Reduced mammographic density with use of a gonadotropin-releasing hormone agonist-based chemoprevention regimen in BRCA1 carriers.
OBJECTIVE
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.


METHODS
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).


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.
Weitzel
Jeffrey N
JN
Department of Clinical Cancer Genetics, City of Hope Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA. jweitzel@coh.org
Buys
Saundra S
SS
Sherman
William H
WH
Daniels
AnnaMarie
A
Ursin
Giske
G
Daniels
John R
JR
MacDonald
Deborah J
DJ
Blazer
Kathleen R
KR
Pike
Malcolm C
MC
Spicer
Darcy V
DV
D000328:Adult; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D015519:Bone Density; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D019398:Genes, BRCA1; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists*; D006579:Heterozygote; D006801:Humans; D008327:Mammography / Q000379:methods*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D009154:Mutation; D011788:Quality of Life; D013256:Steroids / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology; D016896:Treatment Outcome
D016588:Anticarcinogenic Agents; D013256:Steroids; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol; D017258:Medroxyprogesterone Acetate