BRCA 1 and 2 Mutation Status: The Elephant in the Room During Oncofertility Counseling for Young Breast Cancer Patients

S. Paluch-Shimon; F. A. Peccatori

Disclosures

Ann Oncol. 2018;29(1):26-28. 

The impact of BRCA1 or BRCA2 germ-line mutation on women fertility and reproductive outcome has been debated for some years. The biological rationale behind this is that BRCA1/2 play critical roles in homologous repair of DNA double-strand breaks (DSB) and that DNA DSB repair is essential in maintaining ovarian reserve. Animal studies have confirmed that impairment in DNA DSB repair results in accelerated loss of primordial ovarian follicles and that a decline of function of BRCA1 is associated with ovarian ageing.[1,2]

In women, there has been conflicting data on whether or not a germline mutation in BRCA1/2 results in reduced ovarian reserve, poorer response to ovarian stimulation and accelerated ovarian ageing. The largest epidemiological study by Pal et al found no difference in parity between BRCA-carriers and non-carriers[3] while another study found that despite slightly earlier onset of menopause there was no difference in parity and need for fertility treatment between carriers and non-carriers.[4] A further study did not find earlier onset of menopause amongst BRCA-carriers.[5] Several papers have assessed response and oocyte yield after ovarian stimulation for in vitro fertilization (IVF) and preimplantation gestational diagnosis (PGD)[6–8] with conflicting results. Further studies have found lower Anti-Mullerian Hormone (AMH) levels amongst BRCA1/2-mutation carriers,[9–12] while one study found no difference.[13] Moreover, ovarian tissues from unaffected BRCA mutation carriers have lower primordial follicle density and increase in DNA DSB than the controls.[14] Differences in the studies may arise from biases inherent to their retrospective nature, in genetic heterogeneity of the study populations and in associated differences in the specific BRCA mutations.

In this issue of Annals of Oncology, Lambertini et al.[15] present the results of reproductive outcomes from a cohort nested in two prospectively studies that included breast cancer patients.[16,17] They evaluated reproductive potential and outcome of cryopreservation procedures amongst BRCA1/2-positive breast cancer patients by comparing four cohorts—'BRCA1/2-positive', 'BRCA1/2-negative', 'BRCA-untested' and 'other mutations'. Specifically, reproductive potential was assessed by measuring AMH levels, while efficacy of fertility preservation was evaluated by oocyte yield, number of cryopreserved oocytes and poor response rate to ovarian stimulation. In case of ovarian tissue cryopreservation, the number of oocytes per fragment and per mm2 was assessed.

Twenty-nine patients (18.6%) harbored a BRCA1/2 mutation, in keeping with what would be expected from a heterogeneous population of breast cancer patients under the age of 40. The median age of the entire cohort was 31 and there was no difference between the BRCA-positive and BRCA-negative patients. The BRCA-positive cohort had numerically lower AMH levels than the BRCA-negative patients. Carriers also tended to retrieve and cryopreserve fewer oocytes than the non-carriers despite having received higher dosages of gonadotropins for ovarian stimulation. The odds ratio for poor response to ovarian stimulation was 5.3 (95% confidence interval 0.8–37.1; P = 0.091). These data confirm that AMH is a good predictor of oocyte yield before ovarian stimulation.[18] Nonetheless, this does not imply that it should be considered a marker of natural fertility or fecundity, as confirmed by a recently published prospective trial on 750 women between 30–44 years without a history of previous infertility.[19]

Amongst those patients that underwent ovarian tissue cryopreservation, the BRCA-positive cohort tended to have a numerically lower number of oocytes per ovarian cortex fragment (0.08 versus 0.14; P = 0.193) and per mm2 (0.33 versus 0.78; P = 0.153) than those in the BRCA-negative cohort. While none of these differences met statistical significance, the results were consistent with what had been demonstrated in at least another study.[14] Despite the lower number of cortical oocytes described, in this paper Lambertini et al. report the second baby born after ovarian transplantation of a BRCA-positive carrier.

How can we contextualize these results? BRCA1/2-carriers are faced with a multitude of reproductive challenges and their needs are unique. These women are encouraged to undergo risk reducing salpingo-oophorectomy (RRSO) at ages 35–40 for BRCA1-carriers and between 40 and 45 for BRCA2-carriers. They are urged to complete their child-bearing before this, but a significant number may experience a breast cancer diagnosis before RRSO, with a significant risk of chemotherapy-related infertility. Thus, in the context of their oncology care, they should also be offered fertility preservation before therapy.

As for all young women with breast cancer, the standard fertility preservation for BRCA 1/2-carriers should include oocyte cryopreservation or ovarian tissue freezing before treatment and LHRH-analogue (LHRH-a) administration during chemotherapy.[20] While oocyte freezing may be hampered by a low oocytes yield after gonadotropin administration, it may offer the opportunity for PGD in interested patients.[21] Conversely, even if it may seem contradictory to advocate ovarian tissue transplantation for restoring fertility in BRCA 1/2-carriers, bilateral salpingectomy during ovarian cortex biopsy could be discussed with patients, also considering the actual evidences of a possible tubal origin of ovarian cancer in this group of patients.[22] No data are available about the efficacy of LHRH-a administration during chemotherapy in BRCA 1/2-carriers.

Lambertini et al. should be commended for raising the important issue of BRCA1/2 mutation status within the context of the oncofertility counseling. Certainly, further studies are warranted and needed, and international registries of BRCA-carriers and their fertility management should be encouraged. However, the question remains how these women should be counselled in the meantime. The bulk of evidence suggests that there is reasonable concern that BRCA1/2-carriers may have impaired ovarian reserve and may have impaired response to ovarian stimulation. The fact that there is reasonable concern and biological plausibility suggest that we should raise these issues and discuss uncertainty with our patients. While some may be concerned that this may induce further anxiety amongst BRCA-carriers, studies have repeatedly demonstrated long-term resilience in patients' ability of tackling the complexities of BRCA mutation status, breast cancer diagnosis and fertility concerns. While emphasizing the progress and promise of fertility preservation and future parity, we must also respect our patient's autonomy and ensure they make informed decisions by sharing with them the existing knowledge.

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