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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Anti-CD38 monoclonal antibodies have consistently shown increased efficacy when added to standard of care for patients with multiple myeloma. We aimed to assess the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed transplantation-eligible multiple myeloma.This open-label, multicentre, randomised, active-controlled, phase 3 trial was done at 67 academic and oncology practice centres in Germany. This study is ongoing and divided into two parts; herein, we report results from part 1. Eligible patients were aged 18-70 years; had a confirmed diagnosis of untreated multiple myeloma requiring systemic treatment and a WHO performance status of 0-2; and were eligible for induction therapy, high-dose melphalan and autologous haematopoietic stem-cell transplantation, and maintenance treatment. Patients were randomly assigned (1:1) to receive three 42-day cycles of induction therapy either with isatuximab plus lenalidomide, bortezomib, and dexamethasone (isatuximab group) or lenalidomide, bortezomib, and dexamethasone alone (control group) using a web-based system and permuted blocks. Patients in both groups received lenalidomide (25 mg orally on days 1-14 and 22-35), bortezomib (1·3 mg/mBetween Oct 23, 2018, and Sep 22, 2020, 660 patients were included in the ITT analysis (331 in the isatuximab group and 329 in the control group). 654 (99%) patients were White, two were African, one was Arabic, and three were Asian. 250 (38%) were women and 410 (62%) were men. The median age was 59 years (IQR 54-64). MRD negativity after induction therapy was reached in 166 (50%) patients in the isatuximab group versus 117 (36%) in the control group (OR 1·82 [95% CI 1·33-2·48]; p=0·00017). Median follow-up time from start to end of induction therapy was 125 days (IQR 125-131) versus 125 days (125-132). At least one grade 3 or 4 adverse event occurred in 208 (63%) of 330 patients versus 199 (61%) of 328 patients. Neutropenia of grade 3 or 4 occurred in 77 (23%) versus 23 (7%) patients and infections of grade 3 or 4 occurred in 40 (12%) versus 32 (10%) patients. Among 12 deaths during induction therapy, one death due to septic shock in the isatuximab group and four deaths (one cardiac decompensation, one hepatic and renal failure, one cardiac arrest, and one drug-induced enteritis) in the control group were considered treatment-related.Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone for induction therapy improved rates of MRD negativity with no new safety signals in patients with newly diagnosed transplantation-eligible multiple myeloma.Sanofi and Bristol Myers Squibb (Celgene).

Aim: For several years now, medical students have also been taught general practice at academic medical teaching practices. Specialty practices have not yet been included in the curricular education. Since 1998, we have conducted a block seminar in hematology twice per semester for eighth-semester medical students. This block seminar was offered from 1998-2001 to students at the Philipps University in Marburg and since 2001 to students at the Johannes Gutenberg University in Mainz. Since 2010 our block seminar has been part of the curriculum at the Johannes Gutenberg University. Method: Standardized course evaluation by students who had attended our block seminar between January 2010 and March 2022. Courses that were held virtually due to corona were not included in the analysis. The questionnaire used to evaluate courses in the medical degree program at the Johannes Gutenberg University served as the evaluation instrument. Results: Since 1998 more than 1,000 students have attended our seminar. The systematic evaluation of the course by 500 students who participated in the curricular, classroom-based seminar sessions since 2010 shows that the highest ratings possible are given for practical relevance, learning atmosphere, teaching and effectiveness. Conclusion: High quality in teaching curricular courses to medical students at a specialty practice is possible. Insights into the possibilities connected with working in the outpatient setting at a medical practice broadens students’ experience. This teaching format facilitates external university instructors in terms of teaching and, at the same time, relieves the university in terms of staff and financial budget., Zielsetzung: Die Ausbildung von Studierenden der Humanmedizin im Fach Allgemeinmedizin geschieht seit einigen Jahren auch in akademischen Lehrpraxen. Facharztpraxen sind bisher nicht an der curricularen Lehre beteiligt. Seit 1998 führen wir in unserer Gemeinschaftspraxis zweimal pro Semester ein Blockpraktikum Hämatologie für Studierende der Humanmedizin im 8. Fachsemester durch. Das Blockpraktikum wurde von 1998-2001 für Studierende der Philipps-Universität Marburg und seit 2001 für Studierende der Johannes-Gutenberg-Universität Mainz angeboten. Seit 2010 ist unser Blockpraktikum Teil der curricularen Lehre der Johannes-Gutenberg-Universität Mainz. Methodik: Standardisierte Evaluation der akademischen Lehre durch die Studierenden, die im Zeitraum 01/2010-03/2022 an unserem Blockpraktikum teilgenommen haben. Veranstaltungen, die coronabedingt in virtueller Form stattfanden, wurden in der Analyse nicht berücksichtigt. Als Evaluationsinstrument diente der Fragebogen zur Evaluation der Lehre des Fachbereichs Medizin der Universität Mainz. Ergebnisse: Seit 1998 haben mehr als 1.000 Studierende an unseren Seminaren teilgenommen. Die systematische Evaluation des Unterrichts durch 500 Studierende, die an den curricularen Präsenzveranstaltungen seit 2010 teilgenommen haben, ergibt Bestnoten für Praxisrelevanz, Unterrichtsatmosphäre, Didaktik und Effektivität. Schlussfolgerung: Die curriculare Lehre von Studierenden der Humanmedizin in einer Facharztpraxis ist auf hohem Qualitätsniveau möglich. Einblicke in die Möglichkeiten des ärztlichen Arbeitens im niedergelassenen Bereich erweitern den studentischen Erfahrungshorizont. Durch dieses Lehrmodell wird externen Hochschuldozenten der Unterricht erleichtert, gleichzeitig kann die Universität personell und finanziell entlastet werden.

Background Patients with indolent B-cell non-Hodgkin lymphomas (B-NHLs) have an increased risk of infections which is caused by pathomechanisms of the diseases itself but also as a result of anti-tumor therapy. Especially the effects of anti-CD20 antibodies are well understood as these lead to decreased antibody production. Most studies regarding immunodeficiency in B-NHLs were conducted with multiple myeloma and chronic lymphocytic leukemia patients. As these studies not always represent the general population we collected and analyzed real world data from patients with indolent lymphomas and a control group (CG). Results Patients with B-NHLs undergoing therapy or who were regularly monitored in a watch and wait approach had, over the time of one year, an increased rate of infections compared to the CG of 145 healthy volunteers (mean: 11.66 vs. 7.13 infections per 1000 days). Consistent with this finding B-NHL patients received more antibiotic treatment (mean: 11.17 vs. 6.27 days) and were more often hospitalized than persons from the CG (mean: 5.19 vs. 0.99 days per 1000 days). Lymphoma patients without immunodeficiency had a lower infection rate than patients with non-symptomatic and symptomatic immunodeficiency (mean: 10.91 vs. 12.07 and 12.36 per 1000 days). The number of infections differed statistically significant for the subgroups and CG (7.13 per 1000 days). Patients with symptomatic immunodeficiency were mostly treated with regular immunoglobulin substitutions and infection rates were comparable to those of patients with asymptomatic immunodeficiency. Conclusions Our data suggest the use of an approach with regular immune monitoring including the measurement of immunoglobulin levels and regular appointments for clinical assessment of all indolent lymphoma patients in order to identify patients with increased risk of infections. It also raises the question if patients with immunodeficiency should be treated more often with regular immunoglobulin substitution, but so far more studies are necessary to answer this question.

Background: The implementation of immune checkpoint inhibitors in the therapy of different cancer types has provided promising results, but only a limited number of patients respond. Therefore, biomarkers to identify these responding patients are urgently needed. Methods: The GeparNuevo was a randomized, double-blind phase II trial in which triple-negative breast cancer (TNBC) patients were treated with neoadjuvant chemotherapy (NACT) consisting of nanoparticle albumin-bound paclitaxel in an initial phase followed by treatment with epirubicin and cyclophosphamide. Placebo or durvalumab were given throughout the neo-adjuvant treatment and in the “window” sub-cohort also prior to chemotherapy. Primary objective of this report was to evaluate changes in the blood immune cell repertoires of TNBC patients receiving durvalumab (anti-PD-L1) versus placebo in combination with NACT. At up to 4 different time points during therapy, blood samples were taken and underwent immunomonitoring using multicolor flow cytometry. The absolute counts of the major immune cell subtypes in the blood as well as the frequencies of different immune cell subpopulations and their functional phenotypes along treatment were determined and correlated to clinico-pathologic characteristics of the patients and to treatment response. Results: 120 out of 174 patients included in the GeparNuevo trial underwent blood immunomonitoring; 63 patients belonged to the “window” sub-cohort. Durvalumab administration almost completely blocked the detection of the inhibitory ligand PD-L1 and induced changes in the composition of the immune cell subpopulations. Evaluation of the “window” sub-cohort, in which an enhanced, but not significant pathological clinical response was observed within the immunomonitored patients, identified different markers correlating with clinical response to durvalumab. Higher frequencies of CD4+ T cells at recruitment as well as increased frequencies of T cells bearing the gamma delta TCR along treatment were some of the characteristics of patients responding to durvalumab treatment. Conclusions: The flow cytometry-based immunomonitoring of the clinical trial identified different immune-relevant biomarkers at recruitment as well as during treatment that predict clinical response to durvalumab. After validation of this data in an independent patient cohort, these markers could be implemented for an improved patient stratification to immunotherapy. Citation Format: Chiara Massa, Thomas Karn, Karsten Weber, Andreas Schneeweiss, Claus Hanusch, Jens-Uwe Blohmer, Dirk-Michael Zahm, Christian Jackisch, Marion van Mackelenbergh, Jörg Thomalla, Frederik Marmé, Jens Huober, Volkmar Müller, Christian Schem, Anja Müller, Elmar Stickeler, Katharina Biehl, Peter A. Fasching, Michael Untch, Sibylle Loibl, Carsten Denkert, Barbara Seliger. Immunological and clinical consequences of durvalumab treatment in combination to neoadjuvant chemotherapy in triple-negative breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD9-04.

Background: It is well known that immunological pathways are relevant for response to classical neoadjuvant chemotherapy as well as combined chemo-immunotherapy. In addition, it has been shown that combined chemo-immunotherapy significantly improves survival, even in the context of only moderate effects on pCR. Due to the window therapy with durvalumab-alone and the option to analyze multiple consecutive biopsies, the GeparNuevo trial offers the opportunity to 1) determine gene expression patterns for pCR and DDFS endpoints 2) identify pathways most relevant for pCR and DDFS 3) identify genes specifically regulated by immunotherapy (comparison of samples pre-and post-window) 4) identify genes specifically regulated by chemotherapy (comparison of samples pre-Tx and after 4 cycles of chemotherapy 5) identify longitudinal patterns of gene expression by comparison of up to four time points and 6) identify changes in the tumor microenvironment by spatial sequencing of tumor cell and stroma areas. Methods: 292 tumor samples were evaluated by gene expression analysis: 162 pretherapeutic core biopsies, 79 post-window biopsies, 32 biopsies during chemotherapy and 19 biopsies of the residual tumor after therapy. These samples were analyzed by HTG OBP panel targeting 2549 genes which are assigned to 25 different biological mechanisms or cellular pathways. In addition, spatial profiling was compared in a subset of pre-and post-window samples using Nanostring GeoMx spatial profiling system. Endpoints were pCR and DDFS. Results: A total of more than 600 genes were significantly associated with either the pCR or the DDFS endpoint in either the complete GeparNuevo cohort or one of the two therapy arms. Interestingly, there was a large number of predictive or prognostic genes (n=247 for pCR and n=179 for DDFS) in the durvalumab arm, while the number of genes in the placebo arm was considerably lower (n=113 for pCR and n=61 for DDFS). We used existing pathway information for HTG OBP panel to analyze the contribution of different cellular processes to pCR and DDFS signatures in different therapy arms. Immune pathways were particularly relevant for durvalumab signatures (pCR and DDFS), while cell cycle related gene expression patterns were particularly involved in signatures predictive of pCR in both therapy arms. To further assign genes to the cellular response to durvalumab-alone or chemotherapy-alone, we compared gene expression patterns in durvalumab arm before and after the window phase (gene expression patterns induced by one dose of durvalumab) with gene expression patterns in placebo arm before and after 4 cycles of chemotherapy. Further longitudinal alterations were analyzed by comparison of longitudinal samples for 4 different time-points (a: before NACT, n=162; b: after window phase, n=79; c: after 4 cycles, n=31 and d: at surgery, n=19). Using the Nanostring GeoMx spatial RNA profiling system guided by cytokeratine immunofluorescence, we compared areas with high tumor cell content with stromal areas with or without TILs. In combination with the HTG gene expression data, we were able allocate the changes induced by durvalumab vs chemotherapy to the stromal cell and tumor cell compartment, indicating a re-organization of the tumor-microenvironment. Conclusions: In our analysis, we show that immune gene signatures are particularly relevant for neoadjuvant response to durvalumab as well as prognosis after durvalumab treatment, while proliferation signatures are involved in pCR-signatures after durvalumab as well as chemotherapy. The spatial analysis showed that relevant changes occur in the stromal compartment, indicating a re-organization of the tumor microenvironment. The parallel targeting of immune- and proliferation pathways might explain why a combined immunotherapy-chemotherapy approach is more successful than each single therapy strategy alone. Citation Format: Carsten Denkert, Andreas Schneeweiss, Julia Rey, Akira Hattesohl, Thomas Karn, Michael Braun, Paul Jank, Jens Huober, Hans-Peter Sinn, Dirk-Michael Zahm, Claus Hanusch, Frederik Marmé, Jenny Furlanetto, Jörg Thomalla, Jens-Uwe Blohmer, Marion van Mackelenbergh, Thorsten Stiewe, Peter Staib, Christian Jackisch, Julia Teply-Szymanski, Peter A. Fasching, Bruno V. Sinn, Michael Untch, Karsten Weber, Sibylle Loibl. PD4-02 Spatial and temporal heterogeneity of predictive and prognostic signatures in triple-negative breast cancer treated with neoadjuvant combination immune-chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD4-02.

Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC.GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0).A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23-76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ2P = 0.287), corresponding to OR = 1.45 (95% CI 0.80-2.63, unadjusted Wald P = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR = 2.22, 95% CI 1.06-4.64, P = 0.035; interaction P = 0.048). In both arms, significantly increased pCR (P 0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P = 0.045) and for PD-L1-immune cell in placebo arm (P = 0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%.Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy.ClinicalTrials.gov number: NCT02685059.

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive form of breast cancer (BC). Due to the absence of targets such as HER2 or hormone receptors, early TNBC is treated with surgery and chemotherapy. Since TNBC is also considered the most immunogenic type of BC with tumor infiltrating lymphocytes that are predictive for chemotherapy response and prognostic for patients′ survival, many different immunotherapeutic strategies are currently explored in clinical trials for the treatment of this disease. In order to efficiently combine chemotherapy with immunotherapy, it is important to evaluate the effect of chemotherapy on immune cells in vivo.MethodsPeripheral blood was taken from 56 patients with TNBC undergoing neoadjuvant chemotherapy with nanoparticle albumin-bound paclitaxel (Nab-Pac) followed by epirubicin and cyclophosphamide (EC) at three different time points. Multicolor flow cytometry was used to characterize the immune cell composition and functional properties along neoadjuvant chemotherapy.ResultsWhereas the first phase of the neoadjuvant chemotherapy did not significantly alter the patients′ immune cell composition, after the second phase of chemotherapeutic administration most B cells (>90%) were lost and the frequency of natural killer (NK) cells and CD4+ T lymphocytes decreased approximately to 50%. In contrast, the frequency of CD8+ T cells were less affected.ConclusionsDespite late consequences of Nab-Pac cannot be ruled out, these data suggest that different chemotherapeutics might have distinct effects on the immune cell repertoire and that different immune cell populations exhibit a specific susceptibility to these chemotherapies with B and NK cells being more affected than T cells. This might also have an impact on the combination of chemotherapies with immunotherapies.Trial registration numberNCT02685059.

Introduction: 18,000 women die due to metastatic breast cancer in Germany per year. Median survival is 20–28 months after diagnosis. The question we wanted to answer was whether survival has improved in routine care? Methods: Retrospective analysis of all patients with metastatic breast cancer who were treated between 06/1995-12/2017 in 5 community-based oncology group practices in Germany. Results: 1,321 patients were analyzed with a median age of 62 (23–100). Localizations of metastases were distributed as follows: 49% visceral, 33% bone, 6% CNS, 12% others. 79% were hormone-receptor-positive, 20% Her2-positive, 9% triple-negative. Median overall survival was 37 months (95% Confidence Interval: 34–40), survival probability after 5 years 32.5%. Survival was significantly correlated with localizations of metastases, number of metastasized organs, disease free survival since initial diagnosis, hormone- and Her2-receptor status and age. Patients with hormone-receptor-positive tumors had a median overall survival of 39 months, Her2-positive patients of 45 months and triple-negative patients of 20 months. 86% of hormone-receptor-positive patients received antihormonal therapy. 81% of Her2-positive patients received anti-Her2 therapy. Overall survival according to treatment period 1995-2000, 2001-2005, 2006-2011, 2012-2017 was 34, 35, 37 and 38 months respectively. OS of patients with hormone-positive tumors according to treatment period was 35, 43, 38, and 42 months respectively. OS of patients with Her2-positive tumors according to treatment period was 39, 29, 51, and 54 months respectively. OS of patients with triple-negative tumors according to treatment period was 7, 11, 16, and 25 months respectively. Conclusions: Improved survival of patients with metastatic breast cancer in routine care is strongly restricted to hormone receptor- and Her2-positive tumors most likely due to improved targeted therapies directed against the estrogen-receptor and Her2. Citation Format: Weide R, Rendenbach B, Laubenstein H-P, Braun U, Hünermund K, Burkhard O, Ehscheidt P, Feiten S, Chakupurakal G, Friesenhahn V, Kleboth K, Köppler H, Lutschkin J, Thomalla J, van Roye C, Heymanns J. Improved survival of patients with metastatic breast cancer in routine care is restricted to tumors with positive hormone receptor and/or Her2-expression. Survival analysis of 1,321 patients treated between 1995 and 2017 in oncology group practices [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 P1-16-06.

Background: The GeparNuevo trial showed a numerical increase in the pCR rate to 53% vs 44%; p=0.281 compared to placebo in TNBC with the addition of the anti-PD-L1 antibody durvalumab to a neoadjuvant anthracycline-taxane containing chemotherapy (Loibl S et al. ASCO 2018). In a predefined subgroup analysis, a significant increase of the pCR rate was observed for patients that received durvalumab for 2 weeks alone prior to the start of chemotherapy in a window phase (61% vs 41%, p interaction=0.048), while the pCR rate was not increased for the subset of patients that did start durvalumab together with chemotherapy. Here we report the main results of the translational programme for GeparNuevo with a focus on mRNA signatures predictive for pCR in pretherapeutic core biopsies. Methods: A total of 162 baseline FFPE core biopsies were evaluable for expression of 2560 genes using the HTG EdgeSeq® system that combines a modified nuclease protection assay with next generation sequencing. Data was processed as recommended by the HTG and median transformed for further analyses. For differential gene expression analyses, the data was scale-normalized (TMM normalization; EdgeR package) and linear models were fit (limma package). Prior to these analyses, genes were filtered based on minimal expression (> 4) and variability (IQR > 1). As a first step, predefined immune-genes signature (TILs signature) (Denkert et al. JCO 2016) as well as IFN-gamma signatures were evaluated for correlation with pCR in logistic regression models. Subsequently, we performed a differential gene expression analysis according to therapy response for the durvalumab-arm and the placebo arm using the pre-filtered candidate genes. Gene names are not included in this abstract to allow filing of IP, but full gene names will be presented at the SABCS meeting. Results: The predefined TIL- and IFN-gamma signatures were associated with increased pCR rates in the complete cohort (TIL-signature: OR 1.44, 95% CI 1.15-1.82, p=0.002; IFN-Gamma-signature: OR 1.63, 95% CI 1.22-2.24, p=0.002) as well as in the durvalumab arm (p=0.012 and 0.042) and the placebo arm (p=0.050 and 0.011). These signatures were general pCR predictors without specificity for durvalumab response. Additional 44 genes were significantly (p Conclusion: Our results show that specific immune-related gene expression signatures predict response to durvalumab in primary triple negative breast cancer. The trial was financially supported by Astra Zeneca and Celgene Citation Format: Loibl S, Sinn BV, Karn T, Untch M, Treue D, Sinn H-P, Weber KE, Hanusch CA, Fasching PA, Huober J, Zahm D-M, Jackisch C, Thomalla J, Blohmer J-U, Marmé F, Klauschen F, Rhiem K, Felder B, von Minckwitz G, Burchardi N, Schneeweiss A, Denkert C. mRNA signatures predict response to durvalumab therapy in triple negative breast cancer (TNBC)– Results of the translational biomarker programme of the neoadjuvant double-blind placebo controlled GeparNuevo trial [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 PD2-07.

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.

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.

This abstract was withdrawn by the authors.

506 Background: The GeparNuevo trial investigated the addition of durvalumab, an anti-PD-L1 checkpoint inhibitor (CPI), to standard neoadjuvant chemotherapy (NACT) in patients with early TNBC. Durvalumab increased the pathological complete response (pCR) rate particularly in patients treated with durvalumab alone before start of chemotherapy (Loibl et al. Ann Oncol 2019). Methods: GeparNuevo randomized patients with cT1b-cT4a-d tumors and centrally confirmed TNBC to durvalumab (D) 1.5 g i.v. or placebo every 4 weeks. D/placebo monotherapy (0.75 g i.v.) was given for the first 2 weeks (window phase), followed by D/placebo plus nab-paclitaxel 125 mg/m² weekly for 12 weeks, followed by D/placebo plus epirubicin/cyclophosphamide (EC) q2 weeks for 4 cycles. Randomization was stratified by stromal tumor infiltrating lymphocytes (sTILs) (low (≤10%), intermediate (11-59%), high (≥60%)). The primary objective was pCR (ypT0 ypN0). Secondary time-to-event endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). Results: A total of 174 patients were enrolled between June 2016 and September 2017. The pCR rate with durvalumab was 53.4% versus placebo 44.2% (OR 1.45, 95% CI 0.80–2.63, unadjusted Wald p = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR 2.22, 95% CI 1.06–4.64, p = 0.035; interaction p = 0.048). After a median follow-up of 42.2 months, 34 events occurred in 174 patients. 3-year iDFS in pCR vs non pCR was 92.0% vs 71.9% (log-rank p = 0.002). 3-year iDFS was 84.9% with durvalumab vs 76.9% with placebo (HR 0.54, 95%CI 0.27-1.09, stratified log-rank p = 0.0559); 3-year DDFS 91.4% vs 79.5% (HR 0.37, 95%CI 0.15-0.87, p = 0.0148); 3-year OS 95.1% vs 83.1% (HR 0.26, 95%CI 0.09-0.79, p = 0.0076). No difference was seen in iDFS, DDFS and OS between the window and no window cohort. Conclusions: Durvalumab added to neoadjuvant chemotherapy in TNBC significantly improved long-term outcome despite a small pCR increase and no continuation after surgery. It needs to be questioned whether adjuvant therapy with CPI is needed at all. Clinical trial information: NCT02685059.

This abstract was withdrawn by the authors.

Hintergrund und Fragestellung | Bei chronischen lymphoproliferativen Erkrankungen wie indolenten Non-Hodgkin-Lymphomen (iNHL), chronischer lymphatischer Leukamie, follikularem Lymphom und multiplem Myelom sind Infektionen wichtige Komplikationen. Wir berichten uber eine retrospektive Kohorten-Analyse von Patienten mit indolenten Non-Hodgkin-Lymphomen, die in einer Schwerpunktpraxis fur Hamatologie und Onkologie ambulant behandelt wurden. Im Rahmen der Supportivtherapie erhielten sie eine Substitution mit intravenos verabreichtem polyvalentem Immunglobulin G (IVIG). Ziel war die Beschreibung der behandelten iNHL-Population, des Therapieverlaufs sowie der Effekte der IVIG-Gaben auf den Spiegel von Immunglobulin G (IgG), die Infektionshaufigkeit und ggf. die Uberlebenszeit. Patienten und Methodik | Eingeschlossen wurden 57 iNHL-Patienten mit sekundarem Antikorpermangel (n = 46) bzw. IgG-Subklassenmangel (n = 11), die eine Substitutionstherapie mit IVIG erhielten. Im Median erhielten die Patienten 11 IVIG-Gaben mit einer mittleren Dosierung von 28 g uber median 9,5 Monate. Ergebnisse | Der mittlere IgG-Serumspiegel stieg unter IVIG-Substitution auf etwa das Doppelte an und bewegte sich dann im Normbereich. Die Haufigkeit von Infektionen ging bei 46 % der behandelten Patienten zuruck. Effekte auf die Uberlebensraten wurden nicht verzeichnet. Die mediane Gesamtuberlebenszeit betrug in der Gruppe der substituierten Patienten 124 Monate (Bereich 7–124), die Vergleichsgruppe hatte eine mediane Uberlebenszeit von 96 Monaten (Bereich 3–129) (p = 0,537). Folgerung | Der IgG-Spiegel sollte unter IVIG-Substitution in regelmasigen Abstanden uberpruft und die Dosis bzw. das Dosisintervall individuell angepasst werden.

Introduction: Currently, about 360 000 breast cancer patients who could, after completion of their primary therapy, take advantage of follow-up options are living in Germany. Up to now very little is known about the extent to which the available options are used and as to how the follow-up reality is experienced and evaluated. Thus, an explorative examination among the patients and their physicians was undertaken. Patients and Methods: All patients who underwent surgery in a certified breast centre between 2007 and 2013 received a standardised questionnaire; at the same time the physicians responsible for the follow-up were invited to answer a standardised questionnaire. Results: 920 patients (response rate: 61 %) with a median age of 65 years (32–95) could be analysed. 99 % of the participants stated that they regularly attended follow-ups. The personal contact with the physician (mean value: 4.4) and the reassurance that the cancer disease had not recurred (mean value: 4.5) were described on a scale of 0 to 5 to be two of the most important factors of the follow-up. Deficits were expressed with regard to psychosocial care (70 %) and the perception and treatment of physical complaints (55 %). In addition, 105 physicians returned completed questionnaires (response rate: 12 %). For asymptomatic patients the physicians performed the following examinations most frequently: anamnesis (92 %), physical examination (87 %) as well as laboratory tests (63 %) and tumour marker determinations (40 %). Conclusion: On the whole it became clear that the vast majority of the patients took advantage of the follow-up options. From the patientʼs perspective the importance of the follow-up lies in contact to the physician and the comforting assurance that the breast cancer has not relapsed. Deficits are seen in the psychosocial care and the perception and treatment of physical impairments. Not recommended examinations were employed by a significant proportion of the surveyed physicians.

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.

Introduction: Breast cancer treatment leads to long-lasting impairments which, according to international guidelines, have to be identified and treated in follow-up care. It remains unclear how follow-up care is perceived by patients and if all needs are met in routine care. Methods: All breast cancer patients who underwent surgery in a German breast cancer centre from 2007 to 2013 were asked to fill out a standardized scanner-readable questionnaire. Medical data were retrieved from their charts and statistically analyzed together with the questionnaire responses. Physicians who could possibly care for breast cancer patients after primary therapy were invited to fill out a standardized scanner-readable questionnaire as well. Results: 920 questionnaires were filled out and returned (response rate: 61%) by patients. Median age at the time of the survey was 65 years (32-95). 58% of patients still received some form of therapy, 94% of them hormonal therapy. 94% were still in follow-up care, 5% stopped and 1% never went. Intervals of follow-up visits suggested by international guidelines were assessed as "quite right" in 93%. The following examinations were conducted throughout the whole follow-up period at least once: physical examination (93%), mammography (90%), sonography of breast (81%) and liver (22%), laboratory (56%), tumor marker (23%), bone scan (21%), MRI (20%) and CT (15%). Different items were rated on a 6-point scale ranging from "0" "not true at all" to "5" "completely true". Follow-up care was regarded as very important for the own health (4.7), reassuring and calming (4.5), well-being to be looked after (4.4) and well cared for (4.4). A continuous contact between patient and doctor was appreciated (4.4). Visits were connected only to a part with distress (2.1), the median score on the NCCN distress thermometer was 4 (0-10). 105 questionnaires were answered by healthcare professionals (response rate 12%), most of them general practitioners (51%) or gynecologists (30%). Doctors carried out or referred asymptomatic patients most often to the following examinations: medical history taking (92%), physical examination (87%), blood chemistry (63%) and tumor markers (40%). Mammography was mentioned in 45%, sonographic examinations of breast, liver and axilla in 49%, 45% and 38%, respectively. 55% were (very) satisfied with international guidelines on follow-up care. Intervals and duration of follow-up visits were assessed as "quite right" in 88% and 60%, respectively. Different items were rated on a 6-point scale ranging from "0" "not important at all" to "5" "very important". Detection of disease recurrence and secondary tumors (4.8), reassurance of patients (4.7) and detection of treatment toxicities (4.5) were assessed as most important aims in follow-up care. Conclusions: An overwhelming majority of patients makes use of follow-up care. Most important qualities from the patient's perspective are reassurance, a feeling of security, calming and continuous care by their doctor. Examinations which are not recommended in international guidelines are used by a considerable amount of healthcare providers. Citation Format: Weide R, Feiten S, Friesenhahn V, Heymanns J, Köppler H, Meister R, van Roye C, Thomalla J, Wey D, Dünnebacke J. Follow-up care of breast cancer patients who were treated in a German breast cancer centre - Survey of patients and attending physicians and analysis of treatment data. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-10-13.

Due to the increase of oral agents nonadherence is an emerging challenge in cancer care. We evaluated how well different assessments match and how adherence could be measured in routine care. For this purpose patients suffering from metastatic solid tumors who were treated with oral anticancer drugs in an oncology group practice were surveyed. Attending oncologists answered a questionnaire, too, and a retrospective analysis of prescription data was conducted. Caregivers who were eligible for an interview were surveyed additionally. 128 patients (70 % female) with a median age of 69 years (36–88) took part, 95 % of all approached patients. 56 % suffered from metastatic breast cancer, 44 % from other metastatic solid tumors. 65 caregivers (60 % female) with a median age of 62 years (21–82) were interviewed as well. Patients were assessed in 84 % as very reliable in medication-taking by their oncologists. This high adherence rate was supported by patients, caregivers and prescription data. However, concordance between assessments of patients, caregivers and oncologists was not substantial. Our method of considering different perspectives to assess adherence has to be improved and validated but could help to evaluate adherence with oral cancer therapy in routine care.

Bendamustine and bendamustine/rituximab combinations have shown high efficacy in relapsed/refractory chronic lymphocytic leukemia (CLL) and indolent B-cell malignancies (non-Hodgkin lymphoma, NHL). No data exist about bendamustine retreatment after relapse, concerning efficacy and toxicity in this patient population. Eighty-eight outpatients (57 patients with CLL, 31 patients with NHL) who had previously been treated with bendamustine were retreated with a bendamustine regimen. Treatment consisted of bendamustine (B) or bendamustine + mitoxantrone (BM) or bendamustine + rituximab (BR) or bendamustine + mitoxantrone + rituximab (BMR). Median age was 72 years (50-88). A reversible grade 3 or 4 leukocytopenia or thrombocytopenia was observed in 24% and 13%, respectively. The overall response rate (ORR) was 76% (7% complete remission [CR], 69% partial remission [PR]) with 77% (6% CR, 71% PR) in CLL and 71% (8% CR, 63% PR) in NHL. ORR according to regimen was as follows: B: 57% (14% CR, 43% PR), BM: 70% (4% CR, 66% PR), BR: 55% (10% CR, 45% PR), BMR: 84% (7% CR, 78% PR). Bendamustine retreatment is feasible and achieves high response rates and some long lasting remissions.

Objectives: Evaluation of the subjectively experienced physical, psychological, social and job-related consequences of breast cancer. Methods: Standardized paper pencil interview of patients with the initial diagnosis of breast cancer who had their primary surgery between 01/2006 and 12/2010 at an accredited breast cancer centre followed by systemic adjuvant treatment. The data collection was conducted with the help of a self-developed scanner-readable questionnaire which had been evaluated in a pretest. Results: 1260 patients were contacted, 871 completed questionnaires (return rate 72%) were analyzed. Median age of the patients (99.5% women) at the time of the interview was 65 years (30–91). 6% relapsed during the observation period. 91% were “satisfied” or “very satisfied” with the surgical result. 67% indicated a complete freedom of pain. 23% received lymphatic drainage at the time of the questioning (11/2011), 33% complained about limitations of arm and/or shoulder function. 76% received anti-hormonal therapy, 13% stopped the anti-hormonal medication prematurely. Patients received a mean of 1.3 different anti-hormonal therapies, 54% took Tamoxifen. Psychological distress, cognitive limitations and physical consequences were rated on a scale from 1 – “not at all” to 4 – “very much”. The highest average values were found for the items sleep disturbances (2.3) and exhaustion (2.3), the lowest for depression (1.7) and word-finding difficulties (1.8). After therapy only 39% described a complete recovery of their physical capacity, 62% regained their previous mental capacity. 44% were in employment before their disease. 67% returned to their workplace but only 65% of them with their previous number of hours. 15% indicated disadvantages in their workplace due to the breast cancer disease. For 75% their partnership did not change, 12% experienced a deterioration, 13% an improvement. Before the illness 9% consulted a psychiatrist/psychotherapist, after the illness 18%. Before the diagnosis of breast cancer 13% received antipsychotic drugs, after the disease 25%. Conclusions: Breast cancer diagnosis and therapy leads to long lasting impairment of physical, psychological, social and job-related functioning in a significant number of patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-11-11.

Introduction: It is well-known that people who care for patients with a metastatic carcinoma are exposed to an above-average level of psychosocial distress. No data are available concerning the distress of main care-givers of female patients with metastatic breast cancer, who are treated in a community based oncology group practice. Methods: Standardized cross-sectional survey of main care-givers and patients with metastatic breast cancer who were treated in a community based oncology group practice in Germany between 04/2010-03/2011. Psychosocial distress of the patients and their main care-givers were evaluated using the German versions of the Distress Thermometer (DT) and the Problem List (PL). In addition anxiety and depression of the main care-givers were assessed using the Hospital Anxiety and Depression Scale (HADS-D). Results: 83 female patients with a median age of 65 (41-93) were interviewed. 6% did not have a main care-giver, 7% indicated that they needed no support, 48% reported one main care-giver and 39% several. Partners (60%), children (47%), siblings (11%) and friends (10%) were the most important care-givers. 47% of patients preferred visiting the practice in companion with their care-givers. The patients’ median score on the DT was 5 (0-10), with 34% scoring above cut-off (> 5) for psychosocial distress. 52 main care-givers (61% male, 39% female) with a median age of 57.5 (41-86) were interviewed. The relationships to the patients were as follows: partners 62%, children 27%, mothers, siblings and friends each with 4%. The main care-givers themselves were supported by partners (54%), children (21%) friends (17%) and siblings (8%), 23% did not receive any support. The median score on the DT was 5 (0-10), with 44% scoring above cut-off (> 5) for psychosocial distress. According to the HADS-D 37% (cut-off ≥ 8) of the care-givers reported anxiety, with a mean score of 6.6 (0-14). 15% could be regarded as depressed (cut-off ≥ 8), with a mean score of 4.1 (0-15). Conclusions: The main care-givers are distressed even more than the patients themselves. 37% of care-givers reported anxiety; depression can be observed too, but less frequently in 15%. Both issues should be addressed by healthcare professionals. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-17-01.

Background: Systematic evaluation of psychosocial distress in oncology outpatients is an important issue. We assessed feasibility and benefit of standardized routine screening using the Distress Thermometer (DT) and Problem List (PL) in all patients of our community-based hematooncology group practice. Patients and methods: One thousand four hundred forty-six patients were screened between July 2008 and September 2008. Five hundred randomly selected patients were sent a feedback form. Results: The average distress level was 4.7, with 37% indicating a distress level >5. Patients with nonmalignant diseases (81% autoimmune diseases or hereditary hemochromatosis) showed the highest distress level of 5.2. Most distressed were patients who just learned about relapse or metastases (6.4), patients receiving best supportive care (5.4) and patients receiving adjuvant antihormonal therapy (5.4). Ninety-seven percent of patients appreciated to speak to their doctor about their distress. Fifty-six percent felt better than usual after this consultation. Conclusion: DT and PL are feasible instruments to measure distress in hematooncology outpatients receiving routine care. DT and PL are able to improve doctor–patient communication and thus should be implemented in routine patient care. The study shows that distress is distributed differently between individuals, disease groups and treatment phases.

Background In the GeparNuevo trial, the PD-L1 inhibitor durvalumab increased the rate of pathologic complete response (pCR; ypT0 ypN0) in triple-negative breast cancer if treatment started in a two-week window before neoadjuvant taxane/anthracycline chemotherapy (61 % pCR vs. 41%; p = 0.048; Loibl et al. ASCO 2018). Overall, pCR rates increased only numerically from 53 % to 44 % (p = 0.281). Herein, we aimed to evaluate the predictive value of PD-L1 immunohistochemistry in pre-therapeutic core biopsies. In addition, we identified dynamics in gene expression using repeated biopsies. Patients and Methods 174 patients were randomized to receive durvalumab or placebo with neoadjuvant chemotherapy. In the window part, 117 patients received a single dose of durvalumab (or placebo) before chemotherapy. Core biopsies were taken at three times: pre-treatment (“A”; N=174), after the window part (“B”; N=88) and after 12 weeks of nab-Paclitaxel (“C”; N=33). PD-L1 immunohistochemistry in A-biopsies (Ventana SP263 Assay) was recorded as percentage of cells with membranous staining in tumor cells and lymphocytes (TILs). We defined a tumor as PD-L1 high if ≥ 25 % of either compartment was stained. Ki-67 was stained on all available A, B and C biopsies (MIB-1, Dako, 1:100) and recorded as the percentage of tumor cells with nuclear staining. We profiled all available biopsies with targeted RNASeq using the HTG EdgeSeq platform (Oncology Biomarker panel, 2560 genes). Sequencing (IonTorrent S5) was successful in 162 A-, 79 B- and 31 C-biopsies. Results PD-L1 expression was high in 24 % of A-biopsies and was predictive for pCR in the complete cohort (OR 2.561; 1.183-5.554; p = 0.017). PD-L1 status of the TILs, but not of the tumor cells, was predictive (OR 1.313; 1.040-1.656; P= 0.022). The effect was not specific for durvalumab treatment. Higher levels of Ki-67 were predictive for pCR in B- biopsies in all patients (OR 1.399; 1.053-1.858; P =0.021) and in the placebo arm, but not in the durvalumab arm. Ki-67 levels in C-biopsies were not predictive; neither was the change in Ki-67 between pre-treatment and later time points (B vs. A or C vs. A). In a differential mRNA expression analysis (A vs. B), we found seven differentially expressed genes after one dose of durvalumab. We observed strong effects on gene expression after taxane treatment (A vs. C), but no significant difference according to treatment. These genes were associated with biological processes involved in therapy response. The pre-treatment levels of 12 of 69 markedly differentially expressed genes were associated with worse response to chemotherapy. Conclusion In A-biopsies, PD-L1 in TILs was predictive for response, and in B-biopsies, Ki-67 was predictive, but neither marker could specifically predict response to durvalumab. We observed limited effects of a single half-dose of durvalumab on global gene expression, but could identify substantial differential expression after taxane treatment. The evaluation of gene expression dynamic offers a promising approach for the identification of resistance-associated markers. The study was financially supported by AstraZeneca and Celgene Citation Format: Sinn BV, Loibl S, Karn T, Untch M, Kunze CA, Weber KE, Treue D, Wagner K, Hanusch CA, Klauschen F, Fasching PA, Huober J, Zahm D-M, Jackisch C, Thomalla J, Blohmer J-U, van Mackelenbergh M, Rhiem K, Felder B, von Minckwitz G, Burchardi N, Schneeweiss A, Denkert C. Pre-therapeutic PD-L1 expression and dynamics of Ki-67 and gene expression during neoadjuvant immune-checkpoint blockade and chemotherapy to predict response within the GeparNuevo trial [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 PD5-05.

e18770Background: RCT are not transferable to routine care due to necessary inclusion and exclusion criteria. Thus data are needed that reflect treatment reality in routine care to decide whether r...

104Background: Combining immune-checkpoint inhibitors with chemotherapy yielded high response rates in patients (pts) with metastatic TNBC. Therefore, we evaluated the addition of durvalumab, an an...

We have evaluated all outpatients with relapsed or refractory chronic lymphocytic leukemia (CLL) who were treated with bendamustine/mitoxantrone/rituximab (BMR) between May 1999 and December 2008. Treatment consisted of bendamustine 90 mg/m2 on day 1 + 2, Mitoxantrone 6 mg/m2 on day 1, and Rituximab 375 mg/m2 on day 8, 15, 22 + 29. Thirty-nine patients (19 males, 20 females) received BMR with a median age of 69 years (46–81). Nineteen patients (49%) were above 70 years and 13 patients (33%) were 75 years or above. Performance score ranged between 0 and 2. The median number of previous therapies was 2 (1–4). Therapy was tolerated well with two observed therapy-associated hospitalizations. A reversible grade 3 or 4 hematotoxicity was seen in 30 patients (77%). Other reversible grade 3 or 4 toxicities were seen in two patients (5%). The overall response rate was 92% (10% complete remission, 82% partial remission). Median time to next CLL-therapy was 13 months (0–69). We conclude that BMR is a short and effective outpatient chemoimmunotherapy for patients with relapsed or refractory CLL, which can be used safely in elderly patients.

With regard to incidence, ovarian cancer has the highest mortality of all gynecologic cancers.The treatment of 139 consecutive patients with epithelial ovarian cancer who were treated in an oncology group practice in Koblenz, Germany between 1995 and 2003 was evaluated retrospectively.The median age of the patients was 61 years (18-84). FIGO stages were distributed as follows: stage I 15.8%, stage II 12.9%, stage III 53.2%, stage IV 16.5%. 49 patients (35.5%) received surgical treatment at a university hospital or a teaching hospital. 89 patients (64.5%) were operated on in a local or district hospital. A macroscopically complete resection was achieved in only 15 patients (10.8%). The residual tumor was1 cm in 50 patients (36%),1 cm in 24 patients (17.3%), and2 cm in 49 patients (35.5%). 93.3% of the patients received postoperative, platinum-based chemotherapy. Median survival since first diagnosis was 42 months (1-346(+)). The 5-year survival rate of the whole cohort was only 28%.Overall survival in epithelial ovarian cancer was significantly inferior in this patient cohort compared to the results of the FIGO report from 2003. One possible cause may be the suboptimal surgical treatment, with 52.8% of the patients having a postoperative residual tumor larger than 1 cm.

On the basis of a preceding phase I study, the current trial explored bendamustine in combination with mitoxantrone and rituximab (BMR) in patients with stage III/IV relapsed or refractory indolent lymphomas and mantle cell lymphoma (MCL) with or without prior rituximab containing chemo-immunotherapy (R-chemo) treatment. Therapy consisted of bendamustine 90 mg/m(2) days 1 + 2, mitoxantrone 10 mg/m(2) day 1, rituximab 375 mg/m(2) day 8. Treatment was repeated on day 29 for a total of four cycles. Between 3 April and 04 July, 57 patients were recruited from 24 participating institutions, 39% of whom had received prior R-chemo therapy. Median age was 66 years (40 - 83). Lymphoma subtypes were 29 follicular (FL), 18 MCL, and 10 other indolent lymphomas. The overall response rate (ORR) was 89% with 35% CR and 54% PR. ORR in R-chemo pretreated patients was 76% (38% CR, 38% PR). After a median observation time of 27 months (1 - 43), the estimated median progression free survival is 19 months. The 2 year overall survival is 60% for patients with FL and MCL. Treatment related toxicities of grade 3/4 comprised a reversible myelosuppression (10% anemia, 78% leukocytopenia, 46% granulocytopenia, 16% thrombocytopenia). However, unexpected hospitalisations were necessary after 4% of BMR-application only. BMR is a very effective new outpatient immuno-chemotherapy with low toxicity for patients with relapsed/refractory FL, MCL and other indolent lymphomas.

Background: The aim of this study was to evaluate the treatment reality for outpatients with immune thrombocytopenia (ITP) managed by hematologists in routine care. Patients and Methods: All patients with ITP diagnosed between 06/1995 and 12/2014 in a community-based oncology group practice in Germany were retrospectively analyzed. Results: 422 patients with a median age of 55 years (range 7-91 years) were evaluated. 57% were female and 43% male. Only 198 (47%) patients needed therapy. First-line therapy (n = 198) consisted of steroids in 81%, intravenous immunoglobulins (IVIG) in 12%, and IVIG plus steroids in 6%. Patients received a median of 2 (range 1-10) lines of therapy. The most frequently used treatment modalities were steroids in 93%, IVIG in 55%, splenectomy in 21%, and other immunosuppressive agents (OISA) in 23% of patients. Rituximab and thrombopoietin receptor agonists (TRAs) were used in 10% and 6% only. 9 (2%) patients needed hospitalization due to bleeding complications. 72% of patients achieved a durable remission after their last line of therapy. 1 (0.2%) patient died due to bleeding complications. Conclusion: The treatment modalities most frequently used are steroids, immunoglobulins, splenectomy, and OISA. Rituximab and TRAs are only used infrequently. 72% of ITP patients achieve durable remissions. The rate of hospital admissions due to bleeding complications and the ITP-related mortality are low. The majority of ITP patients can be safely managed by hematologists on an outpatient basis.

Background Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400mg/day (n=400) could be optimized by doubling the dose (n=420), adding IFN (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). Methods From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. The impact of patients' and disease factors on survival was prospectively analyzed. At the time of evaluation, at least 62% of patients still received imatinib, 26.2% were switched to 2nd generation tyrosine kinase inhibitors. Results After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival 80% and 10-year relative survival 92%. In spite of a faster response with IM800mg, the survival difference between IM400mg and IM800mg was only 3% at 5 years. In a multivariate analysis, the influence on survival of risk-group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs. other) was significant in contrast to any form of initial treatment optimization. Patients that reached the response milestones 3, 6 and 12 months, had a significant survival advantage of about 6% after 10 years regardless of therapy. The progression probability to blast crisis was 5.8%. Blast crisis was proceeded by high-risk additional chromosomal aberrations. Conclusions For responders, monotherapy with IM400mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease and blast crisis, more life-time can currently be gained by carefully addressing non-CML determinants of survival. Disclosures Hehlmann: Novartis: Research Funding; BMS: Consultancy. Saussele: Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Pfirrmann: BMS: Honoraria; Novartis: Honoraria. Krause: Novartis: Honoraria. Baerlocher: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Bruemmendorf: Novartis: Research Funding. Müller: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Jeromin: MLL Munich Leukemia Laboratory: Employment. Hänel: Roche: Honoraria; Novartis: Honoraria. Burchert: BMS: Honoraria. Waller: Mylan: Consultancy, Honoraria. Mayer: Eisai: Research Funding; Novartis: Research Funding. Link: Novartis: Honoraria. Scheid: Novartis: Honoraria. Schafhausen: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Hochhaus: Incyte: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; ARIAD: Research Funding.

3062 Background: Adding an anti-PD-L1 checkpoint inhibitor durvalumab to standard chemotherapy (CT) may increase pathological complete response (pCR) in patients (pts) with TNBC. Methods: GeparNuevo randomizes pts to durvalumab (D) 1.5 g i.v. or placebo (pl) every 4 weeks (wks). D/pl monotherapy (0.75 g i.v.) is given for the first 2 wks (window phase), followed by a biopsy and D/pl plus nab-paclitaxel (nP) 125 mg/m² weekly for 12 wks, followed by D/pl plus epirubicin/cyclophosphamide (EC) q2 wks for 4 cycles. Randomization is stratified by stromal TILs (sTILs) (low (≤10%), intermediate (11-59%), high (≥60%)). Pts with primary cT1b-cT4a-d disease, centrally confirmed TNBC, and sTILs status can be included. Primary objective compares pCR (ypT0 ypN0) rates. Secondary objectives are pCR rates in stratified subpopulations and according to other pCR definitions; response rates; breast conservation rate; toxicity; compliance and survival. Change in sTILs, Ki67 and other immune biomarkers before CT, after the window phase and after CT will be correlated with outcome. The first 10, 20 and 30 pts will be included in safety interim analyses (SIA). Sample size was planned assuming a pCR rate of 48% for pl (nP treated TNBC cohort in GeparSepto) and of 66% for D (as clinically meaningful benefit), requiring 158 pts to show superiority of D (2-sided α = 0.2, 80% power). Assuming a 10% drop-out rate 174 pts will be randomized. Results: Since 6/2016, 50 pts were recruited within 16 sites; data are presented as available until 01/2017. Median age is 49 years; 86% NST and G3 tumors; sTILs categories 40% low, 40% intermediate and 20% high. Blinded SIA was performed. No pt interrupted D/pl, one nP and one EC. Treatment delay was observed in 9 pts (20.0%) in D/pl, 18 (41.9%) in nP and 2 (13.3%) in EC; dose was reduced in 10 pts (23.3%) in nP and in 4 (26.7%) in EC. 10 pts (20%) had at least one grade 3-4 AE: 4 haematological and 6 non-haematological AEs. 4 SAEs and 5 immune related AEs were reported. 2 pts discontinued study treatment prematurely in the EC phase. Conclusions: The addition of D to standard nP-EC is feasible and does not result in an increased toxicity. Clinical trial information: NCT02685059.

Many women with breast cancer suffer from pain, postmenopausal symptoms, psychosocial stress, depression, sleep disorders, or fatigue (1-3). Although the majority are again taking an active part in life by around a year after their diagnosis, many symptoms persist for months or even years after the end of treatment (4). Particularly in view of the fact that patients often receive treatment that was not strictly necessary, the long-term effects are of considerable importance. Various systemic treatments have been linked with secondary neoplasia, although the overall risk is judged to be slight (5, 6). The incidence of lymphatic edema increases up to 2 years after operation and is estimated at 16 to 21% (7). Radical surgery has been described as a risk factor (7), and meanwhile researchers are questioning the advisability of such extensive interventions (8). Cardiotoxicity is not only a treatment-limiting factor, but has also been identified as a long-term complication of oncological therapy (9). Literature reports vary as to the frequency of cognitive impairments, the prevalence of which is stated to be between 16% and 50% (10). According to a recent review, from an objective viewpoint the influence of treatment on cognitive function is overestimated (5). The data on psychological impairments are also inconsistent: A meta-analysis restricted to studies that had used psychiatric interviews for diagnostic purposes showed that—following ICD criteria—anxiety (prevalence 10%) and depression (16%) were less widespread than commonly thought (11). While cancer patients still had higher rates of anxiety than healthy persons years after the disease, increased rates of depression did not persist as long (12). Moreover, some subgroups suffer more serious impairments than others. While it is often assumed that older women tolerate the treatment less well than the young, in fact large studies have shown the opposite (4). Women under 50 years of age tend to report symptoms such as pain, forgetfulness, problems with their body image, and hot flashes (13). An epidemiological study identified diagnosis at young age, presence of chronic comorbidity, and low socioeconomic status as risk factors for greater difficulty regaining quality of life (1). We set out to investigate the impact of disease and treatment on women's lives in various areas and uncover interrelationships.

Introduction: Psychosocial distress in caregivers of cancer patients is highly prevalent, particularly in advanced stages. Little data is available concerning extent and main issues of caregivers’ distress from patients who receive their treatment in an oncology group practice. Methods: Standardized cross-sectional survey was administered to caregivers and patients with a metastatic solid tumor who were treated in a community based oncology group practice. Patients provided information concerning their caregivers and level of distress. Caregivers assessed level and main issues of distress. The extent of distress was evaluated using the Distress Thermometer (DT), main issues of distress were evaluated by the Hospital Anxiety and Depression Scale (HADS-D). Results: 200 patients (35% male) with a median age of 68 (38 – 93) were interviewed. DT mean score was 4.7, with 35% scoring above cut-off (> 5). 90% named one or more caregiver, 1.3 were named in mean (0 – 4). 137 caregivers (42% male) with a median age of 61.5 (25 – 86) were interviewed. DT mean score was 5.4, with 48% scoring above cut-off (> 5). According to HADS-D 20% were anxious (cut-off >= 11) and 15% depressed (cut-off >= 9) in a clinical sense. With regard to the distress level of caregivers and patients, gender was not found to be a confounding variable although female patients showed higher distress levels than male patients. Conclusion: Caregivers are screened as highly distressed, sometimes even more than the patients themselves. A significant proportion seems to be anxious and depressed and therefore should be offered help.

Purpose: Targeted therapy directed against HER2 has improved the outcome of patients with HER2-positive metastatic breast cancer in prospective clinical trials. No data are available how anti-HER2-therapy has influenced survival of unselected patients with HER2-positive metastatic breast cancer who receive treatment in routine care. Methods: Data of 118 subsequent patients with HER2-positive metastatic breast cancer who were treated in a community-based oncology group practice between 1995 and 2010 were analyzed retrospectively. Results: Median age at initial diagnosis of metastasis was 58 years (33-92). Twenty-two percent were metastasized at diagnosis of breast cancer, seventy-eight percent developed metastases in the course of the disease. Distribution of metastatic sites at initial diagnosis of metastasis was: 23% bone, 58% visceral, 5% CNS, 10% lymph nodes, 4% other. Hormone receptor was positive in 68% and negative in 31%. Palliative treatment consisted of antihormonal therapy in 56%, chemotherapy in 90% and radiotherapy in 50%. Seventy-five percent received anti-HER2-therapy consisting of trastuzumab in 80% and lapatinib in 1%, 19% received trastuzumab + lapatinib sequentially. Twenty-five percent received no anti-HER2-therapy. Median overall survival since initial diagnosis of metastasis was 34 months (0-277+). Conclusion: It could be shown that, compared to historical controls, targeted therapy against HER2 prolongs overall survival of patients with HER2-positive metastatic breast cancer who receive treatment in routine care.

Purpose: To determine the importance of different contact persons for patients with metastatic solid tumours treated in a community-based oncology group practice. Methods: Psychosocial distress was measured between 04-07/2009 using the distress thermometer and problem list. All patients were asked 3 questions: To whom do you talk, when you are distressed? Which persons are helpful to reduce your distress? How did helpful persons help you? Results: 202 patients with a median age of 68 years (37-85) completed the interview. Most important contact persons named by patients were: oncologist (84%), partner (71%), children (64%), friends (53%) and general practitioner (52%). The most helpful persons were oncologist (97%), friends (94%), partner (92%), children (92%) and general practitioner (91%) and the most important qualities of help were listening, patience and mindfulness. The most important qualities of help from the oncologist were: therapy, listening and information/advice. Conclusion: Patients with metastatic solid tumours use a helping network of contact persons when they are distressed. The oncologist, partner, children, friends and general practitioner are key persons. Training of oncologists in distress management is of utmost importance. Furthermore the patient's network should be strengthened by improving the information flow and by continuous support for the main caregivers.