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1. The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group

Author

Khalid El Bairi, Harry R. Haynes, Elizabeth Blackley, Susan Fineberg, Jeffrey Shear, Sophia Turner, Juliana Ribeiro de Freitas, Daniel Sur, Luis Claudio Amendola, Masoumeh Gharib, Amine Kallala, Indu Arun, Farid Azmoudeh-Ardalan, Luciana Fujimoto, Luz F. Sua, Shi-Wei Liu, Huang-Chun Lien, Pawan Kirtani, Marcelo Balancin, Hicham El Attar, Prerna Guleria, Wenxian Yang, Emad Shash, I-Chun Chen, Veronica Bautista, Jose Fernando Do Prado Moura, Bernardo L. Rapoport, Carlos Castaneda, Eunice Spengler, Gabriela Acosta-Haab, Isabel Frahm, Joselyn Sanchez, Miluska Castillo, Najat Bouchmaa, Reena R. Md Zin, Ruohong Shui, Timothy Onyuma, Wentao Yang, Zaheed Husain, Karen Willard-Gallo, An Coosemans, Edith A. Perez, Elena Provenzano, Paula Gonzalez Ericsson, Eduardo Richardet, Ravi Mehrotra, Sandra Sarancone, Anna Ehinger, David L. Rimm, John M. S. Bartlett, Giuseppe Viale, Carsten Denkert, Akira I. Hida, Christos Sotiriou, Sibylle Loibl, Stephen M. Hewitt, Sunil Badve, William Fraser Symmans, Rim S. Kim, Giancarlo Pruneri, Shom Goel, Prudence A. Francis, Gloria Inurrigarro, Rin Yamaguchi, Hernan Garcia-Rivello, Hugo Horlings, Said Afqir, Roberto Salgado, Sylvia Adams, Marleen Kok, Maria Vittoria Dieci, Stefan Michiels, Sandra Demaria, Sherene Loi, and The International Immuno-Oncology Biomarker Working Group

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Published
2021
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2. The tale of TILs in breast cancer : A report from The International Immuno-Oncology Biomarker Working Group

Author

The International Immuno-Oncology Biomarker Working Group, El Bairi, Khalid, Haynes, Harry R., Blackley, Elizabeth, Almangush, Alhadi, Makitie, Antti, Joensuu, Heikki, Lundin, Johan, Department of Pathology, HUS Head and Neck Center, Clinicum, Korva-, nenä- ja kurkkutautien klinikka, Heikki Joensuu / Principal Investigator, HUS Comprehensive Cancer Center, Department of Oncology, Johan Edvard Lundin / Principal Investigator, Institute for Molecular Medicine Finland, and University of Helsinki

Subjects
3122 Cancers, chemical and pharmacologic phenomena
Abstract

Publisher Copyright: © 2021, The Author(s). The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Published
2021

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

Author

International Immuno-Oncology Biomarker Working Group, Hudecek, Jan, Voorwerk, Leonie, Hyytiäinen, Aini, Joensuu, Heikki, Medicum, Research Programs Unit, Heikki Joensuu / Principal Investigator, HUS Comprehensive Cancer Center, and Department of Oncology

Subjects
3122 Cancers
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.

Published
2020

4. The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, El Bairi, Khalid, Haynes, Harry R, Blackley, Elizabeth, Fineberg, Susan, Shear, Jeffrey, Turner, Sophia, de Freitas, Juliana Ribeiro, Sur, Daniel, Amendola, Luis Claudio, Gharib, Masoumeh, Kallala, Amine, Arun, Indu, Azmoudeh-Ardalan, Farid, Fujimoto, Luciana, Sua, Luz F, Liu, Shi-Wei, Lien, Huang-Chun, Kirtani, Pawan, Balancin, Marcelo, El Attar, Hicham, Guleria, Prerna, Yang, Wenxian, Shash, Emad, Chen, I-Chun, Bautista, Veronica, Do Prado Moura, Jose Fernando, Rapoport, Bernardo L, Castaneda, Carlos, Spengler, Eunice, Acosta-Haab, Gabriela, Frahm, Isabel, Sanchez, Joselyn, Castillo, Miluska, Bouchmaa, Najat, Md Zin, Reena R, Shui, Ruohong, Onyuma, Timothy, Yang, Wentao, Husain, Zaheed, Willard-Gallo, Karen, Coosemans, An, Perez, Edith A, Provenzano, Elena, Ericsson, Paula Gonzalez, Richardet, Eduardo, Mehrotra, Ravi, Sarancone, Sandra, Ehinger, Anna, Rimm, David L, Bartlett, John M S, Viale, Giuseppe, Denkert, Carsten, Hida, Akira I, Sotiriou, Christos, Loibl, Sibylle, Hewitt, Stephen M, Badve, Sunil, Symmans, William Fraser, Kim, Rim S, Pruneri, Giancarlo, Goel, Shom, Francis, Prudence A, Inurrigarro, Gloria, Yamaguchi, Rin, Garcia-Rivello, Hernan, Horlings, Hugo, Afqir, Said, Salgado, Roberto, Adams, Sylvia, Kok, Marleen, Dieci, Maria Vittoria, Michiels, Stefan, Demaria, Sandra, Loi, Sherene, International Immuno-Oncology Biomarker Working Group, Van Bockstal, Mieke, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, El Bairi, Khalid, Haynes, Harry R, Blackley, Elizabeth, Fineberg, Susan, Shear, Jeffrey, Turner, Sophia, de Freitas, Juliana Ribeiro, Sur, Daniel, Amendola, Luis Claudio, Gharib, Masoumeh, Kallala, Amine, Arun, Indu, Azmoudeh-Ardalan, Farid, Fujimoto, Luciana, Sua, Luz F, Liu, Shi-Wei, Lien, Huang-Chun, Kirtani, Pawan, Balancin, Marcelo, El Attar, Hicham, Guleria, Prerna, Yang, Wenxian, Shash, Emad, Chen, I-Chun, Bautista, Veronica, Do Prado Moura, Jose Fernando, Rapoport, Bernardo L, Castaneda, Carlos, Spengler, Eunice, Acosta-Haab, Gabriela, Frahm, Isabel, Sanchez, Joselyn, Castillo, Miluska, Bouchmaa, Najat, Md Zin, Reena R, Shui, Ruohong, Onyuma, Timothy, Yang, Wentao, Husain, Zaheed, Willard-Gallo, Karen, Coosemans, An, Perez, Edith A, Provenzano, Elena, Ericsson, Paula Gonzalez, Richardet, Eduardo, Mehrotra, Ravi, Sarancone, Sandra, Ehinger, Anna, Rimm, David L, Bartlett, John M S, Viale, Giuseppe, Denkert, Carsten, Hida, Akira I, Sotiriou, Christos, Loibl, Sibylle, Hewitt, Stephen M, Badve, Sunil, Symmans, William Fraser, Kim, Rim S, Pruneri, Giancarlo, Goel, Shom, Francis, Prudence A, Inurrigarro, Gloria, Yamaguchi, Rin, Garcia-Rivello, Hernan, Horlings, Hugo, Afqir, Said, Salgado, Roberto, Adams, Sylvia, Kok, Marleen, Dieci, Maria Vittoria, Michiels, Stefan, Demaria, Sandra, Loi, Sherene, International Immuno-Oncology Biomarker Working Group, and Van Bockstal, Mieke

Abstract

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Published
2021

5. The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group.

Author

El Bairi, Khalid, El Bairi, Khalid, Haynes, Harry R, Blackley, Elizabeth, Fineberg, Susan, Shear, Jeffrey, Turner, Sophia, de Freitas, Juliana Ribeiro, Sur, Daniel, Amendola, Luis Claudio, Gharib, Masoumeh, Kallala, Amine, Arun, Indu, Azmoudeh-Ardalan, Farid, Fujimoto, Luciana, Sua, Luz F, Liu, Shi-Wei, Lien, Huang-Chun, Kirtani, Pawan, Balancin, Marcelo, El Attar, Hicham, Guleria, Prerna, Yang, Wenxian, Shash, Emad, Chen, I-Chun, Bautista, Veronica, Do Prado Moura, Jose Fernando, Rapoport, Bernardo L, Castaneda, Carlos, Spengler, Eunice, Acosta-Haab, Gabriela, Frahm, Isabel, Sanchez, Joselyn, Castillo, Miluska, Bouchmaa, Najat, Md Zin, Reena R, Shui, Ruohong, Onyuma, Timothy, Yang, Wentao, Husain, Zaheed, Willard-Gallo, Karen, Coosemans, An, Perez, Edith A, Provenzano, Elena, Ericsson, Paula Gonzalez, Richardet, Eduardo, Mehrotra, Ravi, Sarancone, Sandra, Ehinger, Anna, Rimm, David L, Bartlett, John MS, Viale, Giuseppe, Denkert, Carsten, Hida, Akira I, Sotiriou, Christos, Loibl, Sibylle, Hewitt, Stephen M, Badve, Sunil, Symmans, William Fraser, Kim, Rim S, Pruneri, Giancarlo, Goel, Shom, Francis, Prudence A, Inurrigarro, Gloria, Yamaguchi, Rin, Garcia-Rivello, Hernan, Horlings, Hugo, Afqir, Said, Salgado, Roberto, Adams, Sylvia, Kok, Marleen, Dieci, Maria Vittoria, Michiels, Stefan, Demaria, Sandra, Loi, Sherene, International Immuno-Oncology Biomarker Working Group, El Bairi, Khalid, El Bairi, Khalid, Haynes, Harry R, Blackley, Elizabeth, Fineberg, Susan, Shear, Jeffrey, Turner, Sophia, de Freitas, Juliana Ribeiro, Sur, Daniel, Amendola, Luis Claudio, Gharib, Masoumeh, Kallala, Amine, Arun, Indu, Azmoudeh-Ardalan, Farid, Fujimoto, Luciana, Sua, Luz F, Liu, Shi-Wei, Lien, Huang-Chun, Kirtani, Pawan, Balancin, Marcelo, El Attar, Hicham, Guleria, Prerna, Yang, Wenxian, Shash, Emad, Chen, I-Chun, Bautista, Veronica, Do Prado Moura, Jose Fernando, Rapoport, Bernardo L, Castaneda, Carlos, Spengler, Eunice, Acosta-Haab, Gabriela, Frahm, Isabel, Sanchez, Joselyn, Castillo, Miluska, Bouchmaa, Najat, Md Zin, Reena R, Shui, Ruohong, Onyuma, Timothy, Yang, Wentao, Husain, Zaheed, Willard-Gallo, Karen, Coosemans, An, Perez, Edith A, Provenzano, Elena, Ericsson, Paula Gonzalez, Richardet, Eduardo, Mehrotra, Ravi, Sarancone, Sandra, Ehinger, Anna, Rimm, David L, Bartlett, John MS, Viale, Giuseppe, Denkert, Carsten, Hida, Akira I, Sotiriou, Christos, Loibl, Sibylle, Hewitt, Stephen M, Badve, Sunil, Symmans, William Fraser, Kim, Rim S, Pruneri, Giancarlo, Goel, Shom, Francis, Prudence A, Inurrigarro, Gloria, Yamaguchi, Rin, Garcia-Rivello, Hernan, Horlings, Hugo, Afqir, Said, Salgado, Roberto, Adams, Sylvia, Kok, Marleen, Dieci, Maria Vittoria, Michiels, Stefan, Demaria, Sandra, Loi, Sherene, and International Immuno-Oncology Biomarker Working Group

Abstract

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Published
2021

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

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, 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, Van Bockstal, Mieke, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, 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, and Van Bockstal, Mieke

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.

Published
2020

8. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Kos, Zuzana, Roblin, Elvire, Kim, Rim S, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, van de Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil S, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John M S, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew, Hall, Jacqueline A, Kok, Marleen, Horlings, Hugo M, Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Yang, Wentao, AbdulJabbar, Khalid, Yuan, Yinyin, Singh, Rajendra, Hiley, Crispin, Bakir, Maise Al, Lazar, Alexander J, Naber, Stephen, Wienert, Stephan, Castillo, Miluska, Curigliano, Giuseppe, Dieci, Maria-Vittoria, André, Fabrice, Swanton, Charles, Reis-Filho, Jorge, Sparano, Joseph, Balslev, Eva, Chen, I-Chun, Stovgaard, Elisabeth Ida Specht, Pogue-Geile, Katherine, Blenman, Kim R M, Penault-Llorca, Frédérique, Schnitt, Stuart, Lakhani, Sunil R, Vincent-Salomon, Anne, Rojo, Federico, Braybrooke, Jeremy P, Hanna, Matthew G, Soler-Monsó, M Teresa, Bethmann, Daniel, Castaneda, Carlos A, Willard-Gallo, Karen, Sharma, Ashish, Lien, Huang-Chun, Fineberg, Susan, Thagaard, Jeppe, Comerma, Laura, Gonzalez-Ericsson, Paula, Brogi, Edi, Loi, Sherene, Saltz, Joel, Klaushen, Frederick, Cooper, Lee, Amgad, Mohamed, Moore, David A, Salgado, Roberto, International Immuno-Oncology Biomarker Working Group, Van Bockstal, Mieke, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Kos, Zuzana, Roblin, Elvire, Kim, Rim S, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, van de Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil S, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John M S, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew, Hall, Jacqueline A, Kok, Marleen, Horlings, Hugo M, Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Yang, Wentao, AbdulJabbar, Khalid, Yuan, Yinyin, Singh, Rajendra, Hiley, Crispin, Bakir, Maise Al, Lazar, Alexander J, Naber, Stephen, Wienert, Stephan, Castillo, Miluska, Curigliano, Giuseppe, Dieci, Maria-Vittoria, André, Fabrice, Swanton, Charles, Reis-Filho, Jorge, Sparano, Joseph, Balslev, Eva, Chen, I-Chun, Stovgaard, Elisabeth Ida Specht, Pogue-Geile, Katherine, Blenman, Kim R M, Penault-Llorca, Frédérique, Schnitt, Stuart, Lakhani, Sunil R, Vincent-Salomon, Anne, Rojo, Federico, Braybrooke, Jeremy P, Hanna, Matthew G, Soler-Monsó, M Teresa, Bethmann, Daniel, Castaneda, Carlos A, Willard-Gallo, Karen, Sharma, Ashish, Lien, Huang-Chun, Fineberg, Susan, Thagaard, Jeppe, Comerma, Laura, Gonzalez-Ericsson, Paula, Brogi, Edi, Loi, Sherene, Saltz, Joel, Klaushen, Frederick, Cooper, Lee, Amgad, Mohamed, Moore, David A, Salgado, Roberto, International Immuno-Oncology Biomarker Working Group, and Van Bockstal, Mieke

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.

Published
2020

9. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K, Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H, Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M, Horlings, Hugo M, Hudeček, Jan, Ciompi, Francesco, Moore, David A, Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K, Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P, Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J, Lakhani, Sunil R, Rojo, Federico, Comerma, Laura, Badve, Sunil S, Khojasteh, Mehrnoush, Symmans, W Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L, Kim, Rim S, Rimm, David L, Viale, Giuseppe, Hewitt, Stephen M, Bartlett, John M S, Penault-Llorca, Frédérique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G, Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O, Lazar, Alexander J, Bago-Horvath, Zsuzsanna, Kooreman, Loes F S, van der Laak, Jeroen A W M, Saltz, Joel, Gallas, Brandon D, Kurkure, Uday, Barnes, Michael, Salgado, Roberto, Cooper, Lee A D, International Immuno-Oncology Biomarker Working Group, Van Bockstal, Mieke, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K, Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H, Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M, Horlings, Hugo M, Hudeček, Jan, Ciompi, Francesco, Moore, David A, Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K, Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P, Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J, Lakhani, Sunil R, Rojo, Federico, Comerma, Laura, Badve, Sunil S, Khojasteh, Mehrnoush, Symmans, W Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L, Kim, Rim S, Rimm, David L, Viale, Giuseppe, Hewitt, Stephen M, Bartlett, John M S, Penault-Llorca, Frédérique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G, Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O, Lazar, Alexander J, Bago-Horvath, Zsuzsanna, Kooreman, Loes F S, van der Laak, Jeroen A W M, Saltz, Joel, Gallas, Brandon D, Kurkure, Uday, Barnes, Michael, Salgado, Roberto, Cooper, Lee A D, International Immuno-Oncology Biomarker Working Group, and Van Bockstal, Mieke

Abstract

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.

Published
2020

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

Author

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, 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 M, Hall, Jacqueline Anne, Kos, Zuzana, Salgado, Roberto, Kok, Marleen, Horlings, Hugo Mark, International Immuno-Oncology Biomarker Working Group, 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, 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 M, Hall, Jacqueline Anne, Kos, Zuzana, Salgado, Roberto, Kok, Marleen, Horlings, Hugo Mark, and International Immuno-Oncology Biomarker Working Group

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., SCOPUS: re.j, info:eu-repo/semantics/published

Published
2020

11. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer.

Author

Kos, Zuzana, Roblin, Elvire, Kim, Seong-Rim, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, van de Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen M, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John M S, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew M, Hall, Jacqueline Anne, Kok, Marleen, Horlings, Hugo Mark, Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Yang, Wentao, AbdulJabbar, Khalid, Yuan, Yinyin, Singh, Rajendra, Hiley, Crispin, Bakir, Maise Al, Lazar, Alexander J, Naber, Stephen, Wienert, Stephan, Castillo, Miluska, Curigliano, Giuseppe, Dieci, Maria Vittoria, André, Fabrice, Swanton, Charles, Reis-Filho, Jorge Sergio, Sparano, Joseph, Balslev, Eva, Chen, I-Chun, Stovgaard, Elisabeth Ida Specht, Pogue-Geile, Katherine L, Blenman, Kim KRM, Penault-Llorca, Frédérique, Schnitt, Stuart J, Lakhani, Sunil R, Vincent-Salomon, Anne, Rojo, Federico, Braybrooke, Jeremy JP, Hanna, Matthew G, Soler-Monsó, Teresa MT, Bethmann, Daniel, Castaneda, Carlos Altamirano, Willard-Gallo, Karen, Sharma, Ashish, Lien, Huang-Chun, Fineberg, Susan, Thagaard, Jeppe, Comerma, Laura, Gonzalez-Ericsson, Paula, Brogi, Edi, Loi, Sherene, Saltz, Joel, Klaushen, Frederick, Cooper, Lee, Amgad, Mohamed, Moore, David A, Salgado, Roberto, International Immuno-Oncology Biomarker Working Group, Kos, Zuzana, Roblin, Elvire, Kim, Seong-Rim, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, van de Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen M, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John M S, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew M, Hall, Jacqueline Anne, Kok, Marleen, Horlings, Hugo Mark, Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Yang, Wentao, AbdulJabbar, Khalid, Yuan, Yinyin, Singh, Rajendra, Hiley, Crispin, Bakir, Maise Al, Lazar, Alexander J, Naber, Stephen, Wienert, Stephan, Castillo, Miluska, Curigliano, Giuseppe, Dieci, Maria Vittoria, André, Fabrice, Swanton, Charles, Reis-Filho, Jorge Sergio, Sparano, Joseph, Balslev, Eva, Chen, I-Chun, Stovgaard, Elisabeth Ida Specht, Pogue-Geile, Katherine L, Blenman, Kim KRM, Penault-Llorca, Frédérique, Schnitt, Stuart J, Lakhani, Sunil R, Vincent-Salomon, Anne, Rojo, Federico, Braybrooke, Jeremy JP, Hanna, Matthew G, Soler-Monsó, Teresa MT, Bethmann, Daniel, Castaneda, Carlos Altamirano, Willard-Gallo, Karen, Sharma, Ashish, Lien, Huang-Chun, Fineberg, Susan, Thagaard, Jeppe, Comerma, Laura, Gonzalez-Ericsson, Paula, Brogi, Edi, Loi, Sherene, Saltz, Joel, Klaushen, Frederick, Cooper, Lee, Amgad, Mohamed, Moore, David A, Salgado, Roberto, and International Immuno-Oncology Biomarker Working Group

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., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2020

12. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group.

Author

Amgad, Mohamed, Stovgaard, Elisabeth Ida Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K, Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H, Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M, Horlings, Hugo Mark, Hudeček, Jan, Ciompi, Francesco, Moore, David A, Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen JK, Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P, Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J, Lakhani, Sunil R, Rojo, Federico, Comerma, Laura, Badve, Sunil, Khojasteh, Mehrnoush, Symmans, W Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L, Kim, Seong-Rim, Rimm, David L, Viale, Giuseppe, Hewitt, Stephen M, Bartlett, John M S, Penault-Llorca, Frédérique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G, Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O, Lazar, Alexander J, Bago-Horvath, Zsuzsanna, Kooreman, Loes LFS, van der Laak, Jeroen A W M JAWM, Saltz, Joel, Gallas, Brandon D, Kurkure, Uday, Barnes, Michael R., Salgado, Roberto, Cooper, Lee A D, International Immuno-Oncology Biomarker Working Group, Amgad, Mohamed, Stovgaard, Elisabeth Ida Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K, Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H, Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M, Horlings, Hugo Mark, Hudeček, Jan, Ciompi, Francesco, Moore, David A, Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen JK, Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P, Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J, Lakhani, Sunil R, Rojo, Federico, Comerma, Laura, Badve, Sunil, Khojasteh, Mehrnoush, Symmans, W Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L, Kim, Seong-Rim, Rimm, David L, Viale, Giuseppe, Hewitt, Stephen M, Bartlett, John M S, Penault-Llorca, Frédérique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G, Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O, Lazar, Alexander J, Bago-Horvath, Zsuzsanna, Kooreman, Loes LFS, van der Laak, Jeroen A W M JAWM, Saltz, Joel, Gallas, Brandon D, Kurkure, Uday, Barnes, Michael R., Salgado, Roberto, Cooper, Lee A D, and International Immuno-Oncology Biomarker Working Group

Abstract

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., SCOPUS: re.j, info:eu-repo/semantics/published

Published
2020

13. 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.

Author

Gonzalez-Ericsson, Paula I, Stovgaard, Elisabeth ES, Sua, Luz F, Reisenbichler, Emily, Kos, Zuzana, Carter, Jodi M, Michiels, Stefan, Le Quesne, John, Nielsen, Torsten O, Laenkholm, Anne-Vibeke, Fox, Stephen B, Adam, Julien, Bartlett, John Ms, Rimm, David L, Quinn, Cecily, Peeters, Dieter, Dieci, Maria V, Vincent-Salomon, Anne, Cree, Ian, Hida, Akira I, Balko, Justin M, Haynes, Harry HR, Frahm, Isabel, Acosta-Haab, Gabriela, Balancin, Marcelo, Bellolio, Enrique, Yang, Wentao, Kirtani, Pawan, Sugie, Tomoharu, Ehinger, Anna, Castaneda, Carlos Altamirano, Kok, Marleen, McArthur, Heather, Siziopikou, Kalliopi, Badve, Sunil, Fineberg, Susan, Gown, Allen A.M., Viale, Giuseppe, Schnitt, Stuart J, Pruneri, Giancarlo, Penault-Llorca, Frederique, Hewitt, Stephen M, Thompson, E Aubrey, Allison, Kimberly H, Symmans, William Fraser, Bellizzi, Andrew M, Brogi, Edi, Moore, David A, Larsimont, Denis, Dillon, Deborah A, Lazar, Alexander, Lien, Huangchun, Goetz, Matthew P, Broeckx, Glenn, El Bairi, Khalid, Harbeck, Nadia, Cimino-Mathews, Ashley, Sotiriou, Christos, Adams, Sylvia, Liu, Shi-Wei, Loibl, Sibylle, Chen, I-Chun, Lakhani, Sunil R, Juco, Jonathan W, Denkert, Carsten, Blackley, Elizabeth EF, Demaria, Sandra, Leon-Ferre, Roberto, Gluz, Oleg, Zardavas, Dimitrios, Emancipator, Kenneth, Ely, Scott, Loi, Sherene, Salgado, Roberto, Sanders, Melinda M.E., International Immuno-Oncology Biomarker Working Group, Gonzalez-Ericsson, Paula I, Stovgaard, Elisabeth ES, Sua, Luz F, Reisenbichler, Emily, Kos, Zuzana, Carter, Jodi M, Michiels, Stefan, Le Quesne, John, Nielsen, Torsten O, Laenkholm, Anne-Vibeke, Fox, Stephen B, Adam, Julien, Bartlett, John Ms, Rimm, David L, Quinn, Cecily, Peeters, Dieter, Dieci, Maria V, Vincent-Salomon, Anne, Cree, Ian, Hida, Akira I, Balko, Justin M, Haynes, Harry HR, Frahm, Isabel, Acosta-Haab, Gabriela, Balancin, Marcelo, Bellolio, Enrique, Yang, Wentao, Kirtani, Pawan, Sugie, Tomoharu, Ehinger, Anna, Castaneda, Carlos Altamirano, Kok, Marleen, McArthur, Heather, Siziopikou, Kalliopi, Badve, Sunil, Fineberg, Susan, Gown, Allen A.M., Viale, Giuseppe, Schnitt, Stuart J, Pruneri, Giancarlo, Penault-Llorca, Frederique, Hewitt, Stephen M, Thompson, E Aubrey, Allison, Kimberly H, Symmans, William Fraser, Bellizzi, Andrew M, Brogi, Edi, Moore, David A, Larsimont, Denis, Dillon, Deborah A, Lazar, Alexander, Lien, Huangchun, Goetz, Matthew P, Broeckx, Glenn, El Bairi, Khalid, Harbeck, Nadia, Cimino-Mathews, Ashley, Sotiriou, Christos, Adams, Sylvia, Liu, Shi-Wei, Loibl, Sibylle, Chen, I-Chun, Lakhani, Sunil R, Juco, Jonathan W, Denkert, Carsten, Blackley, Elizabeth EF, Demaria, Sandra, Leon-Ferre, Roberto, Gluz, Oleg, Zardavas, Dimitrios, Emancipator, Kenneth, Ely, Scott, Loi, Sherene, Salgado, Roberto, Sanders, Melinda M.E., and International Immuno-Oncology Biomarker Working Group

Abstract

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now 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. 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. Since TILs and PD-L1 are parts of an immunological spectrum in breast cancer, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immune-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with breast cancer. 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 breast cancer. This article is protected by copyright. All rights reserved., SCOPUS: re.j, info:eu-repo/semantics/published

Published
2020

14. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International Immuno- Oncology Biomarker Working Group on Breast Cancer

Author

Dieci, Maria Vittoria, Radosevic-Robin, Nina, Fineberg, Susan, Van den Eynden, Gert, Ternes, Nils, Pénault-Llorca, Frederique, Pruneri, Giancarlo, D'Alfonso, Timothy TM, Demaria, Sandra, Castaneda, Carlos, Sanchez, Joselyn, Badve, Sunil, Michiels, Stefan, Bossuyt, Veerle Ilse Julie, Rojo, Federico, Singh, Baljit, Nielsen, Torsten, Viale, Giuseppe, Kim, Seong-Rim, Hewitt, Stephen M, Wienert, Stephan, Loibl, Sibylle, Rimm, David D.L., Symmans, Fraser, Denkert, Carsten, Adams, Sylvia, Loi, Sherene, Salgado, Roberto, International Immuno-Oncology Biomarker Working Group on Breast Cancer, Universita degli Studi di Padova, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), European Institute of Oncology [Milan] (ESMO), Ctr Biomol Struct & Org, University of Maryland [College Park], University of Maryland System-University of Maryland System, Università degli Studi di Padova = University of Padua (Unipd), Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Méthodologie et épidémiologie clinique en oncologie moléculaire (U1018 (Équipe 2)), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR), Division of Pathology and Laboratory Medicine, Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), Charité, Institute of Pathology, Translational Tumorpathology Unit, Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), and Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO)

Subjects
0301 basic medicine, Oncology, Cancer Research, Neoplasm, Residual, medicine.medical_treatment, Carcinoma in Situ -- immunology, Medical Oncology, Tumor-infiltrating lymphocytes, Biomarkers, Tumor -- immunology, Breast cancer, 0302 clinical medicine, Trastuzumab, Neoplasm, Residual -- immunology, Neoadjuvant therapy, hemic and immune systems, Neoadjuvant Therapy -- methods, Sciences bio-médicales et agricoles, Neoadjuvant Therapy, 3. Good health, 030220 oncology & carcinogenesis, Breast Neoplasms -- immunology, Female, Neoadjuvant, Carcinoma in Situ, medicine.drug, Residual cancer burden, medicine.medical_specialty, Medical Oncology -- methods, Breast Neoplasms, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, breast cancer, ductal carcinoma in situ, neoadjuvant, residual cancer burden, residual disease, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Internal medicine, Biomarkers, Tumor, medicine, Humans, Cancer staging, Tumor marker, business.industry, Carcinoma in situ, Ductal carcinoma in situ, Residual disease, Ductal carcinoma, medicine.disease, Minimal residual disease, 030104 developmental biology, business, Lymphocytes, Tumor-Infiltrating -- immunology
Abstract

Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research. The aim of this report is to update pathologists, clinicians and researchers on TIL assessment in both the post-neoadjuvant residual disease and the ductal carcinoma in situ settings. The International Immuno-Oncology Working Group proposes a method for assessing TILs in these settings, based on the previously published International Guidelines on TIL Assessment in Breast Cancer. In this regard, these recommendations represent a consensus guidance for pathologists, aimed to achieve the highest possible consistency among future studies., info:eu-repo/semantics/published

Published
2018
Full Text
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15. The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group

Author

El Bairi, Khalid, Haynes, Harry R, Blackley, Elizabeth, Fineberg, Susan, Shear, Jeffrey, Turner, Sophia, De Freitas, Juliana Ribeiro, Sur, Daniel, Amendola, Luis Claudio, Gharib, Masoumeh, Kallala, Amine, Arun, Indu, Azmoudeh-Ardalan, Farid, Fujimoto, Luciana, Sua, Luz F, Liu, Shi-Wei, Lien, Huang-Chun, Kirtani, Pawan, Balancin, Marcelo, El Attar, Hicham, Guleria, Prerna, Yang, Wenxian, Shash, Emad, Chen, I-Chun, Bautista, Veronica, Do Prado Moura, Jose Fernando, Rapoport, Bernardo L, Castaneda, Carlos, Spengler, Eunice, Acosta-Haab, Gabriela, Frahm, Isabel, Sanchez, Joselyn, Castillo, Miluska, Bouchmaa, Najat, Md Zin, Reena R, Shui, Ruohong, Onyuma, Timothy, Yang, Wentao, Husain, Zaheed, Willard-Gallo, Karen, Coosemans, An, Perez, Edith A, Provenzano, Elena, Ericsson, Paula Gonzalez, Richardet, Eduardo, Mehrotra, Ravi, Sarancone, Sandra, Ehinger, Anna, Rimm, David L, Bartlett, John MS, Viale, Giuseppe, Denkert, Carsten, Hida, Akira I, Sotiriou, Christos, Loibl, Sibylle, Hewitt, Stephen M, Badve, Sunil, Symmans, William Fraser, Kim, Rim S, Pruneri, Giancarlo, Goel, Shom, Francis, Prudence A, Inurrigarro, Gloria, Yamaguchi, Rin, Garcia-Rivello, Hernan, Horlings, Hugo, Afqir, Said, Salgado, Roberto, Adams, Sylvia, Kok, Marleen, Dieci, Maria Vittoria, Michiels, Stefan, Demaria, Sandra, Loi, Sherene, and International Immuno-Oncology Biomarker Working Group

Subjects
chemical and pharmacologic phenomena, International Immuno-Oncology Biomarker Working Group, 3. Good health
Abstract

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

16. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Author

Kos, Zuzana, Roblin, Elvire, Kim, Rim S, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, Van De Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil S, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John MS, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew, Hall, Jacqueline A, Kok, Marleen, Horlings, Hugo M, Madabhushi, Anant, Van Der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van Den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Yang, Wentao, AbdulJabbar, Khalid, Yuan, Yinyin, Singh, Rajendra, Hiley, Crispin, Bakir, Maise Al, Lazar, Alexander J, Naber, Stephen, Wienert, Stephan, Castillo, Miluska, Curigliano, Giuseppe, Dieci, Maria-Vittoria, André, Fabrice, Swanton, Charles, Reis-Filho, Jorge, Sparano, Joseph, Balslev, Eva, Chen, I-Chun, Stovgaard, Elisabeth Ida Specht, Pogue-Geile, Katherine, Blenman, Kim RM, Penault-Llorca, Frédérique, Schnitt, Stuart, Lakhani, Sunil R, Vincent-Salomon, Anne, Rojo, Federico, Braybrooke, Jeremy P, Hanna, Matthew G, Soler-Monsó, M Teresa, Bethmann, Daniel, Castaneda, Carlos A, Willard-Gallo, Karen, Sharma, Ashish, Lien, Huang-Chun, Fineberg, Susan, Thagaard, Jeppe, Comerma, Laura, Gonzalez-Ericsson, Paula, Brogi, Edi, Loi, Sherene, Saltz, Joel, Klaushen, Frederick, Cooper, Lee, Amgad, Mohamed, Moore, David A, Salgado, Roberto, and International Immuno-Oncology Biomarker Working Group

Subjects
Prognostic markers, Immunosurveillance, 3. Good health
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.

17. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Author

Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K, Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H, Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M, Horlings, Hugo M, Hudeček, Jan, Ciompi, Francesco, Moore, David A, Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K, Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P, Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J, Lakhani, Sunil R, Rojo, Federico, Comerma, Laura, Badve, Sunil S, Khojasteh, Mehrnoush, Symmans, W Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L, Kim, Rim S, Rimm, David L, Viale, Giuseppe, Hewitt, Stephen M, Bartlett, John MS, Penault-Llorca, Frédérique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G, Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O, Lazar, Alexander J, Bago-Horvath, Zsuzsanna, Kooreman, Loes FS, Van Der Laak, Jeroen AWM, Saltz, Joel, Gallas, Brandon D, Kurkure, Uday, Barnes, Michael, Salgado, Roberto, Cooper, Lee AD, and International Immuno-Oncology Biomarker Working Group

Subjects
Tumour biomarkers, Prognostic markers, Breast cancer, Tumour immunology, Cancer imaging, humanities, 3. Good health
Abstract

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 Society, Funder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194, 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.

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

Author

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 MS, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie CU, Tutt, Andrew, Hall, Jacqueline A, Kos, Zuzana, Salgado, Roberto, Kok, Marleen, Horlings, Hugo M, and International Immuno-Oncology Biomarker Working Group

Subjects
Tumour biomarkers, Breast cancer, Tumour immunology, Biomarkers, 3. Good health
Abstract

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006, 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.

19. The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group

Author

El Bairi, Khalid, Haynes, Harry R, Blackley, Elizabeth, Fineberg, Susan, Shear, Jeffrey, Turner, Sophia, De Freitas, Juliana Ribeiro, Sur, Daniel, Amendola, Luis Claudio, Gharib, Masoumeh, Kallala, Amine, Arun, Indu, Azmoudeh-Ardalan, Farid, Fujimoto, Luciana, Sua, Luz F, Liu, Shi-Wei, Lien, Huang-Chun, Kirtani, Pawan, Balancin, Marcelo, El Attar, Hicham, Guleria, Prerna, Yang, Wenxian, Shash, Emad, Chen, I-Chun, Bautista, Veronica, Do Prado Moura, Jose Fernando, Rapoport, Bernardo L, Castaneda, Carlos, Spengler, Eunice, Acosta-Haab, Gabriela, Frahm, Isabel, Sanchez, Joselyn, Castillo, Miluska, Bouchmaa, Najat, Md Zin, Reena R, Shui, Ruohong, Onyuma, Timothy, Yang, Wentao, Husain, Zaheed, Willard-Gallo, Karen, Coosemans, An, Perez, Edith A, Provenzano, Elena, Ericsson, Paula Gonzalez, Richardet, Eduardo, Mehrotra, Ravi, Sarancone, Sandra, Ehinger, Anna, Rimm, David L, Bartlett, John MS, Viale, Giuseppe, Denkert, Carsten, Hida, Akira I, Sotiriou, Christos, Loibl, Sibylle, Hewitt, Stephen M, Badve, Sunil, Symmans, William Fraser, Kim, Rim S, Pruneri, Giancarlo, Goel, Shom, Francis, Prudence A, Inurrigarro, Gloria, Yamaguchi, Rin, Garcia-Rivello, Hernan, Horlings, Hugo, Afqir, Said, Salgado, Roberto, Adams, Sylvia, Kok, Marleen, Dieci, Maria Vittoria, Michiels, Stefan, Demaria, Sandra, Loi, Sherene, and International Immuno-Oncology Biomarker Working Group

Subjects
692/53/2423, review-article, chemical and pharmacologic phenomena, 692/4028/67/1347, Review Article, 3. Good health
Abstract

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

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