Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials
Authors: Hudeček Jan , Voorwerk Leonie , van Seijen Maartje , Nederlof Iris , de Maaker Michiel , van den Berg Jose , van de Vijver Koen K. , Sikorska Karolina , Adams Sylvia , Demaria Sandra , Viale Giuseppe , Nielsen Torsten O. , Badve Sunil S. , Michiels Stefan , Symmans William Fraser , Sotiriou Christos , Rimm David L. , Hewitt Stephen M. , Denkert Carsten , Loibl Sibylle , Loi Sherene , Bartlett John M. S. , Pruneri Giancarlo , Dillon Deborah A. , Cheang Maggie C. U. , Tutt Andrew , Hall Jacqueline A. , Kos Zuzana , Salgado Roberto , Kok Marleen , Horlings Hugo M. ,   International Immuno-Oncology Biomarker Working Group, Hyytiäinen Aini , Hida Akira I. , Thompson Alastair , Lefevre Alex , Lazar Alexander J. , Gown Allen , Lo Amy , Sapino Anna , Madabhushi Anant , Moreira Andre , Richardson Andrea , Vingiani Andrea , Beck Andrew H. , Bellizzi Andrew M. , Guerrero Angel , Grigoriadis Anita , Ehinger Anna , Garrido-Castro Ana , Vincent-Salomon Anne , Laenkholm Anne-Vibeke , Sharma Ashish , Cimino-Mathews Ashley , Srinivasan Ashok , Acs Balazs , Singh Baljit , Calhoun Benjamin , Haibe-Kans Benjamin , Solomon Benjamin , Thapa Bibhusal , Nelson Brad H. , Gallas Brandon D. , Castaneda Carlos , Ballesteros-Merino Carmen , Criscitiello Carmen , Boeckx Carolien , Colpaert Cecile , Quinn Cecily , Chennubhotla Chakra S. , Swanton Charles , Solinas Cinzia , Hiley Crispin , Drubay Damien , Bethmann Daniel , Moore David A. , Larsimont Denis , Sabanathan Dhanusha , Peeters Dieter , Zardavas Dimitrios , Höflmayer Doris , Johnson Douglas B. , Thompson E. Aubrey , Brogi Edi , Perez Edith , ElGabry Ehab A. , Stovgaard Elisabeth Specht , Blackley Elizabeth F. , Roblin Elvire , Reisenbichler Emily , Bellolio Enrique , Balslev Eva , Chmielik Ewa , Gaire Fabien , Andre Fabrice , Lu Fang-I , Azmoudeh-Ardalan Farid , Rojo Federico , Gruosso Tina , Ciompi Francesco , Peale Franklin , Hirsch Fred R. , Klauschen Frederick , Penault-Llorca Frédérique , Acosta Haab Gabriela , Farshid Gelareh , van den Eynden Gert , Curigliano Giuseppe , Floris Giuseppe , Broeckx Glenn , Gonzalez-Ericsson  , Koeppen Harmut , Haynes Harry R. , McArthur Heather , Joensuu Heikki , Olofsson Helena , Lien Huang-Chun , Chen I-Chun , Cree Ian , Frahm Isabel , Brcic Iva , Chan Jack , Ziai James , Brock Jane , Wesseling Jelle , Giltnane Jennifer , Kerner Jennifer K. , Thagaard Jeppe , Braybrooke Jeremy P. , van der Laak Jeroen A. W. M. , Lemonnier Jerome , Zha Jiping , Ribeiro Joana , Lennerz Jochen K. , Carter Jodi M. , Saltz Joel , Hartman Johan , Hainfellner Johannes , Quesne John Le , Juco Jonathon W. , Reis-Filho Jorge , Sanchez Joselyn , Sparano Joseph , Cucherousset Joël , Araya Juan Carlos , Adam Julien , Balko Justin M. , Saeger Kai , Siziopikou Kalliopi , Willard-Gallo Karen , Weber Karsten , Pogue-Geile Katherine L. , Steele Keith E. , Emancipator Kenneth , AbdulJabbar Khalid , El Bairi Khalid , Blenman Kim R. M. , Allison Kimberly H. , Korski Konstanty , Pusztai Lajos , Comerma Laura , Buisseret Laurence , Cooper Lee A. D. , Shi Leming , Kooreman Loes F. S. , Molinero Luciana , Estrada M. Valeria , Lacroix-Triki Magali , Al Bakir Maise , Sebastian Manu M. , van de Vijver Marc , Balancin Marcelo Luiz , Dieci Maria Vittoria , Mathieu Marie-Christine , Rebelatto Marlon C. , Piccart Martine , Hanna Matthew G. , Goetz Matthew P. , Preusser Matthias , Khojasteh Mehrnoush , Sanders Melinda E. , Regan Meredith M. , Barnes Michael , Christie Michael , Misialek Michael , Ignatiadis Michail , van Bockstal Mieke , Castillo Miluska , Amgad Mohamed , Harbeck Nadia , Tung Nadine , Laudus Nele , Sirtaine Nicolas , Burchardi Nicole , Ternes Nils , Radosevic-Robin Nina , Gluz Oleg , Grimm Oliver , Nuciforo Paolo , Jank Paul , Gonzalez-Ericsson Paula , Kirtani Pawan , Jelinic Petar , Watson Peter H. , Savas Peter , Francis Prudence A. , Russell Prudence A. , Singh Rajendra , Kim Rim S. , Pierce Robert H. , Hills Robert , Leon-Ferre Roberto , de Wind Roland , Shui Ruohong , De Clercq Sabine , Leung Sam , Tabbarah Sami , Souza Sandra C. , O’Toole Sandra , Swain Sandra , Dudgeon Sarah , Willis Scooter , Ely Scott , Kim Seong-Rim , Bedri Shahinaz , Irshad Sheeba , Liu Shi-Wei , Goel Shom , Hendry Shona , Bianchi Simonetta , Bragança Sofia , Paik Soonmyung , Wienert Stephan , Fox Stephen B. , Luen Stephen J. , Naber Stephen , Schnitt Stuart J. , Sua Luz F. , Lakhani Sunil R. , Fineberg Susan , Soler Teresa , Gevaert Thomas , D’Alfonso Timothy , John Tom , Sugie Tomohagu , Kurkure Uday , Bossuyt Veerle , Manem Venkata , Cámara Vincente Peg , Tong Weida , Chen Weijie , Yang Wentao , Tran William T. , Wang Yihong , Yuan Yinyin , Allory Yves , Husain Zaheed , Bago-Horvath Zsuzsanna 
Published: May 2020

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.