19 research outputs found
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Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer
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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Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group
Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring
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Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials
Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: 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
Tumour immune microenvironment, genomewide copy number aberrations and their interactions in malignant pleural mesothelioma
© 2017 Dr. Bibhusal ThapaMalignant pleural mesothelioma (MPM) is a rare but deadly malignancy. Despite predictions, worldwide incidences have not significantly diminished and available therapeutic modalities have failed to improve outcomes. There are some indications that immune based therapies and targeted therapies may hold promise but suitable phenotypes have been hard to identify. This thesis describes investigations we conducted into the tumour immune microenvironment, the copy number aberrations (CNAs) and the interaction between the two in MPM.
The findings presented in this thesis elucidate the complexity of the tumour immune microenvironment in MPM. We establish MPM to be immunogenic but also demonstrate that the immune characteristics vary amongst tumours mostly with tumour histological subtype. We reveal sarcomatoid MPMs to be associated with high lymphocytic infiltration but also greater expression of immune checkpoint receptors and their ligands. In addition, we also exhibit the prognostic implications associated with some of these markers.
The genome wide copy number analyses described in this thesis disclose that although copy number aberrations are the commoner of genomic alterations in MPM, their extent and pattern vary amongst tumours. We describe their clinical and pathological associations. We confirm most previously described prominent CNAs but more importantly uncover new ones which may be important in MPM prognostication and therapeutics. We find that greater degree of genomic instability confers a worse prognosis in MPM independent of histology but neither degree of genomic instability nor any specific CNA correlates with the immunological milieu.
Our findings contribute towards the understanding and development of potential prognostic and predictive markers for immunotherapy in MPM. Further, they also reveal potential targets for development of targeted therapies in this disease where none was thought feasible
Outcomes of anti-PD-1 therapy in mesothelioma and correlation with PD-L1 expression
This abstract is freely available on the conference website at (see link below