Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 May 12:6:15.
doi: 10.1038/s41523-020-0155-1. eCollection 2020.

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Jan Hudeček  1 , Leonie Voorwerk  2 , Maartje van Seijen  3 , Iris Nederlof  2 , Michiel de Maaker  3 , Jose van den Berg  4 , Koen K van de Vijver  5 , Karolina Sikorska  6 , Sylvia Adams  7 , Sandra Demaria  8   9 , Giuseppe Viale  10   11 , Torsten O Nielsen  12 , Sunil S Badve  13 , Stefan Michiels  14   15 , William Fraser Symmans  16 , Christos Sotiriou  17 , David L Rimm  18   19 , Stephen M Hewitt  20 , Carsten Denkert  21   22 , Sibylle Loibl  23 , Sherene Loi  24 , John M S Bartlett  25   26   27 , Giancarlo Pruneri  28   29 , Deborah A Dillon  30 , Maggie C U Cheang  31 , Andrew Tutt  32 , Jacqueline A Hall  33 , Zuzana Kos  34 , Roberto Salgado  24   35 , Marleen Kok  2   36 , Hugo M Horlings  3   4 ; International Immuno-Oncology Biomarker Working Group
Collaborators, Affiliations
Review

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Jan Hudeček et al. NPJ Breast Cancer. .

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.

Keywords: Biomarkers; Breast cancer; Tumour biomarkers; Tumour immunology.

PubMed Disclaimer

Conflict of interest statement

Competing interestsJ.H. is the owner of Slide Score. B.V. L.V., M.v.S., I.N., M.d.M., J.v.d.B., K.K.v.d.V., K.S., S.A., S.D., G.V., S.S.B., S.M., W.F.S., C.S., S.M.H., C.D., S.L., G.P., M.C.U.C., Z.K., and H.M.H. have nothing to disclose. T.O.N. has consulted for Nanostring and received compensation and has intellectual property rights/ownership interests from Bioclassifier LLC, not related to the subject material under consideration and received funding support from the Canadian Cancer Society. D.L.R. reports research funding from AstraZeneca, Cepheid, Navigate BioPharma, NextCure, Lilly, and Ultivue; instrument support from Ventana, Akoya/PerkinElmer, and NanoString; advisory board of Amgen, AstraZeneca, Cell Signaling Technology, Cepheid, Daiichi Sankyo, GSK, Konica/Minolta, Merck, NanoString, PerkinElmer, Ventana, and Ultivue; consultancy for Biocept; honorarium and travel support from BMS; royalties from Rarecyte and is a founder and equity holder of PixelGear. Sh.L. receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer, and Eli Lilly, acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca, and Roche-Genentech and acted as consultant (paid to her institution) to Aduro Biotech. J.M.S.B. reports research funding from ThermoFisher, Genoptix, Agendia, NanoString Technologies, Stratifyer GmbH, and Biotheranostics and advisory roles for Insight Genetics, BioNTech AG, Biotheranostics, Pfizer, RNA Diagnostics, and OncoXchange. J.M.S.B. reports the following patents: Methods and Devices for Predicting Anthracycline Treatment Efficacy, US utility (January 2017; 15/325,472; EPO – 15822898.1; Canada – not yet assigned), Systems, Devices and Methods for Constructing and Using a Biomarker, US utility (January 2017; 15/328,108; EPO – 15824751.0; Canada – not yet assigned), Histone gene module predicts anthracycline benefit (October 2016; PCT/CA2016/000247), 95‐Gene Signature of Residual Risk Following Endocrine Treatment (December 2016; PCT/CA2016/000304), Immune Gene Signature Predicts Anthracycline Benefit (December 2016; PCT/CA2016/000305). D.A.D. is on the advisory board and consults for Oncology Analytics Inc., and has consulted for and received travel funds from Novartis for work unrelated to the current manuscript. A.T. reports benefits from ICR’s Inventors Scheme associated with patents for one of PARP inhibitors in BRCA1/2-associated cancers. A.T. also reports Honoraria from Pfizer, Vertex, Prime Oncology, and Artios, honoraria and stock in InBioMotion, honoraria and financial support for research from AstraZeneca, Medivation, Myriad Genetics, and Merck Serono. J.A.H. is the director and owner of Vivactiv Ltd. R.S. reports research funding from Roche, Puma, and Merck; advisory board and consultancy for BMS; travel funding from Roche, Merck, and AstraZeneca, outside the scope of this work. M.K. reports funding to the institute from BMS, Roche and an advisory role for BMS, outside the submitted work.

Figures

Fig. 1
Fig. 1. Organization of a workflow for reliable and timely biomarker scoring in a general single-center or multi-center trial.
Personnel at individual centers scan the slides after processing by the local pathology department. Digital slides are uploaded to a central web-based repository, such as Slide Score. A study-specific identifier is assigned to each sample. The central manager is notified by the system when new slides are available and requests pathologists to review it. When a consensus score is obtained, the trial office is notified for randomization of the patient.
See this image and copyright information in PMC

References

    1. Hall JA, Salgado R, Lively T, Sweep F, Schuh A. A risk-management approach for effective integration of biomarkers in clinical trials: perspectives of an NCI, NCRI, and EORTC working group. Lancet Oncol. 2014;15:e184–193. doi: 10.1016/S1470-2045(13)70607-7. - DOI - PubMed
    1. Loi S, et al. Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. J. Clin. Oncol. 2019;37:559–569. doi: 10.1200/JCO.18.01010. - DOI - PMC - PubMed
    1. Denkert C, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19:40–50. doi: 10.1016/S1470-2045(17)30904-X. - DOI - PubMed
    1. Loi S, et al. LBA13—relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): results from KEYNOTE-086. Ann. Oncol. 2017;28(Suppl_5):v605–49. doi: 10.1093/annonc/mdx440. - DOI
    1. Emens LA, et al. Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 study. JAMA Oncol. 2018 doi: 10.1001/jamaoncol.2018.4224. - DOI - PMC - PubMed