Sir Peter MacCallum Department of Oncology - Research Publications

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    The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group
    El Bairi, K ; Haynes, HR ; Blackley, E ; Fineberg, S ; Shear, J ; Turner, S ; de Freitas, JR ; Sur, D ; Amendola, LC ; Gharib, M ; Kallala, A ; Arun, I ; Azmoudeh-Ardalan, F ; Fujimoto, L ; Sua, LF ; Liu, S-W ; Lien, H-C ; Kirtani, P ; Balancin, M ; El Attar, H ; Guleria, P ; Yang, W ; Shash, E ; Chen, I-C ; Bautista, V ; Do Prado Moura, JF ; Rapoport, BL ; Castaneda, C ; Spengler, E ; Acosta-Haab, G ; Frahm, I ; Sanchez, J ; Castillo, M ; Bouchmaa, N ; Zin, RRM ; Shui, R ; Onyuma, T ; Yang, W ; Husain, Z ; Willard-Gallo, K ; Coosemans, A ; Perez, EA ; Provenzano, E ; Ericsson, PG ; Richardet, E ; Mehrotra, R ; Sarancone, S ; Ehinger, A ; Rimm, DL ; Bartlett, JMS ; Viale, G ; Denkert, C ; Hida, AI ; Sotiriou, C ; Loibl, S ; Hewitt, SM ; Badve, S ; Symmans, WF ; Kim, RS ; Pruneri, G ; Goel, S ; Francis, PA ; Inurrigarro, G ; Yamaguchi, R ; Garcia-Rivello, H ; Horlings, H ; Afqir, S ; Salgado, R ; Adams, S ; Kok, M ; Dieci, MV ; Michiels, S ; Demaria, S ; Loi, S (NATURE PORTFOLIO, 2021-12-01)
    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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    Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer
    Kos, Z ; Roblin, E ; Kim, RS ; Michiels, S ; Gallas, BD ; Chen, W ; van de Vijver, KK ; Goel, S ; Adams, S ; Demaria, S ; Viale, G ; Nielsen, TO ; Badve, SS ; Symmans, WF ; Sotiriou, C ; Rimm, DL ; Hewitt, S ; Denkert, C ; Loibl, S ; Luen, SJ ; Bartlett, JMS ; Savas, P ; Pruneri, G ; Dillon, DA ; Cheang, MCU ; Tutt, A ; Hall, JA ; Kok, M ; Horlings, HM ; Madabhushi, A ; van der Laak, J ; Ciompi, F ; Laenkholm, A-V ; Bellolio, E ; Gruosso, T ; Fox, SB ; Araya, JC ; Floris, G ; Hudecek, J ; Voorwerk, L ; Beck, AH ; Kerner, J ; Larsimont, D ; Declercq, S ; Van den Eynden, G ; Pusztai, L ; Ehinger, A ; Yang, W ; AbdulJabbar, K ; Yuan, Y ; Singh, R ; Hiley, C ; al Bakir, M ; Lazar, AJ ; 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, EIS ; Pogue-Geile, K ; Blenman, KRM ; Penault-Llorca, F ; Schnitt, S ; Lakhani, SR ; Vincent-Salomon, A ; Rojo, F ; Braybrooke, JP ; Hanna, MG ; Soler-Monso, MT ; Bethmann, D ; Castaneda, CA ; 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, DA ; Salgado, R (NATURE RESEARCH, 2020-05-12)
    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.
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    Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group
    Amgad, M ; Stovgaard, ES ; Balslev, E ; Thagaard, J ; Chen, W ; Dudgeon, S ; Sharma, A ; Kerner, JK ; Denkert, C ; Yuan, Y ; AbdulJabbar, K ; Wienert, S ; Savas, P ; Voorwerk, L ; Beck, AH ; Madabhushi, A ; Hartman, J ; Sebastian, MM ; Horlings, HM ; Hudecek, J ; Ciompi, F ; Moore, DA ; Singh, R ; Roblin, E ; Balancin, ML ; Mathieu, M-C ; Lennerz, JK ; Kirtani, P ; Chen, I-C ; Braybrooke, JP ; Pruneri, G ; Demaria, S ; Adams, S ; Schnitt, SJ ; Lakhani, SR ; Rojo, F ; Comerma, L ; Badve, SS ; Khojasteh, M ; Symmans, WF ; Sotiriou, C ; Gonzalez-Ericsson, P ; Pogue-Geile, KL ; Kim, RS ; Rimm, DL ; Viale, G ; Hewitt, SM ; Bartlett, JMS ; Penault-Llorca, F ; Goel, S ; Lien, H-C ; Loibl, S ; Kos, Z ; Loi, S ; Hanna, MG ; Michiels, S ; Kok, M ; Nielsen, TO ; Lazar, AJ ; Bago-Horvath, Z ; Kooreman, LFS ; van der Laak, JAWM ; Saltz, J ; Gallas, BD ; Kurkure, U ; Barnes, M ; Salgado, R ; Cooper, LAD (NATURE RESEARCH, 2020-05-12)
    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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    Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials
    Hudecek, J ; Voorwerk, L ; van Seijen, M ; Nederlof, I ; de Maaker, M ; van den Berg, J ; van de Vijver, KK ; Sikorska, K ; Adams, S ; Demaria, S ; Viale, G ; Nielsen, TO ; Badve, SS ; Michiels, S ; Symmans, WF ; Sotiriou, C ; Rimm, DL ; Hewitt, SM ; Denkert, C ; Loibl, S ; Loi, S ; Bartlett, JMS ; Pruneri, G ; Dillon, DA ; Cheang, MCU ; Tutt, A ; Hall, JA ; Kos, Z ; Salgado, R ; Kok, M ; Horlings, HM (NATURE RESEARCH, 2020-05-12)
    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.