Mark D. Pegram, MD

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Gemcitabine in Combination With Trastuzumab and/or Platinum Salts in Breast Cancer Cells With HER2 Overexpression

December 2nd 2004

Trastuzumab (Herceptin) is an effective treatment in patients withHER2-overexpressing metastatic breast cancer. Risk of trastuzumabinducedcardiotoxicity raises concerns regarding combined use withanthracyclines or other potentially cardiotoxic agents followinganthracycline treatment. We characterized interactions betweentrastuzumab and gemcitabine (Gemzar) and the combination ofgemcitabine and cisplatin or carboplatin (Paraplatin) as such combinationsmight help reduce the risk of cardiotoxicity. Multiple drugeffect/combination index isobologram analysis was used to study theefficacy of chemotherapeutic drug plus trastuzumab combinations inHER2-overexpressing breast cancer cell lines. Combination index valueswere derived from parameters of the median effect plots, and statisticaltests were used to determine whether the mean combinationindex at multiple effect levels significantly differed from a combinationindex value of 1.0 (values < 1.0 indicate synergy; values > 1.0,antagonism; values equal to 1.0, additivity). At a wide range of clinicallyachievable drug concentrations, interactions between trastuzumaband gemcitabine were synergistic at low concentrations of gemcitabineand antagonistic at high concentrations. A consistent synergistic interactionwas observed with the three-drug combination of trastuzumabplus gemcitabine plus carboplatin or cisplatin. Available clinical dataon the use of trastuzumab plus gemcitabine, and trastuzumab plusgemcitabine/paclitaxel, as well as clinical data on the use ofgemcitabine/cisplatin in breast cancer, are discussed. These findingsindicate that trastuzumab plus gemcitabine and trastuzumab plusgemcitabine plus cisplatin or carboplatin are rational combinations toevaluate in clinical trials.