Background Structured and harmonized implementation of molecular tumor boards (MTB) for the clinical interpretation of molecular data presents a current challenge for precision oncology. ...Heterogeneity in the interpretation of molecular data was shown for patients even with a limited number of molecular alterations. Integration of high-dimensional molecular data, including RNA- (RNA-Seq) and whole-exome sequencing (WES), is expected to further complicate clinical application. To analyze challenges for MTB harmonization based on complex molecular datasets, we retrospectively compared clinical interpretation of WES and RNA-Seq data by two independent molecular tumor boards. Methods High-dimensional molecular cancer profiling including WES and RNA-Seq was performed for patients with advanced solid tumors, no available standard therapy, ECOG performance status of 0-1, and available fresh-frozen tissue within the DKTK-MASTER Program from 2016 to 2018. Identical molecular profiling data of 40 patients were independently discussed by two molecular tumor boards (MTB) after prior annotation by specialized physicians, following independent, but similar workflows. Identified biomarkers and resulting treatment options were compared between the MTBs and patients were followed up clinically. Results A median of 309 molecular aberrations from WES and RNA-Seq (n = 38) and 82 molecular aberrations from WES only (n = 3) were considered for clinical interpretation for 40 patients (one patient sequenced twice). A median of 3 and 2 targeted treatment options were identified per patient, respectively. Most treatment options were identified for receptor tyrosine kinase, PARP, and mTOR inhibitors, as well as immunotherapy. The mean overlap coefficient between both MTB was 66%. Highest agreement rates were observed with the interpretation of single nucleotide variants, clinical evidence levels 1 and 2, and monotherapy whereas the interpretation of gene expression changes, preclinical evidence levels 3 and 4, and combination therapy yielded lower agreement rates. Patients receiving treatment following concordant MTB recommendations had significantly longer overall survival than patients receiving treatment following discrepant recommendations or physician's choice. Conclusions Reproducible clinical interpretation of high-dimensional molecular data is feasible and agreement rates are encouraging, when compared to previous reports. The interpretation of molecular aberrations beyond single nucleotide variants and preclinically validated biomarkers as well as combination therapies were identified as additional difficulties for ongoing harmonization efforts. Keywords: Precision oncology, Whole-exome sequencing, RNA-sequencing, Clinical interpretation, Targeted therapy, Molecular tumor board
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We present the Berlin-Tübingen-Oncology corpus (BRONCO), a large and freely available corpus of shuffled sentences from German oncological discharge summaries annotated with diagnosis, treatments, ...medications, and further attributes including negation and speculation. The aim of BRONCO is to foster reproducible and openly available research on Information Extraction from German medical texts.
BRONCO consists of 200 manually deidentified discharge summaries of cancer patients. Annotation followed a structured and quality-controlled process involving 2 groups of medical experts to ensure consistency, comprehensiveness, and high quality of annotations. We present results of several state-of-the-art techniques for different IE tasks as baselines for subsequent research.
The annotated corpus consists of 11 434 sentences and 89 942 tokens, annotated with 11 124 annotations for medical entities and 3118 annotations of related attributes. We publish 75% of the corpus as a set of shuffled sentences, and keep 25% as held-out data set for unbiased evaluation of future IE tools. On this held-out dataset, our baselines reach depending on the specific entity types F1-scores of 0.72-0.90 for named entity recognition, 0.10-0.68 for entity normalization, 0.55 for negation detection, and 0.33 for speculation detection.
Medical corpus annotation is a complex and time-consuming task. This makes sharing of such resources even more important.
To our knowledge, BRONCO is the first sizable and freely available German medical corpus. Our baseline results show that more research efforts are necessary to lift the quality of information extraction in German medical texts to the level already possible for English.
Abstract
The benefit of molecularly-informed therapies in cancer of unknown primary (CUP) is unclear. Here, we use comprehensive molecular characterization by whole genome/exome, transcriptome and ...methylome analysis in 70 CUP patients to reveal substantial mutational heterogeneity with
TP53
,
MUC16
,
KRAS
,
LRP1B
and
CSMD3
being the most frequently mutated known cancer-related genes. The most common fusion partner is
FGFR2
, the most common focal homozygous deletion affects
CDKN2A
. 56/70 (80%) patients receive genomics-based treatment recommendations which are applied in 20/56 (36%) cases. Transcriptome and methylome data provide evidence for the underlying entity in 62/70 (89%) cases. Germline analysis reveals five (likely) pathogenic mutations in five patients. Recommended off-label therapies translate into a mean PFS ratio of 3.6 with a median PFS1 of 2.9 months (17 patients) and a median PFS2 of 7.8 months (20 patients). Our data emphasize the clinical value of molecular analysis and underline the need for innovative, mechanism-based clinical trials.
In precision oncology (PO), clinicians aim to find the best treatment for any patient based on their molecular characterization. A major bottleneck is the manual annotation and evaluation of ...individual variants, for which usually a range of knowledge bases are screened. To incorporate and integrate the vast information of different databases, fast and accurate methods for harmonizing databases with different types of information are necessary. An essential step for harmonization in PO includes the normalization of tumor entities as well as therapy options for patients.
preon is a fast and accurate library for the normalization of drug names and cancer types in large-scale data integration.
preon is implemented in Python and freely available via the PyPI repository. Source code and the data underlying this article are available in GitHub at https://github.com/ermshaua/preon/.
Abstract only
e13634
Background: Cancer patients have an increased risk of developing secondary primary neoplasia (SPN) compared to the general population. These multiple primary malignancies (MMs) ...represent an increasing challenge for patients and physicians. So far, little is known about risk factors, patient characteristics, and survival. The study’s purpose was to obtain an overview of the occurrence and distribution of MMs and the outcome and prognosis of affected patients reporting to a large cancer center in Germany. Methods: The cancer registry data base of the Charité Comprehensive Cancer Center was queried for patients, which had their first cancer diagnosis between 01.01.2009 - 31.01.2010 and consecutively developed at least one more primary cancer within the follow-up period till 31.03.2019. For defining MM the rules from the Surveillance, Epidemiology, and End Results (SEER) Program were used. General tumor and patient characteristics as well as outcome were analyzed. Results: In total, 231 patients (155 male; 76 female) were included in the final analysis. Out of the 231 patients, 203 (87.9 %) presented with 2 primary tumors, 27 patients (11.7 %) with 3 and 1 patient (0.4%) with more than three. MMs occurred mostly in patients > 65 years (59.3%) and between 50-64 years (30.3%). According to the SEER definition 75.3% of the patients had metachronous and 24.7% had synchronous MMs. Most male patients presented initially with cancer of the bladder and the urinary tract (20.6%) and developed SPN in the prostate and the testicles (53.1%). The second most common initial cancer in this cohort was cancer of the prostate and testicles (18.1%) and the subsequent developed SPN was cancer of the bladder and the urinary tract (28.6%). For female patients the most common initial diagnosis was breast cancer (32.9%) followed by breast cancer as SPN in 60%. Overall, most frequent SPN were cancer of the prostate and testicles (13.4%), cancers of the lung and trachea (12.6%), and breast cancer (10.4%). Most patients (37.7%) developed the SPN within the 1st year and 28.6% after 5 years or later. Patients with synchronous MMs had a more than 40 months shorter OS than patients with the metachronous MM (79.00 ± 14.58 months vs. 122.00 ± 9.66 months). Conclusions: We could show that most MMs develop within the first year but that there is another peak after 5 years. However, it is still unclear how often SPN are misinterpreted as progressive disease. Therefore, further analyses and close follow-up are necessary.
Abstract only
3564
Background: The clinical interpretation of molecular data is a bottleneck of precision oncology. High-dimensional molecular data, such as RNA sequencing (RNA-seq) and whole-exome ...sequencing (WES), will likely increase the complexity of clinical interpretation. We compared the recommendations by two molecular tumor boards (MTBs) that independently interpreted the same high-dimensional molecular profiles. Methods: Patients with advanced solid tumors, no available standard therapy, an ECOG performance status of 0-1, and available fresh-frozen tissue underwent WES of tumor tissue and normal blood as well as RNA-seq of tumor tissue within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program of the German Cancer Consortium (DKTK). Data from 46 patients (WES and RNA-seq, n = 41; WES alone, n = 5) were independently discussed by two MTBs. Treatment recommendations were compared with regard to levels of evidence, therapeutic baskets, and types of biomarkers. Results: A total of 51,610 aberrations (median, 393 per patient) were considered for clinical interpretation (34,314 mutations/single-nucleotide variants, 7,115 mRNA expression changes, 6,144 DNA copy number variations, 4,037 gene fusions). 110 and 132 treatment options were identified by the two MTBs, respectively, with an overall agreement rate of 44.1%. The highest agreement rates were identified for treatment options based on clinical levels of evidence (Level 1, 60%; Level 2, 49.6%) and for poly(ADP-ribose)-polymerase inhibition (57.1%). The lowest agreement rates were identified when MTBs opted for traditional chemotherapy (0%), combination therapies (6.9%), therapies based on preclinical levels of evidence (Level 3, 35.9%; Level 4, 32%), and MAPK inhibition (35%). Similar agreement rates, ranging from 39% (gene fusions) to 54% (loss of heterozygosity), were observed for different types of biomarkers. Conclusions: Reproducible, evidence-based annotation of high-dimensional molecular data is feasible. Our experience provides a basis for ongoing harmonization and standardization efforts within the MTBs of the DKTK.
Abstract
Cancers of unknown primary site (CUPs) represent a heterogeneous group of metastatic tumors, which accounts for 3-5% of malignancies. Due to the poor prognosis and limited local and systemic ...treatment options, there is an urgent need for improvement of molecularly driven treatment strategies. We investigated the molecular profile and clinical course of 70 patients enrolled in a prospective precision oncology registry trial conducted by the National Center for Tumor Diseases (NCT) Heidelberg/Dresden and the German Cancer Consortium (DKTK) that addresses younger adults with advanced-stage cancer across histologies as well as patients with rare tumors (NCT/DKTK MASTER). Molecular analyses included whole genome sequencing (WGS, n=29), whole exome sequencing (WES, n=41) and transcriptome analysis (n=55). All patients were diagnosed with CUP-syndrome, 61/70 (87.1%) of diagnoses fulfilled the ESMO Clinical Practice Guidelines. Progression free survival (PFS) of the first treatment based on MASTER (PFS2) was compared to the PFS of the last prior systemic treatment (PFS1) in each individual patient. Within the coding sequence, we identified 0 to 1386 nonsynonymous point mutations (SNVs, median=41) and 0 to 38 insertions/deletions (indels, median=3) per sample. Hypermutation (≥100 SNVs and indels) was observed in 14 samples. Mutations of TP53 and KRAS were significantly enriched. Analysis of copy-number changes (CNVs) was performed in 51 samples (27 WGS and 24 WES) and revealed complex CNV profiles in most cases. Gains and losses involved single arms or whole chromosomes. Gains in chromosome 8q, 1q and 7 and losses in chromosome 6q and 17p occurred in more than 40% of the patients. Fusions of EML4-ALK and FGFR2 were found in three and six cases, respectively. In one case, pathological reevaluation for NUT midline carcinoma was recommended based on a NUTM1-MXI1 fusion. In total, pathological reevaluation based on characteristic genetic events was recommended in five cases. Germline analysis of 70 cases revealed five pathogenic variants (ACMG Class 5) in CHEK2, BRCA1, CDKN2A, NBN and ERCC3. In addition, one likely pathogenic variant (ACMG Class 4) was found in FH. The molecular tumor board recommended targeted therapy in 56/70 (80.0%) patients which could be applied in 20/56 (35.7%) cases. The molecularly driven treatment approaches translated into a median PFS2/1 ratio of 2.25 (n=17). Median PFS1 was 89 days (range 31-304, n=17) compared to a median PFS2 of 180 days (range 50-805, n=17). For three patients in which PFS1 could not be determined median PFS2 was 305 days (range 182-336). We demonstrate that a comprehensive molecular analysis of CUPs provides clinically relevant information and additional, molecularly stratified treatment approaches in many cases. These targeted therapies can be highly beneficial even in heavily pretreated patients.
Citation Format: Maximilian Werner, Lino Möhrmann, Małgorzata Oleś, Andreas Mock, Arne Jahn, Simon Kreutzfeldt, Sebastian Uhrig, Martina Fröhlich, Barbara Hutter, Daniela Richter, Gina Rüter, Ivan Jelas, Rainer Hamacher, Johanna Falkenhorst, Sebastian Wagner, Christian Brandts, Melanie Börries, Anna Illert, Klaus Metzeler, Benedikt Westphalen, Alexander Desuki, Thomas Kindler, Albrecht Stenzinger, Evelin Schröck, Benedikt Brors, Peter Horak, Christoph Heining, Stefan Fröhling, Hanno Glimm. Genomics based personalized oncology of cancer of unknown primary abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 820.
Zusammenfassung
Hintergrund
Die Präzisionsonkologie ist für betroffene Patienten mit großen Hoffnungen auf einen Therapieerfolg verbunden. Die Datenlage zu klinischem Nutzen von ...präzisionsonkologischen Ansätzen ist uneinheitlich und die Komplexität der Thematik stellt hohe Anforderungen an das Patientenverständnis. Die Führung dieser Patienten stellt neue Herausforderungen an die behandelnden Onkologen.
Ziel der Arbeit
Dieser Beitrag berichtet den aktuellen Stand der psychoonkologischen Forschung zu den psychosozialen Belastungen dieser Patientengruppe, deren Informationsbedürfnissen sowie den Herausforderungen für Onkologen im Zusammenhang mit der molekularen Diagnostik.
Methoden
Die Grundlage dafür lieferten eine Literaturreche sowie Ergebnisse einer eigenen Untersuchung.
Ergebnisse
Patienten weisen hohe psychische Belastungen bei gleichzeitig großen Hoffnungen an eine molekulare Diagnostik auf. Eine transparente und kontinuierliche Arzt-Patienten-Kommunikation, welche u. a. eine patientenorientierte Aufklärung und Beratung inkludiert, sind notwendig, um eine informierte Zustimmung im Rahmen der Präzisionsonkologie zu gewährleisten.
Diskussion
Psychische Belastungen bei Patienten im Zusammenhang mit der Präzisionsonkologie sollten systematisch untersucht und frühzeitig identifiziert werden. Diese können durch eine spezifische Arzt-Patienten-Kommunikation abgemildert werden. Es gehört heute zu den Aufgaben der Psychoonkologie, hier unterstützende Maßnahmen bereitzustellen.
PDF
