title: Immunogenic Subtypes of Breast Cancer Delineated by Gene Classifiers of Immune Responsiveness.
abstract: The abundance and functional orientation of tumor-infiltrating lymphocytes in breast cancer is associated with distant metastasis-free survival, yet how this association is influenced by tumor phenotypic heterogeneity is poorly understood. Here, a bioinformatics approach defined tumor biologic attributes that influence this association and delineated tumor subtypes that may differ in their ability to sustain durable antitumor immune responses. A large database of breast tumor expression profiles and associated clinical data was compiled, from which the ability of phenotypic markers to significantly influence the prognostic performance of a classification model that incorporates immune cell-specific gene signatures was ascertained. Markers of cell proliferation and intrinsic molecular subtype reproducibly distinguished two breast cancer subtypes that we refer to as immune benefit-enabled (IBE) and immune benefit-disabled (IBD). The IBE tumors, comprised mostly of highly proliferative tumors of the basal-like, HER2-enriched, and luminal B subtypes, could be stratified by the immune classifier into significantly different prognostic groups, while IBD tumors could not, indicating the potential for productive engagement of metastasis-protective immunity in IBE tumors, but not in IBD tumors. The prognostic stratification in IBE was independent of conventional variables. Gene network analysis predicted the activation of TNFα/IFNγ signaling pathways in IBE tumors and the activation of the transforming growth factor-β pathway in IBD tumors. This prediction supports a model in which breast tumors can be distinguished on the basis of their potential for metastasis-protective immune responsiveness. Whether IBE and IBD represent clinically relevant contexts for evaluating sensitivity to immunotherapeutic agents warrants further investigation. Cancer Immunol Res; 4(7); 600-10. ©2016 AACR.
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina. The Comprehensive Cancer Center of Wake Forest University, Winston Salem, North Carolina. ldmiller@wfubmc.edu.
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Jeff A
authors.initials: JA
authors.lastname: Chou
authors.affiliation: Department of Biochemistry, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Black
authors.affiliation: Department of Molecular Medicine and Pathology and Maurice Wilkins Institute, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
authors.forename: Cristin
authors.initials: C
authors.lastname: Print
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Julia
authors.initials: J
authors.lastname: Chifman
authors.affiliation: The Comprehensive Cancer Center of Wake Forest University, Winston Salem, North Carolina. Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Angela
authors.initials: A
authors.lastname: Alistar
authors.affiliation: Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, National University Hospital, Singapore.
authors.forename: Thomas
authors.initials: T
authors.lastname: Putti
authors.affiliation: Department of Radiology, Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Davide
authors.initials: D
authors.lastname: Bedognetti
authors.affiliation: Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Wouter
authors.initials: W
authors.lastname: Hendrickx
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Ashok
authors.initials: A
authors.lastname: Pullikuth
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rennhack
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan.
authors.forename: Eran R
authors.initials: ER
authors.lastname: Andrechek
authors.affiliation: Department of Radiation Oncology and Pathology, Weill Cornell Medical College, New York, New York.
authors.forename: Sandra
authors.initials: S
authors.lastname: Demaria
authors.affiliation: Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: Office of the Chief Research Officer, Research Branch, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056747:Immunomodulation; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models