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Zusammenfassung Hintergrund Umfangreiche Daten aus prospektiven klinischen Studien liefern einen hohen Evidenzgrad für den Einsatz von CDK4/6-Hemmern in Kombination mit einer endokrinen Therapie (CDK4/6i + ET) als Standard bei der First-Line-Behandlung von metastatischem HER2-negativen hormonrezeptorpositiven (HER2−/HR+) Brustkrebs. Reale Daten von Patientinnengruppen, die damit in der Praxis behandelt wurden, liefern Erkenntnisse über Veränderungen von Patientenmerkmalen und Prognosen im Laufe der Zeit. Methoden Die Daten wurden dem prospektiven praxisbezogenen PRAEGNANT-Register (NCT02 338 167) entnommen. Die eingeschlossenen Patientinnen hatten fortgeschrittenen primären und metastasierten HER2−/HR+ Brustkrebs. Die gewählten Therapien, das progressionsfreie Überleben und das Gesamtüberleben der jeweiligen Therapie sowie die Zeitspanne, während der die Behandlung erfolgte, werden dargelegt. Ergebnisse Nachdem CDK4/6-Hemmer erstmals im November 2016 eingesetzt wurden, stieg die Häufigkeit ihres Einsatzes schnell an. In den letzten Jahren (2018–2022) wurden ca. 70–80 % aller Patientinnengruppen mit CDK4/6-Hemmern behandelt; eine endokrine Monotherapie wurde rund 10 % und eine Chemotherapie ungefähr 15 % aller Patientinnen verabreicht. Die schlechteste Prognose hatten Patientinnen, die eine Chemotherapie erhielten. Seit Kurzem erhalten hauptsächlich Patientinnen mit guter Prognose eine endokrine Monotherapie; Patientinnen, die eine Chemotherapie erhalten, haben eine ungünstigere Prognose. Das progressionsfreie Überleben und das Gesamtüberleben von mit CDK4/6i + ET behandelten Patientinnen blieb über einen längeren Zeitraum ähnlich, obwohl sich die Patientenmerkmale änderten. Schlussfolgerung Die Behandlung mit CDK4/6i + ET entwickelte sich rasch zum First-Line-Therapiestandard für Patienten mit fortgeschrittenem Mammakarzinom. Seit der Einführung von CDK4/6i + ET wird die endokrine Monotherapie nur bei Patientinnen mit einer sehr günstigen Prognose eingesetzt, während Chemotherapie meist nur an Patientinnen verabreicht wird, die eine eher ungünstige Prognose haben. Veränderungen der Patientenmerkmale scheinen die Prognose von mit CDK4/6i + ET behandelten Patientinnen nicht zu beeinflussen.

Background Comprehensive data from prospective clinical trials have led to a high level of evidence establishing CDK4/6 inhibitors in combination with endocrine treatment (CDK4/6i + ET) as a standard for the treatment of HER2-negative, hormone receptor-positive (HER2− HR+) breast cancer patients in the first-line advanced therapy setting. Data on patient populations that have been treated in the real-world setting may provide an insight into changes of patient characteristics and prognosis over time. Methods The data were extracted from the prospective real-world registry PRAEGNANT (NCT02338167). Patients had to have HER2− HR+ advanced breast cancer in the first-line metastatic setting. The chosen therapies were described as well as progression-free survival (PFS) and overall survival (OS) in relation to the given therapies and time periods during which they were indicated. Results CDK4/6 inhibitors have been rapidly implemented since their introduction in November 2016. In recent years (2018 – 2022), about 70 – 80% of the patient population have been treated with CDK4/6 inhibitors, while endocrine monotherapy was given to about 10% and chemotherapy to about 15% of all patients. The prognosis was worst in patients treated with chemotherapy. Recently, mainly patients with a good prognosis are being treated with endocrine monotherapy, and patients who are treated with chemotherapy have an unfavorable prognosis. The PFS and OS of patients treated with CDK4/6i + ET have remained similar over time despite changes in patient characteristics. Conclusion A treatment with CDK4/6i + ET has rapidly become the therapy standard for patients in the first-line advanced breast cancer setting. After the implementation of CDK4/6i + ET, endocrine monotherapy is only given to patients with a very favorable prognosis, while chemotherapy is provided to patients with a rather unfavorable prognosis. These changes in patient characteristics did not seem to influence the prognosis of patients treated with CDK4/6i + ET.

CA extern Simple Summary The emergence of resistant cells remains a major obstacle for chemotherapy treatment of metastatic colorectal cancers. Improvement of the therapeutic response requires a thorough understanding of the mechanisms of resistance as well as informative biomarkers. In the REVEAL study, we have systematically compared the mutational patterns and expression profiles of primary tumor specimens before and after first-line chemotherapy treatment in the metastatic situation. In addition, we analyzed liquid biopsies pre, during, and after treatment. Alterations in gene expression appeared as the major drivers of chemotherapy resistance. We identified a gene expression signature differentiating primary tumors and metastases and validated this signature in two independent patient cohorts. Moreover, we evaluated the expression of two signature genes, SFRP2 and SPP1, as prognostic and potentially druggable biomarkers. Most metastatic colorectal cancer (mCRC) patients succumb to refractory disease due to secondary chemotherapy resistance. To elucidate the molecular changes associated with secondary resistance, we recruited 64 patients with mCRC and hepatic metastases before standard first-line chemotherapy between 2014 and 2018. We subjected DNA from primary tumor specimens (P), hepatic metastasis specimens after treatment (M), and liquid biopsies (L) taken prior to (pre), during (intra), and after (post) treatment to next generation sequencing. We performed Nanostring expression analysis in P and M specimens. Comparative bioinformatics and statistical analysis revealed typical mutational patterns with frequent alterations in TP53, APC, and KRAS in P specimens (n = 48). P and pre-L (n = 42), as well as matched P and M (n = 30), displayed a similar mutation spectrum. In contrast, gene expression profiles classified P (n = 31) and M (n = 23), distinguishable by up-regulation of immune/cytokine receptor and autophagy programs. Switching of consensus molecular subtypes from P to M occurred in 58.3% of cases. M signature genes SFRP2 and SPP1 associated with inferior survival, as validated in an independent cohort. Molecular changes during first-line treatment were detectable by expression profiling rather than by mutational tumor and liquid biopsy analyses. SFRP2 and SPP1 may serve as biomarkers and/or actionable targets.

Screening mammography is a widely used approach for early breast cancer detection, effectively increasing the survival rate of affected patients. According to the Food and Drug Administration’s Mammography Quality Standards Act and Program statistics, approximately 39 million mammography procedures are performed in the United States each year. Therefore, breast cancer screening is among the most common radiological tasks. Interpretation of screening mammograms by a specialist radiologist includes primarily the review of breast positioning quality, which is a key factor affecting the sensitivity of mammography and thus the diagnostic performance. Each mammogram with inadequate positioning may lead to a missed cancer or, in case of false positive signal interpretation, to follow-up activities, increased emotional burden and potential over-therapy and must be repeated, requiring the return of the patient. In this study, we have developed deep convolutional neuronal networks to differentiate mammograms with inadequate breast positioning from the adequate ones. The aim of the proposed automated positioning quality evaluation is to assist radiology technologists in detecting poorly positioned mammograms during patient visits, improve mammography performance, and decrease the recall rate. The implemented models have achieved 96.5% accuracy in cranio-caudal view classification and 93.3% accuracy in mediolateral oblique view regarding breast positioning quality. In addition to these results, we developed a software module that allows the study to be applied in practice by presenting the implemented model predictions and informing the technologist about the missing quality criteria.

Background The observational study HerMES collected primary data on effectiveness and safety of trastuzumab in patients with human epidermal growth receptor 2 (HER2)‐positive cancer of the stomach or gastroesophageal junction (GEJ) in routine clinical practice, exploring the treatment with trastuzumab, chemotherapy backbones used, and the HER2 testing in a real‐world setting in Germany. Subjects, Materials, and Methods This noninterventional study observed patients with histologically confirmed, HER2‐positive metastatic adenocarcinoma of the stomach or GEJ, who were treated with trastuzumab according to the physicians’ judgement and clinical practice. The observation phase per patient took as long as the duration of the trastuzumab therapy, but for a maximum of 12 months. A subsequent extended follow‐up phase lasted until the patient's death or the end of the study, that is, 2 years from start of the follow‐up phase of the last patient. All data were analyzed descriptively. Results Between February 2010 and July 2016, 364 patients were observed at 171 sites throughout Germany. The median overall survival was 14.1 months and the median progression‐free survival was 7.9 months. The overall response rate was 43%. Safety was in line with previous reports. This study observed a high diversity of chemotherapy regimens that were combined with trastuzumab. Post hoc subgroup analyses showed differences in outcomes according to the chemotherapy regimen used. Conclusion Trastuzumab treatment in everyday practice as observed in HerMES confirmed the positive results of the pivotal study ToGA in an observational, real‐world setting. Implications for Practice Real‐world data of trastuzumab treatment of patients with gastroesophageal or gastric metastatic adenocarcinoma confirmed the positive results of the pivotal clinical trial. The observed median overall survival was 14.1 months and the median progression‐free survival was 7.9 months. Although recommendations concerning administration of trastuzumab were well implemented, a high diversity of chemotherapy regimens were combined with trastuzumab. Regimens other than the in‐label regimens, especially oxaliplatin‐based doublets or 5‐fluorouracil, leucovorin, oxaliplatin, taxane triplets, were used in 29% of patients. Observation of a second, marginal HER2‐positivity population confirmed the benefit of trastuzumab predominantly for well‐confirmed human epidermal growth receptor 2 (HER2)‐positive tumors and the requirement of reliable HER2 testing., This article reports the results of the HerMES study on the use of trastuzumab for patients with gastric and gastro‐esophageal junction carcinoma in a real‐world setting in Germany.

Background Increasing knowledge about the genomic changes underpinning cancer development and growth has led to a rapidly expanding number of individualized therapies that specifically target these changes in a patient's tumor. Here we present a case report of a patient with metastatic esophageal carcinoma whose tumor harbored NTRK1 gene amplification and who received targeted systemic therapy with larotrectinib. At initial diagnosis, the patient presented with tumor obstruction of the middle esophagus, simultaneous liver and lung metastases, UICC IV and WHO performance status 3. Materials and Methods The solid tumor genomic profiling test FoundationOne CDx (F1CDx) was used to detect clinically relevant genomic alterations that, in turn, might identify a targeted therapeutic approach if suggested by the findings. The patient was then treated with larotrectinib and had subsequent follow‐up biopsies. Results Simultaneous biopsies of the primary tumor and liver lesions identified a metastatic squamous cell esophageal carcinoma. Comprehensive genomic profiling obtained from liver metastases identified numerous genomic alterations including amplification of NTRK1. Owing to the reduced performance status of the patient, chemotherapy could not be applied and was denied. Although larotrectinib is only approved for the treatment of cancers with NTRK gene fusions, treatment was started and led to a shrinkage of the primary tumor as well as the liver and lung metastases within 6 weeks according to RECIST criteria accompanied by tumor marker decrease. The NTRK1 gene amplification was below the limit of detection in a subsequent liver biopsy. Conclusion The use of comprehensive genomic profiling, specifically F1CDx, enabled the selection of a targeted therapy that led to a rapid reduction of the tumor and its metastases according to RECIST criteria. This case suggests that larotrectinib is not only effective in NTRK fusions but may be efficacious in cases with gene amplification. Key Points Advances in precision medicine have revolutionized the treatment of cancer and have allowed oncologists to perform more individualized therapy.This case shows that larotrectinib could also be effective in cases of NTRK amplification of cancer.Today, there is only limited knowledge about NTRK alterations in squamous epithelial carcinoma of the esophagus. Longitudinal tumor sequencing during the course of the disease may allow for the detection of a molecular genetic cause once the tumor progresses. Additional actionable gene alterations may then be identified, which may provide the rationale for a therapy switch., Knowledge of the efficacy of targeted therapy for TRK gene amplification is still lacking. This report presents the case of a patient with metastatic squamous cell esophageal carcinoma with NTRK1 gene amplification who received targeted therapy with larotrectinib with promising results.

This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23–84) and leiomyosarcoma was the most frequent histotype (n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment (n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3–6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6–21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile.

Simple Summary Molecular tumor signatures are becoming increasingly important in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC). There are few studies available analyzing data from the Caucasian population regarding molecular signatures and biomarkers. In the presented study, we investigated the distribution of gene variants in outpatients with advanced disease at the onset of diagnosis and correlated them with clinically relevant biomarkers according to ESCAT levels. In addition, we compared the results of conventional diagnostics (IHC/ISH) with NGS findings of gene amplifications. We were able to detect clinically relevant biomarkers according to ESCAT level I in approximately one-third of our patients, which have immediate therapeutic implications. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment. Abstract After several years of negative phase III trials in gastric and esophageal cancer, a significant breakthrough in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC) is now becoming evident with the emerging of precision oncology and implementation of molecular targets in tumor treatment. In addition, new generation studies such as umbrella and basket trials are focused on these molecular targets, which makes an early molecular diagnosis based on IHC/ISH and NGS necessary. The required companion diagnostics of Her2neu overamplification or PD-L1 expression is based on immunohistochemistry (IHC) or additionally in situ hybridization (ISH) in case of an IHC Her2neu score of 2+. However, there are investigator-dependent differences in the assessment of Her2neu amplification and different PD-L1 scoring systems obtained by IHC/ISH. The use of high-throughput technologies such as next-generation sequencing (NGS) holds the potential to standardize the analysis and thus make them more comparable. In the presented study, real-world multigene sequencing data of 72 Caucasian patients diagnosed with metastatic adenocarcinomas of GEJ and stomach were analyzed. In the clinical companion diagnostics, we found ESCAT level I molecular targets in one-third of our patients, which directly determined the therapy. In addition, we found potential targets in 14/72 patients (19.4%) who potentially qualify for precision therapies in corresponding molecular studies. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment.

SARS-CoV-2 antibody development and immunity will be crucial for the further course of the pandemic. Until now, it has been assumed that patients who were infected with SARS-CoV-2 develop antibodies as it is the case with other coronaviruses, like MERS-CoV and SARS-CoV. In the present study, we analyzed the antibody development of 77 oncology patients 26 days after positive RT-qPCR testing for SARS-CoV-2. RT-qPCR and anti-SARS-CoV2-antibody methods from BGI (MGIEasy Magnetic Beads Virus DNA/RNA Extraction Kit) and Roche (Elecsys Anti-SARS-CoV-2 immunoassay) were used, respectively, according to the manufacturers’ specifications.Surprisingly, in only 6 of 77 individuals with a confirmed history of COVID-19 antibody development was detected. Despite of multiple testing, the remaining patients did not show measurable antibody concentrations in subsequent tests. These results undermine the previous hypothesis that SARS-CoV-2 infections are regularly associated with antibody development and cast doubt on the provided immunity to COVID-19. Understanding the adaptive and humoral response to SARS-CoV-2 will play a key-roll in vaccine development and gaining further knowledge on the pathogenesis.

Oncologic patients are regarded as the population most at risk of developing a severe course of COVID‐19 due to the fact that malignant diseases and chemotherapy often weaken the immune system. In the face of the ongoing SARS‐CoV‐2 pandemic, how particular patients deal with this infection remains an important question. In the period between the 15 and 26 April 2020, a total of 1227 patients were tested in one of seven oncologic outpatient clinics for SARS‐CoV‐2, regardless of symptoms, employing RT‐qPCR. Of 1227 patients, 78 (6.4%) were tested positive of SARS‐CoV‐2. Only one of the patients who tested positive developed a severe form of COVID‐19 with pneumonia (CURB‐65 score of 2), and two patients showed mild symptoms. Fourteen of 75 asymptomatic but positively tested patients received chemotherapy or chemo‐immunotherapy according to their regular therapy algorithm (±4 weeks of SARS‐CoV‐2 test), and 48 of 78 (61.5%) positive‐tested patients received glucocorticoids as co‐medication. None of the asymptomatic infected patients showed unexpected complications due to the SARS‐CoV‐2 infection during the cancer treatment. These data clearly contrast the view that patients with an oncologic disease are particularly vulnerable to SARS‐CoV‐2 and suggest that compromising therapies could be continued or started despite the ongoing pandemic. Moreover the relatively low appearance of symptoms due to COVID‐19 among patients on chemotherapy and other immunosuppressive co‐medication like glucocorticoids indicate that suppressing the response capacity of the immune system reduces disease severity., Largely unexpected, only 78 of 1227 tested cancer patients showed a COVID‐19 infection of which only three patients were symptomatic, ranging from mild symptoms to pneumonia. These data clearly contrast the view that oncology patients are particularly vulnerable to SARS‐CoV‐2 and suggest that necessary chemotherapies could be continued or started despite the ongoing pandemic. One explanation could be the immunosuppressive effect of simultaneous systemic therapy which will be further investigated.

Background: It is still unclear whether oncological patients harbor a higher risk for an infection with the SARS-CoV-2 and for developing severe forms of COVID-19. Furthermore, it is unclear whether an infection affects essential therapy treatment and if a therapy increases the risk for an infection. Method(s): We tested every patient (n=1286) in 7 different oncology outpatient clinics from 04/15/2020 and 04/26/2020 for COVID-19 infection regardless of whether symptoms were present or not. Virus RNA was extracted using the MGIEasy extraction kit in combination with SP-960 robots and a RT qPCR was performed. Result(s): From 1286 tested patients 40 (3.1%) patients were identified positive. Only two of those (5.0%) had mild symptoms whereas one positive patient (2,5%) was treated stationary with pneumonia. The majority (37/40) was asymptomatic virus-carriers (92,5 %). Noteworthy is the fact that 22 (55%) of the positively tested patients were undergoing systemic therapy of which 10 (45.5%) patients received chemotherapy and 4 (18.2%) patients received immunomodulating antibodies. Conclusion(s): A consequent testing for COVID-19 in cancer patients is obligate to identify asymptomatric positive carrier to separate this potential vector group from COVID negative patients since the majority (37/40) of positive patients was asymptomatic virus-carriers (92,5 %). The data we collected contrasts strongly the hypothesis that cancer patients are suspected to be highly vulnerable for SARS-CoV-2 infections. Only a minority (3/40) of positively tested tumor patients showed symptoms. An asymptomatic COVID-19 infection seems to have no impact on the further course of a chemotherapy. Legal entity responsible for the study: The authors. Funding(s): Has not received any funding. Disclosure: All authors have declared no conflicts of interest. Copyright © 2020

Next generation sequencing (NGS) together with protein expression analysis is back bone of molecularly targeted therapy in precision medicine. Our retrospective study shows our experience with NGS of 324 genes in combination with protein expression in patients with advanced breast cancer (aBC). The primary purpose was to analyze the prevalence of individual genetic alterations combined with protein expression to define potential targets for an individualized therapy. Between April 2018 and September 2019, 41 patients with aBC were offered a NGS test. The test was used to detect clinically relevant genomic alterations and to support further targeted therapy decisions. Hormone receptors, ERBB2 of tumors and PD-L1 was stained by immunohistochemistry. The data was recorded up to September 2019. After prior consent 41 results were available for further analysis. The most common BC subtypes were triple-negative (n = 16), HR+/ERBB2− (n = 15), and ERBB2+ (n = 9), with one missing data of the primary tumor. 27 patients had more than one genetic alteration. The most common alterations were PIK3CA (n = 14) and ERBB2 alterations (n = 11). Followed by ESR1 (n = 10), FGFR1 (n = 7) and PTEN (n = 7). 68% of the alterations were clinically relevant (tier I and II of ESCAT classification). The most common treatment recommendation was ERBB2-directed therapy (single or double blockade, trastuzumab emtansine and lapatinib) followed by alpelisib in combination with fulvestrant. Comprehensive genomic profiling combined with protein expression analysis in aBC allowed a guided personalized therapy for half of our patients. So far there are no well-defined tools allowing interpretations of genomic alterations detected by NGS in combination with protein expression and other factors.

In modern medicine, Clinical Practice Guidelines (CPGs) are well-established resources for the appropriate treatment of diseases. Evidence-based CPGs contain recommendations which are based on the state of the art and which have been achieved by consensus of several experts. Nevertheless, there is a potential for problems in translating guideline documents into specific actions for physicians. Therefore we propose to formalize the treatment process in an understandable representation as UML activities together with a domain expert. This formalization serves as a basis for the transfer of knowledge into a model, in this case PROforma, which directly allows execution in an interactive assistance software. The results of this work are part of an ongoing research project on the treatment of colon cancer based on the corresponding evidence-based CPG.

// Veronika Reidel 1 , Johanna Kauschinger 1 , Richard T. Hauch 1 , Catharina Muller-Thomas 1 , Niroshan Nadarajah 2 , Rainer Burgkart 3 , Burkhard Schmidt 4 , Dirk Hempel 5 , Anne Jacob 1 , Julia Slotta-Huspenina 6 , Ulrike Hockendorf 1 , Christian Peschel 1, 7 , Wolfgang Kern 2 , Torsten Haferlach 2 , Katharina S. Gotze 1, 7 , Stefanie Jilg 1, * and Philipp J. Jost 1, 7, * 1 Medizinische Klinik fur Hamatologie und Internistische Onkologie, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany 2 Munich Leukemia Laboratory (MLL), Munich, Germany 3 Klinik fur Orthopadie und Sportorthopadie, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany 4 Gemeinschaftspraxis Hamato-Onkologie Pasing, Munich, Germany 5 Onkologisches Zentrum Donauworth, Donauworth, Germany 6 Institut fur Pathologie, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany 7 Deutsche Konsortium fur translationale Krebsforschung (DKTK) of the German Cancer Research Center (DKFZ), Heidelberg, Germany * These authors contributed equally to this work Correspondence to: Philipp J. Jost, email: philipp.jost@tum.de Keywords: apoptosis; BCL-2 family; ABT-199; myelodysplastic syndromes; myeloid malignancy; Autophagy Received: November 14, 2017 Accepted: February 25, 2018 Published: April 03, 2018 ABSTRACT Somatic mutations in genes such as ASXL1 , RUNX1 , TP53 or EZH2 adversely affect the outcome of patients with myelodysplastic syndromes (MDS). Since selective BCL-2 inhibition is a promising treatment strategy in hematologic malignancies, we tested the therapeutic impact of ABT-199 on MDS patient samples bearing an adverse mutational profile. By gene expression, we found that the level of pro-apoptotic BIM significantly decreased during MDS disease progression in line with an acquired resistance to cell death. Supporting the potential for ABT-199 treatment in MDS, high-risk MDS patient samples specifically underwent cell death in response to ABT-199 even when harbouring mutations in ASXL1 , RUNX1 , TP53 or EZH2 . ABT-199 effectively targeted the stem- and progenitor compartment in advanced MDS harbouring mutations in ASXL1 , RUNX1 , TP53 or EZH2 and even proved effective in patients harbouring more than one of the defined high-risk mutations. Moreover, we utilized the protein abundance of BCL-2 family members in primary patient samples using flow cytometry as a biomarker to predict ABT-199 treatment response. Our data demonstrate that ABT-199 effectively induces apoptosis in progenitors of high-risk MDS/sAML despite the presence of adverse genetic mutations supporting the notion that pro-apoptotic intervention will hold broad therapeutic potential in high-risk MDS patients with poor prognosis.

Introduction Targeting the cell cycle machinery represents a rational therapeutic approach in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). Despite substantial response rates, clinical use of the PLK inhibitor volasertib has been hampered by elevated side effects such as neutropenia and infections. Objectives The primary objective was to analyse whether a reduced dose of volasertib was able to limit toxic effects on the healthy haematopoiesis while retaining its therapeutic effect. Methods Bone marrow mononuclear cells (BMMNCs) of patients with MDS/sAML (n = 73) and healthy controls (n = 28) were treated with volasertib (1 μM to 1 nM) or vehicle control. Short-term viability analysis was performed by flow cytometry after 72 hours. For long-term viability analysis, colony-forming capacity was assessed after 14 days. Protein expression of RIPK3 and MCL-1 was quantified via flow cytometry. Results Reduced dose levels of volasertib retained high cell death-inducing efficacy in primary human stem and progenitor cells of MDS/sAML patients without affecting healthy haematopoiesis in vitro. Interestingly, volasertib reduced colony-forming capacity and cell survival independent of clinical stage or mutational status. Conclusions Volasertib offers a promising therapeutic approach in patients with adverse prognostic profile. RIPK3 and MCL-1 might be potential biomarkers for sensitivity to volasertib treatment.

Patients with Myelodysplastic Syndromes (MDS) and secondary Acute Myeloid Leukemia (sAML) have a very poor prognosis after failure of hypomethylating agents (HMA). Stem cell transplantation is the only effective salvage therapy, for which only a limited number of patients are eligible due to age and comorbidity. Combination therapy of venetoclax and azacitidine (5-AZA) seems to be a promising approach in myeloid malignancies, but data from patients with HMA failure are lacking. Furthermore, a considerable concern of combination regimens in elderly AML and MDS patients is the toxicity on the remaining healthy hematopoiesis. Here, we report in vitro data showing the impact of venetoclax and 5-AZA, alone or in combination, in a larger cohort of MDS/sAML patients (n = 21), even after HMA failure (n = 13). We especially focused on the effects on healthy hematopoiesis and the impact on colony forming capacity as a parameter for long-term effects. To the best of our knowledge, we show for the first time that venetoclax in combination with capped dose of 5-AZA targets cell malignancies, while sparing healthy hematopoiesis. Electronic supplementary material The online version of this article (10.1186/s40164-019-0133-1) contains supplementary material, which is available to authorized users.

e13005 Background: Next generation sequencing (NGS) together with protein expression analysis is back bone of molecularly targeted therapy in precision medicine. The present study shows the retrospective analysis of our experience with NGS using a panel of 324 genes in combination with protein expression in patients with metastatic breast cancer (mBC) over the last 18 months. The primary objective of this study was to analyze the prevalence of individual genetic alterations combined with protein expression to define potential targets for an individualized therapy. Methods: We analyzed 41 patients with advanced BC using solid tumor genomic profiling test. The test was used to detect clinically relevant genomic alterations (point mutations, indels, rearrangements, CNAs, tumor mutation burden (TMB) and microsatellite instability (MSI)) and to support the selection of appropriate targeted therapy. The protein expression (hormon receptors, ERBB2 and PDL1) of tumors was analyzed by immunohistochemistry (IHC). Results: The most common BC subtypes were HR+/ERBB2- (n = 20), followed by triple-negative (n = 15), and HER2+ BC (n = 9). 41 different genetic alterations were reported. Most patients had more than one genetic alteration (n = 27), as determined by NGS. The most common alterations were PIK3CA (n = 14), out of which 11 (78%) were hormone-receptor positive/ERBB2 negative. Conclusions: The NGS of mBC supports the decision for the most promising treatment option in 58,5% of our patients with a Tier I evidence. For an appropriate treatment decision it is necessary to evaluate gene alterations und protein expression of metastases in account. For an appropriate interpretation of rare gene alterations in mBC basket trials on basis of real world data are necessary. We founded the OnkoVision alliance to bring MTB into clinically routine and to identify appropriate patients for basket trials.

Recommendations for actions included in a Clin- ical Practice Guideline (CPG) provide a reference framework for medical experts during diagnostic processes. To support the implementation of these recommendations, we propose an interactive decision support. In order to realize this, the diagnostic processes in the CPGs of Mantle Cell Lymphoma (MCL) and Multiple Myeloma (MM) are formalized using activities of the Unified Modeling Language (UML). Based on UML activities, a Bayesian Network is generated. The resulting models enable an assistance function allowing for patient specific CPG recommendations and subsequently for a suitable as well as personalized diagnosis embedded in an interactive Decision Support System (DSS).

In contemporary medicine, diagnostic processes provided by Clinical Practice Guidelines (CPGs) play a key role. A CPG provides recommendations that open up a scope of actions for the medical practitioner. But there is a gap between theoretical knowledge and practical solutions. Furthermore, barriers of implementation can arise. Taking these challenges into account, we propose a framework for facilitating the implementation of diagnostic processes. For this reason, the CPGs of Chronic Myeloid Leukemia (CML) and Myelodysplastic Syndromes (MDS) are modeled using Unified Modeling Language (UML). A UML activity serves as a basis for more complex models that are used to provide the actual assistance functions. This paper focuses on the automatic translation of UML activities into Petri nets.

Primary focus of the therapy of metastatic breast cancer is currently a systemic therapy. Surgical therapies are of minor importance. Aim of this study was to investigate the relevance of hepatectomy in case of hepatic breast cancer metastases (HBCM) as an important part of multimodal therapy.From January 2002 to December 2011, 30 patients with HBCM underwent hepatectomy. Criteria for hepatectomy were good condition, technical feasibility and control of extrahepatic metastases. For a heterogeneous group of women with HBCM the 3- and 5-year survival rate was determined by Kalpan-Meier survival estimate.The postoperative morbidity was 13.3%, the mortality rate was 3.3%. Minor hepatectomy has been performed in 62.1% and major hepatectomy in 37.9% of the cases. In all patients a R0 resection margin was performed. At a median follow-up interval of 34.1 months, 16 patients were still alive. The 3- and 5-year survival rates after surgically resection of HBCM in our collective were 31.0% and 20.7%.Hepatectomy is a safe therapy with low morbidity, mortality and improves long-term survival in most patients with limited, resectable HBCM. In our opinion patient selection should not be that strict. The combination of systemic and surgical therapies can improve prognosis and long-term survival of these patients.

e18545Background: The project aims to develop and implement a computerized interactive assistance system for the diagnosis and treatment of CML / MPN and MDS. The system is based on modulated, esta...

The project aims to develop and implement a computerized interactive assistance system for the diagnosis and treatment of CML / MPN and MDS. The system is based on modulated, established medical guidelines with reference to the individual patient information. The user is navigated through the complex recommendations of current guidelines and decision trees of the CML/MPN and MDS, similarly to a car navigation system. The system was developed in cooperation between the Steinbeis Institute for Clinical haematooncology and the Fraunhofer IOSB in Karlsruhe. In addition to the guidelines, recommendations on current evidence-based research results will be incorporated into the expert system. The medical user is hereby offered a systematic decision support. In addition, the decisions are documented and visualized in an intuitive user interface. The expert system is also able to point to currently recruiting therapy studies. The future system is planned to be self-learning by weighing the decision criteria. It will adjust the decision criteria by increasing usage and possibly readjusted criteria. Technical implementation and advantages of this solution: From a technical perspective, the knowledge-based system should be implemented as a client-server architecture. The server acts as a central data storage, for example, in the form of a database. As a client, for example, Internet browsers can be used. So it is possible to centrally reproach the accumulated knowledge and to present the current results to each user. The advantage of such a technical solution compared to guidelines-books is rapidly adaptable knowledge on new research results, as well as the implementation of a self-learning system. The system design has to pay particular attention to an intuitive user interface. On the server's side, the knowledge of guidelines and interviews with experts have to be formalized in an appropriate manner. There are approaches based on an ontological or logic-based modeling. On the client's, side the system suggests the user appropriate decision for the diagnosis and further treatment of diseases. The underlying methodology is based on approaches from artificial intelligence, such as the Bayesian inference or machine learning methods. Disclosures Hempel: Novartis and Celgene: Research Funding.

131 Introduction. Autologous stem cell transplantation (ASCT) after cytoreductive induction is considered standard of care for younger patients (pts) with multiple myeloma (MM). The previous standard of induction, the Vincristin-Adriamycin-Dexamethasone (VAD) combination, achieves inferior results compared with induction regimens which combine the proteasome inhibitor Velcade (V = Bortezomib) with Dexamethasone (D)(=VD) and a cytostatic drug such as Doxorubicin (PAD = VD plus Doxorubicin). Velcade-based induction therapy was shown to translate into better myeloma control after high dose melphalan and to lead to prolonged progression-free survival. In order to find a more efficacious and safer drug combination for induction therapy in MM, we tested the combination of Velcade with Cyclophosphamide and Dexamethasone (VCD). Methods. This trial was designed as an open, prospective, multi-center, uncontrolled, combined phase II/III study. As previously reported (Kropff M et al., Ann Hematol 2009), in the first 30 pts the optimal dose of iv Cyclophosphamide in combination with V and D was defined as 900 mg/m2 on d1. Between 03/2006 and 03/2009 we enrolled an additional 370 pts up to 60 years of age with untreated MM to receive three 3-week cycles of induction treatment with V 1.3 mg/m2 iv d1,4,8,11; D 40 mg/d orally d1,2,4,5,8,9,11,12; and C 900mg/m2 iv d1 before scheduled high dose melphalan and ASCT. The primary endpoint of the study is response rate on day 63 after 3 cycles of VCD according to EBMT and IMWG criteria. Results. Final data from 400 pts from 39 German centers will be presented at the meeting. In the currently evaluable 300 pts (mean age 52.3 years; 1.7% stage I, 21.3% stage II, 77.0% stage III) molecular cytogenetic analysis showed a prevalence of 13q- in 38%, of t[4;14] in 13% and of 17p- in 12% of pts (no changes in 35%). All 300 pts (88.3% of whom completed three cycles) were included in the intent-to-treat analysis. Overall response rate (ORR = CR+PR) was 84%, with 10% CR and 74% PR, 5.7% MR, 7.3% NC and 2.3% PD. The negative prognostic impact of 13q- or t[4;14] was abrogated (ORR normal 87.3%, 13q- 83.7%, t[4;14] 90.0%), the unfavorable influence of p53 loss in the 17p- subgroup was still detectable (ORR 69.2%) but this did not reach statistical significance. VGPR rates will be reported at the meeting. Serious adverse events were documented in 78/300 (26.0%) patients. Death rate was remarkably low (1.3%, of which one was not related to the trial medication). 155/300 (52%) of pts experienced grade 3/4 non-serious AEs and of these leucopenia (93/300 pts= 31%), thrombocytopenia (7%), neutropenia (6%), anaemia (5%) were the most frequent events. 80 AEs grade 3 or 4 and 45 SAEs were of infectious origin and occurred in 47/300 pts. 80/130 SAEs (61.5%) were at least possibly related to Velcade. 101/300 pts (34%) developed episodes of peripheral neuropathy. PNP was grade 1 in 62/300 pt (20.7%), grade 2 in 31/300 pt (10.3%) and grade 3 in 7/300 pts (2.3%). Conclusion. This analysis demonstrates that proteasome inhibition by Velcade in combination with Dexamethasone and iv Cyclophosphamide (VCD) is an induction regimen for newly diagnosed MM which is highly effective in a short period of time, has a rather low toxicity profile and is feasible for administration in an outpatient setting. Based on these characteristics, VCD qualifies to become a new standard for MM induction therapy. | Response to VCD | % | |:---------------:| --- | | ORR | 84 | | CR | 10 | | PR | 74 | | MR | 5.7 | | SD | 7.3 | | PD | 2.3 | Table 1: Response to study therapy (intent-to-treat set, according to investigator, n=300) | | Responding patients (≥ PR) | |:-------------------:| -------------------------- | ---- | | n | % | | No FISH abnormality | 69/79 | 87.3 | | 13q- | 72/86 | 83.7 | | t(4;14) | 27/30 | 90 | | 17p- | 18/26 | 69.2 | | Other | 68/77 | 88.3 | Table 2: Response by result of cytogenetic analysis (intent-to-treat set, according to investigator, n=300) Disclosures: Einsele: OrthioBiotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Bortezomib is licensed as monotherapy for use in relapsed/refractory MM and in combination with melphalan/Prednisone in the first-line treatment of MM pts ineligible for HD-MEL and ASCT. . Liebisch: OrthoBiotech: Consultancy, Honoraria. Langer: OrthoBiotech: Consultancy. Kropff: OrthoBiotech: Consultancy, Honoraria. Kroger: OrthoBiotech: Honoraria. Ostermann: OrthoBiotech: Honoraria. Mugge: OrthoBiotech: Honoraria. Wolf: OrthoBiotech: Honoraria. Gramatzki: OrthoBiotech: Consultancy, Honoraria. Maschmeyer: OrthoBiotech: Travel Grant. Sezer: OrthoBiotech: Consultancy, Honoraria. Heidemann: OrthoBiotech: Honoraria. Jager: OrthoBiotech: Honoraria. Dechow: Celgene: Research Funding. Simon: OrthoBiotech: Honoraria. Straka: OrthoBiotech: Consultancy, Honoraria, Research Funding. Fingerle-Rowson: orthoBiotech: Employment. Knop: OrthoBiotech: Honoraria.