title: Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials.
abstract: BACKGROUND
  Tumor-infiltrating lymphocytes (TILs) are emerging as strong prognostic factor for early breast cancer patients, especially in the triple-negative subtype. Here, we aim to validate previous findings on the prognostic role of TIL in the context of two randomized adjuvant trials and to investigate whether lymphocyte infiltrates can predict benefit from adjuvant anthracyclines.
  
  
  METHODS
  A total of 816 patients enrolled and treated at the Gustave Roussy in the context of two multicentric randomized trials comparing adjuvant anthracyclines versus no chemotherapy were included in the present analysis. Primary end point was overall survival (OS). Hematoxilin and eosin slides of primary tumors were retrieved and evaluated for the percentage of intratumoral (It) and stromal (Str) TIL. Each case was also defined as high-TIL or low-TIL breast cancer adopting previously validated cutoffs.
  
  
  RESULTS
  TIL were assessable for 781 of 816 cases. High-TIL cases were more likely grade 3 and estrogen receptor (ER)-negative (P < 0.001). In multivariate analysis, both continuous It-TIL and Str-TIL were strong prognostic factors for OS [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95 P = 0.003; HR 0.89, 95% CI 0.81-0.96, P = 0.005 for It-TIL and Str-TIL, respectively]. The prognostic effect of continuous TIL was limited to triple-negative and HER2-positive patients. Ten-year OS rates were: 89% and 68% for triple-negative high-TIL and low-TIL, respectively (HR 0.44, 95% CI 0.18-1.10, P = 0.07) and 78% and 57% for HER2-positive high-TIL versus low-TIL, respectively (HR 0.46, 95% CI 0.20-1.11, P = 0.08). Either continuous or binary TIL variables did not predict for the efficacy of anthracyclines. Test for interaction P value was not significant in the whole study population and in subgroups (ER+/HER2-, HER2+, ER-/HER2-).
  
  
  CONCLUSIONS
  We confirmed the prognostic role of TIL in triple-negative early breast cancer and suggested a prognostic impact in HER2+ patients as well. Basing on our data, TIL should not be used as a parameter to select patients for anthracyclines chemotherapy.
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: M V
authors.initials: MV
authors.lastname: Dieci
authors.affiliation: Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Mathieu
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Guarneri
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Conte
authors.affiliation: INSERM, Unit U981, Gustave Roussy, Villejuif Department of Medical Oncology, Gustave Roussy, Villejuif.
authors.forename: S
authors.initials: S
authors.lastname: Delaloge
authors.affiliation: INSERM, Unit U981, Gustave Roussy, Villejuif Department of Medical Oncology, Gustave Roussy, Villejuif Université Paris Sud, Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: Andre
authors.affiliation: INSERM, Unit U981, Gustave Roussy, Villejuif aicha.goubar@gustaveroussy.fr.
authors.forename: A
authors.initials: A
authors.lastname: Goubar
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013629:Tamoxifen / Q000008:administration & dosage; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*
chemical_list: D003520:Cyclophosphamide; D004317:Doxorubicin; D015251:Epirubicin; D005472:Fluorouracil; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C508053:ERBB2 protein, human
keywords: adjuvant chemotherapy; anthracyclines; breast cancer; tumor-infiltrating lymphocytes