Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer

J Natl Cancer Inst. 2004 May 19;96(10):739-49. doi: 10.1093/jnci/djh131.

Abstract

Background: Trastuzumab, a humanized anti-HER2 antibody, increases the clinical benefit of first-line chemotherapy in patients with metastatic breast cancers that overexpress HER2. We characterized interactions between trastuzumab and chemotherapeutic agents commonly used in the treatment of breast cancer.

Methods: Multiple drug effect/combination index isobologram analysis was used to study the efficacy of chemotherapeutic drug plus trastuzumab combinations tested against four HER2-overexpressing breast cancer cell lines (SK-BR-3, BT-474, MDA-MB-361, and MDA-MB-453). Combination index values were derived from parameters of the median effect plots, and statistical tests were used to determine whether the mean combination index values at multiple effect levels were statistically significantly different from a combination index value of 1.0. Values less than 1.0 indicate synergistic interactions, values greater than 1.0 indicate antagonistic interactions, and values equal to 1.0 indicate additive interactions.

Results: At a wide range of clinically achievable drug concentrations, synergistic interactions were observed in all four breast cancer cell lines for trastuzumab plus carboplatin (mean combination index values ranged from 0.32 [P<.001] to 0.53 [P<.001]), 4-hydroxycyclophosphamide (mean combination index values ranged from 0.38 [P<.001] to 0.73 [P =.010]), docetaxel (mean combination index values ranged from 0.30 [P<.001] to 0.62 [P<.001]), and vinorelbine (mean combination index values ranged from 0.24 [P<.001] to 0.78 [P<.034]). Additive interactions were observed in all four cell lines with trastuzumab plus doxorubicin, epirubicin, and paclitaxel. Interactions between trastuzumab and gemcitabine were synergistic at low concentrations of gemcitabine and antagonistic at high concentrations. A synergistic interaction was observed with a three-drug combination of docetaxel plus carboplatin plus trastuzumab in SK-BR-3 cells (mean combination index value = 0.09; P<.001).

Conclusion: Consistent synergistic interactions of trastuzumab plus carboplatin, 4-hydroxycyclophosphamide, docetaxel, or vinorelbine across a wide range of clinically relevant concentrations in HER2-overexpressing breast cancer cells indicate that these are rational combinations to test in human clinical trials.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Carboplatin / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclophosphamide / analogs & derivatives*
  • Cyclophosphamide / pharmacology
  • DNA, Neoplasm / drug effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Disease Models, Animal
  • Docetaxel
  • Doxorubicin / pharmacology
  • Drug Synergism
  • Enzyme-Linked Immunosorbent Assay
  • Epirubicin / pharmacology
  • Female
  • Floxuridine / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects
  • Paclitaxel / pharmacology
  • Proto-Oncogene Proteins / drug effects
  • Receptor, ErbB-2 / drug effects*
  • Receptor, ErbB-2 / metabolism*
  • Taxoids / pharmacology
  • Transplantation, Heterologous
  • Trastuzumab
  • Tumor Stem Cell Assay
  • Up-Regulation
  • Vinblastine / analogs & derivatives*
  • Vinblastine / pharmacology
  • Vinorelbine

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • DNA, Neoplasm
  • Guanine Nucleotide Exchange Factors
  • MCF2 protein, human
  • Mcf2 protein, mouse
  • Proto-Oncogene Proteins
  • Taxoids
  • Floxuridine
  • Deoxycytidine
  • Docetaxel
  • 4-hydroxycyclophosphamide
  • Epirubicin
  • Vinblastine
  • Doxorubicin
  • Cyclophosphamide
  • gemcitabine
  • Carboplatin
  • Receptor, ErbB-2
  • Trastuzumab
  • Paclitaxel
  • Vinorelbine
  • doxifluridine