Influence of activation state of ErbB-2 (HER-2) on response to adjuvant cyclophosphamide, doxorubicin, and fluorouracil for stage II, node-positive breast cancer: study 8541 from the Cancer and Leukemia Group B.
OBJECTIVE
ErbB-2 (human epidermal growth factor receptor 2) overexpression may be predictive of relative resistance and/or sensitivity to specific chemotherapeutic agents. Results from a previous study from the Cancer and Leukemia Group B (CALGB 8541) demonstrated an interaction between ErbB-2 and increasing dose of adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) chemotherapy. Other studies have suggested that evaluation of the phosphorylated/activated form of ErbB-2 might be more precise in defining the impact of ErbB-2 in breast cancer. We have evaluated tumor tissue sections from CALGB 8541 patients to determine whether the interaction of ErbB-2 with CAF dose is dependent on ErbB-2 activation state, and whether phosphorylated ErbB-2 is an adverse prognostic factor in patients treated with CAF.


METHODS
Patients were randomly assigned to one of three dosing regimens of CAF. Paraffin samples from 992 of 1,572 patients who participated in CALGB 8541 were available. Of the 570 tumors with any staining for ErbB-2, 488 had tissue available for assay for phosphorylated ErbB-2, which was performed by immunohistochemistry.


RESULTS
Of 910 total assessable cases, 112 of 488 ErbB-2-positive cases (23%) stained positively for phosphorylated ErbB-2. The previously described interaction of dosing regimen of CAF with ErbB-2 was not dependent on phosphorylation status of ErbB-2.


CONCLUSIONS
Monitoring phosphorylation of ErbB-2 with an antiphospho-ErbB-2 antibody did not add further precision to identifying those patients most likely to benefit from increased dose of anthracycline-based adjuvant chemotherapy. Favorable outcomes are observed in ErbB-2-overexpressing patients treated with high-dose CAF regardless of ErbB-2 phosphorylation state.
DiGiovanna
Michael P
MP
Yale University School of Medicine, Section of Medical Oncology, 333 Cedar St, Room WWW 217, New Haven, CT 06510, USA. michael.digiovanna@yale.edu
Stern
David F
DF
Edgerton
Susan
S
Broadwater
Gloria
G
Dressler
Lynn G
LG
Budman
Daniel R
DR
Henderson
I Craig
IC
Norton
Larry
L
Liu
Edison T
ET
Muss
Hyman B
HB
Berry
Donald A
DA
Hayes
Daniel F
DF
Thor
Ann D
AD
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008207:Lymphatic Metastasis; D009367:Neoplasm Staging; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D003520:Cyclophosphamide; D004317:Doxorubicin; D005472:Fluorouracil; D018719:Erb-b2 Receptor Tyrosine Kinases