Rational Combinations of Trastuzumab With Chemotherapeutic Drugs Used in the Treatment of Breast Cancer

• Published in: JNCI : Journal of the National Cancer Institute Vol. 96; no. 10; pp. 739 - 749
• Main Authors: Pegram, Mark D., Konecny, Gottfried E., O'Callaghan, Carminda, Beryt, Malgorzata, Pietras, Richard, Slamon, Dennis J.
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 19.05.2004; Oxford Publishing Limited (England)
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Carboplatin - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Cyclophosphamide - analogs & derivatives; Cyclophosphamide - pharmacology; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Disease Models, Animal; DNA, Neoplasm - drug effects; Docetaxel; Doxorubicin - pharmacology; Drug Synergism; Drug therapy; Enzyme-Linked Immunosorbent Assay; Epirubicin - pharmacology; Female; Floxuridine - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Guanine Nucleotide Exchange Factors; Humans; Medical sciences; Medical treatment; Mice; Mice, Nude; Neoplastic Stem Cells - drug effects; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Proto-Oncogene Proteins - drug effects; Receptor, ErbB-2 - drug effects; Receptor, ErbB-2 - metabolism; Taxoids - pharmacology; Transplantation, Heterologous; Trastuzumab; Tumor Stem Cell Assay; Tumors; Up-Regulation; Vinblastine - analogs & derivatives; Vinblastine - pharmacology; Vinorelbine; Antineoplastic agent; Human; Drug combination; Docetaxel; Breast cancer; Monoclonal antibody; Immunomodulator; Alkaloid; Oxazaphosphinane derivatives; Alkylating agent; Chemotherapy; Cyclophosphamide; Nitrogen mustard; Taxane derivatives; Immunotherapy; Carboplatin; Combined treatment; Antimitotic; Trastuzumab; Vinorelbine; Platinum II Complexes
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djh131

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.