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16 results on '"Cheang, M. C. U."'

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

Author

Kos, Z., Roblin, E., Kim, R. S., Michiels, S., Gallas, B. D., Chen, W., van de Vijver, K. K., Goel, S., Adams, S., Demaria, S., Viale, G., Nielsen, T. O., Badve, S. S., Symmans, W. F., Sotiriou, C., Rimm, D. L., Hewitt, S., Denkert, C., Loibl, S., Luen, S. J., Bartlett, J. M. S., Savas, P., Pruneri, G., Dillon, D. A., Cheang, M. C. U., Tutt, A., Hall, J. A., Kok, M., Horlings, H. M., Madabhushi, A., van der Laak, J., Ciompi, F., Laenkholm, A. -V., Bellolio, E., Gruosso, T., Fox, S. B., Araya, J. C., Floris, G., Hudecek, J., Voorwerk, L., Beck, A. H., Kerner, J., Larsimont, D., Declercq, S., Van den Eynden, G., Pusztai, L., Ehinger, A., Yang, W., Abduljabbar, K., Yuan, Y., Singh, R., Hiley, C., Bakir, M., Lazar, A. J., Naber, S., Wienert, S., Castillo, M., Curigliano, G., Dieci, M. -V., Andre, F., Swanton, C., Reis-Filho, J., Sparano, J., Balslev, E., Chen, I. -C., Stovgaard, E. I. S., Pogue-Geile, K., Blenman, K. R. M., Penault-Llorca, F., Schnitt, S., Lakhani, S. R., Vincent-Salomon, A., Rojo, F., Braybrooke, J. P., Hanna, M. G., Soler-Monso, M. T., Bethmann, D., Castaneda, C. A., Willard-Gallo, K., Sharma, A., Lien, H. -C., Fineberg, S., Thagaard, J., Comerma, L., Gonzalez-Ericsson, P., Brogi, E., Loi, S., Saltz, J., Klaushen, F., Cooper, L., Amgad, M., Moore, D. A., Salgado, R., Hyytiainen, A., Hida, A. I., Thompson, A., Lefevre, A., Gown, A., Lo, A., Sapino, A., Moreira, A. M., Richardson, A., Vingiani, A., Bellizzi, A. M., Guerrero, A., Grigoriadis, A., Garrido-Castro, A. C., Cimino-Mathews, A., Srinivasan, A., Acs, B., Singh, B., Calhoun, B., Haibe-Kans, B., Solomon, B., Thapa, B., Nelson, B. H., Ballesteroes-Merino, C., Criscitiello, C., Boeckx, C., Colpaert, C., Quinn, C., Chennubhotla, C. S., Solinas, C., Drubay, D., Sabanathan, D., Peeters, D., Zardavas, D., Hoflmayer, D., Johnson, D. B., Thompson, E. A., Perez, E., Elgabry, E. A., Blackley, E. F., Reisenbichler, E., Chmielik, E., Gaire, F., F. -I., Lu, Azmoudeh-Ardalan, F., Peale, F., Hirsch, F. R., Acosta-Haab, G., Farshid, G., Broeckx, G., Koeppen, H., Haynes, H. R., Mcarthur, H., Joensuu, H., Olofsson, H., Cree, I., Nederlof, I., Frahm, I., Brcic, I., Chan, J., Ziai, J., Brock, J., Weseling, J., Giltnane, J., Lemonnier, J., Zha, J., Ribeiro, J., Lennerz, J. K., Carter, J. M., Hartman, J., Hainfellner, J., Le Quesne, J., Juco, J. W., van den Berg, J., Sanchez, J., Cucherousset, J., Adam, J., Balko, J. M., Saeger, K., Siziopikou, K., Sikorska, K., Weber, K., Steele, K. E., Emancipator, K., El Bairi, K., Allison, K. H., Korski, K., Buisseret, L., Shi, L., Kooreman, L. F. S., Molinero, L., Estrada, M. V., Van Seijen, M., Lacroix-Triki, M., Sebastian, M. M., Balancin, M. L., Mathieu, M. -C., van de Vijver, M., Rebelatto, M. C., Piccart, M., Goetz, M. P., Preusser, M., Khojasteh, M., Sanders, M. E., Regan, M. M., Barnes, M., Christie, M., Misialek, M., Ignatiadis, M., de Maaker, M., Van Bockstal, M., Harbeck, N., Tung, N., Laudus, N., Sirtaine, N., Burchardi, N., Ternes, N., Radosevic-Robin, N., Gluz, O., Grimm, O., Nuciforo, P., Jank, P., Kirtani, P., Watson, P. H., Jelinic, P., Francis, P. A., Russell, P. A., Pierce, R. H., Hills, R., Leon-Ferre, R., de Wind, R., Shui, R., Leung, S., Tabbarah, S., Souza, S. C., O'Toole, S., Swain, S., Dudgeon, S., Willis, S., Ely, S., Bedri, S., Irshad, S., Liu, S., Hendry, S., Bianchi, S., Braganca, S., Paik, S., Luz, S., Gevaert, T., D'Alfons, T., John, T., Sugie, T., Kurkure, U., Bossuyt, V., Manem, V., Camaea, V. P., Tong, W., Tran, W. T., Wang, Y., Allory, Y., Husain, Z., Bago-Horvath, Z., Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Division of Pathology and Laboratory Medicine, Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Charité, Institute of Pathology, Translational Tumorpathology Unit, German Breast Group, University of the Sunshine Coast (USC), European Institute of Oncology [Milan] (ESMO), Breakthrough Breast Cancer Centre, London Institute of Cancer, Department of Pathology, The Netherlands Cancer Institute, Division of Experimental Therapy, The Netherlands Cancer Institute NKI/AvL, Odense University Hospital, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Breast Medical Oncology [Houston], The University of Texas M.D. Anderson Cancer Center [Houston], Helsingborg Hospital, Division of Experimental Therapeutics [Milan, Italy], Département de médecine oncologique [Gustave Roussy], Cancer Research UK Lung Cancer Centre of Excellence [Londres, Royaume-Uni], University College of London [London] (UCL), Memorial Sloane Kettering Cancer Center [New York], Herlev and Gentofte Hospital, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Southern Queensland (USQ), Pharmacogenomics Unit [Paris], Department of Genetics [Paris], Institut Curie [Paris]-Institut Curie [Paris], Instituto de Física Teórica UAM/CSIC (IFT), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Ctr Biomol Struct & Org, University of Maryland [College Park], University of Maryland System-University of Maryland System, The University of Sydney, Breast Cancer Translational Research Laboratory, Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Innovation North - Faculty of Information and Technology, Leeds Metropolitan University, Int Immuno-Oncology Biomarker, Graduate School, CCA - Cancer biology and immunology, Pathology, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), German Breast Group (GBG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Gallas, Brandon D [0000-0001-7332-1620], van de Vijver, Koen K [0000-0002-2026-9790], Demaria, Sandra [0000-0003-4426-0499], Badve, Sunil S [0000-0001-8861-9980], Symmans, W Fraser [0000-0002-1526-184X], Rimm, David L [0000-0001-5820-4397], Savas, Peter [0000-0001-5999-428X], Hall, Jacqueline A [0000-0003-0708-1360], Horlings, Hugo M [0000-0003-4782-8828], van der Laak, Jeroen [0000-0001-7982-0754], Bellolio, Enrique [0000-0003-0079-5264], Araya, Juan Carlos [0000-0003-3501-8203], Floris, Giuseppe [0000-0003-2391-5425], Hudeček, Jan [0000-0003-1071-5686], Ehinger, Anna [0000-0001-9225-7396], Lazar, Alexander J [0000-0002-6395-4499], Castillo, Miluska [0000-0002-0111-3176], Curigliano, Giuseppe [0000-0003-1781-2518], Sparano, Joseph [0000-0002-9031-2010], Braybrooke, Jeremy P [0000-0003-1943-7360], Hanna, Matthew G [0000-0002-7536-1746], Willard-Gallo, Karen [0000-0002-1150-1295], Sharma, Ashish [0000-0002-1011-6504], Comerma, Laura [0000-0002-0249-4636], Gonzalez-Ericsson, Paula [0000-0002-6292-6963], Loi, Sherene [0000-0001-6137-9171], Cooper, Lee [0000-0002-3504-4965], Apollo - University of Cambridge Repository, Research Programs Unit, Heikki Joensuu / Principal Investigator, HUS Comprehensive Cancer Center, Department of Oncology, Medicum, Gallas, Brandon D. [0000-0001-7332-1620], van de Vijver, Koen K. [0000-0002-2026-9790], Badve, Sunil S. [0000-0001-8861-9980], Symmans, W. Fraser [0000-0002-1526-184X], Rimm, David L. [0000-0001-5820-4397], Hall, Jacqueline A. [0000-0003-0708-1360], Horlings, Hugo M. [0000-0003-4782-8828], Lazar, Alexander J. [0000-0002-6395-4499], Braybrooke, Jeremy P. [0000-0003-1943-7360], and Hanna, Matthew G. [0000-0002-7536-1746]

Subjects
Oncology, [SDV]Life Sciences [q-bio], THERAPY, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], Prognostic markers, 0302 clinical medicine, Breast cancer, Medicine and Health Sciences, Pharmacology (medical), Lymphocytes, Stromal tumor, health care economics and organizations, 0303 health sciences, CHEMOTHERAPY, Sciences bio-médicales et agricoles, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], PROGNOSTIC VALUE, Clinical Practice, 030220 oncology & carcinogenesis, Educational resources, Immunosurveillance, medicine.medical_specialty, 3122 Cancers, [SDV.CAN]Life Sciences [q-bio]/Cancer, IMMUNITY, lcsh:RC254-282, Article, Limfòcits, Càncer de mama, 03 medical and health sciences, Gastrointestinal cancer, SDG 3 - Good Health and Well-being, Internal medicine, 692/53/2422, medicine, Radiology, Nuclear Medicine and imaging, Càncer gastrointestinal, 030304 developmental biology, Predictive biomarker, Tumor-infiltrating lymphocytes, business.industry, Médecine pathologie humaine, medicine.disease, Cancérologie, Human medicine, business, SYSTEM, 631/67/580/1884
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., info:eu-repo/semantics/published

Published
2020

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

Author

Hudecek, J., Voorwerk, L., van Seijen, M., Nederlof, I., de Maaker, M., van den Berg, J., van de Vijver, K. K., Sikorska, K., Adams, S., Demaria, S., Viale, G., Nielsen, T. O., Badve, S. S., Michiels, S., Symmans, W. F., Sotiriou, C., Rimm, D. L., Hewitt, S. M., Denkert, C., Loibl, S., Loi, S., Bartlett, J. M. S., Pruneri, G., Dillon, D. A., Cheang, M. C. U., Tutt, A., Hall, J. A., Kos, Z., Salgado, R., Kok, M., Horlings, H. M., Hyytiainen, A., Hida, A. I., Thompson, A., Lefevre, A., Lazar, A. J., Gown, A., Lo, A., Sapino, A., Madabhushi, A., Moreira, A., Richardson, A., Vingiani, A., Beck, A. H., Bellizzi, A. M., Guerrero, A., Grigoriadis, A., Ehinger, A., Garrido-Castro, A., Vincent-Salomon, A., Laenkholm, A. -V., Sharma, A., Cimino-Mathews, A., Srinivasan, A., Acs, B., Singh, B., Calhoun, B., Haibe-Kans, B., Solomon, B., Thapa, B., Nelson, B. H., Gallas, B. D., Castaneda, C., Ballesteros-Merino, C., Criscitiello, C., Boeckx, C., Colpaert, C., Quinn, C., Chennubhotla, C. S., Swanton, C., Solinas, C., Hiley, C., Drubay, D., Bethmann, D., Moore, D. A., Larsimont, D., Sabanathan, D., Peeters, D., Zardavas, D., Hoflmayer, D., Johnson, D. B., Thompson, E. A., Brogi, E., Perez, E., Elgabry, E. A., Stovgaard, E. S., Blackley, E. F., Roblin, E., Reisenbichler, E., Bellolio, E., Balslev, E., Chmielik, E., Gaire, F., Andre, F., F. -I., Lu, Azmoudeh-Ardalan, F., Rojo, F., Gruosso, T., Ciompi, F., Peale, F., Hirsch, F. R., Klauschen, F., Penault-Llorca, F., Acosta Haab, G., Farshid, G., van den Eynden, G., Curigliano, G., Floris, G., Broeckx, G., Gonzalez-Ericsson, Koeppen, H., Haynes, H. R., Mcarthur, H., Joensuu, H., Olofsson, H., Lien, H. -C., Chen, I. -C., Cree, I., Frahm, I., Brcic, I., Chan, J., Ziai, J., Brock, J., Wesseling, J., Giltnane, J., Kerner, J. K., Thagaard, J., Braybrooke, J. P., van der Laak, J. A. W. M., Lemonnier, J., Zha, J., Ribeiro, J., Lennerz, J. K., Carter, J. M., Saltz, J., Hartman, J., Hainfellner, J., Quesne, J. L., Juco, J. W., Reis-Filho, J., Sanchez, J., Sparano, J., Cucherousset, J., Araya, J. C., Adam, J., Balko, J. M., Saeger, K., Siziopikou, K., Willard-Gallo, K., Weber, K., Pogue-Geile, K. L., Steele, K. E., Emancipator, K., Abduljabbar, K., El Bairi, K., Blenman, K. R. M., Allison, K. H., Korski, K., Pusztai, L., Comerma, L., Buisseret, L., Cooper, L. A. D., Shi, L., Kooreman, L. F. S., Molinero, L., Estrada, M. V., Lacroix-Triki, M., Al Bakir, M., Sebastian, M. M., van de Vijver, M., Balancin, M. L., Dieci, M. V., Mathieu, M. -C., Rebelatto, M. C., Piccart, M., Hanna, M. G., Goetz, M. P., Preusser, M., Khojasteh, M., Sanders, M. E., Regan, M. M., Barnes, M., Christie, M., Misialek, M., Ignatiadis, M., van Bockstal, M., Castillo, M., Amgad, M., Harbeck, N., Tung, N., Laudus, N., Sirtaine, N., Burchardi, N., Ternes, N., Radosevic-Robin, N., Gluz, O., Grimm, O., Nuciforo, P., Jank, P., Gonzalez-Ericsson, P., Kirtani, P., Jelinic, P., Watson, P. H., Savas, P., Francis, P. A., Russell, P. A., Singh, R., Kim, R. S., Pierce, R. H., Hills, R., Leon-Ferre, R., de Wind, R., Shui, R., De Clercq, S., Leung, S., Tabbarah, S., Souza, S. C., O'Toole, S., Swain, S., Dudgeon, S., Willis, S., Ely, S., Kim, S. -R., Bedri, S., Irshad, S., Liu, S. -W., Goel, S., Hendry, S., Bianchi, S., Braganca, S., Paik, S., Wienert, S., Fox, S. B., Luen, S. J., Naber, S., Schnitt, S. J., Sua, L. F., Lakhani, S. R., Fineberg, S., Soler, T., Gevaert, T., D'Alfonso, T., John, T., Sugie, T., Kurkure, U., Bossuyt, V., Manem, V., Camara, V. P., Tong, W., Chen, W., Yang, W., Tran, W. T., Wang, Y., Yuan, Y., Allory, Y., Husain, Z., Bago-Horvath, Z., Division of Pathology and Laboratory Medicine, Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Charité, Institute of Pathology, Translational Tumorpathology Unit, German Breast Group, Breast Cancer Translational Research Laboratory, Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), University of the Sunshine Coast (USC), European Institute of Oncology [Milan] (ESMO), Breakthrough Breast Cancer Centre, London Institute of Cancer, Department of Pathology, The Netherlands Cancer Institute, Division of Experimental Therapy, The Netherlands Cancer Institute NKI/AvL, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Hudeček, Jan [0000-0003-1071-5686], van de Vijver, Koen K [0000-0002-2026-9790], Demaria, Sandra [0000-0003-4426-0499], Badve, Sunil S [0000-0001-8861-9980], Symmans, William Fraser [0000-0002-1526-184X], Rimm, David L [0000-0001-5820-4397], Loi, Sherene [0000-0001-6137-9171], Hall, Jacqueline A [0000-0003-0708-1360], Horlings, Hugo M [0000-0003-4782-8828], Apollo - University of Cambridge Repository, van de Vijver, Koen K. [0000-0002-2026-9790], Badve, Sunil S. [0000-0001-8861-9980], Rimm, David L. [0000-0001-5820-4397], Hall, Jacqueline A. [0000-0003-0708-1360], Horlings, Hugo M. [0000-0003-4782-8828], Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, German Breast Group (GBG), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], medicine.medical_treatment, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review Article, lcsh:RC254-282, 631/67/1857, Tumour biomarkers, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 692/53, Internal medicine, Medicine and Health Sciences, medicine, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, 692/4028/67/580, Stromal tumor, Biomarkers, Tumour immunology, business.industry, Risk management framework, review-article, Médecine pathologie humaine, 631/67/1347, Immunotherapy, Sciences bio-médicales et agricoles, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Review article, Clinical trial, Cancérologie, 030104 developmental biology, 030220 oncology & carcinogenesis, Biomarker (medicine), business
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., info:eu-repo/semantics/published

Published
2020

7. Molecular Characterization of Basal-Like and Non-Basal-Like Triple-Negative Breast Cancer

Author

Cheang, M. C. U., Anders, C. K., Prat, A., Adamo, B., Carey, L. A., and Perou, C. M.

Subjects
skin and connective tissue diseases
Abstract

Triple-negative (TN) and basal-like (BL) breast cancer definitions have been used interchangeably to identify breast cancers that lack expression of the hormone receptors and overexpression and/or amplification of HER2. However, both classifications show substantial discordance rates when compared to each other. Here, we molecularly characterize TN tumors and BL tumors, comparing and contrasting the results in terms of common patterns and distinct patterns for each. In total, when testing 412 TN and 473 BL tumors, 21.4% and 31.5% were identified as non-BL and non-TN, respectively. TN tumors identified as luminal or HER2-enriched (HER2E) showed undistinguishable overall gene expression profiles when compared versus luminal or HER2E tumors that were not TN. Similar findings were observed within BL tumors regardless of their TN status, which suggests that molecular subtype is preserved regardless of individual marker results. Interestingly, most TN tumors identified as HER2E showed low HER2 expression and lacked HER2 amplification, despite the similar overall gene expression profiles to HER2E tumors that were clinically HER2-positive. Lastly, additional genomic classifications were examined within TN and BL cancers, most of which were highly concordant with tumor intrinsic subtype. These results suggest that future clinical trials focused on TN disease should consider stratifying patients based upon BL versus non-BL gene expression profiles, which appears to be the main biological difference seen in patients with TN breast cancer.

Published
2013
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8. Predicting response and survival in chemotherapy-treated triple-negative breast cancer

Author

Prat, A, primary, Lluch, A, additional, Albanell, J, additional, Barry, W T, additional, Fan, C, additional, Chacón, J I, additional, Parker, J S, additional, Calvo, L, additional, Plazaola, A, additional, Arcusa, A, additional, Seguí-Palmer, M A, additional, Burgues, O, additional, Ribelles, N, additional, Rodriguez-Lescure, A, additional, Guerrero, A, additional, Ruiz-Borrego, M, additional, Munarriz, B, additional, López, J A, additional, Adamo, B, additional, Cheang, M C U, additional, Li, Y, additional, Hu, Z, additional, Gulley, M L, additional, Vidal, M J, additional, Pitcher, B N, additional, Liu, M C, additional, Citron, M L, additional, Ellis, M J, additional, Mardis, E, additional, Vickery, T, additional, Hudis, C A, additional, Winer, E P, additional, Carey, L A, additional, Caballero, R, additional, Carrasco, E, additional, Martín, M, additional, Perou, C M, additional, and Alba, E, additional

Published
2014
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9. The responsiveness of intrinsic subtypes to adjuvant anthracyclines versus nonanthracyclines in NCIC.CTG MA.5 randomized trial.

Author

Cheang, M. C. U., primary, Voduc, D., additional, Tu, D., additional, Jiang, S., additional, Leung, S., additional, Chia, S. K. L., additional, Shepherd, L. E., additional, Levine, M. N., additional, Pritchard, K. I., additional, Vickery, T., additional, Davies, S., additional, Stijleman, I. J., additional, Davis, C., additional, Parker, J. S., additional, Ellis, M. J., additional, Bernard, P. S., additional, Perou, C. M., additional, and Nielsen, T. O., additional

Published
2011
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13. Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen

Author

Prat, A., Ellis, M. J., Perou, C. M., Bernard, P. S., Parker, J. S., Nielsen, T. O., Bergh, J., Cheang, M. C. U., Miller, L. D., Fan, C., Chia, S. K. L., and Carey, L. A.

Subjects
3. Good health
Abstract

BackgroundER-positive (ER+ ) breast cancer includes all of the intrinsic molecular subtypes, although the luminal A and B subtypes predominate. In this study, we evaluated the ability of six clinically relevant genomic signatures to predict relapse in patients with ER+ tumors treated with adjuvant tamoxifen only.MethodsFour microarray datasets were combined and research-based versions of PAM50 intrinsic subtyping and risk of relapse (PAM50-ROR) score, 21-gene recurrence score (OncotypeDX), Mammaprint, Rotterdam 76 gene, index of sensitivity to endocrine therapy (SET) and an estrogen-induced gene set were evaluated. Distant relapse-free survival (DRFS) was estimated by Kaplan–Meier and log-rank tests, and multivariable analyses were done using Cox regression analysis. Harrell's C-index was also used to estimate performance.ResultsAll signatures were prognostic in patients with ER+ node-negative tumors, whereas most were prognostic in ER+ node-positive disease. Among the signatures evaluated, PAM50-ROR, OncotypeDX, Mammaprint and SET were consistently found to be independent predictors of relapse. A combination of all signatures significantly increased the performance prediction. Importantly, low-risk tumors (>90% DRFS at 8.5 years) were identified by the majority of signatures only within node-negative disease, and these tumors were mostly luminal A (78%–100%).ConclusionsMost established genomic signatures were successful in outcome predictions in ER+ breast cancer and provided statistically independent information. From a clinical perspective, multiple signatures combined together most accurately predicted outcome, but a common finding was that each signature identified a subset of luminal A patients with node-negative disease who might be considered suitable candidates for adjuvant endocrine therapy alone.

14. Luminal A vs. Basal-like Breast Cancer: time dependent changes in the risk of relapse in the absence of treatment.

Author

Cheang, M. C. U., Parker, J., DeSchryver, K., Snider, J., Walsh, T., Davies, S., Prat, A., Vickery, T., Reed, J., Zehnbauer, B., Leung, S., Voduc, D., Nielsen, T., Mardis, E., Bernard, P., Perou, C., and Ellis, M.

Subjects
*CLINICAL trials, *TAMOXIFEN, *DRUG therapy, *BREAST cancer, *CANCER
Abstract

Background: Numerous retrospective analyses of prospective randomized clinical trials of patients treated with adjuvant tamoxifen and chemotherapy have demonstrated that the breast cancer intrinsic subtype Luminal A tumors generally have favorable early initial outcomes, while basal-like tumors are associated with a marked risk of early relapse. To determine the extended natural history of the intrinsic subtypes across two decades of follow up the PAM50 "non-commercial open source bioinformatics" qPCR assay was conducted on node negative tumors accrued through the Cooperative Breast Cancer Tissue Registry (CBCTR) from patients who did not receive systemic therapy. Methods: Intrinsic subtype calls were obtained from 331 CBCTR cases treated with local interventions only. Tumors were classified into Luminal A (LumA), Luminal B (LumB), HER2-enriched (HER2-E) and Basal-like (BLBC), and correlated relapse-free (RFS). Patient survival and hazard rate were estimated using Kaplan-Meier plots and log-rank test. Multivariable Cox regression analyses were used to determine the significance of the intrinsic subtypes, adjusted with standard clinicopathological variables including tumor size, age at diagnosis, grade, radiation therapy treatment, centralized reviewed estrogen receptor, progesterone receptor and human epidermal growth factor 2 status measured by immunohistochemistry. Patients were diagnosed from 1978 to 1992, with a mean follow-up time of 13 years (range 0.5-31). Results: Of the 331 tumors tested, 51% of cases were classified as LumA, 18% as LumB, 11 % as HER2-E and 20% as BLBC. Although LumA was associated with the best outcome for the first 10-year of follow-up, the final number of RFS events were eventually comparable with those observed for BLBC with prolonged follow up (Table 1). In the multivariable Cox model, only BLBC tumors were associated with worse prognosis than LumA with borderline significance (Hazard ratio: 2.0 (95% Cl 0.9-5), p = 0.07). BLBC had the highest hazard rates for the first 5 years (7% at first year to 5% at 5 yr), consistent with previous observations. Interestingly, in the absence of treatment, the slow growing LumA subtype had a gradual increase of hazard for an RFS event from 3% at 5 yrs to 4% at 10 yrs to 7% at 20 yrs. The hazard rates of LumA cross with those of BLBC at 10 years. Conclusions: Basal-like breast cancers are associated with an early risk of relapse that decreases over time. In contrast, Luminal A breast cancer has a low risk of relapse at the outset but the risk of relapse increases over time and is responsible of the majority of the RFS events after 20 years of follow up. Luminal A breast cancers are therefore not truly low risk, particularly if they do not receive endocrine therapy; and may experience the consequences of inadequate treatment decades after diagnosis. [ABSTRACT FROM AUTHOR]

Published
2012
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15. A survival benefit from locoregional radiotherapy for node-positive and CMF treated breast cancer is most significant in Luminal A tumors.

Author

Voduc, D., Cheang, M. C. U., Tyldesley, S., Chia, S., Gelmon, K., Speers, C., and Nielsen, T. O.

Subjects
*BREAST cancer research, *PERIMENOPAUSE, *MASTECTOMY, *CANCER-related mortality, BREAST cancer chemotherapy
Abstract

Background: Between 1978-1986, 318 premenopausal women treated with mastectomy for lymph node positive breast cancer, were randomized to CMF chemotherapy alone vs. CMF chemotherapy and adjuvant radiotherapy (RT) to the chest wall and regional lymph nodes. After 15 years of follow-up, post-mastectomy RT was associated with a statistically significant 29% relative risk reduction in mortality. Recent evidence suggests that Luminal A tumors, identified using hormone receptors and Ki67, have a particularly favorable prognosis. We retrospectively identified the Luminal A tumors from this clinical trial cohort to determine if the response to postmastectomy RT differed among Luminal A and non- Luminal A tumors. Methods: 203 archival breast tumor samples from this study were used to construct a tissue microarray. Luminal A tumors were identified using an immunopanel consisting of: estrogen receptor, progestorone receptor, Her2, and Ki67. Luminal A tumors were defined as either ER or PR positive, Her2 negative, and Ki67 < 14%. Kaplan-Meier estimates and the log-rank test were used to test the differences in locoregional relapse free survival (LRFS) and breast cancer specific survival (BCSS). Interaction between treatment and Luminal A/Non-luminal A were tested using Cox regression analysis. Results: The intrinsic subtype was successfully determined in 144 breast tumors, and 49 were classified as Luminal A (34%). Survival outcomes at 10 years are summarized in Table 1: Conclusion: Our study examines the outcome of Luminal A tumors in patients with higher risk (premenopausal and lymph node positive) breast cancer treated with CMF chemotherapy. We observed that both subjects with Luminal A tumors and non-Luminal A tumors appear to demonstrate improved locoregional control with post-mastectomy RT, although this was only significant for Luminal A tumors. The non-significant interaction test suggests that there is no observable difference in radiosensitivity in this limited study population. However, the improvement in BCSS with post-mastectomy RT was only significant in the subjects with Luminal A tumors, and the interaction test was statistically significant. Our results raise the possibility that patients with non-Luminal A breast tumors are at higher risk of occult metastatic disease at presentation, and may not derive a survival benefit with improved locoregional control in the setting of CMF chemotherapy. In contrast, locoregional control has a significant effect on survival with Luminal A tumors. Our study suggests that a favorable Luminal A diagnosis should not be a reason to omit regional radiotherapy in node positive patients, as it is this subgroup that may derive the greatest benefit. [ABSTRACT FROM AUTHOR]

Published
2012
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16. Assessment of structural chromosomal instability phenotypes as biomarkers of carboplatin response in triple negative breast cancer: the TNT trial.

Author

Sipos O, Tovey H, Quist J, Haider S, Nowinski S, Gazinska P, Kernaghan S, Toms C, Maguire S, Orr N, Linn SC, Owen J, Gillett C, Pinder SE, Bliss JM, Tutt A, Cheang MCU, and Grigoriadis A

Subjects
Biomarkers, Carboplatin therapeutic use, Chromosomal Instability genetics, Humans, Phenotype, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics
Abstract

Background: In the TNT trial of triple negative breast cancer (NCT00532727), germline BRCA1/2 mutations were present in 28% of carboplatin responders. We assessed quantitative measures of structural chromosomal instability (CIN) to identify a wider patient subgroup within TNT with preferential benefit from carboplatin over docetaxel., Patients and Methods: Copy number aberrations (CNAs) were established from 135 formalin-fixed paraffin-embedded primary carcinomas using Illumina OmniExpress SNP-arrays. Seven published [allelic imbalanced CNA (AiCNA); allelic balanced CNA (AbCNA); copy number neutral loss of heterozygosity (CnLOH); number of telomeric allelic imbalances (NtAI); BRCA1-like status; percentage of genome altered (PGA); homologous recombination deficiency (HRD) scores] and two novel [Shannon diversity index (SI); high-level amplifications (HLAMP)] CIN-measurements were derived. HLAMP was defined based on the presence of at least one of the top 5% amplified cytobands located on 1q, 8q and 10p. Continuous CIN-measurements were divided into tertiles. All nine CIN-measurements were used to analyse objective response rate (ORR) and progression-free survival (PFS)., Results: Patients with tumours without HLAMP had a numerically higher ORR and significantly longer PFS in the carboplatin (C) than in the docetaxel (D) arm [56% (C) versus 29% (D), P HLAMP,quiet  = 0.085; PFS 6.1 months (C) versus 4.1 months (D), P interaction/HLAMP  = 0.047]. In the carboplatin arm, patients with tumours showing intermediate telomeric NtAI and AiCNA had higher ORR [54% (C) versus 20% (D), P NtAI,intermediate  = 0.03; 62% (C) versus 33% (D), P AiCNA,intermediate  = 0.076]. Patients with high AiCNA and PGA had shorter PFS in the carboplatin arm [3.4 months (high) versus 5.7 months (low/intermediate); and 3.8 months (high) versus 5.6 months (low/intermediate), respectively; P interaction/AiCNA  = 0.027, P adj.interaction/AiCNA  = 0.125 and P interaction/PGA  = 0.053, P adj.interaction/PGA  = 0.176], whilst no difference was observed in the docetaxel arm., Conclusions: Patients with tumours lacking HLAMP and demonstrating intermediate CIN-measurements formed a subgroup benefitting from carboplatin relative to docetaxel treatment within the TNT trial. This suggests a complex and paradoxical relationship between the extent of genomic instability in primary tumours and treatment response in the metastatic setting., Competing Interests: Disclosure AT, HT, MCUC, SK, PG, AG, SEP and JMB report that their institutional departments have received grants from Breast Cancer Now and/or Cancer Research UK and other support for costs or consumables in this research from Myriad Genetics Inc. and NanoString Technologies Inc. during the conduct of the TNT trial. Furthermore, the salary of HT has been part supported by educational grants from Merck Sharp & Dohme Ltd and Pfizer Inc. MCUC has a patent: US Patent No. 9,631,239 with royalties paid. SCL received institutional research support funding from Agendia, Amgen, AstraZeneca, Eurocept, Genentech, Roche, Sanofi and Tesaro. SCL is an advisory board member for Cergentis, IBM, Novartis, Pfizer, Roche and Sanofi. JMB also reports grants and non-financial support from AstraZeneca, Novartis, Janssen-Cilag, Merck Sharpe & Dohme, Pfizer, Roche, and Clovis Oncology outside the submitted work. All remaining authors have declared no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2021
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