Individuals22Median age, years (range)48

Individuals22Median age, years (range)48.9 (31C70)Progressive disease at research entryNo8Yes14Progressive disease to Her combination7Progressive disease to Her alone4Progressive disease to non Her containing therapy*3Number of sites1129 312Tumor sitesLung5Liver14Bone12Lymphnodes8CNS9Various other10Previous treatment with Herceptin alone1Previous treatment with Herceptin in combination161 line82 lines43 lines4Previous treatment with Herceptin alone and Herceptin in combination52 lines43 lines1Herceptin + Vinorelbine11Herceptin + Taxanes15Herceptin + Others5ER and PgR negative15ER and/or PgR positive7Ki 67 20%120%12Unknown9Her2/Neu overexpression2+13+21 Open in another window *a single progressed towards the last trastuzumab-containing program also Oral cyclophosphamide in addition methotrexate in conjunction with trastuzumab produced 4 PRs providing a target response rate of 18% (95% CI 5C40%). system (CNS) (9 pts). We observed 4 partial remission (PR) (18%, 95% CI 5C40%), 10 stable disease (SD) (46%, 95% CI 24C68%), and 8 PD (36%, CI 17C59%). The clinical benefit (RP plus RC plus SD for 24 weeks) in all pts and in pts with disease resistant to previous trastuzumab therapy were 46% (95% CI, 24C68%) and 27% (95% CI, 6C61%), respectively. Median time to progression was 6 months and median duration of treatment was 5 months (range, 0,7 to 18.4 months and range, 1 to 18 months, respectively). Overall clinical toxicity was generally mild. Grade GNE-495 2 reversible liver toxicity and leukopenia were reported in 5 and 3 pts, respectively. Conclusion The combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this combination to delay acquired trastuzumab resistance. Background Malignant tumors secrete factors that enable them to trigger their own angiogenesis. The initiation of angiogenesis requires acquisition of MMP10 the angiogenic phenotype through a series of molecular events leading to increased expression of angiogenic factors and down-regulation of natural inhibitors [1]. Her2/neu is a 185-kilodalton transmembrane receptor tyrosine kinase that belongs to the epidermal growth factor receptor family [2,3]. Tumor overexpression of HER2/neu is present in about 30% of patients with breast cancer and is associated with a worse histological grade, decreased overall survival and altered sensitivity to chemotherapeutic agents [4,5]. Recently, Her2/neu has been implicated in tumor angiogenesis. Experimental studies suggest that neutralizing antibodies against Her2/neu or EGFR results in down-regulation of angiogenesis, through VEGF gene suppression [6]. It is reported in the literature that such interaction occurs em via /em abrogation of the increased synthesis of HIF1 em a /em (hypoxia inducible factor-1 em a /em ) induced by c-erbB2 activation by ligands (i.r. heregulin) [7]. Moreover, a hypoxic-independent mechanims has been recently advocated in the angiogenetic involvement of HER2-/neu [8]. Trastuzumab (Herceptin?; Genentech, South San Francisco, CA), a recombinant humanized anti-erbB2/HER-2 monoclonal antibody (MoAb) used in erbB2-overexpressing breast carcinoma, has been shown to have GNE-495 antiangiogenic properties [9]. Trastuzumab can induce normalization and regression of the vasculature in an experimental human breast tumor which overexpresses HER2 in mice, by modulating the effects of different pro- and anti-angiogenic factors [9]. GNE-495 The combination of trastuzumab with chemotherapeutic agents (paclitaxel, docetaxel) has been shown to increase the efficacy of trastuzumab in reducing angiogenesis in erbB2-overexpressing cells more than either therapy alone both in animal models and clinical studies [10,11]. We previously demonstrated the antitumor activity of oral low-dose methotrexate and cyclophosphamide delivered as metronomic chemotherapy in metastatic breast cancer and we have shown the correlation with vascular endothelial growth factor levels [12,13]. Other authors previously showed that long-term, low dose chemotherapy could elicit an antiangiogenic effect [14]. Based on these considerations, we evaluated the activity and tolerability of the combination trastuzumab plus low-dose oral cyclophosphamide and methotrexate in patients with metastatic breast cancer with overexpression or amplification of Her2-/neu and pre-treated with trastuzumab. Methods Patient selection Patients included were required to have histologically confirmed metastatic breast carcinoma that either had, or had not, progressed after a line of trastuzumab alone or in combination with chemotherapy for metastatic disease. Other inclusion criteria were: measurable disease, age 80 years, performance status ECOG 3, adequate bone marrow reserve defined as white blood cells 4,000 mm3 and platelets 100,000 mm3, adequate renal function (serum creatinine 120 mol/l) and hepatic function (serum bilirubin 20 mol/l, AST (SGOT) 60 IU/l). It was mandatory that all patients.