title: Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial.
abstract: OBJECTIVE
  To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2-positive breast cancer.
  
  
  METHODS
  DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme.
  
  
  RESULTS
  Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene-enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95% CI, 0.22 to 0.55; P < .001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95% CI, 0.62 to 1.28; P = .53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95% CI, 0.60 to 1.37; P = .64).
  
  
  CONCLUSIONS
  Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA. perez.edith@mayo.edu.
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: E Aubrey
authors.initials: EA
authors.lastname: Thompson
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Karla V
authors.initials: KV
authors.lastname: Ballman
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: S Keith
authors.initials: SK
authors.lastname: Anderson
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Yan W
authors.initials: YW
authors.lastname: Asmann
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Kalari
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Amylou C
authors.initials: AC
authors.lastname: Dueck
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Tenner
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Jin
authors.initials: J
authors.lastname: Jen
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Xochiquetzal J
authors.initials: XJ
authors.lastname: Geiger
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Ann E
authors.initials: AE
authors.lastname: McCullough
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Beiyun
authors.initials: B
authors.lastname: Chen
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Gralow
authors.affiliation: Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Reinholz
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D017024:Chemotherapy, Adjuvant; D004273:DNA, Neoplasm / Q000032:analysis; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D059467:Transcriptome; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human