title: Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles 90095-7077, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pegram
authors.forename: Gottfried E
authors.initials: GE
authors.lastname: Konecny
authors.forename: Carminda
authors.initials: C
authors.lastname: O'Callaghan
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Beryt
authors.forename: Richard
authors.initials: R
authors.lastname: Pietras
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D016190:Carboplatin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D015251:Epirubicin / Q000494:pharmacology; D005260:Female; D005467:Floxuridine / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology; D014183:Transplantation, Heterologous; D000068878:Trastuzumab; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016190:Carboplatin; D003520:Cyclophosphamide; D004273:DNA, Neoplasm; D003841:Deoxycytidine; D000077143:Docetaxel; D004317:Doxorubicin; D015251:Epirubicin; D005467:Floxuridine; D020662:Guanine Nucleotide Exchange Factors; D017239:Paclitaxel; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; D014747:Vinblastine; D000077235:Vinorelbine; D000093542:Gemcitabine; C057811:MCF2 protein, human; C512843:Mcf2 protein, mouse; C012358:4-hydroxycyclophosphamide; C025034:doxifluridine