Review: Prophylactic Surgery for Women at Risk of Hereditary Ovarian or Endometrial Cancer

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Certain inherited germline mutations dramatically increase the risk of ovarian or endometrial cancer. For the small number of women who have these mutations, prophylactic surgery has great potential to reduce the risk of cancer.

In the Journal of Surgical Oncology, OB/GYN resident Alexandra S. Bercow, MD, and Eric L. Eisenhauer, MD, chief of the Division of Gynecologic Oncology in the Department of Obstetrics and Gynecology at Massachusetts General Hospital, review how women with hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome can reduce their risk of ovarian and endometrial cancer through surgery.

HBOC Syndrome

HBOC syndrome, the most common genetic syndrome linked to ovarian cancer, is most frequently associated with mutations in the BRCA1 and BRCA2 tumor suppressor genes. The lifetime risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers is 44% and 17%, respectively, compared with 1.3% in the general population.

HBOC syndrome can also be associated with germline mutations in a number of other homologous recombination repair genes.

Peutz-Jeghers syndrome, which results from mutations in the STK11 gene, has been associated with a 21% lifetime risk of ovarian cancer, which is usually diagnosed in young adulthood or even childhood.

Screening

Before undergoing BRCA testing, women who have a significant family history of breast or ovarian cancer should consult a genetic counselor for formal risk assessment. The United States Preventive Services Task Force, the American College of Medical Genetics and Genomics and the National Comprehensive Cancer Network have published guidelines about when to refer to a genetic counselor.

Risk-reducing Surgery

Bilateral salpingo-oophorectomy (BSO) is the standard surgical prophylaxis for patients with HBOC syndrome. It has been linked to significantly improved cancer-specific mortality for ovarian, fallopian tube, peritoneal and breast cancers, as well as improved all-cause mortality in BRCA mutation carriers.

Many women with BRCA mutations wish to delay BSO until they complete childbearing. BRCA2 mutation carriers are at lower lifetime risk of ovarian cancer than BRCA1 mutation carriers and are more likely to be diagnosed later in life (at average age 60 vs. age 35 for BRCA1 carriers). Therefore, they may elect to defer BSO to a later age. However, they must be counseled that they might not receive the benefit of decreased breast cancer risk.

The Society of Gynecologic Oncology (SGO) recommends that if a BRCA mutation carrier refuses BSO, she should be offered bilateral salpingectomy with delayed oophorectomy, with the caution that it does not decrease the risk of primary ovarian cancer or breast cancer. Unfortunately, annual monitoring with pelvic ultrasound and CA125 levels have not been shown to reduce cancer mortality in this high-risk population.

Lynch Syndrome

Patients with Lynch syndrome are carriers of mutations in one of four tumor suppressor genes: MLH1, MSH2, MSH6 or PMS2. These genes identify base-pair mismatches during DNA synthesis and repair them.

Lynch syndrome was formerly known as hereditary nonpolyposis colorectal cancer. However, women with Lynch syndrome also have a 24% to 51% lifetime risk of endometrial cancer, depending on mutation type, compared with 2.9% in the general population. The average age at diagnosis of endometrial cancer is 47 to 51 years in Lynch syndrome compared with age 60 for average-risk women.

Lynch syndrome is also associated with increased risk of other malignancies, including colon, urothelial, gastric, small-bowel, pancreatic, hepatobiliary and brain cancer.

Screening

Screening for Lynch syndrome should be done according to the revised Amsterdam criteria published in the Journal of Medical Genetics. The SGO incorporates those criteria in its guidelines on cancer risk assessment, adding that pathologic specimens from all women diagnosed with endometrial cancer should be tested for DNA mismatch repair mutations.

Risk-reducing Surgery

The standard risk-reducing surgery for Lynch-associated gynecologic cancers is total hysterectomy with or without BSO or bilateral salpingectomy. In the largest study to date, led by researchers at the University of Texas M.D. Anderson Cancer Center, prophylactic surgery was associated with a significantly lower risk of both endometrial cancer and ovarian cancer.

Because of the younger ages at which endometrial and ovarian cancer are diagnosed in women with Lynch syndrome, prophylactic surgery should be performed directly after completion of childbearing.

Patient Counseling About BSO

BSO is generally performed laparoscopically and is considered a low-risk procedure, especially if performed at a high-volume institution. However, there is a 4% to 8% chance of discovering an occult malignancy at the time of BSO or on final pathology. Patients should be consented for more extensive surgery if metastatic disease is found and made aware that a second surgery may be necessary if final pathology shows a malignancy.

Women should also be counseled that BSO will result in surgical menopause. Non-hormonal agents should be used as a first-line therapy. Unlike BRCA mutations, Lynch syndrome does not carry an increased risk of breast cancer, so the theoretical risk from estrogen-progesterone hormone replacement therapy is low.

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