Comparison of HER2 status by fluorescence in situ hybridization and immunohistochemistry to predict benefit from dose escalation of adjuvant doxorubicin-based therapy in node-positive breast cancer patients.
OBJECTIVE
HER2 is a clinically important tumor marker in breast cancer; however, there is controversy regarding which method reliably measures HER2 status. We compared three HER2 laboratory methods: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR), to predict disease-free survival (DFS) and overall survival (OS) after adjuvant doxorubicin-based therapy in node-positive breast cancer patients.


METHODS
This is a Cancer and Leukemia Group B (CALGB) study, using 524 tumor blocks collected from breast cancer patients registered to clinical trial CALGB 8541. IHC employed CB11 and AO-11-854 monoclonal antibodies; FISH used PathVysion HER2 DNA Probe kit; PCR utilized differential PCR (D-PCR) methodology.


RESULTS
Cases HER2 positive by IHC, FISH and D-PCR were 24%, 17%, and 18%, respectively. FISH and IHC were clearly related (kappa = 64.8%). All three methods demonstrated a similar relationship for DFS and OS. By any method, for patients with HER2-negative tumors, there was little or no effect of dose of adjuvant doxorubicin-based therapy. For patients with HER2-positive tumors, all three methods predicted a benefit from dose-intense (high-dose) compared with low- or moderate-dose adjuvant doxorubicin-based therapy.


CONCLUSIONS
FISH is a reliable method to predict clinical outcome following adjuvant doxorubicin-based therapy for stage II breast cancer patients. There is a moderate level of concordance among the three methods (IHC, FISH, PCR). None of the methods is clearly superior. Although IHC-positive/FISH-positive tumors yielded the greatest interaction with dose of therapy in predicting outcome, no combination of assays tested was statistically superior.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB 7295, Mason Farm Rd, Chapel Hill, NC 27599-7295, USA. dressler@med.unc.edu
Lynn G
LG
Dressler
Donald A
DA
Berry
Gloria
G
Broadwater
David
D
Cowan
Kelly
K
Cox
Stephanie
S
Griffin
Ashley
A
Miller
Jessica
J
Tse
Debra
D
Novotny
Diane L
DL
Persons
Maurice
M
Barcos
I Craig
IC
Henderson
Edison T
ET
Liu
Ann
A
Thor
Dan
D
Budman
Hy
H
Muss
Larry
L
Norton
Daniel F
DF
Hayes
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D008207:Lymphatic Metastasis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D016019:Survival Analysis; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D004317:Doxorubicin; D005472:Fluorouracil; D018719:Erb-b2 Receptor Tyrosine Kinases