High-dose neoadjuvant fulvestrant tested

SAN ANTONIO-In the neoadjuvant treatment of early breast cancer, fulvestrant (Faslodex) 500 mg effected a greater reduction in biomarkers of proliferation and produced more responses than the standard 250 mg dose, in a study reported at the San Antonio Breast Cancer Symposium (abstract 23).

Irene Kuter, MD, DPhil, of Massachusetts General Hospital, reported the results of the randomized, open-label, international phase II NEWEST trial (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) of 211 postmenopausal women with ER-positive, locally advanced breast cancer.

The study compared the standard dose to a higher dose that is aimed at achieving a steady-state level sooner. With 250 mg, it may take at least 3 months to reach steady-state levels, Dr. Kuter explained. Pharmacokinetic models have predicted that steady-state fulvestrant levels should be attained within 1 month with a more dose-dense approach.

In a related poster presentation (abstract 2092), investigators from AstraZeneca reported that a loading dose regimen of 500 mg (via 2 250 mg) followed by 250 mg on day 14 and day 28 (then monthly) did attain steady-state levels within 1 month of initiating therapy in 30 patients.

The NEWEST study compared fulvestrant at the approved dosage of 250 mg/month to a high-dose regimen of 500 mg/month plus 500 mg on day 14 of the first month, given monthly for 16 weeks as neoadjuvant therapy. Core biopsies were taken at baseline, week 4, and week 16 (at surgery), and tumors were assessed for changes in the Ki67 labeling index and in ER and PR expression.

Primary endpoint met

The primary endpoint-a difference between the two arms in the reduction of Ki67 labeling index at 4 weeks-was met. The mean reduction in Ki67 was 79% in the high-dose arm and 47% in the standard-dose arm (P < .0001).

The greater reduction in Ki67 labeling index with the higher dose corresponded to a significantly greater reduction in ER expression at 4 weeks (approximately 23% vs 15% for 250 mg; P < .0003). Differences were still observed at 16 weeks.

The overall response rates at week 16 in the intent-to-treat population were not significantly different between the arms: 23% with high-dose fulvestrant and 21% with the standard dose. At 4 weeks, stable disease was noted for 60% and 75%, respectively. In a post-hoc analysis of evaluable patients, response rates at week 16 were 36% and 30% and stable disease was noted for 37% and 40%, respectively.

"This response rate seems low, but there were some very robust responses," Dr. Kuter noted. In NEWEST, a partial response was defined as a 65% or greater reduction in tumor volume, she added.

Well tolerated

Both doses were well tolerated over the treatment period. The rate of grade 3-4 adverse events was 14% with high-dose fulvestrant and 12% with the standard-dose regimen. There were no adverse effects on bone, and endometrial thickness was decreased by about 25% in both groups.

Dr. Kuter concluded that high-dose fulvestrant "could offer additional benefits" to postmenopausal women with ER-positive advanced breast cancer.

The high-dose fulvestrant regimen is currently being investigated in the metastatic setting.