`
`
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`Proceedings
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`Basic and Clinical Aspects of Breast Cancer
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`A Special Conference of the
`American Association for Cancer Research
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`Supported by a Generous Grant from the
`National Institute of Environmental Health Sciences
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`(N.I.E.H.S.)
`
`Qfie Keystone Resort
`Keystone, Co[orodo
`{Moron 7-12, 1997
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`Conference Co-Cfloirpersons
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`J. Carl Barrett
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`Karen S. H. Antman
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`N.I.E.H.S.
`Research Triangle Park, NC
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`Columbia University
`New York, NY
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`Mary-Claire King
`University of Washington
`Seattle, WA
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`Page 001
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`Genentech 2135
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`A-39
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`THERAPEUTIC ADVANTAGE OF CHEMOTHERAPY DRUGS IN COMBINATION WITH RECOMBINANT,
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`HUMANIZED, ANTI-HER-2/NEU MONOCLONAL ANTIBODY (rhuMAb HER-2) AGAINST HUMAN BREAST
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`CANCER CELLS AND XENOGRAFI'S WITH HER-2/NEU OVEREXPRESSION
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`Sheree Hsu. Mark Pegram, Richard Pietras. Malgorzata Beryt, and Dennis Siamon
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`Division of Hematology-Oncology, UCLA School of Medicine. Los Angeles, CA 90095
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`We have previously demonstrated a synergistic interaction between rhuMAb HER-2 and the cytotoxic drug
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`cisplatin in human breast and ovarian cancer cells (Pietras, et al, Oncogene, 9: 1829-38, 1994). To
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`characterize the nature of the interaction between rhuMAb HER-2 and other classes of cytotoxic drugs, we
`used multiple drug effect analysis (Chou, et al, Adv Enz Reg. 22: 27-55, 1984) to determine combination
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`index values for drug/antibody combinations in an in vitro cytotoxicity assay. SKBR-S cells, human breast
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`cancer cells with HER-e/neu amplification/overexpression, served as the target cell
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`line in these
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`experiments.
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`In the cytotoxicity assay, rhuMAb HER-2 exhibited synergistic effects in combination with
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`cisplatin, thiotepa, and etoposide. When used in combination with doxorubicin, taxol, or vinblastine, rhuMAb
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`HER-2 had additive cytotoxic effects. One drug, 5-fluorouracil, was found to be antagonistic with rhuMAb
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`HER-2 in vitro.
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`In vivo studies were conducted in an athymic mouse model with HER-Zneu—transfected MCF-
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`7 human breast cancer xenografts which,
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`in contrast to SKBR-3 cells, are tumorigenic in athymic mice.
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`Combinations of rhuMAb HER-2 plus cyclophosphamide, doxorubicin, methotrexate. etoposide, and
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`vinblastine resulted in a significant reduction in xenograft volume compared to drug alone or rhuMAb HER-2
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`alone controls (p<0.05). Xenografts treated with rhuMAb HER-2 plus taxol or 5-fluorouracil were not
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`significantly different from drug alone controls with the doses and dose schedules tested in this model. A
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`phase III, randomized clinical trial is in progress. testing chemotherapy alone vs. chemotherapy plus rhuMAb
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`HER-2 in patients with advanced, HER-2/neu-overexpressing breast cancer.
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`(Supported by K12 CA01714,
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`R01 CA86827, R29 CA60835, the U.S. Army Breast Cancer Research Program DAMD 17-94-J-4370, and
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`the Revlon/UCLA Women's Cancer Research Program)
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