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

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.

doi:10.1038/s41523-020-0156-0

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.