title: Association of Stromal Tumor-Infiltrating Lymphocytes With Recurrence-Free Survival in the N9831 Adjuvant Trial in Patients With Early-Stage HER2-Positive Breast Cancer.
abstract: OBJECTIVE
  The presence of tumor-infiltrating lymphocytes at diagnosis is reported to be prognostic in triple-negative breast cancer.
  
  
  OBJECTIVE
  To evaluate the association of stromal tumor-infiltrating lymphocytes (STILs) with recurrence-free survival (RFS) in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with chemotherapy or chemotherapy plus trastuzumab in the N9831 trial.
  
  
  METHODS
  Hematoxylin-eosin-stained tumor slides from patients with early-stage HER2-positive breast cancer in 2 of the 3 arms of the N9831 trial were assessed for STILs at an academic medical center. The amounts of STILs were quantitated in deciles, and a level of at least 60% STILs was used for the prespecified categorical cutoff. The association between STILs and RFS was evaluated with Cox models.
  
  
  METHODS
  Standard chemotherapy consisting of doxorubicin-cyclophosphamide followed by weekly paclitaxel (arm A) or doxorubicin-cyclophosphamide followed by weekly paclitaxel plus trastuzumab followed by trastuzumab alone (arm C).
  
  
  METHODS
  Stromal tumor-infiltrating lymphocytes and their association with RFS.
  
  
  RESULTS
  A total of 489 patients from arm A and 456 patients from arm C were assessed with a median (range) follow-up of 4.4 (0-13.6) years. The 10-year Kaplan-Meier estimates for RFS in arm A were 90.9% and 64.5% for patients with high and low levels of STILs, respectively (hazard ratio [HR], 0.23 [95% CI, 0.07-0.73]; P = .01). The 10-year estimates for RFS in arm C were 80.0% and 80.1% for patients with high and low levels of STILs, respectively (HR, 1.26 [95% CI, 0.50-3.17]; P = .63). The test for interaction between trastuzumab treatment and STIL status was statistically significant (P = .03). In a multivariable analysis, STIL status remained significantly associated with RFS in arm A and not significantly associated in arm C (HR, 1.01 [95% CI, 0.89-1.15]; interaction P = .04).
  
  
  CONCLUSIONS
  This analysis of participants in the N9831 trial found that the presence of STILs was prognostically associated with RFS in patients treated with chemotherapy alone but not in patients treated with chemotherapy plus trastuzumab. High levels of STILs were associated with lack of trastuzumab therapy benefit, in contrast to a previously reported association between increased levels of STILs and increased trastuzumab benefit in HER2-positive patients.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00005970.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Jacksonville, Florida.
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Health Science Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Karla V
authors.initials: KV
authors.lastname: Ballman
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Health Science Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Tenner
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Jacksonville, Florida3Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.
authors.forename: E Aubrey
authors.initials: EA
authors.lastname: Thompson
authors.affiliation: Department of Pathology, Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana.
authors.forename: Sunil S
authors.initials: SS
authors.lastname: Badve
authors.affiliation: Genomic Health Inc, Redwood City, California.
authors.forename: Helen
authors.initials: H
authors.lastname: Bailey
authors.affiliation: Genomic Health Inc, Redwood City, California6Department of Pathology, University of California, San Francisco.
authors.forename: Frederick L
authors.initials: FL
authors.lastname: Baehner
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000037:antagonists & inhibitors; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology*; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D017239:Paclitaxel / Q000008:administration & dosage; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000037:antagonists & inhibitors; D012189:Retrospective Studies; D012307:Risk Factors; D017154:Stromal Cells / Q000276:immunology*; D013997:Time Factors; D000068878:Trastuzumab / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D004317:Doxorubicin; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human