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Cyclic mastalgia eased by topical afinoxifene gel.

SAN ANTONIO -- Topical afinoxifene proved effective for the treatment of cyclic mastalgia and also showed potential for reduction of mammographic breast density in separate phase II clinical trials presented at a breast cancer symposium sponsored by the Cancer Therapy and Research Center.

Afinoxifene is a highly potent tamoxifen metabolite formulated in a topical alcohol-based gel. Applied to the breast, it avoids first-pass liver metabolism and thereby results in high levels of the antiestrogen in target breast tissue with very low systemic exposure. The result is an agent designed to have a far quicker onset of benefit than oral tamoxifen, which is prescribed for 5 years for chemoprevention.

Dr. Robert E. Mansel reported on 130 premenopausal women with a history of moderate to severe cyclic mastalgia who were randomized to receive 2 mg or 4 mg/day of afinoxifene or placebo for four menstrual cycles in a double-blind multi-center trial.

The primary end point was change in breast pain assessed by patients on a visual analog scale from baseline through the fourth treatment cycle. The 4-mg dose significantly outperformed placebo as evidenced by a mean 32-point reduction from a baseline of 72 points on the 0-100 scale, compared with reductions of 19 points with placebo and 25 points with 2 mg/day of afinoxifene.

The 4-mg dose also outperformed placebo in the secondary end points of blinded physician-assessed breast pain, nodularity, and tenderness, with 67%-70% reductions being recorded relative to placebo in each of these domains, added Dr. Mansel, professor and chairman of the department of surgery at the University of Wales, Cardiff.

Rates of hot flashes, night sweats, and nipple discharge were similar in the three groups. Application site skin reactions occurred in 4% of women on 4 mg/day of the topical antiestrogen. Duration of menses, cycle length, and estrogen and progesterone levels were unaffected in the three study arms.

Dr. Jennifer A. Harvey reported on 61 premenopausal women with 50%-80% breast tissue density and 19 with greater than 80% breast density on a screening digital mammogram performed within the prior 42 days who were randomized to 2 mg/day of afinoxifene or placebo in a double-blind study.

Mammographic breast density in the 80% range has been shown to be a biomarker conferring a four- to fivefold increased risk of developing cancer. But unlike many breast cancer risk factors, breast density is modifiable.

Radiodense glandular epithelium and connective tissue also interfere with early diagnosis of breast cancer by hiding mammographic abnormalities, explained Dr. Harvey of the University of Virginia, Charlottesville.

Results of the trial were mixed: Five of 32 afinoxifene-treated patients and 0 of 29 placebo-treated patients with 50%-80% baseline mammographic breast density showed at least a 10% reduction in density after 4 months, but there was no significant difference between the two study arms at 6 months. Moreover, none of the 19 patients with greater than 80% baseline breast density showed a 10% improvement at 4 months. In light of the success of 4 mg but not 2 mg/day of afinoxifene in the mastalgia trial, further studies using the higher dosage are planned.

Four of five afinoxifene responders were aged younger than 40 years. This suggests afinoxifene may have potential as a chemo-preventive agent in young high-risk women who avoid oral tamoxifen because of side effects, she added.

The trials were sponsored by Ascend Therapeutics.


Denver Bureau
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Title Annotation:Women's Health
Author:Jancin, Bruce
Publication:Family Practice News
Geographic Code:1USA
Date:Jan 15, 2006
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