Relationship of epidermal growth factor receptor expression to ErbB-2 signaling activity and prognosis in breast cancer patients.
OBJECTIVE
To examine the relationship of epidermal growth factor receptor (EGFR) expression to ErbB-2 signaling activity in breast cancer and the impact that this interaction has on the prognosis of patients with early-stage breast cancer.


METHODS
Paraffin tumor sections were collected retrospectively from 807 breast cancer patients diagnosed between 1976 and 1983. Immunohistochemical assays for ErbB-2, phosphorylated (activated) ErbB-2, and EGFR were performed, and the results were correlated with clinicopathologic variables and outcome.


RESULTS
EGFR expression was detectable in 15% of 807 invasive breast cancers, including 35% of the 306 ErbB-2-positive patients. Conversely, the majority (87%) of EGFR-positive tumors co-overexpressed ErbB-2. Ninety-seven percent of tumors with phosphorylated ErbB-2 co-overexpressed EGFR. Patients whose cancers demonstrated ErbB-2 phosphorylation or co-overexpression of ErbB-2 and EGFR had the shortest survival. In contrast, patients whose tumors were negative for all three markers and those tumors that expressed only EGFR or only nonphosphorylated ErbB-2 had a relatively favorable outcome.


CONCLUSIONS
These data provide the first clinical evidence that EGFR expression is linked to activation of ErbB-2 in human breast cancers. We have further shown that the adverse prognostic value of ErbB-2 overexpression is observed only when ErbB-2 is in the phosphorylated (activated) state or coexpressed with EGFR. These data suggest that ligand-dependent mechanisms of ErbB-2 activation are important in human breast cancer. These results also suggest that agents targeting EGFR may be useful in the treatment of tumors with activated ErbB-2.
DiGiovanna
Michael P
MP
Department of Internal Medicine, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Stern
David F
DF
Edgerton
Susan M
SM
Whalen
Steve G
SG
Moore
Dan
D
Thor
Ann D
AD
D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012189:Retrospective Studies; D015398:Signal Transduction; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases