Validation of the DNA Damage Immune Response Signature in Patients With Triple-Negative Breast Cancer From the SWOG 9313c Trial

J Clin Oncol. 2019 Dec 20;37(36):3484-3492. doi: 10.1200/JCO.19.00693. Epub 2019 Oct 28.


Purpose: To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313.

Methods: Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size.

Results: Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density ≥ 20% v < 20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v < 20%). DDIR signature score and sTILs density were moderately correlated (r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively.

Conclusion: The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / immunology*
  • Cyclophosphamide / therapeutic use
  • DNA Damage
  • Disease-Free Survival
  • Doxorubicin / therapeutic use
  • Female
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Middle Aged
  • Prognosis
  • Transcriptome
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / immunology*
  • Triple Negative Breast Neoplasms / mortality


  • Biomarkers, Tumor
  • Doxorubicin
  • Cyclophosphamide