Gefitinib in Breast Cancer

Gefitinib is a low molecular weight, highly selective, and reversible tyrosine kinase inhibitor of the EGFR (60). It is a potent inhibitor of proliferation not only in cells overexpressing EGFR, but also in those that additionally overexpress HER2, possibly mediated by gefitinib reduction of EGFR/HER2 heterodimer phosphorylation (61-63).

In the clinical setting, phase I trials of gefitinib have been generally well tolerated with the majority of events being that of grade 1 and 2 gastrointestinal or skin toxicities (64-67). Anti-tumor activity was demonstrated in a broad range of tumors including the observation of prolonged stable disease in patients with breast cancer.

A phase II study by Albain et al. (68) evaluated the efficacy and safety of gefi-tinib in patients with metastatic breast cancer who had progressed on previous hormonal and cytotoxic agents. Gefitinib was delivered at 500mg/day until disease progression or toxicity. The primary objective of the study was to evaluate the clinical benefit rate (defined as complete response plus partial response plus stable disease greater than or equal to six months). Sixty-three patients were enrolled. The median age of the patients was 52 years (range: 34-81). Patient characteristics included 27 (43%) patients with hormone receptor-positive disease and 17

patients (27%) with HER2/neu overexpressing tumors. Seventy-nine percent of patients had involvement of the viscera. The majority of individuals (78%) had received at least two prior cytotoxic treatments and all ErbB2 positive patients (36%) had been previously treated with trastuzumab. The treatment was well tolerated with the exception of diarrhea. The results, however, noted minimal response. One patient had a partial response and five patients had stable disease lasting at least four months in duration. Median overall survival was 144 days (range: 110242 days). Median progression-free survival was 57 days (range: 16-205+ days). The authors noted that some patients experienced an improvement in symptoms such as bone pain. Five patients (42%) experienced palliation of pain. Similar to previous studies, toxicities consisted of grade 3 diarrhea, nausea, vomiting, and a rash. Skin rash occurred in 44% of patients (n = 28), four of which had grade 3 rash. Four patients required a dose reduction of gefitinib to 250 mg/day. The authors noted that several hypotheses could have accounted for the low-response rate observed in this trial, namely, a heavily pretreated patient population with chemotherapy and hormonal therapy, the lack of activating mutations as found in nonsmall cell lung cancer and perhaps an inferior dose of the agent.

Von Minckwitz et al. (69) reported on 46 breast cancer patients treated with gefitinib. Again, the dose utilized was 500 mg/day. After 12 weeks of therapy, one (2.2%) patient had partial response and three (6.5%) patients had stable disease. Forty-two patients experienced progressive disease.

Baselga et al. (70) reported a multicenter phase II trial and pharmacodynamic study of gefitinib in patients with advanced breast cancer. In this study, patients received gefitinib 500 mg/day, apart from day 1 when patients received gefitinib 500 mg/day followed a second dose 12 hours later. Each treatment cycle was 28 days. Patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. The primary objective was to assess the objective response rate of this agent in patients with locally advanced or metastatic disease. The pharmacodynamic profile of gefitinib in skin and tumor tissues as well as the safety profile of the drug were secondary objectives. Patients enrolled in this clinical trial were women with histologically confirmed stage IIIb/IV advanced breast cancer that were resistant to one or two prior chemotherapy regimens. The trial aimed at achieving a patient cohort that was at least 50% EGFR-positive. A two-stage design was employed. Several pharmacodynamic markers were assessed. These included EGFR expression, activated/ phosphorylated EGFR (pEFGR), the ligand TGF-alpha, the downstream signaling markers including phosphorylated MAPK (pMAPK) and protein kinase B (pAKT), the proliferation markers Ki67 and the cyclin-dependent kinase inhibitor, p27. All markers were evaluated by IHC. Of the 31 evaluable patients who received treatment for a median duration of eight weeks, 12 (38.7%) patients had stable disease including three (9.7%) patients with recurrent breast cancer that had stable disease for six months or greater. The duration of stable disease was 84 to 349 days. No complete or partial responses were noted. Progressive disease occurred in 19 (61.3%) patients with a median time to progression of 55 days (95% CI, 42-88). Median overall survival was 503 days. The most prevalent drug-related adverse effects included diarrhea, skin rash, and asthenia.

Pretreatment tumor samples were available in all patients. EGFR expression was detected in 15 (48%) patients. A significant relationship was established between EGFR expression and the expression of TGF-alpha (P = 0.007), p-EGFR

(P < 0.001), p-MAPK (P = 0.033), and Ki67 (P = 0.036) utilizing a Spearman's correlation test in pretreatment tumors. Correlative studies including basal expression of EGFR, pEGFR, pMAPK, TGF-alpha, Ki67, and p27 were analyzed in skin biopsies compared with expression on day 28 following gefitinib treatment. Gefitinib inhibited the phosphorylation of EGFR and mAPk, decreased the expression of Ki67, and resulted in an increase in expression of inhibitor p27 in the skin keratinocytes. In tumor samples, treatment with gefitinib inhibited phosphorylation of EGFR and MAPK in tumor biopsies. Gefitinib did not result in inhibition of pAKT and did not decrease proliferation or increase p27 levels. There was discordance in the skin and the tumor samples between Ki67 and p27. Of note, in EGFR-positive tumors, treatment with gefitinib increased the apoptotic index. In addition, the authors did not appreciate any significant difference in EGFR expression between patients with stable disease versus those with progressive disease.

Robertson et al. (71) also evaluated the activity of gefitinib in breast cancer patients. The authors noted that gefitinib was active in breast cancer patients with tamoxifen-resistant breast cancer. A disease control rate of 66.6% was observed in a small cohort of ER+ tamoxifen-resistant breast cancer patients. Toxicities were similar to previous studies with skin rash, diarrhea and nausea, and vomiting being the most prevalent adverse event.

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