Mark O'Loughlin1, Xavier Andreu2, Simonetta Bianchi3, Ewa Chemielik4, Alicia Cordoba5, Gábor Cserni6,7, Paulo Figueiredo8, Giuseppe Floris9, Maria P Foschini10, Päivi Heikkilä11, Janina Kulka12, Inta Liepniece-Karele13, Peter Regitnig14, Angelika Reiner15, Ales Ryska16, Anna Sapino17, Aliaa Shalaby1, Elisabeth Specht Stovgaard18, Cecily Quinn19,20, Elaine M Walsh1, Vicky Zolota21, Sharon A Glynn1, Grace Callagy22,23. 1. Discipline of Pathology, National University of Ireland, Galway, Ireland. 2. Pathology Department, UDIAT, Centre Diagnostic, Corporacio Sanitaria del Parc Taulí-Institut Universitari Parc Taulí-UAB, Sabadell, Spain. 3. Department of Surgery and Translational Medicine, AOU Careggi, University of Florence, Largo G. Brambilla 3, 50134, Florence, Italy. 4. Tumor Pathology Department, Maria Sklodowska-Curie Institute-Oncology Center, Gliwice, Poland. 5. Department of Pathology Section A, Navarra Health Service, Hospital Complex of Navarra, Irunlarrea 4, 31008, Pamplona, Spain. 6. Department of Pathology, Bács-Kiskun County Teaching Hospital, Nyiri ut 38., 6000, Kecskemét, Hungary. 7. Department of Pathology, University of Szeged, Állomás u. 1, 6725, Szeged, Hungary. 8. Lab Histopatologia, Av Bissaya Barreto, Apartado 2005, 3001-651, Coimbra, Portugal. 9. Department of Pathology, University Hospitals Leuven, Leuven, Belgium. 10. Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology University of Bologna, Ospedale Bellaria Via Altura 3, 40139, Bologna, Italy. 11. Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland. 12. 2nd Department of Pathology, Semmelweis University Budapest, Üllői út 93, 1091, Budapest, Hungary. 13. Pathology Centre, Riga East Clinical University Hospital, Riga, Latvia. 14. Medizinische Universität Graz, Institut für Pathologie, Graz, Austria. 15. Institute of Pathology, Danube Hospital, Langobardenstrasse 122, 1220, Vienna, Austria. 16. Department of Pathology, Charles University Medical Faculty Hospital, Hradec Kralove, Czech Republic. 17. Dip. di Scienze Mediche, Candiolo Cancer Institute - FPO, IRCCS, Università di Torino, Turin, Italy. 18. Pathology Department, Herlev University Hospital, Herlev, Denmark. 19. Irish National Breast Screening Programme, BreastCheck, Dublin, Ireland. 20. School of Medicine, University College Dublin, Dublin, Ireland. 21. Department of Pathology, Rion University Hospital, University of Patras, Medical School, Patras, Greece. 22. Discipline of Pathology, National University of Ireland, Galway, Ireland. grace.callagy@nuigalway.ie. 23. Division of Anatomic Pathology, Galway University Hospital, Newcastle Road, Galway, Ireland. grace.callagy@nuigalway.ie.
Abstract
BACKGROUND: Several studies have demonstrated a prognostic role for stromal tumour infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC). The reproducibility of scoring sTILs is variable with potentially excellent concordance being achievable using a software tool. We examined agreement between breast pathologists across Europe scoring sTILs on H&E-stained sections without software, an approach that is easily applied in clinical practice. The association between sTILs and response to anthracycline-taxane NACT was also examined. METHODOLOGY: Pathologists from the European Working Group for Breast Screening Pathology scored sTILs in 84 slides from 75 TNBCs using the immune-oncology biomarker working group guidance in two circulations. There were 16 participants in the first and 19 in the second circulation. RESULTS: Moderate agreement was achieved for absolute sTILs scores (intraclass correlation coefficient (ICC) = 0.683, 95% CI 0.601-0.767, p-value < 0.001). Agreement was less when a 25% threshold was used (ICC 0.509, 95% CI 0.416-0.614, p-value < 0.001) and for lymphocyte predominant breast cancer (LPBC) (ICC 0.504, 95% CI 0.412-0.610, p-value < 0.001). Intra-observer agreement was strong for absolute sTIL values (Spearman ρ = 0.727); fair for sTILs ≥ 25% (κ = 0.53) and for LPBC (κ = 0.49), but poor for sTILs as 10% increments (κ = 0.24). Increasing sTILs was significantly associated with an increased likelihood of a pathological complete response (pCR) on multivariable analysis. CONCLUSION: Increasing sTILs in TNBCs improves the likelihood of a pCR. However, inter-observer agreement is such that H&E-based assessment is not sufficiently reproducible for clinical application. Other methodologies should be explored, but may be at the cost of ease of application.
BACKGROUND: Several studies have demonstrated a prognostic role for stromal tumour infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC). The reproducibility of scoring sTILs is variable with potentially excellent concordance being achievable using a software tool. We examined agreement between breast pathologists across Europe scoring sTILs on H&E-stained sections without software, an approach that is easily applied in clinical practice. The association between sTILs and response to anthracycline-taxane NACT was also examined. METHODOLOGY: Pathologists from the European Working Group for Breast Screening Pathology scored sTILs in 84 slides from 75 TNBCs using the immune-oncology biomarker working group guidance in two circulations. There were 16 participants in the first and 19 in the second circulation. RESULTS: Moderate agreement was achieved for absolute sTILs scores (intraclass correlation coefficient (ICC) = 0.683, 95% CI 0.601-0.767, p-value < 0.001). Agreement was less when a 25% threshold was used (ICC 0.509, 95% CI 0.416-0.614, p-value < 0.001) and for lymphocyte predominant breast cancer (LPBC) (ICC 0.504, 95% CI 0.412-0.610, p-value < 0.001). Intra-observer agreement was strong for absolute sTIL values (Spearman ρ = 0.727); fair for sTILs ≥ 25% (κ = 0.53) and for LPBC (κ = 0.49), but poor for sTILs as 10% increments (κ = 0.24). Increasing sTILs was significantly associated with an increased likelihood of a pathological complete response (pCR) on multivariable analysis. CONCLUSION: Increasing sTILs in TNBCs improves the likelihood of a pCR. However, inter-observer agreement is such that H&E-based assessment is not sufficiently reproducible for clinical application. Other methodologies should be explored, but may be at the cost of ease of application.
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