Fertility Preservation in BRCA -Mutated Women: When and How?

Abstract

BRCA 1 and 2 genes play a critical role in the safeguarding of DNA integrity. It is now well established that BRCA1 and BRCA2-mutated women are at increased risk of breast and ovarian cancers. However, several lines of evidence indicate that this genetic status may also be associated with ovarian dysfunction, in particular a reduced ovarian reserve. Considering the gonadal toxicity of cancer treatments and the recommendation of prophylactic bilateral salpingo-oophorectomy around 40 years, young BRCA mutation carriers are confronted with difficult family planning decisions. Recent development in fertility preservation offers new possibilities for these women, not only before a potential cancer treatment, but also in healthy carriers. If the pregnancy seems to be safe in this population, oocyte vitrification following ovarian stimulation might help BRCA-mutated patients to conceive after cancer treatment or to undergo prenatal genetic diagnosis in order to avoid the risk of transmitting the genetic abnormality to their offspring. The present article aims to extensively discuss the fertility issues related to BRCA gene mutations and the questions raised by the possibility of fertility in this population.

Fertility preservation in patients with BRCA mutations or Lynch syndrome

“…The prevalence of BRCA deleterious mutations is approximately 1:300-500 in the general population. 10 Overall, BRCA mutations account for 17-65.5% of breast cancers and 16.2-40% of ovarian cancers. Of specific relevance for the present review is the fact that BRCA related malignancies are characterized by a precocious onset.…”

“…For a similar patient with a BRCA2 mutation, these risks are 7.5% and 0.7%, respectively. 10 Considering the current trend to postpone pregnancy to later in life, especially in Western countries, it is anticipated that an increasing proportion of young women will be diagnosed with cancer before completing childbearing. The most effective measure to reduce the risk of ovarian cancer in BRCA mutated patients is risk reducing salpingo-oophorectomy at age 35-40, but this impairs fertility, inducing a premature menopause.…”

“…Ovarian tissue cryopreservation might be proposed to selected patients, including some cancer patients scheduled for highly gonadotoxic treatment, but in particular if treatment initiation cannot be delayed, in the case of prior exposure to chemotherapy, when ovarian stimulation is a contraindication, or to prepubertal women. 10 Ovarian tissue is surgically retrieved and cryopreserved. After being thawed, ovarian tissue is grafted back to the patient, on either the orthotopic (into the pelvic cavity) or heterotopic site (subcutaneous regions such as the forearm or abdominal wall).…”

Single nucleotide polymorphisms in breast cancer susceptibility gene 1 are associated with susceptibility to lung cancer

“…In addition, BRCA may affect the mismatch repair complex by reducing its activity (23). Theoretically, toxicity derived from agents (such as tobacco), that promote double-strand DNA damage, emphasizes the role of BRCA in promoting DNA repair (24); therefore, a SNP may negatively influence BRCA. Thus, the differences remained statistically significant after adjusting for sex (OR, 0.730 and P=0.008 for C/T; OR, 0.667 and P=0.020 for T/T), smoking status (OR, 0.737 and P=0.019 for C/T; OR, 0.609 and P=0.010 for T/T) or both (OR, 0.741 and P=0.021 for C/T; OR, 0.610 and P=0.011 for T/T).…”

Association of BRCA Mutations and Anti-müllerian Hormone Level in Young Breast Cancer Patients

“…Considering that it is currently recommended for BRCA -mutation carriers to complete childbearing by age 40 and to undergo a risk-reducing salpingo-oophorectomy, and that breast cancer patients with BRCA mutation are at increased risk of infertility as a result of anticancer treatment (18), issues of fertility preservation should be a priority for young patients.…”