-rank p = 0.025) and 4-year OS with iddEPC (94.7% iddEPC versus 80.1% PM, HR = 3.26 [95%CI 1.06-10.00], log-rank p = 0.029). Conclusion While there was no difference in survival for the entire cohort, the HR+/HER2-subgroup significantly benefits from iddEPC. This supports the concept of an additional effect of NACT beyond pCR in patients with HR+/HER2- BC. CLINICALTRIALS. Gov identifier NCT02125344.

Background: Women with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NACT) or hormone-receptor (HR)-positive/HER2-negative breast cancer (BC) with a CPS (clinical and post treatment pathological stage) +EG (estrogen receptor status and grade) score ≥3 or score 2 and nodal involvement after NACT (ypN+) are at high risk of recurrence. SG is approved by the Food and Drug Administration for the treatment of patients with metastatic TNBC who received at least two prior therapies for metastatic disease and has shown activity in heavily pretreated patients with metastatic HR-positive/HER2-negative BC. SG may represent a new option against residual disease after NACT. Trial Design: SASCIA is a phase III, prospective, international, multicenter, randomized, open label, parallel group study (NCT04595565) of the GBG in collaboration with the AGO-B. Eligible patients must have received taxane-based NACT for 16 weeks, including 6 weeks of a taxane. Patients should have centrally confirmed HER2-negative BC (IHC score 0-1 or FISH negative) and either HR-negative ( ypT1mi or HR-positive (≥1%), with a CPS+EG score ≥3 or CPS+EG score 2 and ypN+ using local ER and grade assessed on core biopsies taken before NACT. Radiotherapy should be delivered before study treatment start. Patients are randomized 1:1 to receive either SG 10 mg/kg body weight (days 1, 8 q3w for eight cycles) or treatment of physician´s choice (capecitabine 2000 mg/m² day 1-14 q21 or platinum-based chemotherapy i.e. carboplatin AUC 5 q3w or AUC 1.5 weekly for eight 3 weekly cycles or observation). Randomization is stratified by HR status (positive, negative) and nodal involvement after NACT (ypN+, ypN0). Endocrine-based therapy will be administered according to local guidelines in patients with HR-positive BC. The primary endpoint is invasive disease-free survival (iDFS). Secondary endpoints include comparison of overall survival (OS, key secondary endpoint), distant disease-free survival, locoregional recurrences-free interval, safety, compliance, iDFS and OS according to stratified and - predefined subgroups, patient reported outcome, and quality of life between treatment arms. As of 21st June 2021, 57/1200 patients have been randomized in Germany. Citation Format: Frederik Marmé, Marcus Schmidt, Jenny Furlanetto, Carsten Denkert, Anthony Goncalves, Elmar Stickeler, Mattea Reinisch, Silvia Antolín, Toralf Reimer, Wolfgang Janni, Philippe Aftimos, Michael Untch, Laura Michel, Marija Balic, Bruno Sinn, Volker Möbus, Patrick Morris, Laura Schöllhorn, Sabine Schmatloch, Julia Rey, Sibylle Loibl. Phase III postneoadjuvant study evaluating sacituzumab govitecan (SG), an antibody drug conjugate in primary HER2-negative breast cancer patients with high relapse risk after standard neoadjuvant treatment - SASCIA [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-02-01.

Information on deaths occurring during oncological clinical trials has never been systematically assessed. Here, we examine the incidence of death and the profile of patients who died during randomized clinical breast cancer (BC) trials. Information on fatal events during German Breast Group (GBG) led BC trials was prospectively captured. Data were derived from the trial databases and death narratives. All deaths were evaluated for possible causes, underlying conditions, treatment relatedness, time point and rate of autopsies. From 12/1996 to 01/2017, 23,387 patients were treated within 32 trials. Of those 88 (0.4%) died on therapy within 17 trials. Median age was 64 [range 35–84] years, 63.2% of patients had a body mass index (BMI) ≥ 25 kg/m2; 65.9% 1–3 and 22.7% ≥ 4 comorbidities; 61.4% 1–2 cardiovascular risk factors (CRFs); 26.4% took > 3 drugs; 81.7% had ECOG 0; 50.0% stage III, 76.7% luminal BC. The main causes of death were infection (38.6%; of those, 82.3% sepsis, 17.6% pneumonia), heart failure (14.8%), and pulmonary embolism (13.6%). Fatal events mainly occurred within the first 4 therapy cycles (55.7%), in the investigational arm (66.7%) and under anthracycline–taxane-based chemotherapy (51.1%). A relationship with the treatment was declared in 27.3% of the cases. An autopsy was performed in 13.6% of patients. Death during study treatment was mainly related to infections, and patients with advanced disease, high BMI, underlying comorbidities, CRFs and concomitant medications. If considered for study participation these patients need careful monitoring due to their higher risk for death on study.

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.

Introduction Breast cancer diagnosed in young women who are 40 years (yrs) or younger is a relatively rare disease. However, it represents the most common cause of cancer-related deaths in this age-group. Furthermore, young age at diagnosis is associated with an increased risk of recurrence and worse survival. To date, general concepts concerning oncological cancer management should be driven by clinicopathological tumor characteristics and should adhere to standardized protocols for patients in general, but little is known about the oncological cancer treatment and outcome of this very young women in today's clinical practice. Patients and Methods The breast cancer in pregnancy registry study (BCP/GBG29/BIG 03-02) is a multicenter, international, observational study. BCP was established to investigate the oncological management and outcome of breast cancer in pregnancy. Since 2014 non-pregnant patients who are 40 yrs or younger are eligible if diagnosed with histological confirmed invasive breast cancer, independent of the type of treatment as control cohort. All patients received oncological treatment according to local standards. In this study the following endpoints will be analyzed descriptively for the young non-pregnant women cohort: breast cancer staging at diagnosis, biological characteristics of breast cancer at diagnosis, diagnostic procedures, treatment modalities, toxicity, pathological complete response after neoadjuvant chemotherapy, disease-free survival and overall survival. Results From February 2014 until June 2018, 969 non-pregnant patients ≤40 yrs have been registered. The median age at diagnosis was 35 yrs (range 19-40). Overall, 90.1% of patients had a stage T1-2 at diagnosis and 67.1% of patients had negative lymph nodes. 86.7% of tumors were invasive ductal carcinomas and 4.1% lobular carcinomas. Grading (G) 3 was reported in 55.5%. 26.6% of tumors were luminal A-like (ER- and/or PgR-positive, HER2-negative, G1-2), 40.0% luminal B-like (ER- and/or PgR-positive, HER2-negative, G3 or ER- and/or PgR-positive, HER2-positive, any G), 7.7% HER2 positive non-luminal-like, and 25.7% triple negative breast cancers. 3.8% of young non-pregnant patients had metastatic disease at primary diagnosis. Conclusion This registry comprises a large cohort of young non-pregnant patients with breast cancer diagnosed at the age of 40 yrs or younger and provides important data about a modern breast cancer treatment as well as oncological outcome in this setting of young women. Further results including oncological management, toxicity, and survival will be presented at the meeting. Citation Format: Seiler S, Schmatloch S, Reinisch M, Neunhöffer T, Schmidt M, Bechtner C, Marmé F, Wagner M, Möbus V, Reimer T, Kleine-Tebbe A, Sinn B, Stickeler E, Untch M, Janni W, Seither F, Loibl S. Cancer management and outcome of very young non-pregnant patients with breast cancer diagnosed at 40 years or younger– GBG 29 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-07.

Background GeparOcto compared efficacy and safety of two chemotherapy regimens in high-risk early breast cancer (BC): sequential treatment with intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly treatment with paclitaxel plus non-pegylated liposomal doxorubicin (M, Myocet®) with additional carboplatin (PM(Cb)) in triple-negative BC (TNBC). Patients and methods Patients with cT1c-cT4a-d and centrally assessed human epidermal growth factor receptor (HER)2-positive BC or TNBC were eligible, irrespective of nodal status, luminal B-like tumours only if pN+. Patients were randomised (stratified by BC subtype, Ki67, lymphocyte-predominant BC) to receive 18 weeks of E (150 mg/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w for 3 cycles or weekly P (80 mg/m2) plus M (20 mg/m2) plus, in TNBC, Cb (area under curve (AUC) 1.5). HER2-positive BC patients additionally received trastuzumab (6 [loading dose 8]mg/kg q3w) and pertuzumab (420 [840]mg q3w) with all P and C cycles. Primary end-point was pathological complete response (pCR, ypT0/is ypN0), secondary end-points included other pCR definitions, pCR in stratified subpopulations, tolerability and compliance. This trial is registered with ClinicalTrials.gov number NCT02125344 . Results 945/961 randomised patients started treatment. The median age was 48 years; 7.6% had cT3-4, 46% cN+, 66% G3, 40% HER2-positive, 43% TNBC. pCR rate with iddEPC was 48.3%, with PM(Cb) 48.0%, respectively (PM(Cb) versus iddEPC odds ratio 0.99; 95% confidence interval 0.77–1.28, P = 0.979) with no significant differences observed in TNBC, HER2-positive, luminal B-like subtypes. 16.4% with iddEPC and 34.1% with PM(Cb) discontinued treatment (P Conclusions In high-risk early BC there is no difference in pCR rates following neoadjuvant treatment with iddEPC or weekly PM(Cb), respectively. iddEPC is one of the effective dose-dense regimens feasible in daily practice.

Oncologic therapy is currently undergoing significant changes. A number of innovative targeted medications currently in clinical development have raised high expectations. With that in mind, discussions about terms such as "clinical benefit" and "clinical relevance" are highly topical. This also applies to further developments in the field of adjuvant systemic therapies for early-stage breast cancer. As the treatment aim is curative, assessment of the clinical benefit of adjuvant therapies must be largely based on efficacy outcomes. The focus must be on improving disease-free survival rates and lowering the risk of recurrence. Because of the current low mortality rates, statements about overall survival rates are only possible after very long observation periods. Consequently, new drugs in adjuvant therapies should be considered as offering a clinical benefit, if they reduce the risk of recurrence below current low levels of risk. The evidence for established adjuvant therapy standards in early-stage breast cancer can be used as objective criteria for comparison. This review article considers the requirements for clinical benefit of new adjuvant therapies for early breast cancer, based on examples from adjuvant endocrine therapy, adjuvant polychemotherapy and adjuvant anti-HER2 therapy. Die onkologische Therapie befindet sich im Umbruch. Hohe Erwartungen sind mit einer Reihe innovativer zielgerichteter Medikamente verknüpft, die sich derzeit in der klinischen Entwicklung befinden. Vor diesem Hintergrund erfahren Diskussionen um die Begriffe klinischer Nutzen oder klinische Relevanz neue Aktualität. Dies gilt auch für die Weiterentwicklungen der adjuvanten systemischen Therapie des frühen Mammakarzinoms. In Anbetracht der kurativen Zielsetzung erfolgt die Beurteilung des klinischen Nutzens einer adjuvanten Therapie maßgeblich anhand von Wirksamkeitsendpunkten. Der Fokus liegt hierbei auf Verbesserungen des krankheitsfreien Überlebens und des Rezidivrisikos. Eine Aussage zum Gesamtüberleben ist aufgrund der heute erreichten niedrigen Mortalitätsraten erst nach sehr langen Beobachtungszeiten möglich. Folgerichtig sollte neuen Medikamenten für die adjuvante Therapie ein klinischer Nutzen zugesprochen werden, wenn sie eine weitere Reduktion des Rezidivrisikos über den heutigen hohen Standard hinaus ermöglichen. Die Evidenz für etablierte adjuvante Therapiestandards beim frühen Mammakarzinom kann als objektiver Maßstab zum Vergleich herangezogen werden. Am Beispiel der adjuvanten endokrinen Therapie, der adjuvanten Polychemotherapie und der adjuvanten Anti-HER2-Therapie werden in diesem Übersichtsartikel die Anforderungen für den klinischen Nutzen neuer adjuvanter Therapien beim frühen Mammakarzinom abgeleitet.

Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer (BC) patients with BM in the Brain Metastases in the German Breast Cancer (BMBC) registry. The median age at diagnosis of BM was 57 years. All in all, 22.3% of patients (n = 197) had triple-negative, 33.4% (n = 295) luminal A like, 25.1% (n = 221) luminal B/HER2-enriched like and 19.2% (n = 169) HER2 positive like BC. Age ≥60 years, evidence of extracranial metastases (ECM), higher number of BM, triple-negative subtype and low Karnofsky-Performance-Status (KPS) were all associated with worse overall survival (OS) in univariate analysis (p < 0.001 each). All three GPA-scores were associated with OS. The breast-GPA showed the highest probability of classifying patients with survival above 12 months in the best prognostic group (specificity 68.7% compared with 48.1% for the updated breast-GPA and 21.8% for the original GPA). Sensitivities for predicting 3 months survival were very low for all scores. In this analysis, all GPA-scores showed only moderate diagnostic accuracy in predicting the OS of BC patients with BM., publishedVersion

IMPORTANCE: The extent of changes in estradiol levels in male patients with hormone receptor–positive breast cancer receiving standard endocrine therapies is unknown. The sexual function and quality of life related to those changes have not been adequately evaluated. OBJECTIVE: To assess the changes in estradiol levels in male patients with breast cancer after 3 months of therapy. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 2 randomized clinical trial assessed 56 male patients with hormone receptor–positive breast cancer. Patients were recruited from 24 breast units across Germany between October 2012 and May 2017. The last patient completed 6 months of treatment in December 2017. The analysis data set was locked on August 24, 2018, and analysis was completed on December 19, 2018. INTERVENTIONS: Patients were randomized to 1 of 3 arms: tamoxifen alone or tamoxifen plus gonadotropin-releasing hormone analogue (GnRHa) or aromatase inhibitor (AI) plus GnRHa for 6 months. MAIN OUTCOMES AND MEASURES: The primary end point was the change in estradiol levels from baseline to 3 months. Secondary end points were changes of estradiol levels after 6 months, changes of additional hormonal parameters, adverse effects, sexual function, and quality of life after 3 and 6 months. RESULTS: In this phase 2 randomized clinical trial, a total of 52 of 56 male patients with a median (range) age of 61.5 (37-83) years started treatment. A total of 3 patients discontinued study treatment prematurely, 1 in each arm. A total of 50 patients were evaluable for the primary end point. After 3 months the patients’ median estradiol levels increased by 67% (a change of +17.0 ng/L) with tamoxifen, decreased by 85% (−23.0 ng/L) with tamoxifen plus GnRHa, and decreased by 72% (−18.5 ng/L) with AI plus GnRHa (P

Geburtshilfe und Frauenheilkunde 81(10), 1112-1120 (2021). doi:10.1055/a-1499-8431, Published by Thieme, Stuttgart

BMC cancer 21(1), 920 (2021). doi:10.1186/s12885-021-08656-0, Published by Springer, Berlin ; Heidelberg

Background:\ud State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin–paclitaxel or carboplatin–gemcitabine) or the most active non-bevacizumab regimen: carboplatin–pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin–pegylated liposomal doxorubicin combined with bevacizumab.\ud Methods:\ud This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m 2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m 2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251.\ud Findings:\ud Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin–pegylated liposomal doxorubicin–bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin–gemcitabine–bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3–21·7) in the experimental group and 11·3 months (8·0–18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7–14·2) in the experimental group versus 11·6 months (11·0–12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68–0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (

IMPORTANCE: The GeparOcto randomized clinical trial compared the efficacy of 2 neoadjuvant breast cancer (BC) treatment regimens: sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) vs weekly paclitaxel and nonpegylated liposomal doxorubicin (PM) in patients with different biological BC subtypes. Patients with triple-negative BC (TNBC) randomized to the PM arm received additional carboplatin (PMCb). Overall, no difference in pathologic complete response (pCR) rates was observed between study arms. It remained elusive whether the germline variant status of BRCA1/2 and further BC predisposition genes are associated with treatment outcome. OBJECTIVE: To determine treatment outcome for BC according to germline variant status. DESIGN, SETTING, AND PARTICIPANTS: This retrospective biomarker study is a secondary analysis of the GeparOcto multicenter prospective randomized clinical trial conducted between December 2014 and June 2016. Genetic analyses assessing for variants in BRCA1/2 and 16 other BC predisposition genes in 914 of 945 women were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany, from August 2017 through December 2018. MAIN OUTCOMES AND MEASURES: Proportion of patients who achieved pCR (ypT0/is ypN0 definition) after neoadjuvant treatment according to germline variant status. RESULTS: In the study sample of 914 women with different BC subtypes with a mean (range) age at BC diagnosis of 48 (21-76) years, overall higher pCR rates were observed in patients with BRCA1/2 variants than in patients without (60.4% vs 46.7%; odds ratio [OR], 1.74; 95% CI, 1.13-2.68; P = .01); variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response. Patients with TNBC with BRCA1/2 variants achieved highest pCR rates. In the TNBC subgroup, a positive BRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0% without BRCA1/2 variant; OR, 3.26; 95% CI, 1.44-7.39; P = .005) and the iddEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P = .04). A positive BRCA1/2 variant status was also associated with elevated pCR rates in patients with ERBB2-negative, hormone receptor–positive BC (31.8% vs 11.9%; OR, 3.44; 95% CI, 1.22-9.72; P = .02). CONCLUSIONS AND RELEVANCE: Effective chemotherapy for BRCA1/2-mutated TNBC is commonly suggested to be platinum based. With a pCR rate of 64.7%, iddEPC may also be effective in these patients, though further prospective studies are needed. The elevated pCR rate in BRCA1/2-mutated ERBB2-negative, hormone receptor–positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02125344

Simple Summary The extent of axillary surgery has been reduced in recent years to minimize side effects. However, a negative impact of reduced surgery on outcome must be avoided. We investigated for whom the extent of surgery can be safely reduced by examining early-stage breast cancer patients converting from lymph node (LN)-positive to LN-negative disease after neoadjuvant systemic treatment (NAST). Of 242 initially LN-positive patients treated within the GeparOcto trial, 54.5% were classified as LN-negative after NAST, 31.8% as LN-positive, and for 13.6% data were missing. Overall, 92.1% of patients underwent complete axillary LN dissection, with 6.6% undergoing sentinel LN dissection only. At surgery, 55.4% of patients had no signs of cancer in the LN, 45.0% had no signs of cancer in the breast (of those 8.3% had involved LN), and 41.3% had no signs of cancer at all. Patients with involved LN still had a bad prognosis. Conversion from LN-positive to LN-negative after NAST is of highest prognostic value. Surgical axillary staging after NAST is essential in these patients to offer tailored treatment. Abstract Background: The conversion of initially histologically confirmed axillary lymph node-positive (pN+) to ypN0 after neoadjuvant systemic treatment (NAST) is an important prognostic factor in breast cancer (BC) patients and may influence surgical de-escalation strategies. We aimed to determine pCR rates in lymph nodes (pCR-LN), the breast (pCR-B), and both (tpCR) in women who present with pN+ BC, to assess predictors for response and the impact of pCR-LN, pCR-B, and tpCR on invasive disease-free survival (iDFS). Methods: Retrospective, exploratory analysis of 242 patients with pN+ at diagnosis from the multicentric, randomized GeparOcto trial. Results: Of 242 patients with initially pN+ disease, 134 (55.4%) had a pCR-LN, and 109 (45.0%) a pCR-B. Of the 109 pCR-B patients, 9 (8.3%) patients had involved LN, and 100 (41.3%) patients had tpCR. Those with involved LN still had a bad prognosis. As expected, pCR-B and intrinsic subtypes (TNBC and HER2+) were identified as independent predictors of pCR-LN. pCR-LN (ypN0; hazard ratio 0.42; 95%, CI 0.23–0.75; p = 0.0028 for iDFS) was the strongest independent prognostic factor. Conclusions: In initially pN+ patients undergoing NAST, the conversion to ypN0 is of high prognostic value. Surgical axillary staging after NAST is still essential in these patients to offer tailored treatment.

Brain metastases (BMs) have a major impact on life expectancy and quality of life for many breast cancer patients. Knowledge about treatment patterns and outcomes is limited.We analysed clinical data of 1712 patients diagnosed with BMs from breast cancer between January 2000 and December 2016 at 80 institutions.Median age at diagnosis of BMs was 56 years (22-90 years). About 47.8% (n = 732) of patients had HER2-positive, 21.4% (n = 328) had triple-negative and 30.8% (n = 471) had hormone receptor (HR)-positive, HER2-negative (luminal-like) primary tumours. The proportion of patients with HER2-positive BMs decreased comparing the years 2000-2009 with 2010-2015 (51%-44%), whereas the percentage of patients with luminal-like tumours increased (28%-34%; p = 0.0331). Patients with BMs in the posterior fossa were more often HER2 positive (n = 169/314, 53.8%) than those diagnosed with triple-negative (n = 65/314, 20.7%) or luminal-like primary breast cancer (n = 80/314, 25.5%), (p 0.0001). Median overall survival (OS) time after development of BMs for the overall cohort was 7.4 months (95% confidence interval [CI]: 6.7-8.0 months). One-year survival rate was 37.7% (95% CI: 35.2-40.1). Patients with HER2-positive tumours had the longest median OS of 11.6 months (95% CI: 10.0-13.4) compared with 5.9 months (95% CI: 5.0-7.2) for patients with luminal-like and 4.6 months (95% CI: 3.9-5.4) for patients with triple-negative tumours. Patients with HER2-positive tumours who received anti-HER2 treatment had longer median OS than those without (17.1 months versus 7.2 months, p 0.0001).Prognosis of patients after developing BMs varies significantly according to the subtype. The outcome in this cohort is similarly poor in triple-negative and HR-positive/HER2-negative patients. Our results underline the high medical need for improvement of treatment and prevention strategies for BMs in breast cancer patients.

Background In women with early breast cancer, a pathological complete response (pCR) after neoadjuvant chemotherapy is reported to be associated with an improvement of the survival. The aim of this survey among physicians was to investigate whether the probability of achieving pCR in patients with a hormone receptor-positive, HER2-negative disease encourages physicians to recommend neoadjuvant chemotherapy. Methods The study was conducted via an online survey that was sent to 493 physicians, who were either known as members of national guideline committees, heads of breast cancer centers, being high recruiters in clinical trials or leading a private practice. Participants were asked about a specific case that should resemble patients for whom it is unclear, whether they should be treated with chemotherapy. Results 113 (24.5%) physicians participated at the survey, out of which 96.5% had a work experience of more than 10 years and 94.7% were board certified in their specialty. A total of 84.1% would consider pCR for a decision concerning neoadjuvant chemotherapy. With regard to the pCR probability, 2.7 and 10.6% of the participants demanded at least a pCR rate of 5 and 10%, respectively, while 25.7% were satisfied with 20% probability, and another 25.7% with a pCR rate of 30%. Conclusions The vast majority of the long-term experienced physicians would embrace the implementation of a further method such as the prediction of pCR probability in clinical routine to support decision making regarding the necessity of neoadjuvant chemotherapy. The cut-off of around 30% pCR probability seems to be a realizable rate to distinguish patient groups.

Background A new subcutaneous (s.c.) formulation of trastuzumab became available in 2013 based on equivalent efficacy, pharmacokinetic (PK) profile and safety with the standard intravenous (i.v.) administration, where the s.c. trastuzumab was administered only into the thigh. As an s.c. injection into the abdominal wall (abdw) might be more convenient for patients (pts) and health care professionals, the PK profile of s.c. trastuzumab injected into the thigh vs the abdw in pts with HER2+ early BC needs to be evaluated. Methods GAIN-2 study compared two intense dose-dense (idd) anthracycline/taxane containing regimens. After completion of the anthracycline and i.v. trastuzumab given concurrently with taxanes, HER2+ BC pts were randomized in a 1:1 ratio to continue adjuvant s.c. trastuzumab 600mg fixed dose injected every 3 weeks either into the thigh or the abdw. Randomization was stratified according to CT arm [(iddEnPC) vs tailored dd CT (dtEC-dtD)] and age (≤50 vs >50). Pts in the EnPC arm received 14 and in the dtEC-dtD arm 15 cycles of s.c. trastuzumab. For the PK profile of s.c. trastuzumab serum samples collected before cycle 7, on days 2, 4, 8, 15 and 21 of cycle 7 are evaluated. With a total sample size of 30 (15 per group), the simulated 90% two-sided CI for the area under the plasma concentration (AUC0-last) will be (0.79-1.27) and for the peak drug concentration (Cmax) will be (0.77-1.30). Allowing for a dropout rate of 15%, 18 pts per group will be included in the PK analysis. The primary objective was to assess the PK profile of s.c. trastuzumab injected into the thigh vs the abdw. The secondary objectives included safety and tolerability. Results The per-protocol (pp) set consists of 30 pts (17 in the thigh group and 13 in the abdw group). Baseline characteristics were well balanced between the groups. The log-transformed Geometric Least Square Means (GLSM) for Cmax were 11.77 and 11.52 in the thigh and the abdw group, respectively. The geo-mean ratio (on the original scale) for Cmax was 1.29 (90% CI 1.05-1.58). The log-transformed GLSM for AUC0-last were 14.54 and 14.28 in the thigh and the abdw group, respectively. The geo-mean ratio for AUC0-last was 1.29 (90% CI 1.02-1.63). Overall 29 pts (96.7%) reported any grade and 5 pts (16.7%) high grade adverse events (AEs). The incidence of any grade AEs was similar between the two groups. The most common AEs were anemia (70.6% for the thigh vs 61.5% for the abdw group, p=0.705), leukopenia (80.0% for both groups, p=1.000) and fatigue (47.1% for the thigh vs 76.9% for the abdw group, p=0.141). 6 serious AEs were reported (2 in the thigh vs 4 in the abdw group). The final PK results of s.c. trastuzumab will be presented at the meeting. Conclusions Bioavailability of s.c. trastuzumab as reflected by peak and total exposure measured in cycle 7 was approx. 30% higher if administered into the thigh than into the abdw in pts with HER2+ primary BC treated after dose-dense CT plus i.v. trastuzumab. However, no increased toxicity was observed. Study limitations were that no cross-over design was used and number of pts satisfying criteria for pp-set were different in the arms. Citation Format: Möbus V, Mahlberg R, Janni W, Tomé O, Marmé F, Forstbauer H, Reimer T, von der Assen A, Reinisch M, Lorenz R, Schmatloch S, Schmidt M, Sinn B, Klutinus N, Stickeler E, Untch M, Seiler S, Burchardi N, von Minckwitz G, Loibl S. Pharmacokinetic results of a subcutaneous injection of trastuzumab into the thigh versus into the abdominal wall in patients with HER2-positive primary breast cancer (BC) treated within the neo-/adjuvant GAIN-2 study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-09.

Background Chemotherapy (CTx) is a cornerstone in HR+/HER2- advanced/metastatic breast cancer (a/mBC) after failure of endocrine treatment. In this indication, vinorelbine (VRL) is a well-established cytotoxic drug. There is a high medical need for new options that prolong the time between endocrine failure and intensive CTx, which is commonly associated with impaired quality of life and serious side effects. Metronomic CTx was shown to induce disease control in a/mBC with a favorable safety profile. This innovative approach involving continuous daily dosing of oral VRL, which could provide anti-angiogenic and immune-modulatory properties, has not been investigated so far in this indication. Trial Design VinoMetro is an open-label, single-arm, phase II study (Simon two-stage minimax) of metronomic daily oral VRL (30 mg/day) as first-line CTx. The study involves strict safety monitoring with an initial safety run-in. It is accompanied by a steering committee and supervised by an independent data safety and monitoring board (DSMB). The main objectives are to estimate efficacy in terms of clinical benefit rate after 24 weeks of treatment (primary endpoint) and the progression-free survival, amongst others, as well as the assessment of safety and quality of life. Patients with HR+/HER2- a/mBC having failed or being no candidate for endocrine therapy (targeted combinations allowed) and being naïve to palliative CTx are eligible, if they exhibit ECOG 0-1. The main exclusion criteria are prior vinca-alkaloids, aggressive disease requiring combination CTx and CNS involvement. Until 2017-05-31, 7 patients were enrolled. It is planned to include 45 (39 evaluable) patients at 8 German sites until 09/2018. Scheduled completion date is 09/2019. Two interim analyses are planned (first analysis: safety evaluation based on the 10 initial patients with predefined stopping rules). Depending on recruitment, it is planned to include the interim safety data in the congress presentation. VinoMetro is an investigator initiated trial (NCT03007992) sponsored by the University Medical Centre of Johannes Gutenberg-University Mainz, Germany, and supported by an unrestricted grant provided by Pierre Fabre Pharma GmbH (Freiburg, Germany). Citation Format: Schmidt M, Decker T, Fehm T, Fuxius S, Harbeck N, Juhasz-Böss I, Thomssen C, Seehase M, Schollenberger L, Ruckes C, Möbus V. A phase II study of metronomic daily oral vinorelbine as first-line chemotherapy in advanced/metastatic hormone receptor positive (HR+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer resistant to endocrine therapy - VinoMetro [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-05-02.

Background Primary breast cancer (BC) patients with extensive axillary lymph-node involvement have a limited prognosis. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) trial compared intense dose-dense (idd) adjuvant chemotherapy with conventionally scheduled chemotherapy in high-risk BC patients. Here we report the final, 10-year follow-up analysis. Patients and methods Enrolment took place between December 1998 and April 2003. A total of 1284 patients with 4 or more involved axillary lymph nodes were randomly assigned to receive 3 courses each of idd sequential epirubicin, paclitaxel and cyclophosphamide (iddEPC) q2w or standard epirubicin/cyclophosphamide followed by paclitaxel (EC → P) q3w. Event-free survival (EFS) was the primary end point. Results A total of 658 patients were assigned to receive iddEPC and 626 patients were assigned to receive EC →P. The median duration of follow-up was 122 months. EFS was 47% (95% CI 43% to 52%) in the standard group and 56% (95% CI 52% to 60%) in the iddEPC group [hazard ratio (HR) 0.74, 95% CI 0.63–0.87; log-rank P = 0.00014, one-sided]. This benefit was independent of menopausal, hormone receptor or HER2 status. Ten-year overall survival (OS) was 59% (95% CI 55% to 63%) for patients in the standard group and 69% (95% CI 65% to 73%) for patients in the iddEPC group (HR = 0.72, 95% CI 0.60–0.87; log-rank P = 0.0007, two-sided). Nine versus two cases of secondary myeloid leukemia/myelodysplastic syndrome were observed in the iddEPC and the EC → P arm, respectively. Conclusion The previously reported OS benefit of iddEPC in comparison to conventionally dosed EC → P has been further increased and achieved an absolute difference of 10% after 10 years of follow-up.

For many decades, the standard procedure to treat breast cancer included complete dissection of the axillary lymph nodes. The aim was to determine histological node status, which was then used as the basis for adjuvant therapy, and to ensure locoregional tumour control. In addition to the debate on how to optimise the therapeutic strategies of systemic treatment and radiotherapy, the current discussion focuses on improving surgical procedures to treat breast cancer. As neoadjuvant chemotherapy is becoming increasingly important, the surgical procedures used to treat breast cancer, whether they are breast surgery or axillary dissection, are changing. Based on the currently available data, carrying out SLNE prior to neoadjuvant chemotherapy is not recommended. In contrast, surgical axillary management after neoadjuvant chemotherapy is considered the procedure of choice for axillary staging and can range from SLNE to TAD and ALND. To reduce the rate of false negatives during surgical staging of the axilla in pN+

BMC cancer 21(1), 1024 (2021). doi:10.1186/s12885-021-08754-z, Published by BioMed Central, London

ZusammenfassungSeit über 30 Jahren findet regelmäßig (in den letzten 6 Jahren alle 2 Jahre) die internationale St. Gallen-Konsensuskonferenz zur Behandlung von Patientinnen mit primärem Mammakarzinom statt. Die Ergebnisse des internationalen St. Gallen-Konsensus-Panels wurden auch dieses Jahr wieder von einer deutschen Arbeitsgruppe führender Brustkrebsexperten für den Klinikalltag in Deutschland diskutiert. Fünf der Brustkrebsexperten aus Deutschland sind zugleich Mitglieder des diesjährigen St. Gallen-Panels. Der Vergleich der St. Gallen-Empfehlungen mit den jährlich aktualisierten Therapieempfehlungen der Arbeitsgemeinschaft Gynäkologische Onkologie (AGO-Mamma 2017) und der aktuell im Jahre 2017 abgestimmten S3-Leitlinie ist sinnvoll. Die Empfehlungen des St. Gallen-Panels stellen ein Meinungsbild von Experten unterschiedlicher Länder und Fachdisziplinen dar, wohingegen S3-Leitlinie und AGO-Empfehlungen evidenzbasiert sind. Die diesjährige 15. St. Gallen-Konsensuskonferenz stand unter dem Motto „Escalating and De-Escalating“, das sich durch alle Therapiebereiche zog, die zur Abstimmung standen. Ziel war es, Patientinnen individuellere Therapieoptionen anzubieten und das Risiko einer Über- bzw. Untertherapie zu vermeiden.

Purpose: The BRCA1-like profile identifies tumors with a defect in homologous recombination due to inactivation of BRCA1. This profile has been shown to predict which stage III breast cancer patients benefit from myeloablative, DNA double-strand-break-inducing chemotherapy. We tested the predictive potential of the BRCA1-like profile for adjuvant non-myeloablative, intensified dose-dense chemotherapy in the GAIN trial. Methods: Lymph node positive breast cancer patients were randomized to 3 × 3 dose-dense cycles of intensified epirubicin, paclitaxel, and cyclophosphamide (ETC) or 4 cycles concurrent epirubicin and cyclophosphamide followed by 10 cycles of weekly paclitaxel combined with 4 cycles capecitabine (EC-TX). Only triple negative breast cancer patients (TNBC) for whom tissue was available were included in these planned analyses. BRCA1-like or non-BRCA1-like copy number profiles were derived from low coverage sequencing data. Results: 119 out of 163 TNBC patients (73%) had a BRCA1-like profile. After median follow-up of 83 months, disease free survival (DFS) was not significantly different between BRCA1-like and non-BRCA1-like patients [adjusted hazard ratio (adj.HR) 1.02; 95% confidence interval (CI) 0.55–1.86], neither was overall survival (OS; adj.HR 1.26; 95% CI 0.58–2.71). When split by BRCA1-like status, DFS and OS were not significantly different between treatments. However, EC-TX seemed to result in a trend to an improvement in DFS in patients with a BRCA1-like tumor, while the reverse accounted for ETC treatment in patients with a non-BRCA1-like tumor (p for interaction = 0.094). Conclusions: The BRCA1-like profile is not associated with survival benefit for a non-myeloablative, intensified regimen in this study population. Considering the limited cohort size, capecitabine might have additional benefit for TNBC patients.

Background Reduced quality of life during chemotherapy is often due to fatigue and dyspnea caused by chemotherapy-induced anemia. In breast cancer patients the incidence is estimated to be above 50% and rising during the course of treatment resulting as well in therapy delays. Despite red blood cell transfusion the administration of erythrocyte stimulating factors (ESF) serves as a treatment option. In comparison with conventional chemotherapy intense dose dense regimens have proven to be beneficial in high-risk breast cancer patients, but higher incidences of anemia have been reported. In the GAIN trial two dose dense regimens were evaluated and patients received either Darbepoetin alfa or Epoetin beta. The aim of this subanalysis was to analyse the efficacy and safety of the application of two different ESF during adjuvant chemotherapy for primary node positive breast cancer. Methods Patients were randomly assigned to receive three courses each of epirubicin (E), paclitaxel (T), cyclophosphamide (C) all given at 2-week intervals i.v. (idd ETC-regimen) or ddEC followed by paclitaxel weekly (Tw) plus capecitabine (X)(EC-TX-regimen).All patients received either primary prophylaxis with Epoetin beta (Epo) (450IE/kg weekly) or Darbepoetin alfa (D) (4,5μg/kg biweekly).Allocation happened alternately by date of randomization. Patient outcome (rate of anemia and thromboembolic events, disease free survival (DFS), overall survival (OS)), overall and by regimen were compared according to ESF type applied and in subgroups defined by age. Results 2994 patients were randomized to receive one of the dose dense chemotherapies and of these 1482 patients were given Darbepoetin alfa and 1512 received Epoetin beta. In the trial 84.7% of patients suffered from anemia in the Darbepoetin as well as in the Epoetin group and grade 3/4 anemia was observed in 3.6% vs 3.1% of patients, respectively. In the ETC arm anemia rates, especially grade 3/4 were slightly higher, but there was no significant difference within the treatment arms according to ESF applied (anemia any grade: D 86.1% vs. Epo 87.2%; EC-TX: D 83.2% vs. Epo 82.3%). In the ETC arm anemia was most frequently observed in patients aged 60+ years, but there was no significant difference between the ESF (D 90.5% vs. Epo 89.8%). No significant differences in the incidence of anemia by ESF treatment were observed in various age groups of the EC-TX arm. Thromboembolic events occurred in 9.1% in the Darbepoetin group and in 10.1% of patients treated with Epoetin (p=0.355). Interestingly there were more thromboembolic events in the EC-TX arm compared to the ETC arm (p OS and DFS analyses showed no difference between ESF treatment overall as well as stratified by chemotherapy regimen. Conclusion High risk breast cancer patients treated with two different dose dense chemotherapy schedules have comparable incidences of anemia, thromboembolic events and a similar long term outcome if they receive a preventive treatment with either Darbepoetin alfa or Epoetin beta. The trial is financially supported by Amgen and Roche. Citation Format: van Mackelenbergh M, Loibl S, Jackisch C, Lück H-J, Schneeweiss A, Tesch H, Harbeck N, Schmatloch S, Fehm T, Huober J, Müller V, Bauerfeind I, Untch M, von Minckwitz G, Nekljudova V, Möbus V. Efficacy and safety of darbepoetin alfa or epoetin beta in 2994 high risk early breast cancer patients participating in the German adjuvant intergroup node-positive study (GAIN) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-04.

This abstract was withdrawn by the authors.

Every year the Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO), a group of gynecological oncologists specialized in breast cancer and interdisciplinary members specialized in pathology, radiologic diagnostics, medical oncology, and radiation oncology, prepares and updates evidence-based recommendations for the diagnosis and treatment of patients with early and metastatic breast cancer. Every update is performed according to a documented rule-fixed algorithm, by thoroughly reviewing and scoring the recent publications for their scientific validity and clinical relevance. This current publication presents the 2019 update on the recommendations for metastatic breast cancer.

Purpose: The aim of this study was to evaluate the feasibility and the accuracy of a secondary, metachronous ultrasound (US)-guided marking of the stereotactic vacuum-assisted breast biopsy (ST-VABB) area. Materials and Methods: The institutional ethics committee approved the study. The retrospective study included 98 patients. In ST-VABB of 45 women, no tissue markers were deployed at the biopsy site, even if no residual calcifications remained. After histology proved the necessity for a subsequent operation, the biopsy site was marked under US guidance using a coil marker. All interventions were technically successful. No complications occurred. Mammography was done to visualize the coil deployment. The distances from the center of the lesion and the biopsy cavity to the coil location were measured in both planes to evaluate the accuracy of the marking procedure. Results: In 24 of the 46 cases, the whole lesion was biopsied without residual elements. The mean time between ST-VABB and sonographic marking of the lesion was 9.7 days (median 6.5). The biopsy cavity could be detected in 40 (87%) cases and thus marked exactly. The mean time of US-guided marking was 12.5 min. The mean distance between the coil and the target lesion was 0.6 ± 1.5 cm in the craniocaudal (cc) view and 0.5 ± 1.5 cm in the mediolateral (ml) view for all markings. The mean delta value from the distance nipple–original lesion and from the distance nipple–coil was 0.85 ± 1.2 cm (median 0.5) in the cc view and 0.88 ± 1.2 cm (median 0.6) in the ml view for all cases. Clip migration was not observed. Conclusion: Our study demonstrates the feasibility and the technical success of secondary metachronous coil marking of the biopsy site under US guidance after receipt of histology. This approach seems to be a cost-effective alternative to the standard procedure of the primary coil marking especially in all completely removed lesions. It may offer advantages for allergic patients.

BACKGROUND: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. METHODS: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m2) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. FINDINGS: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7-34·2), 626 patients had progression-free survival events (405 [60%] of 678 in the trebananib group and 221 [66%] of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0-17·6]) and the placebo group (15·0 months [12·6-16·1]) groups (hazard ratio 0·93 [95% CI 0·79-1·09]; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%] vs placebo 126 [38%]) anaemia (76 [11%] vs 40 [12%]), and leucopenia (81 [12%] vs 35 [10%]). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. INTERPRETATION: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. FUNDING: Amgen. ispartof: LANCET ONCOLOGY vol:20 issue:6 pages:862-876 ispartof: location:England status: published