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Title: High-Dose Fulvestrant Reduces Tumor Cell Growth: Presented at SABCS

"High-Dose Fulvestrant Reduces Tumor Cell Growth: Presented at SABCS"

By Janet Fricker SAN ANTONIO, TX -- December 17, 2007 -- A high-dose regimen of fulvestrant significantly reduces levels of an important marker of tumor growth compared with the approved 250-mg dose, according to data from a phase 2 study of neoadjuvant treatment presented here at the 30th Annual San Antonio Breast Cancer Symposium (SABCS). Fulvestrant, an estrogen-receptor antagonist administered once a month as an intramuscular injection, represents the first of a new type of endocrine therapy that accelerates the breakdown of the estrogen receptor (a process known as estrogen receptor down-regulation) and disrupts the multiple signaling pathways essential for tumor growth. The rationale for using fulvestrant rather than treatments that block or reduce the amount of estrogen circulating in the blood is that there is considered to be less risk of activating the estrogen receptor by alternative pathways. "Most clinical studies have used the 250-mg fulvestrant dose, but while studies have shown that the 250-mg dose is equal to anastrozole, they have also shown that the 125-mg dose is inferior, raising the question of whether an even higher dose might be more effective," said presenter Irene Kuter, MD, Assistant Professor, Department of Medicine, Harvard Medical School, Associate Physician, Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts. In the phase 2 Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors (NEWEST) open-label study, 211 postmenopausal hormone-receptor-positive women with locally advanced breast cancer were randomized to receive either fulvestrant at the approved dose of 250 mg/month (n = 102) or a high-dose regimen of 500 mg/month plus 500 mg on day 14 of month 1 (n = 109). Efficacy was assessed using levels of Ki67, a marker of tumor cell growth, which has been directly related to long-term prognosis when levels are measured at diagnosis. Patients received treatment for 16 weeks immediately prior to surgery. Results showed that at 4 weeks fulvestrant 500 mg significantly reduced Ki67 levels by more than 78.8% and that fulvestrant 250 mg reduced it by 47.3% ([P <.0001). There were also significant differences in the expression of downgraded estrogen receptors between the two doses in favor of the 500-mg dose (P <.0003). Both doses were well tolerated and consistent with the known toxicity profile of fulvestrant.

"This is the first time we have seen data suggesting that the 500-mg dose might be better [than the 250-mg dose]," said Dr. Kuter. "Used in the metastatic setting the higher dose might help us to achieve the goal of seeing a more rapid response. But there's lots to be sorted out and we are only just beginning to piece together the data."

[Presentation title: Fulvestrant 500 mg Vs 250 mg. First Results From NEWEST, a Randomized Phase II Neoadjuvant Trial in Postmenopausal Women With Locally Advanced, Estrogen Receptor-Positive Breast Cancer. Abstract 23]

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