Abstract
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. The 12-month open label clinical trial used the GnRHA deslorelin, ultra-low-dose estradiol (E(2)), 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). 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. 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.
Highlights
Women with a BRCA1 mutation (BRCA1mut) need risk reduction options beyond mastectomy and oophorectomy
Because of the extraordinary risk for both breast and ovarian cancer, mastectomy is one current risk reduction option for BRCA mutation (BRCAmut) carriers, and salpingo-oophorectomy is recommended after completion of childbearing (1 – 5)
A prototype gonadotropin-releasing hormone agonist (GnRHA) hormonal chemoprevention regimen, which used 7.5-mg leuprolide acetate depot by intramuscular injection every 28 days and oral administration of conjugated equine estrogen and intermittent progestins in women who were at increased risk of breast cancer based on empirical risk models, showed decreased mammographic densities compared with placebo and excellent patient acceptability [10, 11]
Summary
Women with a BRCA1 mutation (BRCA1mut) need risk reduction options beyond mastectomy and oophorectomy. Conclusions: The GnRHA deslorelin, with low-dose add-back steroids, was well tolerated and significantly decreased mammographic percent density in BRCA1mut carriers. This regimen may reduce breast cancer risk and improve the usefulness of mammographic surveillance by reducing density. A lesser reduction in the levels of premenopausal ovarian hormones than is achieved with oophorectomy has the potential to decrease breast cancer risk (7 – 9) Such a reduction can be achieved with the use of a gonadotropin-releasing hormone agonist (GnRHA) with add-back low-dose sex steroids. A prototype GnRHA hormonal chemoprevention regimen, which used 7.5-mg leuprolide acetate depot by intramuscular injection every 28 days and oral administration of conjugated equine estrogen and intermittent progestins in women who were at increased risk of breast cancer based on empirical risk models, showed decreased mammographic densities compared with placebo and excellent patient acceptability [10, 11]
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