| 1. |
- Barack, Leor, et al.
(författare)
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Black holes, gravitational waves and fundamental physics : a roadmap
- 2019
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Ingår i: Classical and quantum gravity. - : IOP Publishing. - 0264-9381 .- 1361-6382. ; 36:14
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Forskningsöversikt (refereegranskat)abstract
- The grand challenges of contemporary fundamental physics dark matter, dark energy, vacuum energy, inflation and early universe cosmology, singularities and the hierarchy problem all involve gravity as a key component. And of all gravitational phenomena, black holes stand out in their elegant simplicity, while harbouring some of the most remarkable predictions of General Relativity: event horizons, singularities and ergoregions. The hitherto invisible landscape of the gravitational Universe is being unveiled before our eyes: the historical direct detection of gravitational waves by the LIGO-Virgo collaboration marks the dawn of a new era of scientific exploration. Gravitational-wave astronomy will allow us to test models of black hole formation, growth and evolution, as well as models of gravitational-wave generation and propagation. It will provide evidence for event horizons and ergoregions, test the theory of General Relativity itself, and may reveal the existence of new fundamental fields. The synthesis of these results has the potential to radically reshape our understanding of the cosmos and of the laws of Nature. The purpose of this work is to present a concise, yet comprehensive overview of the state of the art in the relevant fields of research, summarize important open problems, and lay out a roadmap for future progress. This write-up is an initiative taken within the framework of the European Action on 'Black holes, Gravitational waves and Fundamental Physics'.
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| 2. |
- Davies, Helen R., et al.
(författare)
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HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures
- 2017
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 23:4, s. 517-525
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition.
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| 3. |
- Gonzalez-Ericsson, Paula, et al.
(författare)
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The path to a better biomarker: application of a risk management framework for the implementation of PD‐L1 and TILs as immuno‐oncology biomarkers into breast cancer clinical trials and daily practice
- 2020
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Ingår i: Journal of Pathology. - : Wiley. - 1096-9896 .- 0022-3417. ; 250:5, s. 667-684
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Forskningsöversikt (refereegranskat)abstract
- Immune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC.
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| 4. |
- Hudeček, Jan, et al.
(författare)
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Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials
- 2020
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Ingår i: npj Breast Cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 6:1
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Forskningsöversikt (refereegranskat)abstract
- Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting.
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| 5. |
- Hudson, Thomas J., et al.
(författare)
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International network of cancer genome projects
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Tidskriftsartikel (refereegranskat)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 6. |
- Ju, Young Seok, et al.
(författare)
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Somatic mutations reveal asymmetric cellular dynamics in the early human embryo
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 543:7647, s. 714-718
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Tidskriftsartikel (refereegranskat)abstract
- Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.
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| 7. |
- Kos, Zuzana, et al.
(författare)
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Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer
- 2020
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Ingår i: npj Breast Cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.
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| 8. |
- Matikas, Alexios, et al.
(författare)
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PD-1 protein and gene expression as prognostic factors in early breast cancer
- 2020
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Ingår i: ESMO Open. - : BMJ Publishing Group Ltd. - 2059-7029. ; 5:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is a paucity of data on the prognostic value of programmed cell death protein 1 (PD-1) protein and gene expression in early breast cancer (BC) and the present study's aim was to comprehensively investigate it.Methods: The study consisted of three parts: a correlative analysis of PD-1 protein and gene expression from an original patient cohort of 564 patients with early BC; a systematic review and trial-level meta-analysis on the association between PD-1 protein expression and disease-free survival/overall survival (OS) in early BC; and a pooled gene expression analysis from publicly available transcriptomic datasets regarding PDCD1 expression.Results: In the study cohort, PD-1 protein, but not gene expression, was associated with improved OS (HRadj=0.73, 95% CI 0.55 to 0.97, p=0.027 and HRadj=0.88, 95% CI 0.68 to 1.13, p=0.312, respectively). In the trial-level meta-analysis, PD-1 protein expression was not found to be statistically significantly associated with outcomes in the overall population. Finally, in the pooled gene expression analysis, higher PDCD1 expression was associated with better OS in multivariable analysis in the entire population (HRadj=0.89, 95% CI 0.80 to 0.99, p=0.025) and in basal-like tumours.Conclusions: PD-1 protein and gene expression seem to be promising prognostic factors in early BC. Standardisation of detection and assessment methods is of utmost importance.
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| 9. |
- Matikas, Alexios, et al.
(författare)
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Prognostic implications of PD-L1 expression in breast cancer : systematic review and meta-analysis of immunohistochemistry and pooled analysis of transcriptomic data
- 2019
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 25:18, s. 5717-5726
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Forskningsöversikt (refereegranskat)abstract
- PURPOSE: Conflicting data have been reported on the prognostic value of PD-L1 protein and gene expression in breast cancer.EXPERIMENTAL DESIGN: Medline, Embase, Cochrane Library and Web of Science Core Collection were searched and data were extracted independently by two researchers. Outcomes included pooled PD-L1 protein positivity in tumor cells, immune cells or both, per subtype and per antibody used; and its prognostic value for disease-free and overall survival. A pooled gene expression analysis of 39 publicly available transcriptomic datasets was also performed.RESULTS: Of the initial 4184 entries, 38 retrospective studies fulfilled the predefined inclusion criteria. The overall pooled PD-L1 protein positivity rate was 24% (95% CI 15 - 33%) in tumor cells and 33% (95% CI 14 - 56%) in immune cells. PD-L1 protein expression in tumor cells was prognostic for shorter overall survival (HR = 1.63; 95% CI 1.07 - 2.46, p=0.02); there was significant heterogeneity (I2 = 80%, pheterogeneity<0.001). In addition, higher PD-L1 gene expression predicted better survival in multivariate analysis in the entire population (HR=0.82, 95% CI 0.74 - 0.90, p<0.001 for OS) and in basal-like tumors (HR=0.64, 95% CI 0.52 - 0.80, p<0.001 for OS), pinteraction 0.005.CONCLUSION: The largest to our knowledge meta-analysis on the subject informs on PD-L1 protein positivity rates and its prognostic value in breast cancer. Standardization is needed prior to routine implementation. PD-L1 gene expression is a promising prognostic factor, especially in basal-like BC. Discrepant prognostic information might be related to PD-L1 gene expression in the stroma.
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| 10. |
- Matikas, Alexios, et al.
(författare)
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Prognostic implications of PD-L1 expression in breast cancer at the protein and mRNA levels
- 2019
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 37:15
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Conflicting data have been reported on the prognostic value of PD-L1 expression per immunohistochemistry (IHC) in breast cancer (BC). There is a paucity of data on the role of PD-L1 gene expression (GE).Methods: Medline, Embase, Cochrane Library and Web of Science Core Collection were searched and data were extracted independently by two researchers. Outcomes included pooled PD-L1 positivity in tumor cells, immune cells or both, per subtype and per antibody used; and the prognostic value of PD-L1 positivity for DFS and OS. Heterogeneity was assessed using the Q and I2 statistics. A pooled GE analysis of 39 publicly available transcriptomic datasets was also performed.Results: Of the initial 4184 entries, 38 retrospective studies fulfilled the inclusion criteria. The overall pooled PD-L1 positivity rate in tumor cells was 24%, 33% in immune cells and 25% in both; highest positivity was reported with Dako 28-8 clone. PD-L1 IHC expression in tumor cells was prognostic for shorter DFS (HR = 1.36, 95% CI 1.02 – 1.83, p < 0.04) and OS (HR = 1.66; 95% CI 1.09 – 2.50, p = 0.02); there was significant heterogeneity. PD-L1 IHC expression in immune cells was associated with better DFS (HR = 0.61; 95% CI 0.51 – 0.73, p < 0.001) and OS (HR = 0.53, 95% CI 0.39 – 0.73, p < 0.001) in TNBC. In addition, higher PD-L1 GE predicted better survival in multivariate analysis in the entire population (HR = 0.70, 95% CI 0.60 – 0.82, p < 0.001 for DFS and HR = 0.84, 95% CI 0.75 – 0.93, p = 0.001 for OS) and in basal-like tumors (HR = 0.55, 95% CI 0.38 – 0.80, p = 0.001 for DFS and HR = 0.63, 95% CI 0.50 – 0.79, p < 0.001 for OS), pinteraction 0.124 for DFS and 0.005 for OS.Conclusions: The largest to our knowledge meta-analysis on IHC PD-L1 expression in BC informs on PD-L1 positivity rates and its prognostic value. Standardization is needed prior to routine implementation. PD-L1 GE is a promising prognostic factor, especially in basal-like BC.
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