title: Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.
abstract: OBJECTIVE
  Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case, anthracycline-only CT-in selected BC subtypes.
  
  
  METHODS
  We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years.
  
  
  RESULTS
  There was no significant prognostic association in the global nor estrogen receptor (ER) -positive/human epidermal growth factor receptor 2 (HER2) -negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018).
  
  
  CONCLUSIONS
  In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes.
authors: Breast Cancer Translational Research Laboratory (BCTL) J.C. Heuson, Institut Jules Bordet, Blvd de Waterloo, 125, 1000 Brussels, Belgium. sherene.loi@bordet.be
authors: Sherene
authors: S
authors: Loi
authors: Nicolas
authors: N
authors: Sirtaine
authors: Fanny
authors: F
authors: Piette
authors: Roberto
authors: R
authors: Salgado
authors: Giuseppe
authors: G
authors: Viale
authors: Françoise
authors: F
authors: Van Eenoo
authors: Ghizlane
authors: G
authors: Rouas
authors: Prudence
authors: P
authors: Francis
authors: John P A
authors: JP
authors: Crown
authors: Erika
authors: E
authors: Hitre
authors: Evandro
authors: E
authors: de Azambuja
authors: Emmanuel
authors: E
authors: Quinaux
authors: Angelo
authors: A
authors: Di Leo
authors: Stefan
authors: S
authors: Michiels
authors: Martine J
authors: MJ
authors: Piccart
authors: Christos
authors: C
authors: Sotiriou
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D016246:Lymphocytes, Tumor-Infiltrating; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D000077143:Docetaxel; D004317:Doxorubicin; D005472:Fluorouracil; D008727:Methotrexate; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D043823:Taxoids; C508053:ERBB2 protein, human