Management of Fertility and Hormonal Health in Women at Risk for Hereditary Gynecologic Cancers – Endocrinology Advisor

Hereditary cancer syndromes account for approximately 5% to 10% of all cancers, including those of the female reproductive organs.1 It is important to identify patients at risk for inherited cancer syndromes to manage and prevent various syndrome-associated malignancies.

The management of women at increased risk for hereditary gynecologic cancer specifically has to take into consideration unique concerns regarding fertility and hormonal health, with the use of appropriate fertility preservation strategies and hormone therapy, according to an evidence-based review by the Society of Gynecologic Oncology and American Society for Reproductive Medicine published jointly in Gynecologic Oncology and Fertility & Sterility.2

The most common conditions associated with gynecologic cancers include hereditary breast and ovarian cancer and hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome.2 Other genetic cancer syndromes that have been linked to increased risk for gynecologic malignancy include Peutz-Jeghers syndrome and Cowden syndrome.1

Hereditary breast and ovarian cancer accounts for approximately 5% of breast cancers and 10% to 25% of ovarian cancers.2 Mutations of the genes breast cancer 1 (BRCA1) and 2 (BRCA2) account for the majority of hereditary ovarian, tubal, and peritoneal cancers.3

Several other pathogenic variants are associated with an increased risk for ovarian cancer but not breast cancer, including variants in BRIP1, RAD51C, and RAD51D. Other pathogenic variants that are associated with an increased risk for breast cancer without a significantly increased risk for ovarian cancer include variants in TP53, CDH1, CHEK2, and ATM.2

Lynch syndrome is associated with increased risk for various solid malignancies other than gynecologic cancers, especially colorectal cancer, with Lynch genes varying in penetrance.2

The International Federation of Gynecology and Obstetrics (FIGO) guidelines detail criteria for genetic risk assessment in hereditary breast and ovarian cancer, based on personal or family history of ovarian and breast cancer, age at diagnosis of the breast or ovarian cancer, or having a close relative with a known mutation or a family history indicative of Lynch syndrome.4

Once a mutation is identified, the patient should be counseled regarding risk-reducing surgery, other risk-reduction strategies, and altered screening.

Screening: Although early detection of malignancies may improve prognosis, there are no effective screening tests for ovarian cancer, even in those at high risk for the malignancy. Transvaginal ultrasound and the cancer antigen 125 (CA 125) test may have a role in these cases.2

Chemoprevention: Several classes of drugs have been investigated for chemoprevention of ovarian cancer, but only oral contraceptives were found to potentially reduce risk for the malignancy. However, several studies have reported a possible increased risk for breast cancer with oral contraceptive in the general population and in women with BRCA1 or BRCA2 mutations.2

Risk-reducing surgery: Women with BRCA1 or BRCA2 mutations should be offered risk-reducing salpingo-oophorectomy by age 35 years or when childbearing is complete, but some countries recommend surgery at age 40 years or at an age that is 5 years younger than the youngest affected family member.4 Women with Lynch syndrome should be offered prophylactic total hysterectomy and bilateral salpingo-oophorectomy after the completion of childbearing, especially after age 40 years, as these measures have been shown to decrease the risk for endometrial and ovarian cancer in this patient population.2

There are multiple fertility-preservation and family-building strategies that can be used to help women achieve their goals, including oocyte and/or embryo cryopreservation; use of donor oocytes, donor embryos, and/or gestational carriers; and adoption.2

Women with BRCA1 or BRCA2 pathogenic variants should be referred early to reproductive endocrinologists, as discussions with physicians and ovarian reserve testing may help inform patients decisions on if and when to pursue fertility preservation.2

Patients have the option to cryopreserve and store oocytes and/or embryos using assisted reproductive technology. Although embryo cryopreservation is an effective strategy for fertility preservation, the success rate is dependent on multiple factors. The use of fertility drugs is not associated with a greater risk for invasive breast, ovarian, or uterine cancer in the general population. There is also no known increased risk for breast cancer with fertility medications in BRCA mutation carriers, but there are limited data on the risk for ovarian cancer in these patients.2

Additional options for parenthood include hormonally priming the uterus for embryo transfer after risk-reducing salpingo-oophorectomy. Even women who have undergone hysterectomy but who have retained ovaries can have children using their own gametes through in vitro fertilization with a gestational carrier. Uterine transplantation is still a novel procedure and its role in fertility preservation has not yet been determined.2

Embryo biopsies for preimplantation genetic testing (PGT) should be offered to carriers of known pathogenic gene variants. Analysis for monogenic/single gene defects (PGT-M) can aid in selecting embryos for intrauterine transfer and serve as an alternative to prenatal testing. However, one study found that only approximately one-third of high-risk women would theoretically use PGT-M themselves.2

Chorionic villus sampling and amniocentesis may be used to assess fetal karyotype and certain chromosomal abnormalities, but as of 2018, it is still considered a screening test primarily for aneuploidy that should not be used for prenatal diagnosis of a cancer risk gene.5

Surgical intervention can result in menopausal symptoms at a young age, including vasomotor symptoms, cognitive changes, increased risk for cardiovascular disease, and osteoporosis. Hormonal therapy may alleviate some of these symptoms, but its use in patients at greater risk for gynecologic and breast cancers is controversial and limited data are available on the safety of hormonal therapy for women with BRCA1 or BRCA2 mutations or those with Lynch syndrome. As the benefits of hormone therapy may outweigh the risks secondary to premature estrogen loss, this option should be considered for women without a personal history of breast cancer.2

Nonhormonal options to reduce vasomotor symptoms include selective serotonin reuptake inhibitors, alpha-2 adrenergic agonists, dietary and lifestyle changes, and alternative medicine approaches.2

Providers who care for women at risk for hereditary gynecologic cancers must consider the impact of these conditions on reproductive and hormonal health, stated the authors of the Society of Gynecologic Oncology and American Society for Reproductive Medicine review. These considerations include discussions about options for cancer prevention, fertility preservation and family planning, and management of early surgical menopause in these patients.

References

1. Ballinger LL. Hereditary gynecologic cancers: risk assessment, counseling, testing and management. Obs Gynecol Clin N Am. 2012;39(2):165-181.

2. Chen L-M, Blank SV, Burton E, Glass K, Penick E, Woodard T. Reproductive and hormonal considerations in women at increased risk for hereditary gynecologic cancers: Society of Gynecologic Oncology and American Society for Reproductive Medicine evidence-based review. Fertil Steril. 2019;112(6):1034-1042.

3. Shaw PA, Clarke BA. Prophylactic gynecologic specimens from hereditary cancer carriers. Surg Pathol. 2016;9(2):307-328.

4. Mutch D, Denny L, Quinn M; for the FIGO Committee on Gynecologic Oncology. Hereditary gynecologic cancers. Int J Gynecol Obstet. 2014;124(3):189-192.

5. American College of Obstetricians and Gynecologists Committee on Practice Bulletins. Practice bulletin No. 163 summary: screening for fetal aneuploidy. Obs Gynecol. 2016;127(5):979-981.

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Management of Fertility and Hormonal Health in Women at Risk for Hereditary Gynecologic Cancers - Endocrinology Advisor

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