Publications by authors named "Christoph Heining"

21 Publications

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Sarcoma classification by DNA methylation profiling.

Authors:
Christian Koelsche Daniel Schrimpf Damian Stichel Martin Sill Felix Sahm David E Reuss Mirjam Blattner Barbara Worst Christoph E Heilig Katja Beck Peter Horak Simon Kreutzfeldt Elke Paff Sebastian Stark Pascal Johann Florian Selt Jonas Ecker Dominik Sturm Kristian W Pajtler Annekathrin Reinhardt Annika K Wefers Philipp Sievers Azadeh Ebrahimi Abigail Suwala Francisco Fernández-Klett Belén Casalini Andrey Korshunov Volker Hovestadt Felix K F Kommoss Mark Kriegsmann Matthias Schick Melanie Bewerunge-Hudler Till Milde Olaf Witt Andreas E Kulozik Marcel Kool Laura Romero-Pérez Thomas G P Grünewald Thomas Kirchner Wolfgang Wick Michael Platten Andreas Unterberg Matthias Uhl Amir Abdollahi Jürgen Debus Burkhard Lehner Christian Thomas Martin Hasselblatt Werner Paulus Christian Hartmann Ori Staszewski Marco Prinz Jürgen Hench Stephan Frank Yvonne M H Versleijen-Jonkers Marije E Weidema Thomas Mentzel Klaus Griewank Enrique de Álava Juan Díaz Martín Miguel A Idoate Gastearena Kenneth Tou-En Chang Sharon Yin Yee Low Adrian Cuevas-Bourdier Michel Mittelbronn Martin Mynarek Stefan Rutkowski Ulrich Schüller Viktor F Mautner Jens Schittenhelm Jonathan Serrano Matija Snuderl Reinhard Büttner Thomas Klingebiel Rolf Buslei Manfred Gessler Pieter Wesseling Winand N M Dinjens Sebastian Brandner Zane Jaunmuktane Iben Lyskjær Peter Schirmacher Albrecht Stenzinger Benedikt Brors Hanno Glimm Christoph Heining Oscar M Tirado Miguel Sáinz-Jaspeado Jaume Mora Javier Alonso Xavier Garcia Del Muro Sebastian Moran Manel Esteller Jamal K Benhamida Marc Ladanyi Eva Wardelmann Cristina Antonescu Adrienne Flanagan Uta Dirksen Peter Hohenberger Daniel Baumhoer Wolfgang Hartmann Christian Vokuhl Uta Flucke Iver Petersen Gunhild Mechtersheimer David Capper David T W Jones Stefan Fröhling Stefan M Pfister Andreas von Deimling

Nat Commun 2021 01 21;12(1):498. Epub 2021 Jan 21.

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
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http://dx.doi.org/10.1038/s41467-020-20603-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819999PMC
January 2021

Prolonged Survival of a Patient with Advanced-Stage Combined Hepatocellular-Cholangiocarcinoma.

Case Rep Gastroenterol 2020 Sep-Dec;14(3):658-667. Epub 2020 Dec 10.

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Combined hepatocellular-cholangiocarcinoma (cHCC/CCA) represents a rare type of primary liver cancer with a very limited prognosis. Although just recently genomic studies have contributed to a better understanding of the disease's genetic landscape, therapeutic options, especially for advanced-stage patients, are limited and often experimental, as no standardized treatment protocols have been established to date. Here, we report the case of a 38-year-old male patient who was diagnosed with extensive intrahepatic cHCC/CCA in an otherwise healthy liver without signs of chronic liver disease. An interdisciplinary stepwise therapeutic approach including locoregional liver-targeted therapy, systemic chemotherapy, liver transplantation, surgical pulmonary metastasis resection, and next-generation sequencing-based targeted therapy led to a prolonged overall survival beyond 5 years with an excellent quality of life. This case report comprises several provocative treatment decisions that are extensively discussed in light of the existing literature on this rare but highly aggressive malignancy.
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http://dx.doi.org/10.1159/000511034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772835PMC
December 2020

Integrating proteomics into precision oncology.

Int J Cancer 2021 Mar 25;148(6):1438-1451. Epub 2020 Sep 25.

Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.

DNA sequencing and RNA sequencing are increasingly applied in precision oncology, where molecular tumor boards evaluate the actionability of genetic events in individual tumors to guide targeted treatment. To work toward an additional level of patient characterization, we assessed the abundance and activity of 27 proteins in 134 patients whose tumors had previously undergone whole-exome and RNA sequencing within the Molecularly Aided Stratification for Tumor Eradication Research (MASTER) program of National Center for Tumor Diseases, Heidelberg. Proteomic and phosphoproteomic targets were selected to reflect the most relevant therapeutic baskets in MASTER. Among six different therapeutic baskets, the proteomic data supported treatment recommendations that were based on DNA and RNA analyses in 10% to 57% and frequently suggested alternative treatment options. In several cases, protein activities explained the patients' clinical course and provided potential explanations for treatment failure. Our study indicates that the integrative analysis of DNA, RNA and protein data may refine therapeutic stratification of individual patients and, thus, holds potential to increase the success rate of precision cancer therapy. Prospective validation studies are needed to advance the integration of proteomic analysis into precision oncology.
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http://dx.doi.org/10.1002/ijc.33301DOI Listing
March 2021

Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series.

Oncologist 2021 Jan 23;26(1):7-16. Epub 2020 Sep 23.

University of British Columbia, BC Cancer, Vancouver, British Columbia, Canada.

Background: Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors.

Patients And Methods: This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib.

Results: The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day.

Conclusion: This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors.

Key Points: NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.
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http://dx.doi.org/10.1634/theoncologist.2020-0379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794194PMC
January 2021

Germline SDHB-inactivating mutation in gastric spindle cell sarcoma.

Genes Chromosomes Cancer 2020 10 26;59(10):601-608. Epub 2020 Jun 26.

Department of Translational Medical Oncology, National Center for Tumor Diseases Heidelberg and German Cancer Research Center, Heidelberg, Germany.

Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. Inactivating mutations or epigenetic deregulation of succinate dehydrogenase complex (SDH) genes are considered defining features of a subset of GIST occurring in the stomach. Based on comprehensive molecular profiling and biochemical analysis within a precision oncology program, we identified hallmarks of SDH deficiency (germline SDHB-inactivating mutation accompanied by somatic loss of heterozygosity, lack of SDHB expression, global DNA hypermethylation, and elevated succinate/fumarate ratio) in a 40-year-old woman with undifferentiated gastric spindle cell sarcoma that did not meet the diagnostic criteria for other mesenchymal tumors of the stomach, including GIST. These data reveal that the loss of SDH function can be involved in the pathogenesis of non-GIST sarcoma of the gastrointestinal tract.
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http://dx.doi.org/10.1002/gcc.22876DOI Listing
October 2020

The landscape of chromothripsis across adult cancer types.

Nat Commun 2020 05 8;11(1):2320. Epub 2020 May 8.

Group Genome Instability in Tumors, DKFZ, Heidelberg, Germany.

Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. Here we analyse chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals insights in the clonal evolution of tumours with chromothripsis.
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http://dx.doi.org/10.1038/s41467-020-16134-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210959PMC
May 2020

Metastatic adult pancreatoblastoma: Multimodal treatment and molecular characterization of a very rare disease.

Pancreatology 2020 Apr 29;20(3):425-432. Epub 2020 Feb 29.

Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) and DKFZ Dresden, Dresden, Germany; Center for Personalized Oncology, National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus Dresden at TU Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany. Electronic address:

Background: Pancreatoblastoma is a rare malignancy that occurs predominantly in children. Less than 50 adult cases, including 17 patients with metastatic disease, have been published to date. Recent outcome data from children with advanced-stage disease suggest an intensive multimodal treatment approach; however, little is known about the most beneficial therapy in adults. Molecular characterization of pancreatoblastoma is limited to a small number of pediatric cases and revealed few recurrent genetic events without immediate clinical relevance.

Methods: Patients were treated between 2013 and 2018 at a high-volume German university cancer center. Molecular analyses included whole genome, exome, transcriptome, and fusion gene panel sequencing. Molecularly guided treatment recommendations were discussed within a dedicated molecular tumor board (MTB) embedded in a precision oncology program (NCT MASTER).

Results: We identified four adult patients with metastatic pancreatoblastoma. In three patients, local approaches were combined with systemic treatment. Oxaliplatin-containing protocols showed an acceptable tumor control as well as an adequate toxicity profile. Overall survival was 15, 17, 18 and 24 months, respectively. Three tumors harbored genetic alterations involving the FGFR pathway that included an oncogenic FGFR2 fusion.

Conclusion: Oxaliplatin-containing chemotherapy seems to be a reasonable approach in adult patients with advanced pancreatoblastoma, whereas the benefit of intensified treatment including local ablative techniques or surgical resection remains unclear. Our finding of FGFR alterations in three of four cases indicates a potential role of FGFR signaling in adult pancreatoblastoma whose clinical significance warrants further study.
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http://dx.doi.org/10.1016/j.pan.2020.02.017DOI Listing
April 2020

Targetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumors.

J Clin Invest 2020 05;130(5):2488-2495

Heidelberg Center for Personalized Oncology (HIPO), DKFZ, Heidelberg, Germany.

BACKGROUNDNeurofibroma/schwannoma hybrid nerve sheath tumors (N/S HNSTs) are neoplasms associated with larger nerves that occur sporadically and in the context of schwannomatosis or neurofibromatosis type 2 or 1. Clinical management of N/S HNSTs is challenging, especially for large tumors, and established systemic treatments are lacking.METHODSWe used next-generation sequencing and array-based DNA methylation profiling to determine the clinically actionable genomic and epigenomic landscapes of N/S HNSTs.RESULTSWhole-exome sequencing within a precision oncology program identified an activating mutation (p.Asp769Tyr) in the catalytic domain of the ERBB2 receptor tyrosine kinase in a patient with schwannomatosis-associated N/S HNST, and targeted treatment with the small-molecule ERBB inhibitor lapatinib led to prolonged clinical benefit and a lasting radiographic and metabolic response. Analysis of a multicenter validation cohort revealed recurrent ERBB2 mutations (p.Leu755Ser, p.Asp769Tyr, p.Val777Leu) in N/S HNSTs occurring in patients who met diagnostic criteria for sporadic schwannomatosis (3 of 7 patients), but not in N/S HNSTs arising in the context of neurofibromatosis (6 patients) or outside a tumor syndrome (1 patient), and showed that ERBB2-mutant N/S HNSTs cluster in a distinct subgroup of peripheral nerve sheath tumors based on genome-wide DNA methylation patterns.CONCLUSIONThese findings uncover a key biological feature of N/S HNSTs that may have important diagnostic and therapeutic implications.FUNDINGThis work was supported by grant H021 from DKFZ-HIPO, the University Cancer Center Frankfurt, and the Frankfurt Research Funding Clinician Scientist Program.
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http://dx.doi.org/10.1172/JCI130787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190903PMC
May 2020

Community-driven development of a modified progression-free survival ratio for precision oncology.

ESMO Open 2019 13;4(6):e000583. Epub 2019 Nov 13.

Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Objective: Measuring the success of molecularly guided therapies is a major challenge in precision oncology trials. A commonly used endpoint is an intra-patient progression-free survival (PFS) ratio, defined as the PFS interval associated with molecularly guided therapy (PFS2) divided by the PFS interval associated with the last prior systemic therapy (PFS1), above 1.3 or, in some studies, above 1.33 or 1.5.

Methods: To investigate if the concept of PFS ratios is in agreement with actual response evaluations by physicians, we conducted a survey among members of the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Programme of the German Cancer Consortium who were asked to classify the success of molecularly guided therapies in 194 patients enrolled in the MOSCATO 01 trial based on PFS1 and PFS2 times.

Results: A comparison of classification profiles revealed three distinct clusters of PFS benefit assessments. Only 29% of assessments were consistent with a PFS ratio threshold of 1.3, whereas the remaining 71% of participants applied a different classification scheme that did not rely on the relation between PFS times alone, but also took into account absolute PFS1 intervals. Based on these community-driven insights, we developed a modified PFS ratio that incorporates the influence of absolute PFS1 intervals on the judgement of clinical benefit by physicians. Application of the modified PFS ratio to outcome data from two recent precision oncology trials, MOSCATO 01 and WINTHER, revealed significantly improved concordance with physician-perceived clinical benefit and identified comparable proportions of patients who benefited from molecularly guided therapies.

Conclusions: The modified PFS ratio may represent a meaningful clinical endpoint that could aid in the design and interpretation of future precision oncology trials.
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http://dx.doi.org/10.1136/esmoopen-2019-000583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863673PMC
June 2020

Identification and characterization of a BRAF fusion oncoprotein with retained autoinhibitory domains.

Oncogene 2020 01 26;39(4):814-832. Epub 2019 Sep 26.

Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Fusion proteins involving the BRAF serine/threonine kinase occur in many cancers. The oncogenic potential of BRAF fusions has been attributed to the loss of critical N-terminal domains that mediate BRAF autoinhibition. We used whole-exome and RNA sequencing in a patient with glioblastoma multiforme to identify a rearrangement between TTYH3, encoding a membrane-resident, calcium-activated chloride channel, and BRAF intron 1, resulting in a TTYH3-BRAF fusion protein that retained all features essential for BRAF autoinhibition. Accordingly, the BRAF moiety of the fusion protein alone, which represents full-length BRAF without the amino acids encoded by exon 1 (BRAF), did not induce MEK/ERK phosphorylation or transformation. Likewise, neither the TTYH3 moiety of the fusion protein nor full-length TTYH3 provoked ERK pathway activity or transformation. In contrast, TTYH3-BRAF displayed increased MEK phosphorylation potential and transforming activity, which were caused by TTYH3-mediated tethering of near-full-length BRAF to the (endo)membrane system. Consistent with this mechanism, a synthetic approach, in which BRAF was tethered to the membrane by fusing it to the cytoplasmic tail of CD8 also induced transformation. Furthermore, we demonstrate that TTYH3-BRAF signals largely independent of a functional RAS binding domain, but requires an intact BRAF dimer interface and activation loop phosphorylation sites. Cells expressing TTYH3-BRAF exhibited increased MEK/ERK signaling, which was blocked by clinically achievable concentrations of sorafenib, trametinib, and the paradox breaker PLX8394. These data provide the first example of a fully autoinhibited BRAF protein whose oncogenic potential is dictated by a distinct fusion partner and not by a structural change in BRAF itself.
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http://dx.doi.org/10.1038/s41388-019-1021-1DOI Listing
January 2020

Finding Options Beyond Standard of Care in Oncology: A Proposal for Workflows Utilizing Knowledge Databases.

Stud Health Technol Inform 2019 Aug;264:950-953

Division of Medical Informatics for Translational Oncology, German Cancer Research Center (DKFZ), Heidelberg, Baden Württemberg, Germany.

With the novel approach of molecularly stratified therapies based on genetic characteristics of individual tumors, the need for databases providing information on molecular alterations and targeted treatment options is increasing rapidly. In Molecular Tumor Boards (MTB) professionals discuss molecular alterations and provide biological context for therapeutic options using external knowledge databases. The identification of informative databases and the information on their specific contents can greatly facilitate and standardize the functioning of a MTB. In this work we present a list of databases which have been deemed useful and relevant for MTB in a clinical setting. We describe workflows to recommend the use of specific databases at different steps in the clinical curation process. Information obtained from these databases is a necessary prerequisite to evaluate molecular alterations and devise rational targeted therapies in MTB.
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http://dx.doi.org/10.3233/SHTI190364DOI Listing
August 2019

Variant classification in precision oncology.

Int J Cancer 2019 12 21;145(11):2996-3010. Epub 2019 May 21.

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Next-generation sequencing has become a cornerstone of therapy guidance in cancer precision medicine and an indispensable research tool in translational oncology. Its rapidly increasing use during the last decade has expanded the options for targeted tumor therapies, and molecular tumor boards have grown accordingly. However, with increasing detection of genetic alterations, their interpretation has become more complex and error-prone, potentially introducing biases and reducing benefits in clinical practice. To facilitate interdisciplinary discussions of genetic alterations for treatment stratification between pathologists, oncologists, bioinformaticians, genetic counselors and medical scientists in specialized molecular tumor boards, several systems for the classification of variants detected by large-scale sequencing have been proposed. We review three recent and commonly applied classifications and discuss their individual strengths and weaknesses. Comparison of the classifications underlines the need for a clinically useful and universally applicable variant reporting system, which will be instrumental for efficient decision making based on sequencing analysis in oncology. Integrating these data, we propose a generalizable classification concept featuring a conservative and a more progressive scheme, which can be readily applied in a clinical setting.
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http://dx.doi.org/10.1002/ijc.32358DOI Listing
December 2019

Defective homologous recombination DNA repair as therapeutic target in advanced chordoma.

Nat Commun 2019 04 9;10(1):1635. Epub 2019 Apr 9.

German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.

Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.
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http://dx.doi.org/10.1038/s41467-019-09633-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456501PMC
April 2019

Response to olaparib in a germline mutated prostate cancer and genetic events associated with resistance.

Cold Spring Harb Mol Case Stud 2019 04 1;5(2). Epub 2019 Apr 1.

Department of Urology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.

Prostate cancers harboring DNA repair gene alterations are particularly sensitive to PARP inhibitor treatment. We report a case of an advanced prostate cancer patient profiled within the NCT-MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program using next-generation sequencing. Comprehensive genomic and transcriptomic analysis identified a pathogenic germline variant as well as a mutational signature associated with disturbed homologous recombination together with structural genomic rearrangements. A molecular tumor board identified a potential benefit of targeted therapy and recommended PARP inhibition and platinum-based chemotherapy. Single-agent treatment with the PARP inhibitor olaparib as well as subsequent combination with platinum-based chemotherapy resulted in disease stabilization and substantial improvement of clinical symptoms. Upon progression, we performed whole-exome and RNA sequencing of a liver metastasis, which demonstrated up-regulation of several genes characteristic for the neuroendocrine prostate cancer phenotype as well as a novel translocation resulting in an in-frame, loss-of-function fusion of We suggest that multidimensional genomic characterization of prostate cancer patients undergoing PARP inhibitor therapy will be necessary to capture and understand predictive biomarkers of PARP inhibitor sensitivity and resistance.
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http://dx.doi.org/10.1101/mcs.a003657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549578PMC
April 2019

Fusions in Wild-Type Pancreatic Cancer.

Cancer Discov 2018 09 25;8(9):1087-1095. Epub 2018 May 25.

Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany.

We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with wild-type () tumors (4 of 17). These alterations included recurrent rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in 2 patients with -rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC. Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as fusions as disease-driving events in tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0036DOI Listing
September 2018

From somatic variants towards precision oncology: Evidence-driven reporting of treatment options in molecular tumor boards.

Genome Med 2018 03 15;10(1):18. Epub 2018 Mar 15.

Department of Medical Statistics, University Medical Center Göttingen, 37073, Göttingen, Germany.

Background: A comprehensive understanding of cancer has been furthered with technological improvements and decreasing costs of next-generation sequencing (NGS). However, the complexity of interpreting genomic data is hindering the implementation of high-throughput technologies in the clinical context: increasing evidence on gene-drug interactions complicates the task of assigning clinical significance to genomic variants.

Methods: Here we present a method that automatically matches patient-specific genomic alterations to treatment options. The method relies entirely on public knowledge of somatic variants with predictive evidence on drug response. The output report is aimed at supporting clinicians in the task of finding the clinical meaning of genomic variants. We applied the method to 1) The Cancer Genome Atlas (TCGA) and Genomics Evidence Neoplasia Information Exchange (GENIE) cohorts and 2) 11 patients from the NCT MASTER trial whose treatment discussions included information on their genomic profiles.

Results: Our reporting strategy showed a substantial number of patients with actionable variants in the analyses of TCGA and GENIE samples. Notably, it was able to reproduce experts' treatment suggestions in a retrospective study of 11 patients from the NCT MASTER trial. Our results establish a proof of concept for comprehensive, evidence-based reports as a supporting tool for discussing treatment options in tumor boards.

Conclusions: We believe that a standardized method to report actionable somatic variants will smooth the incorporation of NGS in the clinical context. We anticipate that tools like the one we present here will become essential in summarizing for clinicians the growing evidence in the field of precision medicine. The R code of the presented method is provided in Additional file 6 and available at https://github.com/jperera-bel/MTB-Report .
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http://dx.doi.org/10.1186/s13073-018-0529-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856211PMC
March 2018

Precision oncology based on omics data: The NCT Heidelberg experience.

Int J Cancer 2017 09 21;141(5):877-886. Epub 2017 Jun 21.

Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Precision oncology implies the ability to predict which patients will likely respond to specific cancer therapies based on increasingly accurate, high-resolution molecular diagnostics as well as the functional and mechanistic understanding of individual tumors. While molecular stratification of patients can be achieved through different means, a promising approach is next-generation sequencing of tumor DNA and RNA, which can reveal genomic alterations that have immediate clinical implications. Furthermore, certain genetic alterations are shared across multiple histologic entities, raising the fundamental question of whether tumors should be treated by molecular profile and not tissue of origin. We here describe MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a clinically applicable platform for prospective, biology-driven stratification of younger adults with advanced-stage cancer across all histologies and patients with rare tumors. We illustrate how a standardized workflow for selection and consenting of patients, sample processing, whole-exome/genome and RNA sequencing, bioinformatic analysis, rigorous validation of potentially actionable findings, and data evaluation by a dedicated molecular tumor board enables categorization of patients into different intervention baskets and formulation of evidence-based recommendations for clinical management. Critical next steps will be to increase the number of patients that can be offered comprehensive molecular analysis through collaborations and partnering, to explore ways in which additional technologies can aid in patient stratification and individualization of treatment, to stimulate clinically guided exploratory research projects, and to gradually move away from assessing the therapeutic activity of targeted interventions on a case-by-case basis toward controlled clinical trials of genomics-guided treatments.
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http://dx.doi.org/10.1002/ijc.30828DOI Listing
September 2017

Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with amplification.

Cold Spring Harb Mol Case Stud 2016 11;2(6):a001180

Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;; Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany;; German Cancer Consortium (DKTK), Heidelberg 69120, Germany.

Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision-making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multiagent chemotherapy. Molecular profiling within a clinical whole-exome and transcriptome sequencing program revealed a heterozygous, highly amplified G12S mutation, compound-heterozygous mutation/deletion, high mutational load, and focal high-level amplification of Chromosomes 9p (including [] and ) and 10p (including ). Integrated analysis of molecular data and histopathology provided a rationale for immune checkpoint inhibitor (ICI) therapy with pembrolizumab, which resulted in rapid clinical improvement and a lasting partial remission. Histopathological analyses ruled out sarcoma and established the diagnosis of a poorly differentiated adenocarcinoma. Although neither histopathology nor molecular data were able to pinpoint the tissue of origin, our analyses established several differential diagnoses including triple-negative breast cancer (TNBC). We analyzed 157 TNBC samples from The Cancer Genome Atlas, revealing copy number gains coinciding with excessive mRNA expression in 24% of cases. Collectively, these results illustrate the impact of multidimensional tumor profiling in cases with nondescript histology and immunophenotype, show the predictive potential of amplification for immune checkpoint inhibitors (ICIs) and suggest a targeted therapeutic strategy in Chromosome 9p24.1/-amplified cancers.
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http://dx.doi.org/10.1101/mcs.a001180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111004PMC
November 2016

Targeting Fibroblast Growth Factor Receptor 1 for Treatment of Soft-Tissue Sarcoma.

Clin Cancer Res 2017 Feb 17;23(4):962-973. Epub 2016 Aug 17.

Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Altered FGFR1 signaling has emerged as a therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties of FGFR1 and its potential as a drug target in patients with STS. The frequency of amplification and overexpression, as assessed by FISH, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis. Increased copy number was detected in 74 of 190 (38.9%; cohort 1), 13 of 79 (16.5%; cohort 2), and 80 of 254 (31.5%; cohort 3) patients. overexpression occurred in 16 of 79 (20.2%, cohort 2) and 39 of 254 (15.4%; cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK-ERK1/2 axis as critical FGFR1 effector pathway. These data identify as a driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to the FGFR1 expression and monitoring of MAPK-ERK1/2 signaling, as a therapeutic option in this challenging group of diseases. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0860DOI Listing
February 2017

Dose-intensified bendamustine followed by autologous peripheral blood stem cell support in relapsed and refractory multiple myeloma with impaired bone marrow function.

Hematol Oncol 2016 Dec 18;34(4):200-207. Epub 2015 Mar 18.

Max-Eder-Group 'Experimental Therapies for Hematologic Malignancies', Department of Medicine V, Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Therapeutic options in heavily pretreated relapsed/refractory multiple myeloma patients are often very limited because of impaired bone marrow function. Bendamustine is effective in multiple myeloma and has a favourable toxicity profile. We hypothesized that dose-intensified bendamustine (180 mg/m , day 1 and 2) followed by autologous blood stem cell support (ASCS) would improve bone marrow function with low post-transplant toxicity in patients with severely impaired haematopoiesis. We analyzed 28 consecutive myeloma patients, with a median of three prior lines of therapy (range 2-7), who had relapsed from the last treatment with very limited bone marrow function and were therefore ineligible for conventional chemotherapy, novel agents or trial enrolment. Dose-intensified bendamustine with ASCS improved haematopoiesis as reflected by increased platelet counts (median 40/nl vs 94/nl, p = 0.0004) and white blood cell counts (3.0/nl vs 4.8/nl, p = 0.02) at day +100. The median time until engraftment of platelets (>50/nl) was 11 days (0-24 days) and of white cell counts (>1.0/nl) 0 days (0-24 days). At least, a minimal response was achieved in 36% of patients. The disease stabilization rate was 50% while the median progression-free survival rate was limited to 2.14 months. Most importantly, patients were once again eligible for alternative treatments including enrolment into clinical trials. We conclude that dose-intensified bendamustine followed by ASCS is safe and feasible for multiple myeloma patients with very limited bone marrow reserve. Copyright © 2015 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/hon.2199DOI Listing
December 2016

Targeting the BRAF V600E mutation in multiple myeloma.

Cancer Discov 2013 Aug 23;3(8):862-9. Epub 2013 Apr 23.

Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

In multiple myeloma, there has been little progress in the specific therapeutic targeting of oncogenic mutations. Whole-genome sequencing data have recently revealed that a subset of patients carry an activating mutation (V600E) in the BRAF kinase. To uncover the clinical relevance of this mutation in multiple myeloma, we correlated the mutation status in primary tumor samples from 379 patients with myeloma with disease outcome. We found a significantly higher incidence of extramedullary disease and a shorter overall survival in mutation carriers when compared with controls. Most importantly, we report on a patient with confirmed BRAF V600E mutation and relapsed myeloma with extensive extramedullary disease, refractory to all approved therapeutic options, who has rapidly and durably responded to low doses of the mutation-specific BRAF inhibitor vermurafenib. Collectively, we provide evidence for the development of the BRAF V600E mutation in the context of clonal evolution and describe the prognostic and therapeutic relevance of this targetable mutation.
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http://dx.doi.org/10.1158/2159-8290.CD-13-0014DOI Listing
August 2013