HER-2/neu overexpression and in vitro chemosensitivity to CMF and FEC in primary breast cancer.
Available clinical and experimental data on the effect of HER-2/neu overexpression on chemosensitivity are controversial. It was the purpose of this in vitro study to define the association between HER-2/neu overexpression and the sensitivity to the chemotherapeutic drug combinations of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and 5-fluorouracil, epirubicin and cyclophosphamide (FEC) of breast cancer cells derived from 140 chemotherapy-naïve patients at the time of primary surgery. Both drug combinations were tested at six different concentrations ranging from 6.25-200% peak plasma concentration (PPC). Immunohistochemical detection of HER-2/neu overexpression was performed with the HER-2/neu antibodies, CB11, TAB250 and AO485, in the same tumor specimens. Immunoreactions were determined as negative (0/1+), weakly positive (2+) and strongly positive (3+). However, the antibodies varied in their degrees of sensitivity. Breast cancer samples with strong (3+) HER-2/neu overexpression demonstrated 90% growth inhibition (IC90) at significantly lower PPC values, using the CB11 (p = 0.048), TAB250 (p = 0.007) and AO485 (p < or =0.01) antibodies, and showed 50% growth inhibition (IC50) at significantly lower PPC values, using the CB11 antibody (p = 0.01) compared to their counterparts with lower levels of HER-2/neu expression. When analyzing the group of patients with intermediate and strong HER-2/neu overexpression (2+ and 3+), an association between HER-2/neu overexpression and increased chemosensitivity was seen with the TAB250 (p = 0.044) and AO485 (p = 0.032) antibodies, but not with the CB11 antibody (p =0.8) at the IC90 level. Differences in chemosensitivity between samples with strong HER-2/neu overexpression and those with lower levels were then analyzed separately for CMF and FEC. Both regimens achieved 90% tumor growth inhibition at lower PPC values in samples with strong HER-2/neu overexpression (3+) compared to their counterparts with lower expression levels (AO485 p = 0.011 for CMF, and p = 0.09 for FEC). Cumulative concentration-response plots of tumors responding in vitro with 90% tumor cell inhibition showed a stronger dose dependence for both CMF and FEC among tumor samples with strong HER-2/neu overexpression compared to those with lower levels of expression. In conclusion, the data show that HER-2/neu overexpression was not associated with in vitro drug resistance to CMF or FEC. In contrast, tumors with strong HER-2/neu overexpression demonstrated increased dose-dependent in vitro sensitivity to both the FEC and CMF regimens.
Konecny
G
G
Department of Medicine, UCLA School of Medicine, 90095-1678, USA. gkonecny@ucla.edu
Fritz
M
M
Untch
M
M
Lebeau
A
A
Felber
M
M
Lude
S
S
Beryt
M
M
Hepp
H
H
Slamon
D
D
Pegram
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D015854:Up-Regulation
D003520:Cyclophosphamide; D015251:Epirubicin; D005472:Fluorouracil; D008727:Methotrexate; D018719:Erb-b2 Receptor Tyrosine Kinases