Breast Cancer Research and Treatment

, Volume 131, Issue 3, pp 871–880 | Cite as

A signature of immune function genes associated with recurrence-free survival in breast cancer patients

  • Maria Libera Ascierto
  • Maciej Kmieciak
  • Michael O. Idowu
  • Rose Manjili
  • Yingdong Zhao
  • Margaret Grimes
  • Catherine Dumur
  • Ena Wang
  • Viswanathan Ramakrishnan
  • Xiang-Yang Wang
  • Harry D. Bear
  • Francesco M. Marincola
  • Masoud H. ManjiliEmail author
Preclinical study


The clinical significance of tumor-infiltrating immune cells has been reported in a variety of human carcinomas including breast cancer. However, molecular signature of tumor-infiltrating immune cells and their prognostic value in breast cancer patients remain elusive. We hypothesized that a distinct network of immune function genes at the tumor site can predict a low risk versus high risk of distant relapse in breast cancer patients regardless of the status of ER, PR, or HER-2/neu in their tumors. We conducted retrospective studies in a diverse cohort of breast cancer patients with a 1–5 year tumor relapse versus those with up to 7 years relapse-free survival. The RNAs were extracted from the frozen tumor specimens at the time of diagnosis and subjected to microarray analysis and real-time RT-PCR. Paraffin-embedded tissues were also subjected to immunohistochemistry staining. We determined that a network of immune function genes involved in B cell development, interferon signaling associated with allograft rejection and autoimmune reaction, antigen presentation pathway, and cross talk between adaptive and innate immune responses were exclusively upregulated in patients with relapse-free survival. Among the 299 genes, five genes which included B cell response genes were found to predict with >85% accuracy relapse-free survival. Real-time RT-PCR confirmed the 5-gene prognostic signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint panel and from the Oncotype DX recurrence score assay panel. These data suggest that neoadjuvant immunotherapy in patients with high risk of relapse may reduce tumor recurrence by inducing the immune function genes.


Breast cancer prognosis Tumor relapse Tumor microenvironment Immune response Neoadjuvant immunotherapy 



This study was supported by NIH R01 CA104757 Grant (M. H. Manjili), Massey Cancer Center Pilot Project Program 2006FPP-04 (M. H. Manjili), and VCU Technology Transfer Fund. We gratefully acknowledge the support of VCU Massey Cancer Center and the Commonwealth Foundation for Cancer Research. We thank Dr. K. Najarian for his review of the statistical analysis.

Supplementary material

10549_2011_1470_MOESM1_ESM.doc (43 kb)
Supplementary material 1 (DOC 43 kb)
10549_2011_1470_MOESM2_ESM.docx (24 kb)
Supplementary material 2 (DOCX 23 kb)
10549_2011_1470_MOESM3_ESM.docx (13 kb)
Supplementary material 3 (DOCX 12 kb)
10549_2011_1470_MOESM4_ESM.ppt (532 kb)
Supplementary Fig. 1. Significant pathways at the nominal 0.001 level of the unpaired Student’s t test. a B cell development, b antigen presentation, c GVHD signaling, d interferon signaling, and e primary immunodeficiency signaling. (PPT 532 kb)


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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Maria Libera Ascierto
    • 1
  • Maciej Kmieciak
    • 2
  • Michael O. Idowu
    • 3
  • Rose Manjili
    • 2
  • Yingdong Zhao
    • 4
  • Margaret Grimes
    • 3
  • Catherine Dumur
    • 3
  • Ena Wang
    • 1
  • Viswanathan Ramakrishnan
    • 5
  • Xiang-Yang Wang
    • 6
  • Harry D. Bear
    • 7
  • Francesco M. Marincola
    • 1
  • Masoud H. Manjili
    • 2
    Email author
  1. 1.Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine and Center for Human ImmunologyNational Institutes of HealthBethesdaUSA
  2. 2.Department of Microbiology & ImmunologyVirginia Commonwealth University Massey Cancer CenterRichmondUSA
  3. 3.Department of PathologyVirginia Commonwealth University Massey Cancer CenterRichmondUSA
  4. 4.Division of Cancer Treatment and DiagnosisNational Institutes of HealthBethesdaUSA
  5. 5.Department of BiostatisticsVirginia Commonwealth University Massey Cancer CenterRichmondUSA
  6. 6.Department of Human and Molecular GeneticsVirginia Commonwealth University Massey Cancer CenterRichmondUSA
  7. 7.Department of SurgeryVirginia Commonwealth University Massey Cancer CenterRichmondUSA

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