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 overexp ression on chemosensitivity are controversial. It was the purpose of this i n vitro study to define the association between HER-2/neu overexpression an d the sensitivity to the chemotherapeutic drug combinations of cyclophospha mide, methotrexate and 5-fluorouracil (CMF) and 5-fluorouracil, epirubicin and cyclophosphamide (FEC) of breast cancer cells derived from 140 chemothe rapy-naive patients at the time of primary surgery. Both drug combinations were tested at six different concentrations ranging from 6.25-200% peak pla sma concentration (PPC). Immunohistochemical detection of HER-2/neu overexp ression 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 antib odies varied in their degrees of sensitivity. Breast cancer samples with st rong (3+) HER-2/neu overexpression demonstrated 90% growth inhibition (IC(9 )0) at significantly lower PPC values, using the CB11 (p = 0.048), TAB250 ( p = 0.007) and AO485 (p less than or equal to 0.01) antibodies, and showed 50% growth inhibition (IC(5)0) 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 intermed iate and strong HER-2/neu overexpression (2+ and 3+), an association betwee n 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 IC(9)0 level. Differences in chemosensitivity be tween samples with strong HER-2/neu overexpression and those with lower lev els were then analyzed separately for CMF and FEC. Both regimens achieved 9 0% tumor growth inhibition at lower PPC values in samples with strong HER-2 /neu overexpression (3+) compared to their counterparts with lower expressi on levels (AO485 p = 0.011 for CMF, and p = 0.09 for FEC). Cumulative conce ntration-response plots of tumors responding in vitro with 90% tumor cell i nhibition showed a stronger dose dependence for both CMF and FEC among tumo r samples with strong HER-2/neu overexpression compared to those with lower levels of expression. In conclusion, the data show that HER-2/neu overexpr ession was not associated with in vitro drug resistance to CMF or FEC. In c ontrast, tumors with strong HER-2/neu overexpression demonstrated increased dose-dependent in vitro sensitivity to both the FEC and CMF regimens.