title: A 3-gene proliferation score (TOP-FOX-67) can re-classify histological grade-2, ER-positive breast cancers into low- and high-risk prognostic categories.
abstract: The goal of this study was to assess the prognostic value of a 3-gene (TOP2A, FOXM1, and MKI67) proliferation score and use it to risk stratify grade-2, estrogen receptor (ER)-positive breast cancers into low- and high-risk groups. We used 4 different breast cancer gene expression datasets including two cohorts of patients who received no systemic adjuvant therapy (Mainz: n = 206, TRANSBIG: n = 134) and two other cohorts that received adjuvant tamoxifen (JBI: n = 227, MDACC/SET: n = 192). We compared individual and combined expression values of the 3 genes between grade 1, 2, and 3 tumors and plotted distant metastasis-free survival (DMFS) curves by the 3-gene score for grade-2 cancers. We compared the prognostic value of the 3-gene score to the Genomic Grade Index (GGI). The individual and combined expression of TOP2A, FOXM1, and MKI67 were significantly different between the 3 histological grade groups with the highest expression in grade-3 and the lowest in grade-1 cancers. Expression levels were variable in grade-2 cancers. Grade-2 tumors with high expression of the 3 genes (>median) showed significantly worse DMFS in one prognostic and one tamoxifen-treated set and showed a similar but non-significant trend for worse survival in the remaining two datasets. The 3-gene score performed equally well in risk stratification as the GGI. A 3-gene proliferation score shows similar prognostic value as the GGI in ER-positive, grade-2 cancers and may serve as basis for a PCR-based assay that could aid prognostic prediction for clinically intermediate-risk cancers.
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary. szekelybora@gmail.com
authors.forename: Borbala
authors.initials: B
authors.lastname: Szekely
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iwamoto
authors.forename: A Marcell
authors.initials: AM
authors.lastname: Szasz
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qi
authors.forename: Junji
authors.initials: J
authors.lastname: Matsuoka
authors.forename: W Fraser
authors.initials: WF
authors.lastname: Symmans
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Tokes
authors.forename: Janina
authors.initials: J
authors.lastname: Kulka
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D049109:Cell Proliferation; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D030541:Databases, Genetic; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D011237:Predictive Value of Tests; D011379:Prognosis; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D019394:Ki-67 Antigen; D000075223:Poly-ADP-Ribose Binding Proteins; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human