Preclinical study

Breast Cancer Research and Treatment

, Volume 131, Issue 3, pp 871-880

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

  • Maria Libera AsciertoAffiliated withInfectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine and Center for Human Immunology, National Institutes of Health
  • , Maciej KmieciakAffiliated withDepartment of Microbiology & Immunology, Virginia Commonwealth University Massey Cancer Center
  • , Michael O. IdowuAffiliated withDepartment of Pathology, Virginia Commonwealth University Massey Cancer Center
  • , Rose ManjiliAffiliated withDepartment of Microbiology & Immunology, Virginia Commonwealth University Massey Cancer Center
  • , Yingdong ZhaoAffiliated withDivision of Cancer Treatment and Diagnosis, National Institutes of Health
  • , Margaret GrimesAffiliated withDepartment of Pathology, Virginia Commonwealth University Massey Cancer Center
  • , Catherine DumurAffiliated withDepartment of Pathology, Virginia Commonwealth University Massey Cancer Center
  • , Ena WangAffiliated withInfectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine and Center for Human Immunology, National Institutes of Health
  • , Viswanathan RamakrishnanAffiliated withDepartment of Biostatistics, Virginia Commonwealth University Massey Cancer Center
    • , Xiang-Yang WangAffiliated withDepartment of Human and Molecular Genetics, Virginia Commonwealth University Massey Cancer Center
    • , Harry D. BearAffiliated withDepartment of Surgery, Virginia Commonwealth University Massey Cancer Center
    • , Francesco M. MarincolaAffiliated withInfectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine and Center for Human Immunology, National Institutes of Health
    • , Masoud H. ManjiliAffiliated withDepartment of Microbiology & Immunology, Virginia Commonwealth University Massey Cancer Center Email author 

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Abstract

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.

Keywords

Breast cancer prognosis Tumor relapse Tumor microenvironment Immune response Neoadjuvant immunotherapy