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Association of BRCA1 mutations with diminished ovarian reserve: A common genetic mechanism for breast/ovarian cancer, and infertility?

11039 Background: 25% of all breast cancers (BC) occur prior to menopause and preservation of fertility is an important quality of life issue for these women. We recently reported an ovarian stimulation (OS) protocol utilizing letrozole for women with BC who wish to preserve their fertility by embryo freezing. Because BRCA+ young women are highly represented among those undergoing fertility preservation, and because knock out models showed a relationship between DNA repair genes and germ cell development, we hypothesized that women with BRCA mutations have diminished oocyte reserve (DOR).


METHODS
We analyzed the letrozole-OS data to assess the association between BRCA mutations and number of oocytes retrieved, which is the most direct non-invasive method of assessing ovarian reserve. Women with infertility history and age>37 were excluded.


RESULTS
Of 125 BC patients who underwent OS between 5/03 and 11/08, 82 met the criteria, of which 47 (57%) had BRCA testing. Of those, 14 (30%) were BRCA+; 9 BRCA1+, 4 BRCA2+, and 1 + for both. Mean ages of those untested, BRCA-, and + women were similar (33.0±2.9 vs 32.8±2.9 vs 33.0±2.8; p=0.97)). Age-adjusted poor response (PR) rate (<4 oocytes retrieved) was significantly higher in BRCA+ (28.6%; 4/14) compared to BRCA- (3%;1/33, p=0.009) and untested (2.9%; 1/35, p=0.007). All poor responders were BRCA1+ with one also having a mutation in BRCA2. A BRCA mutation was associated with 17.7 times the relative risk (RR) of PR (95% CI 1.4-214; p=0.024). The mean number of oocytes was significantly lower in BRCA1+ but not BRCA2+ compared to BRCA- and untested (p=0.05). BRCA1 but not BRCA2 mutations were associated with PR with a RR of 24.0 (95% CI 1.9-298; p=0.013). When only mutations of known clinical significance were included, the RR for PR further increased (RR=36, 95% CI 2.5-503; p=0.008) suggesting a common mechanism between BRCA-induced cancer and premature diminishment of oocyte reserve.


CONCLUSIONS
Because women with BRCA1 mutations may have DOR prematurely, they should be counseled for possible higher risk of ovarian failure and infertility after chemotherapy, and referred for fertility preservation. Diminished ovarian reserve may be a new component of the Hereditary Breast Ovarian Cancer Syndrome. No significant financial relationships to disclose.