Triantafyllia Koletsa1, Vassiliki Kotoula2,3, Georgia-Angeliki Koliou4, Kyriaki Manousou4, Sofia Chrisafi3, Flora Zagouri5, Maria Sotiropoulou6, George Pentheroudakis7,8, Alexandra Papoudou-Bai9, Christos Christodoulou10, Grigorios Xepapadakis11, George Zografos12, Kalliopi Petraki13, Elissavet Pazarli14, Angelos Koutras15, Helen P Kourea16, Dimitrios Bafaloukos17, Kyriakos Chatzopoulos3, Alexandros Iliadis2, Christos Markopoulos18, Vasileios Venizelos19, Niki Arnogiannaki20, Konstantine T Kalogeras3,21, Ioannis Kostopoulos2, Helen Gogas22, George Fountzilas3,23. 1. Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloníki, Greece. tkoletsa@auth.gr. 2. Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloníki, Greece. 3. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki, Thessaloníki, Greece. 4. Section of Biostatistics, Hellenic Cooperative Oncology Group, Athens, Greece. 5. Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. 6. Department of Pathology, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. 7. Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece. 8. Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece. 9. Department of Pathology, Ioannina University Hospital, Ioannina, Greece. 10. Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece. 11. Breast Clinic, REA Hospital, Piraeus, Greece. 12. Breast Unit, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. 13. Pathology Department, Metropolitan Hospital, Piraeus, Greece. 14. Department of Pathology, Papageorgiou Hospital, Thessaloníki, Greece. 15. Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece. 16. Department of Pathology, University Hospital of Patras, Rion, Greece. 17. First Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece. 18. Second Department of Prop. Surgery, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. 19. Breast Unit, Metropolitan Hospital, Piraeus, Greece. 20. Department of Surgical Pathology, Saint Savvas Anticancer Hospital, Athens, Greece. 21. Translational Research Section, Hellenic Cooperative Oncology Group, Athens, Greece. 22. First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. 23. Aristotle University of Thessaloniki, Thessaloníki, Greece.
Abstract
BACKGROUND: Tumor-infiltrating lymphocytes (TILs) and their subsets contribute to breast cancer prognosis. We investigated the prognostic impact of CD3+, CD8+ and FOXP3+ TILs in patients with early intermediate/high-risk breast cancer treated with adjuvant anthracycline-based chemotherapy within two randomized trials conducted by our Group. METHODS: We examined 1011 patients (median follow-up 130.9 months) and their tumors for total, stromal (s) and intratumoral (i) CD3, CD8 and FOXP3 lymphocyte density (counts/mm2) on tissue-microarray cores by immunohistochemistry. Morphological sTIL density on whole H&E-stained sections was also evaluated. RESULTS: The majority of TILs were CD3+. Total CD3 and CD8, sCD3 and sCD8, iCD3 and iCD8, sFOXP3 and iFOXP3 were strongly correlated (Spearman's rho values > 0.6). High individual lymphocytic subsets and sTIL density were strongly associated with high tumor grade, higher proliferation and HER2-positive and triple-negative tumors (all p values < 0.001). Higher sTIL density (10% increments), high density of almost each individual marker and all-high profiles conferred favorable prognosis. However, when adjusted for sTIL density, stromal and intratumoral lymphocytic subsets lost their prognostic significance, while higher sTIL density conferred up to 15% lower risk for relapse. Independently of sTIL density, higher total CD3+ and CD8+ TILs conferred 35% and 28% lower risk for relapse, respectively. CONCLUSIONS: Stromal and intratumoral CD3+, CD8+ and FOXP3+ TIL density do not seem to add prognostic information over the morphologically assessed sTIL density, which is worth introducing in routine histology reports.
BACKGROUND:Tumor-infiltrating lymphocytes (TILs) and their subsets contribute to breast cancer prognosis. We investigated the prognostic impact of CD3+, CD8+ and FOXP3+ TILs in patients with early intermediate/high-risk breast cancer treated with adjuvant anthracycline-based chemotherapy within two randomized trials conducted by our Group. METHODS: We examined 1011 patients (median follow-up 130.9 months) and their tumors for total, stromal (s) and intratumoral (i) CD3, CD8 and FOXP3 lymphocyte density (counts/mm2) on tissue-microarray cores by immunohistochemistry. Morphological sTIL density on whole H&E-stained sections was also evaluated. RESULTS: The majority of TILs were CD3+. Total CD3 and CD8, sCD3 and sCD8, iCD3 and iCD8, sFOXP3 and iFOXP3 were strongly correlated (Spearman's rho values > 0.6). High individual lymphocytic subsets and sTIL density were strongly associated with high tumor grade, higher proliferation and HER2-positive and triple-negative tumors (all p values < 0.001). Higher sTIL density (10% increments), high density of almost each individual marker and all-high profiles conferred favorable prognosis. However, when adjusted for sTIL density, stromal and intratumoral lymphocytic subsets lost their prognostic significance, while higher sTIL density conferred up to 15% lower risk for relapse. Independently of sTIL density, higher total CD3+ and CD8+ TILs conferred 35% and 28% lower risk for relapse, respectively. CONCLUSIONS: Stromal and intratumoral CD3+, CD8+ and FOXP3+ TIL density do not seem to add prognostic information over the morphologically assessed sTIL density, which is worth introducing in routine histology reports.
Authors: Bozena Smolkova; Zuzana Cierna; Katarina Kalavska; Svetlana Miklikova; Jana Plava; Gabriel Minarik; Tatiana Sedlackova; Dana Cholujova; Paulina Gronesova; Marina Cihova; Karolina Majerova; Marian Karaba; Juraj Benca; Daniel Pindak; Jozef Mardiak; Michal Mego Journal: Int J Mol Sci Date: 2020-12-12 Impact factor: 5.923
Authors: Nanna Jørgensen; Thomas Vauvert F Hviid; Lise B Nielsen; Ida M H Sønderstrup; Jens Ole Eriksen; Bent Ejlertsen; Anne-Marie Gerdes; Torben A Kruse; Mads Thomassen; Maj-Britt Jensen; Anne-Vibeke Lænkholm Journal: Br J Cancer Date: 2021-08-07 Impact factor: 9.075