@article{3003327,
    title = "Prognostic impact of stromal and intratumoral CD3, CD8 and FOXP3 in adjuvantly treated breast cancer: do they add information over stromal tumor-infiltrating lymphocyte density?",
    author = "Koletsa, T. and Kotoula, V. and Koliou, G.-A. and Manousou, K. and Chrisafi, S. and Zagouri, F. and Sotiropoulou, M. and Pentheroudakis, G. and Papoudou-Bai, A. and Christodoulou, C. and Xepapadakis, G. and Zografos, G. and Petraki, K. and Pazarli, E. and Koutras, A. and Kourea, H.P. and Bafaloukos, D. and Chatzopoulos, K. and Iliadis, A. and Markopoulos, C. and Venizelos, V. and Arnogiannaki, N. and Kalogeras, K.T. and Kostopoulos, I. and Gogas, H. and Fountzilas, G.",
    journal = "Cancer Immunology, Immunotherapy",
    year = "2020",
    volume = "69",
    number = "8",
    pages = "1549-1564",
    publisher = "Springer-Verlag",
    issn = "0340-7004, 1432-0851",
    doi = "10.1007/s00262-020-02557-0",
    keywords = "antineoplastic agent;  CD3 antigen;  CD8 antigen;  epirubicin;  paclitaxel;  transcription factor FOXP3;  CD3 antigen;  CD8 antigen;  forkhead transcription factor;  FOXP3 protein, human;  tumor marker, adjuvant therapy;  adult;  aged;  Article;  breast cancer;  cancer combination chemotherapy;  cancer grading;  cancer prognosis;  cancer recurrence;  cell density;  cell proliferation;  controlled study;  female;  follow up;  human;  human cell;  human epidermal growth factor receptor 2 positive breast cancer;  human tissue;  immunohistochemistry;  luminal A breast cancer;  luminal B breast cancer;  lymphocyte subpopulation;  major clinical study;  priority journal;  prognostic assessment;  randomized controlled trial;  stroma cell;  tissue microarray;  triple negative breast cancer;  tumor associated leukocyte;  adjuvant chemotherapy;  adjuvant radiotherapy;  breast tumor;  immunology;  metabolism;  middle aged;  pathology;  prognosis;  tumor associated leukocyte;  young adult, Adult;  Aged;  Biomarkers, Tumor;  Breast Neoplasms;  CD3 Complex;  CD8 Antigens;  Chemotherapy, Adjuvant;  Female;  Follow-Up Studies;  Forkhead Transcription Factors;  Humans;  Lymphocyte Subsets;  Lymphocytes, Tumor-Infiltrating;  Middle Aged;  Prognosis;  Radiotherapy, Adjuvant;  Stromal Cells;  Young Adult",
    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. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature."
}