Addition of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) to Trastuzumab Stabilizes Disease in Patients with Trastuzumab-Resistant, HER2+ Metastatic Breast Cancer.

Abstract

Abstract Introduction: Trastuzumab with or without chemotherapy is the standard of care for patients with HER2+ metastatic breast cancer. The proposed mechanism of trastuzumab-induced regression of HER2+ tumors includes inhibition of tumor cell proliferation, potentiation of chemotherapy, and facilitation of immune function through antibody-dependent cell-mediated cytotoxicity. GM-CSF (Leukine) is a cytokine that mediates antibody-dependent cell-mediated cytotoxicity. We studied the feasibility and efficacy of adding GM-CSF to trastuzumab in patients with trastuzumab-resistant, HER2+ metastatic breast cancer.Patients and Methods: Patients with measurable, HER2+ metastatic breast cancer that progressed after treatment with trastuzumab with or without chemotherapy were continued on trastuzumab alone at 2 mg/kg intravenous weekly. GM-CSF (250 μg/m2 subcutaneous daily) was added until the absolute neutrophil count (ANC) was greater than 10,000/mm3, then given every other day while the ANC was maintained below 10,000/mm3. Disease was restaged every 8 weeks. Treatment with trastuzumab and GM-CSF was continued until disease progression or intolerable toxicity.Results: Of 18 eligible patients with progressive HER2+ metastatic breast cancer, 17 (median age 48 yr, range 27–75 yr) were evaluable. Nine had hormone receptor–positive disease. The median number of metastatic sites was 2 (range 1–3); the most common site was the liver (n=10). The median number of prior regimens (trastuzumab with or without chemotherapy) for metastatic disease was 2 (range 1–5). One patient developed rapidly progressive disease 2 weeks after the start of study therapy and died soon after. The other 16 patients continued treatment until disease progression. No disease response was observed, but 5 patients (29%) had stable disease with a median duration of 15.8 weeks (range 10–53.9 weeks). Thirteen patients had grade 1 toxic effects; 6 patients, grade 2; and 2 patients, grade 3 (fatigue and muscle aches). The most common toxic effect was rash at the injection site, followed by skin rash, fatigue, and muscle aches. No grade 4 or irreversible toxic effect was seen.Conclusion: The addition of GM-CSF to trastuzumab alone in patients with trastuzumab-resistant, HER2+ metastatic breast cancer stabilizes the disease for a median duration of 15.8 weeks without causing any significant toxic effects in 29% of heavily pretreated patients. Its administration is simple, safe, and feasible. This regimen, trastuzumab and GM-CSF, needs further evaluation in combination with chemotherapy or other biological agents. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5103.