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HER-2/neu overexpression and in vitro chemosensitivity to CMF and FEC in primary breast cancer

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Abstract

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≤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.

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Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, UCLA School of Medicine, Los Angeles, CA, 90095-1678

    Gottfried Konecny, Malgorzata Beryt, Dennis Slamon & Mark Pegram

  2. Department of Pathology, Ludwig Maximillians Universität München, München, Germany

    Manuel Fritz & Annette Lebeau

  3. Department of Obstetrics & Gynecology, Klinikum Grosshadern, Ludwig Maximillians Universität München, München, Germany

    Michael Untch, Margrit Felber, Sandra Lude & Hermann Hepp

Authors
  1. Gottfried Konecny
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  2. Manuel Fritz
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  3. Michael Untch
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  4. Annette Lebeau
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  5. Margrit Felber
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  7. Malgorzata Beryt
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  9. Dennis Slamon
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  10. Mark Pegram
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Konecny, G., Fritz, M., Untch, M. et al. HER-2/neu overexpression and in vitro chemosensitivity to CMF and FEC in primary breast cancer. Breast Cancer Res Treat 69, 53–63 (2001). https://doi.org/10.1023/A:1012226006395

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