Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression.
OBJECTIVE
Breast cancer arising in young women is correlated with inferior survival and higher incidence of negative clinicopathologic features. The biology driving this aggressive disease has yet to be defined.


METHODS
Clinically annotated, microarray data from 784 early-stage breast cancers were identified, and prospectively defined, age-specific cohorts (young: </= 45 years, n = 200; older: >/= 65 years, n = 211) were compared by prognosis, clinicopathologic variables, mRNA expression values, single-gene analysis, and gene set enrichment analysis (GSEA). Univariate and multivariate analyses were performed.


RESULTS
Using clinicopathologic variables, young women illustrated lower estrogen receptor (ER) positivity (immunohistochemistry [IHC], P = .027), larger tumors (P = .012), higher human epidermal growth factor receptor 2 (HER-2) overexpression (IHC, P = .075), lymph node positivity (P = .008), higher grade tumors (P < .0001), and trends toward inferior disease-free survival (DFS; hazard ratio = 1.32; P = .094). Using genomic expression analysis, tumors arising in young women had significantly lower ERalpha mRNA (P < .0001), ERbeta (P = .02), and progesterone receptor (PR) expression (P < .0001), but higher HER-2 (P < .0001) and epidermal growth factor receptor (EGFR) expression (P < .0001). Exploratory analysis (GSEA) revealed 367 biologically relevant gene sets significantly distinguishing breast tumors arising in young women. Combining clinicopathologic and genomic variables among tumors arising in young women demonstrated that younger age and lower ERbeta and higher EGFR mRNA expression were significant predictors of inferior DFS.


CONCLUSIONS
This large-scale genomic analysis illustrates that breast cancer arising in young women is a unique biologic entity driven by unifying oncogenic signaling pathways, is characterized by less hormone sensitivity and higher HER-2/EGFR expression, and warrants further study to offer this poor-prognosis group of women better preventative and therapeutic options.
Anders
Carey K
CK
Duke University Medical Center, Box 3841, 3829 Duke South, Red Zone, Durham, NC 27710, USA. ander118@mc.duke.edu
Hsu
David S
DS
Broadwater
Gloria
G
Acharya
Chaitanya R
CR
Foekens
John A
JA
Zhang
Yi
Y
Wang
Yixin
Y
Marcom
P Kelly
PK
Marks
Jeffrey R
JR
Febbo
Phillip G
PG
Nevins
Joseph R
JR
Potti
Anil
A
Blackwell
Kimberly L
KL
D000328:Adult; D000367:Age Factors; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018773:Genes, erbB-1; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D006801:Humans; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011336:Probability; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone