The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice

Paula I Gonzalez-Ericsson¹, Elisabeth S Stovgaard², Luz F Sua³, Emily Reisenbichler⁴, Zuzana Kos⁵, Jodi M Carter⁶, Stefan Michiels⁷, John Le Quesne^{8

9}, Torsten O Nielsen¹⁰, Anne-Vibeke Laenkholm¹¹, Stephen B Fox^{12

13}, Julien Adam¹⁴, John Ms Bartlett^{15

16}, David L Rimm⁴, Cecily Quinn¹⁷, Dieter Peeters^{18

19}, Maria V Dieci^{20

21}, Anne Vincent-Salomon²², Ian Cree²³, Akira I Hida²⁴, Justin M Balko^{1

25

26}, Harry R Haynes^{27

28}, Isabel Frahm²⁹, Gabriela Acosta-Haab³⁰, Marcelo Balancin³¹, Enrique Bellolio³², Wentao Yang³³, Pawan Kirtani³⁴, Tomoharu Sugie³⁵, Anna Ehinger³⁶, Carlos A Castaneda³⁷, Marleen Kok³⁸, Heather McArthur³⁹, Kalliopi Siziopikou⁴⁰, Sunil Badve⁴¹, Susan Fineberg⁴², Allen Gown⁴³, Giuseppe Viale^{44

45}, Stuart J Schnitt^{46

47}, Giancarlo Pruneri^{45

48}, Frederique Penault-Llorca^{49

50}, Stephen Hewitt⁵¹, E Aubrey Thompson⁵², Kimberly H Allison⁵³, William F Symmans⁵⁴, Andrew M Bellizzi⁵⁵, Edi Brogi⁵⁶, David A Moore⁵⁷, Denis Larsimont⁵⁸, Deborah A Dillon⁴⁶, Alexander Lazar⁵⁴, Huangchun Lien⁵⁹, Matthew P Goetz⁶⁰, Glenn Broeckx⁶¹, Khalid El Bairi⁶², Nadia Harbeck⁶³, Ashley Cimino-Mathews⁶⁴, Christos Sotiriou⁶⁵, Sylvia Adams⁶⁶, Shi-Wei Liu⁶⁷, Sibylle Loibl⁶⁸, I-Chun Chen⁶⁹, Sunil R Lakhani⁷⁰, Jonathan W Juco⁷¹, Carsten Denkert⁷², Elizabeth F Blackley⁷³, Sandra Demaria⁷⁴, Roberto Leon-Ferre⁶⁰, Oleg Gluz⁷⁵, Dimitrios Zardavas⁷⁶, Kenneth Emancipator⁷¹, Scott Ely⁷⁷, Sherene Loi^{13

78}, Roberto Salgado^{78

79}, Melinda Sanders^{1

26}; International Immuno-Oncology Biomarker Working Group

Affiliations

¹ Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN, USA.
² Department of Pathology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark.
³ Department of Pathology and Laboratory Medicine, Fundación Valle del Lili, and Faculty of Health Sciences, Universidad ICESI, Cali, Colombia.
⁴ Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
⁵ Department of Pathology, BC Cancer Agency, Vancouver, Canada.
⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁷ Biostatistics and Epidemiology Service, Centre de Recherche en Epidémiologie et Santé des Populations, Gustave Roussy, Université Paris-Sud, Villejuif, France.
⁸ Leicester Cancer Research Centre, University of Leicester, Leicester, UK.
⁹ MRC Toxicology Unit, University of Cambridge, Leicester, UK.
¹⁰ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
¹¹ Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark.
¹² Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.
¹³ Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
¹⁴ Department of Pathology, Gustave Roussy, Grand Paris, France.
¹⁵ Ontario Institute for Cancer Research, Toronto, Canada.
¹⁶ Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Edinburgh, UK.
¹⁷ Department of Pathology, St Vincent's University Hospital and University College Dublin, Dublin, Ireland.
¹⁸ HistoGeneX NV, Antwerp, Belgium.
¹⁹ AZ Sint-Maarten Hospital, Mechelen, Belgium.
²⁰ Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
²¹ Medical Oncology 2, Istituto Oncologico Veneto - IRCCS, Padova, Italy.
²² Department of Pathology, Insitut Curie, Paris, France.
²³ International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France.
²⁴ Department of Pathology, Matsuyama Shimin Hospital, Matsuyama, Japan.
²⁵ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁶ Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁷ Department of Cellular Pathology, North Bristol NHS Trust, Bristol, UK.
²⁸ Translational Health Sciences, University of Bristol, Bristol, UK.
²⁹ Department of Pathology, Sanatorio Mater Dei, Buenos Aires, Argentina.
³⁰ Department of Pathology, Hospital de Oncología Maria Curie, Buenos Aires, Argentina.
³¹ Department of Pathology, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
³² Department of Pathology, Universidad de La Frontera, Temuco, Chile.
³³ Department of Pathology, Fudan University Shanghai Cancer Centre, Shanghai, PR China.
³⁴ Department of Histopathology, Manipal Hospitals Dwarka, New Delhi, India.
³⁵ Breast Surgery, Kansai Medical University Hospital, Hirakata, Japan.
³⁶ Department of Clinical Genetics and Pathology, Skane University Hospital, Lund University, Lund, Sweden.
³⁷ Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.
³⁸ Divisions of Medical Oncology, Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
³⁹ Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁴⁰ Department of Pathology, Breast Pathology Section, Northwestern University, Chicago, IL, USA.
⁴¹ Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, USA.
⁴² Department of Pathology, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY, USA.
⁴³ PhenoPath Laboratories, Seattle, WA, USA.
⁴⁴ Department of Pathology, Istituto Europeo di Oncologia IRCCS, Milan, Italy.
⁴⁵ University of Milan, Milan, Italy.
⁴⁶ Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴⁷ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁴⁸ Department of Pathology, IRCCS Fondazione Instituto Nazionale Tumori, Milan, Italy.
⁴⁹ Department of Biology and Pathology, Centre Jean Perrin, Clermont Ferrand, France.
⁵⁰ UMR INSERM 1240, Université Clermont Auvergne, Clermont Ferrand, France.
⁵¹ Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵² Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
⁵³ Department of Pathology, Stanford University, Stanford, CA, USA.
⁵⁴ Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
⁵⁵ Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
⁵⁶ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁵⁷ CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, and Department of Cellular Pathology, UCLH, London, UK.
⁵⁸ Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
⁵⁹ Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan.
⁶⁰ Department of Oncology, Mayo Clinic, Rochester, MN, USA.
⁶¹ Department of Pathology, University Hospital Antwerp, Edegem, Belgium.
⁶² Cancer Biomarkers Working Group, Faculty of Medicine and Pharmacy, Mohamed Ist University, Oujda, Morocco.
⁶³ Breast Center, Department of OB&GYN and CCC (LMU), University of Munich, Munich, Germany.
⁶⁴ Department of Pathology and Oncology, The Johns Hopkins Hospital, Baltimore, MD, USA.
⁶⁵ Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
⁶⁶ Perlmutter Cancer Center, New York University Medical School, New York, NY, USA.
⁶⁷ Sichuan Cancer Hospital, Chengdu, PR China.
⁶⁸ German Breast Group, Neu-Isenburg, Germany.
⁶⁹ Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
⁷⁰ The University of Queensland, Centre for Clinical Research, and Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, Australia.
⁷¹ Translational Medicine, Merck & Co, Inc, Kenilworth, NJ, USA.
⁷² Institute of Pathology, Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg and Philipps-Universität Marburg, Marburg, Germany.
⁷³ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
⁷⁴ Department of Radiation Oncology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
⁷⁵ Johanniter GmbH - Evangelisches Krankenhaus Bethesda Mönchengladbach, West German Study Group, Mönchengladbach, Germany.
⁷⁶ Oncology Clinical Development, Bristol-Myers Squibb, Princeton, NJ, USA.
⁷⁷ Translational Medicine, Bristol-Myers Squibb, Princeton, NJ, USA.
⁷⁸ Division of Research, Peter MacCallum Cancer Centre, Melbourne, Australia.
⁷⁹ Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium.

PMID: 32129476
DOI: 10.1002/path.5406

Free article

Review

The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice

Paula I Gonzalez-Ericsson et al. J Pathol. 2020 Apr.

Free article

. 2020 Apr;250(5):667-684.

doi: 10.1002/path.5406. Epub 2020 Apr 9.

Authors

Affiliations

¹ Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN, USA.
² Department of Pathology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark.
³ Department of Pathology and Laboratory Medicine, Fundación Valle del Lili, and Faculty of Health Sciences, Universidad ICESI, Cali, Colombia.
⁴ Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
⁵ Department of Pathology, BC Cancer Agency, Vancouver, Canada.
⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁷ Biostatistics and Epidemiology Service, Centre de Recherche en Epidémiologie et Santé des Populations, Gustave Roussy, Université Paris-Sud, Villejuif, France.
⁸ Leicester Cancer Research Centre, University of Leicester, Leicester, UK.
⁹ MRC Toxicology Unit, University of Cambridge, Leicester, UK.
¹⁰ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
¹¹ Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark.
¹² Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.
¹³ Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
¹⁴ Department of Pathology, Gustave Roussy, Grand Paris, France.
¹⁵ Ontario Institute for Cancer Research, Toronto, Canada.
¹⁶ Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Edinburgh, UK.
¹⁷ Department of Pathology, St Vincent's University Hospital and University College Dublin, Dublin, Ireland.
¹⁸ HistoGeneX NV, Antwerp, Belgium.
¹⁹ AZ Sint-Maarten Hospital, Mechelen, Belgium.
²⁰ Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
²¹ Medical Oncology 2, Istituto Oncologico Veneto - IRCCS, Padova, Italy.
²² Department of Pathology, Insitut Curie, Paris, France.
²³ International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France.
²⁴ Department of Pathology, Matsuyama Shimin Hospital, Matsuyama, Japan.
²⁵ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁶ Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁷ Department of Cellular Pathology, North Bristol NHS Trust, Bristol, UK.
²⁸ Translational Health Sciences, University of Bristol, Bristol, UK.
²⁹ Department of Pathology, Sanatorio Mater Dei, Buenos Aires, Argentina.
³⁰ Department of Pathology, Hospital de Oncología Maria Curie, Buenos Aires, Argentina.
³¹ Department of Pathology, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
³² Department of Pathology, Universidad de La Frontera, Temuco, Chile.
³³ Department of Pathology, Fudan University Shanghai Cancer Centre, Shanghai, PR China.
³⁴ Department of Histopathology, Manipal Hospitals Dwarka, New Delhi, India.
³⁵ Breast Surgery, Kansai Medical University Hospital, Hirakata, Japan.
³⁶ Department of Clinical Genetics and Pathology, Skane University Hospital, Lund University, Lund, Sweden.
³⁷ Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.
³⁸ Divisions of Medical Oncology, Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
³⁹ Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁴⁰ Department of Pathology, Breast Pathology Section, Northwestern University, Chicago, IL, USA.
⁴¹ Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, USA.
⁴² Department of Pathology, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY, USA.
⁴³ PhenoPath Laboratories, Seattle, WA, USA.
⁴⁴ Department of Pathology, Istituto Europeo di Oncologia IRCCS, Milan, Italy.
⁴⁵ University of Milan, Milan, Italy.
⁴⁶ Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴⁷ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁴⁸ Department of Pathology, IRCCS Fondazione Instituto Nazionale Tumori, Milan, Italy.
⁴⁹ Department of Biology and Pathology, Centre Jean Perrin, Clermont Ferrand, France.
⁵⁰ UMR INSERM 1240, Université Clermont Auvergne, Clermont Ferrand, France.
⁵¹ Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵² Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
⁵³ Department of Pathology, Stanford University, Stanford, CA, USA.
⁵⁴ Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
⁵⁵ Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
⁵⁶ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁵⁷ CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, and Department of Cellular Pathology, UCLH, London, UK.
⁵⁸ Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
⁵⁹ Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan.
⁶⁰ Department of Oncology, Mayo Clinic, Rochester, MN, USA.
⁶¹ Department of Pathology, University Hospital Antwerp, Edegem, Belgium.
⁶² Cancer Biomarkers Working Group, Faculty of Medicine and Pharmacy, Mohamed Ist University, Oujda, Morocco.
⁶³ Breast Center, Department of OB&GYN and CCC (LMU), University of Munich, Munich, Germany.
⁶⁴ Department of Pathology and Oncology, The Johns Hopkins Hospital, Baltimore, MD, USA.
⁶⁵ Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
⁶⁶ Perlmutter Cancer Center, New York University Medical School, New York, NY, USA.
⁶⁷ Sichuan Cancer Hospital, Chengdu, PR China.
⁶⁸ German Breast Group, Neu-Isenburg, Germany.
⁶⁹ Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
⁷⁰ The University of Queensland, Centre for Clinical Research, and Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, Australia.
⁷¹ Translational Medicine, Merck & Co, Inc, Kenilworth, NJ, USA.
⁷² Institute of Pathology, Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg and Philipps-Universität Marburg, Marburg, Germany.
⁷³ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
⁷⁴ Department of Radiation Oncology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
⁷⁵ Johanniter GmbH - Evangelisches Krankenhaus Bethesda Mönchengladbach, West German Study Group, Mönchengladbach, Germany.
⁷⁶ Oncology Clinical Development, Bristol-Myers Squibb, Princeton, NJ, USA.
⁷⁷ Translational Medicine, Bristol-Myers Squibb, Princeton, NJ, USA.
⁷⁸ Division of Research, Peter MacCallum Cancer Centre, Melbourne, Australia.
⁷⁹ Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium.

PMID: 32129476
DOI: 10.1002/path.5406

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. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: PD-L1; TILs; biomarker risk-management; breast cancer; immunotherapy.

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References

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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 in breast cancer clinical trials and daily practice

Affiliations

The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice

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