A phase II neoadjuvant trial of anastrozole, fulvestrant, and gefitinib in patients with newly diagnosed estrogen receptor positive breast cancer

Abstract

Endocrine therapy in patients with breast cancer can be limited by the problem of resistance. Preclinical studies suggest that complete blockade of the estrogen receptor (ER) combined with inhibition of the epidermal growth factor receptor can overcome endocrine resistance. We tested this hypothesis in a phase II neoadjuvant trial of anastrozole and fulvestrant combined with gefitinib in postmenopausal women with newly diagnosed ER-positive breast cancer. After a baseline tumor core biopsy, patients were randomized to receive anastrozole and fulvestrant or anastrozole, fulvestrant, and gefitinib (AFG) for 3 weeks. After a second biopsy at 3 weeks, all patients received AFG for 4 months and surgery was done if the tumor was operable. The primary endpoint was best clinical response by RECIST criteria and secondary endpoints were toxicity and change in biomarkers. The study closed after 15 patients were enrolled because of slow accrual. Median patient age was 67 years and median clinical tumor size was 7 cm. Four patients had metastatic disease present. Three patients withdrew before response was assessed. In the remaining 12 patients, there were two complete clinical responses (17%), three partial responses (25%), five had stable disease (41%), and two (17%) had progressive disease. Most common adverse events were rash in four patients, diarrhea in four, joint symptoms in three, and abnormal liver function tests in three. There were no grade 4 toxicities and all toxicities were reversible. At 3 weeks, cell proliferation as measured by Ki-67 was significantly reduced in the AFG group (P value = 0.01), with a parallel reduction in the expression of the Cyclin D1 (P value = 0.02). RNA microarray data showed a corresponding decrease in the expression of cell cycle genes. These results suggest that AFG was an effective neoadjuvant therapy and consistently reduced proliferation in ER-positive tumors.

Trial registration: ClinicalTrials.gov NCT00206414.

Figures

Fig. 1

Clinical trial schema. After baseline biopsy, patients were initially randomized to AF vs. AFG for 3 weeks and then a second biopsy was obtained. After 3 weeks all patients received AFG to complete a total of 4 months of preoperative treatment.

Fig. 2

Graphic comparison within individual patient paired samples between the AF and AFG treatment groups on Day 1 vs. Day 21. Results are shown ER, PR, and Bcl-2 using the Allred scoring method. *Paired t-tests were used to compare pre- vs. post-treatment scores within each arm and the p-values are outlined in table 3.

Fig. 3

Graphic comparison in individual patient paired samples between the AF and AFG treatment groups (Day 1 vs. Day 21). Biomarkers shown are Ki-67, cyclin D1, p-MAPK, and p-AKT. Ki-67 is represented by percent of nuclear staining, while cyclin D1, p-AKT, and p-MAPK are scored using the Allred method. *Paired t-tests were used to compare pre- vs. post-treatment scores within each arm and the p-values are outlined in table 4.