title: The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression-Based Meta-Analysis.
abstract: OBJECTIVE
  To provide further insight into the role of proliferation and other cellular processes in chemosensitivity and resistance, we evaluated the association of a diverse set of gene expression signatures with response to neoadjuvant chemotherapy (NAC) in breast cancer.
  
  
  METHODS
  Expression data from primary breast cancer biopsies for 1,419 patients in 17 studies prior to NAC were identified and aggregated using common normalization procedures. Clinicopathologic characteristics, including response to NAC, were collected. Scores for 125 previously published breast cancer-related gene expression signatures were calculated for each tumor.
  
  
  RESULTS
  Within each receptor-based subgroup or PAM50 subtype, breast tumors with high proliferation signature scores were significantly more likely to achieve pathologic complete response to NAC. To distinguish "proliferation-associated" from "proliferation-independent" signatures, we used correlation and linear modeling approaches. Most signatures associated with response to NAC were proliferation associated: 90.5% (38/42) in ER+/HER2-and 63.3% (38/60) in triple-negative breast cancer (TNBC). Proliferation-independent signatures predictive of response to NAC in ER+/HER2-breast cancer were related to immune activity, while those in TNBC comprised a diverse set of signatures, including immune, DNA damage, signaling pathways (PI3K, AKT, Ras, and EGFR), and "stemness" phenotypes.
  
  
  CONCLUSIONS
  Proliferation differences account for the vast majority of predictive capacity of gene expression signatures in neoadjuvant chemosensitivity for ER+/HER2-breast cancers and, to a lesser extent, TNBCs. Immune activation signatures are proliferation-independent predictors of pathologic complete response in ER+/HER2-breast cancers. In TNBCs, significant proliferation-independent signatures include gene sets that represent a diverse set of cellular processes. Clin Cancer Res; 22(24); 6039-50. ©2016 AACR.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Stover
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Coloff
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Brugge
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. laura_selfors@hms.harvard.edu eric_winer@dfci.harvard.edu.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts. laura_selfors@hms.harvard.edu eric_winer@dfci.harvard.edu.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Selfors
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D009367:Neoplasm Staging / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen