Impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcomes in young women with breast cancer

Abstract

Purpose To determine the impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcome. The main purpose and research question of the study is to determine the impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcomes. Methods Prospective study: 67 breast cancer patients between 18 and 40 years old, undergoing a fertility preservation by means of oocyte storage were considered. Inclusions criteria for the study were age between 18 and 40 years old, BMI between 18 and 28, breast cancer neoplasm stage I and II according to American Joint Committee on Cancer classification (2017) and no metastasis. Exclusion criteria: age over 40 years old, BMI < 18 and > 28, breast cancer neoplasm stage III and IV and do not performed the BRCA test. A total of 21 patients had not performed the test and were excluded. Patients were divided into four groups: Group A was composed by 11 breast cancer patients with BRCA 1 mutations, Group B was composed by 11 breast cancer patients with BRCA 2 mutations, Group C was composed by 24 women with breast cancer without BRCA mutations, and Group D (control) was composed by 181 normal women. Results Group A showed significant lower AMH levels compared to Group C and D (1.2 ± 1.1 vs 4.5 ± 4.1 p < 0.05 and 1.2 ± 1.1 vs 3.8 ± 2.5 p < 0.05). BRCA1 mutated patients showed a significant lower rate of mature oocytes (MII) compared to Group C (3.1 ± 2.3 vs 7.2 ± 4.4 p < 0,05) and Group D (3.1 ± 2.3 vs 7.3 ± 3.4; p < 0,05). Breast cancer patients needed a higher dose of gonadotropins compared to controls (Group A 2206 ± 1392 Group B2047.5 ± 829.9 Group C 2106 ± 1336 Group D 1597 ± 709 p < 0,05). No significant differences were found among the groups considering basal FSH levels, duration of stimulation, number of developed follicles, and number of total retrieved oocytes. Regarding BRCA2 mutation, no effect on fertility was shown in this study. Conclusions The study showed that BRCA1 patients had a higher risk of premature ovarian insufficiency (POI) confirmed by a diminished ovarian reserve and a lower number of mature oocytes suitable for cryopreservation.

Fertility preservation in patients with BRCA mutations or Lynch syndrome

“…They found that patients in the BRCA positive cohort, especially BRCA1 positive patients, needed a higher dose of gonadotropins, a longer duration of stimulation, and a statistically significant lower number of oocytes cryopreserved. 17 In conclusion, there is growing evidence indicating that BRCA mutations may be associated with decreased ovarian reserve and premature menopause, especially for BRCA1 mutation patients. Therefore, some authors suggest systematic fertility preservation in this population.…”

“…In our search, 11 articles [17][18][19][20][21][22][23][24][25][26][27] considered anti-Mullerian hormone and antral follicular count as indexes of ovarian function in BRCA mutation carriers compared with wild-type controls (Table 1). In fact, anti-Müllerian hormone levels and antral follicular count are considered predictors of ovarian response during in vitro fertilization techniques, with lower levels suggestive of a poor response.…”

“…Several studies have validated anti-Müllerian hormone as a direct biomarker for ovarian aging, which reflects the decline in reproductive capacity. 29 30 In our search, we considered 11 studies [17][18][19][20][21][22][23][24][25][26][27] evaluating anti-Müllerian hormone levels as an index of the ovarian reserve, comparing BRCA carriers with wild-type controls. Four studies concluded that BRCA mutation carriers had lower levels of anti-Müllerian hormone compared with BRCA wild-type patients 17 20 22 23 while five studies had the opposite results, reporting BRCA patients who had higher anti-Müllerian hormone levels compared with BRCA wild-type patients.…”

Meiotic Recombination Defects and Premature Ovarian Insufficiency

“…Although its function in mammalian meiosis was unclear, Brca1 mutant mice had impaired reproductive capacity and decreased primordial follicle counts ( Titus et al, 2013 ). Women with BRCA1 variations also presented with accelerated ovarian reserve decline ( Lin et al, 2017 ; Porcu et al, 2020 ). Therefore, BRCA1 was a potential causative gene of POI, which required comprehensive evaluation of somatic characteristics like BRCA2.…”

Fertility preservation in endocrine responsive breast cancer: data and prejudices

“…Age is the most crucial factor swaying the success rate of FP: the efficacy of oocyte/embryo cryopreservation is strictly related to the number of mature oocytes retrieved, that is age-dependent, dropping precipitously after 35 years of age [ 53 , 54 ]. Moreover, the effectiveness of COS may be negatively impacted by BRCA status, considering the emerging evidence of a diminished ovarian reserve and a poor response to ovarian stimulation in BRCA1/2 -mutation carriers [ 55 , 56 ].…”