BRCA1 AND DEPLETION OF OOCYTE RESERVE

October 26, 2009 (Atlanta, Georgia) — BRCA1 gene mutations appear to be associated with early depletion of oocyte reserve, supporting the link between breast and ovarian cancer risk and infertility.

Kutluk Oktay, MD, from the Department of Obstetrics & Gynecology at the Westchester Medical Center-New York Medical College in Valhalla, presented the findings here at the American Society for Reproductive Medicine 65th Annual Meeting.

According to the researchers, murine models suggest a relation between DNA repair gene function and germ cell reserve. Their study sought to determine a link between deleterious mutations in BRCA genes and diminished oocyte reserve, as assessed by response to ovarian stimulation.

Dr. Oktay and colleagues analyzed previous data from 82 women with breast cancer who underwent oocyte/embryo freezing. Patients younger than 38 years with normal baseline ovarian reserve received 5 mg/day of letrozole and 150 to 300 IU/day of follicle stimulating hormone (FSH) prior to chemotherapy.

Of the 82 women, 57% were tested for BRCA mutations. Of those tested, 14 (30%) did have a BRCA mutation (9 had a BRCA1 mutation, 4 had a BRCA2 mutation, and 1 had both BRCA1 and BRCA2 mutations).

Poor ovarian response rate was significantly higher in patients with a BRCA1 and/or 2 mutation (33.3%) than in those who did not have the mutation (3.3%; P = .014) and in BRCA untested women (2.9%; P = .012). All poor responders were BRCA1-positive, and none had only a BRCA2 mutation.

After controlling for age, FSH level, and body mass index, the researchers found a significantly increased risk for poor response in women who were BRCA-positive, compared with those who were BRCA-negative, with an odds ratio of 28.7 (95% confidence interval, 1.8 - 447.0; P =.016).

BRCA-positive women also tended to have lower oocyte numbers (P = .025), and BRCA1 but not BRCA2 mutations were associated with poor response (P = .001).

According to Dr. Oktay, BRCA mutations are found in 1 in 1000 females in the general population and in up to 2.5% of Jewish-Ashkenazi patients. "Poor response to in vitro fertilization with a family history of breast and/or ovarian cancer should raise the flag that a BRCA mutation might be involved," he told Medscape Ob/Gyn & Women's Health.

"The finding that oocyte numbers may be diminished with BRCA mutations is not surprising, since BRCA is a DNA repair gene and oocytes may not survive if that mechanism is deficient," he said. "We need to do basic research studies to determine the mechanism by which BRCA mutations result in diminished egg reserve, as well as a larger clinical study," he added.

"These findings are very novel," said Dr. Keefe, chair of the Department of Obstetrics and Gynecology at the NYU Langone Medical Center in New York CIty, "but based on what we now know from this work, women with BRCA mutations should be advised that they may lose their eggs earlier than women of the same age without BRCA mutations," he told Medscape Ob/Gyn & Women's Health.

Dr. Keefe also noted that women with BRCA mutations considering preimplantation genetic diagnosis (PGD) should be aware that they might not have as many eggs and embryos to test as women of their same age undergoing PGD for other indications.

According to Dr. Keefe, most egg problems may eventually be linked to one or another specific genetic change, just like fever has been linked to specific bacteria.

This study was supported by a National Institutes of Health grant. Dr. Oktay and Dr. Keefe have disclosed no relevant financial relationships..

American Society for Reproductive Medicine (ASRM) 65th Annual Meeting: Abstract O-103. Presented October 21, 2009.