Browsing by Author "Denkert, Carsten"

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    Assessing tumor infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the International Immuno-Oncology Biomarkers Working Group: Part 1: Assessing the host immune response, TILs in invasive breast carcinoma and ductal carcinoma in situ, metastatic tumor deposits and areas for further research
    (Wolters Kluwer, 2017-09) Hendry, Shona; Salgado, Roberto; Gevaert, Thomas; Russell, Prudence; John, Tom; Thapa, Bibhusal; Christie, Michael; van de Vijver, Koen; Estrada, M. V.; Gonzalez-Ericsson, Paula; Sanders, Melinda; Soloman, Benjamin; Solinas, Cinzia; Van den Eynden, Gert; Allory, Yves; Preusser, Matthias; Hainfellner, Johannes; Pruneri, Giancarlo; Vingiani, Andrea; Demaria, Sandra; Symmans, Fraser; Nuciforo, Paolo; Comerma, Laura; Thompson, E. A.; Lakhani, Sunil; Kim, Seong-Rim; Schnitt, Stuart; Colpaert, Cecile; Sotiriou, Christos; Scherer, Stefan; Ignatiadis, Michail; Badve, Sunil S.; Pierce, Robert; Viale, Giuseppe; Sirtaine, Nicolas; Penault-Llorca, Frederique; Sugie, Tomohagu; Fineberg, Susan; Paik, Soonmyung; Srinivasan, Ashok; Richardson, Andrea; Wang, Yihong; Chmielik, Ewa; Brock, Jane; Johnson, Douglas; Balko, Justin; Wienert, Stephan; Bossuyt, Veerle; Michiels, Stefan; Ternes, Nils; Burchardi, Nicole; Luen, Stephen; Savas, Peter; Klauschen, Frederick; Watson, Peter; Nelson, Brad; Criscitiello, Carmen; O'Toole, Sandra; Larsimont, Denis; de Wind, Roland; Curigliano, Giuseppe; André, Fabrice; Lacroix-Triki, Magali; van de Vijver, Mark; Rojo, Federico; Floris, Giuseppe; Bedri, Shahinaz; Sparano, Joseph; Rimm, David; Nielsen, Torsten; Kos, Zuzana; Hewitt, Stephen; Singh, Baljit; Farshid, Gelareh; Loibl, Sibylle; Allison, Kimberly; Tung, Nadine; Adams, Sylvia; Willard-Gallo, Karen; Horlings, Hugo; Gandhi, Leena; Moreira, Andre; Hirsch, Fred; Dieci, Maria; Urbanowicz, Maria; Brcic, Iva; Korski, Konstanty; Gaire, Fabien; Koeppen, Hartmut; Lo, Amy; Giltnane, Jennifer; Rebelatto, Marlon; Steele, Keith; Zha, Jiping; Emancipator, Kenneth; Juco, Jonathan; Denkert, Carsten; Reis-Filho, Jorge; Loi, Sherene; Fox, Stephen; Pathology and Laboratory Medicine, School of Medicine
    Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.
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    Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group Part 2 TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors
    (Wolters Kluwer, 2017-11) Hendry, Shona; Salgado, Roberto; Gevaert, Thomas; Russell, Prudence A.; John, Tom; Thapa, Bibhusal; Christie, Michael; van de Vijver, Koen; Estrada, M. V.; Gonzalez-Ericsson, Paula I.; Sanders, Melinda; Solomon, Benjamin; Solinas, Cinzia; Van den Eynden, Gert G. G. M.; Allory, Yves; Preusser, Matthias; Hainfellner, Johannes; Pruneri, Giancarlo; Vingiani, Andrea; Demaria, Sandra; Symmans, Fraser; Nuciforo, Paolo; Comermo, Laura; Thompson, E. A.; Lakhani, Sunil; Kim, Seong-Rim; Schnitt, Stuart; Colpaert, Cecile; Sotiriou, Christos; Scherer, Stefan J.; Ignatiadis, Michail; Badve, Sunil S.; Pierce, Robert H.; Viale, Giuseppe; Sirtaine, Nicolas; Penault-Llorca, Frederique; Sugie, Tomohagu; Fineberg, Susan; Paik, Soonmyung; Srinivasan, Ashok; Richardson, Andrea; Wang, Yihong; Chmielik, Ewa; Brock, Jane; Johnson, Douglas B.; Balko, Justin; Wienert, Stephan; Bossuyt, Veerle; Michiels, Stefan; Ternes, Nils; Burchardi, Nicole; Luen, Stephen J.; Savas, Peter; Klauschen, Frederick; Watson, Peter H.; Nelson, Brad H.; Criscitiello, Carmen; O'Toole, Sandra; Larsimont, Denis; de Wind, Roland; Curigliano, Giuseppe; André, Fabrice; Lacroix-Triki, Magali; van de Vijver, Mark; Rojo, Federico; Floris, Giuseppe; Bedri, Shahinaz; Sparano, Joseph; Rimm, David; Nielsen, Torsten; Kos, Zuzana; Hewitt, Stephen; Singh, Baljit; Farshid, Gelareh; Loibl, Sibylle; Allison, Kimberly H.; Tung, Nadine; Adams, Sylvia; Willard-Gallo, Karen; Horlings, Hugo M.; Gandhi, Leena; Moreira, Andre; Hirsch, Fred; Dieci, Maria V.; Urbanowicz, Maria; Brcic, Iva; Korski, Konstanty; Gaire, Fabien; Koeppen, Hartmut; Lo, Amy; Giltnane, Jennifer; Rebelatto, Marlon C.; Steele, Keith E.; Zha, Jiping; Emancipator, Kenneth; Juco, Jonathan W.; Denkert, Carsten; Reis-Filho, Jorge; Loi, Sherene; Fox, Stephen B.; Pathology and Laboratory Medicine, School of Medicine
    Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.
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    Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group
    (Oxford University Press, 2021) Nielsen, Torsten O.; Leung, Samuel C. Y.; Rimm, David L.; Dodson, Andrew; Acs, Balazs; Badve, Sunil; Denkert, Carsten; Ellis, Matthew J.; Fineberg, Susan; Flowers, Margaret; Kreipe, Hans H.; Laenkholm, Anne-Vibeke; Pan, Hongchao; Penault-Llorca, Frédérique M.; Polley, Mei-Yin; Salgado, Roberto; Smith, Ian E.; Sugie, Tomoharu; Bartlett, John M. S.; McShane, Lisa M.; Dowsett, Mitch; Hayes, Daniel F.; Pathology and Laboratory Medicine, School of Medicine
    Ki67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor-positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.
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    Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group
    (Nature Research, 2020-05-12) 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; Pathology and Laboratory Medicine, School of Medicine
    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.
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    Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: recommendations from an international working group
    (Nature, 2015-07) Provenzano, Elena; Bossuyt, Veerle; Viale, Giuseppe; Cameron, David; Badve, Sunil; Denkert, Carsten; MacGrogan, Gaëtan; Penault-Llorca, Frédérique; Boughey, Judy; Curigliano, Giuseppe; Dixon, J. Michael; Esserman, Laura; Fastner, Gerd; Kuehn, Thorsten; Peintinger, Florentia; von Minckwitz, Gunter; White, Julia; Yang, Wei; Symmans, W. Fraser; Department of Pathology & Laboratory Medicine, IU School of Medicine
    Neoadjuvant systemic therapy is being used increasingly in the treatment of early-stage breast cancer. Response, in the form of pathological complete response, is a validated and evaluable surrogate end point of survival after neoadjuvant therapy. Thus, pathological complete response has become a primary end point for clinical trials. However, there is a current lack of uniformity in the definition of pathological complete response. A review of standard operating procedures used by 28 major neoadjuvant breast cancer trials and/or 25 sites involved in such trials identified marked variability in specimen handling and histologic reporting. An international working group was convened to develop practical recommendations for the pathologic assessment of residual disease in neoadjuvant clinical trials of breast cancer and information expected from pathology reports. Systematic sampling of areas identified by informed mapping of the specimen and close correlation with radiological findings is preferable to overly exhaustive sampling, and permits taking tissue samples for translational research. Controversial areas are discussed, including measurement of lesion size, reporting of lymphovascular space invasion and the presence of isolated tumor cells in lymph nodes after neoadjuvant therapy, and retesting of markers after treatment. If there has been a pathological complete response, this must be clearly stated, and the presence/absence of residual ductal carcinoma in situ must be described. When there is residual invasive carcinoma, a comment must be made as to the presence/absence of chemotherapy effect in the breast and lymph nodes. The Residual Cancer Burden is the preferred method for quantifying residual disease in neoadjuvant clinical trials in breast cancer; other methods can be included per trial protocols and regional preference. Posttreatment tumor staging using the Tumor–Node–Metastasis system should be included. These recommendations for standardized pathological evaluation and reporting of neoadjuvant breast cancer specimens should improve prognostication for individual patients and allow comparison of treatment outcomes within and across clinical trials.
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    The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group
    (Springer Nature, 2021-12-01) 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; Gonzalez Ericsson, Paula; 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; Pathology and Laboratory Medicine, School of Medicine
    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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    Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer
    (Springer, 2022-01-11) Loi, Sherene; Salgado, Roberto; Adams, Sylvia; Pruneri, Giancarlo; Francis, Prudence A.; Lacroix-Triki, Magali; Joensuu, Heikki; Dieci, Maria Vittoria; Badve, Sunil; Demaria, Sandra; Gray, Robert; Munzone, Elisabetta; Drubay, Damien; Lemonnier, Jerome; Sotiriou, Christos; Kellokumpu-Lehtinen, Pirkko Liisa; Vingiani, Andrea; Gray, Kathryn; André, Fabrice; Denkert, Carsten; Piccart, Martine; Roblin, Elvire; Michiels , Stefan; Surgery, School of Medicine
    The importance of integrating biomarkers into the TNM staging has been emphasized in the 8th Edition of the American Joint Committee on Cancer (AJCC) Staging system. In a pooled analysis of 2148 TNBC-patients in the adjuvant setting, TILs are found to strongly up and downstage traditional pathological-staging in the Pathological and Clinical Prognostic Stage Groups from the AJJC 8th edition Cancer Staging System. This suggest that clinical and research studies on TNBC should take TILs into account in addition to stage, as for example patients with stage II TNBC and high TILs have a better outcome than patients with stage I and low TILs.
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    Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer
    (Springer Nature, 2022-01-11) Loi, Sherene; Salgado, Roberto; Adams, Sylvia; Pruneri, Giancarlo; Francis, Prudence A.; Lacroix-Triki, Magali; Joensuu, Heikki; Dieci, Maria Vittoria; Badve, Sunil; Demaria, Sandra; Gray, Robert; Munzone, Elisabetta; Drubay, Damien; Lemonnier, Jerome; Sotiriou, Christos; Kellokumpu-Lehtinen, Pirkko Liisa; Vingiani, Andrea; Gray, Kathryn; André, Fabrice; Denkert, Carsten; Piccart, Martine; Roblin, Elvire; Michiels, Stefan; Pathology and Laboratory Medicine, School of Medicine
    The importance of integrating biomarkers into the TNM staging has been emphasized in the 8th Edition of the American Joint Committee on Cancer (AJCC) Staging system. In a pooled analysis of 2148 TNBC-patients in the adjuvant setting, TILs are found to strongly up and downstage traditional pathological-staging in the Pathological and Clinical Prognostic Stage Groups from the AJJC 8th edition Cancer Staging System. This suggest that clinical and research studies on TNBC should take TILs into account in addition to stage, as for example patients with stage II TNBC and high TILs have a better outcome than patients with stage I and low TILs.
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    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
    (Elsevier, 2017-10-09) Dieci, Maria Vittoria; Radosevic-Robin, Nina; Fineberg, Susan; van den Eynden, Gert; Ternes, Nils; Penault-Llorca, Frederique; Pruneri, Giancarlo; D’Alfonso, Timothy M.; Demaria, Sandra; Castaneda, Carlos; Sanchez, Joselyn; Badve, Sunil; Michiels, Stefan; Bossuyt, Veerle; Rojo, Federico; Singh, Baljit; Nielsen, Torsten; Viale, Giuseppe; Kim, Seong-Rim; Hewitt, Stephen; Wienert, Stephan; Loibl, Sybille; Rimm, David; Symmans, Fraser; Denkert, Carsten; Adams, Sylvia; Loi, Sherene; Salgado, Roberto; Pathology and Laboratory Medicine, School of Medicine
    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.