A major goal of this project is to identify and study important new therapeutic options for patients with metastatic breast cancer. These options include biologics and molecularly targeted therapy such as erlotonib, an epidermal growth factor receptor tyrosine kinase inhibitor. Description of the progress on several of these trials is discussed below. Also two new therapeutic agents will be place in clinical trials under this project. These include pertuzumab and lapatinib.ErlotinibThe epidermal growth factor receptor (EGFR) is expressed in several solid tumors, including breast cancer. Its expression in breast carcinomas is reported to be in the range of 14% to 91% and has been associated with poor prognosis, increased risk of recurrence, and poor response to hormonal therapy. Upon ligand binding, EGFR tyrosine kinase (EGFR-TK) is activated. It is this tyrosine kinase activity that is the target of several EGFR-TK inhibitors, such as erlotinib (OSI-774, Tarceva??; OSI Pharmaceuticals, Melville, NY). Erlotinib represents a class of compounds that can prevent EGFR activation and interrupts downstream signaling, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/AKT pathways, both of which are important in tumor cell proliferation. Erlotinib has been shown to inhibit EGFR-TK in vitro (IC50 of 2 nM) and reduce EGFR autophosphorylation in intact tumor cells (IC50 of 20 nM). Because of problems inherent in evaluating tumor-specific activity of EGFR-TK inhibitors, there is a need for an appropriate surrogate tissue for evaluating activity. The skin is one such tissue because it expresses EGFR, is readily accessible, and is a site of frequently occurring toxicity. EGFR has also been shown to be present in human buccal mucosa. The pharmacodynamic effects of erlotinib and gefitinib, another EGFR-TK inhibitor, have been described in pre- and post-treatment normal skin specimens. Therapy directed at EGFR-TK represented a potentially novel therapeutic approach in metastatic breast cancer. Because erlotinib targets the EGFR-TK, we hypothesized it would have inhibitory effects on intermediate points in the EGFR signaling pathway. We conducted a pilot study in 18 patients, in which we treated them with erlotinib 150 mg daily and performed serial biopsies on tumor, buccal mucosa, and skin. We evaluated levels of Ki67, EGFR, phosphorylated-EGFR (phospho-EGFR), -MAPK (phospho-MAPK) and -AKT (phospho-AKT), in all three tissues.We also determined drug pharmacokinetics pre- and post-treatment with erlotinib. We found that the stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment with erlotinib (P = 0.0005 and P = 0.0003, respectively). No significant change in Ki67 was detected in 15 tumors and no responses were observed. Only one of 15 tumors expressed EGFR, and this tumor displayed heterogeneous expression of the receptor. In the EGFR-positive tumor, levels of phospho-EGFR, phospho-MAPK, and phospho-AKT, but not Ki67, were reduced after treatment. We concluded that erlotinib had inhibitory biologic effects on normal surrogate tissues and in the one EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of EGFR in this patient and absence of an appropriate drug target in this cohort of heavily pretreated patients. In addition, 1 of 10 patients had an EGFR-positive tumor. Eroltinib down-regulated MMP-3 and collagen type 1 alpha 2. Gene changes in EGFR-negative tumors were attributable to those of G-protein linked and cell surface receptor linked signaling.? ? Ixabepilone(NSC 710428), an investigational agent, is a semi-synthetic analog of the natural product epothilone B.
| Denduluri, Neelima; Lee, James J; Walshe, Janice et al. (2007) Phase II trial of ixabepilone, an epothilone B analog, given daily for three days every three weeks, in metastatic breast cancer. Invest New Drugs 25:63-7 |
| Walshe, Janice M; Denduluri, Neelima; Berman, Arlene W et al. (2006) A phase II trial with trastuzumab and pertuzumab in patients with HER2-overexpressed locally advanced and metastatic breast cancer. Clin Breast Cancer 6:535-9 |
| Lee, James J; Low, Jennifer A; Croarkin, Earllaine et al. (2006) Changes in neurologic function tests may predict neurotoxicity caused by ixabepilone. J Clin Oncol 24:2084-91 |
| Low, Jennifer A; Wedam, Suparna B; Lee, James J et al. (2005) Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol 23:2726-34 |
