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Reduced Mammographic Density with Use of a Gonadotropin-Releasing Hormone Agonist–Based Chemoprevention Regimen in BRCA1 Carriers

Authors' Affiliations: ¹ Department of Clinical Cancer Genetics, City of Hope Cancer Center, Duarte, California; Departments of ² Preventive Medicine, and ³ Medicine, USC/Norris Cancer Center, University of Southern California, Los Angeles, California; ⁴ Department of Medicine, Huntsman Cancer Institute at the University of Utah, Salt Lake City, Utah; ⁵ Herbert Irving Cancer Center, New York Presbyterian Hospital, New York, New York; ⁶ Balance Pharmaceuticals, Inc., Santa Monica, California; and ⁷ Department of Nutrition, University of Oslo, Oslo, Norway

Requests for reprints: Jeffrey N. Weitzel, City of Hope Cancer Center, 1500 East Duarte Road, Duarte, CA 91010. Phone: 626-256-8662, ext. 2; Fax: 626-930-5495; E-mail: jweitzel{at}coh.org.

Purpose: Women with a BRCA1 mutation (BRCA1^mut) need risk reduction options beyond mastectomy and oophorectomy. We evaluated the efficacy, safety, and tolerability of hormonal chemoprevention with a gonadotropin-releasing hormone agonist (GnRHA) with low-dose add-back steroids in BRCA1^mut carriers.

Experimental Design: The 12-month open label clinical trial used the GnRHA deslorelin, ultra-low-dose estradiol (E₂), and replacement testosterone, administered via daily intranasal spray in premenopausal women with a BRCA1^mut, and intermittent oral medroxyprogesterone acetate. The end points included mammographic percent density, bone mineral density, endometrial hyperplasia, symptom inventory, and quality of life (Medical Outcomes SF-36 survey).

Results: Six of eight BRCA1^mut women (mean age, 30.3 years; range, 25-36 years) completed the study. Mammographic percent density was significantly reduced at 12 months (median absolute mammographic percent density decrease, 8.3%; P = 0.043), representing a 29.2% median reduction in mammographic percent density. Bone mineral density remained within reference limits for all participants; there were no cases of atypical endometrial hyperplasia and menses resumed within a median of 67 days (range, 35-110 days) after last drug treatment day. The treatment was well tolerated; hypoestrogenic side effects were minimal and transient; and there were no significant changes in quality of life.

Conclusions: The GnRHA deslorelin, with low-dose add-back steroids, was well tolerated and significantly decreased mammographic percent density in BRCA1^mut carriers. This regimen may reduce breast cancer risk and improve the usefulness of mammographic surveillance by reducing density. This is the first demonstration, to our knowledge, of a direct reduction of mammographic densities in young BRCA1^mut carriers.

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