Age-specific differences in oncogenic pathway deregulation seen in human breast tumors.
OBJECTIVE
To define the biology driving the aggressive nature of breast cancer arising in young women.


METHODS
Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young <or=45 years; older >or=65 years), 411 eligible patients (n = 200<or=45 years; n = 211>or=65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts.


RESULTS
In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value.


CONCLUSIONS
Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.
Anders
Carey K
CK
Division of Medical Oncology, Department of Medicine, Duke University, Durham, North Carolina, USA.
Acharya
Chaitanya R
CR
Hsu
David S
DS
Broadwater
Gloria
G
Garman
Katherine
K
Foekens
John A
JA
Zhang
Yi
Y
Wang
Yixin
Y
Marcom
Kelly
K
Marks
Jeffrey R
JR
Mukherjee
Sayan
S
Nevins
Joseph R
JR
Blackwell
Kimberly L
KL
Potti
Anil
A
D000328:Adult; D000367:Age Factors; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008875:Middle Aged; D009857:Oncogenes