Managing the Inherited Risk of Ovarian Cancer

By Kara Long Roche, MD,

Friday, September 16, 2016

Since there is no effective screening test for ovarian cancer, the gold standard management approach for women who are at an increased risk for developing ovarian cancer is a risk-reducing salpingo-oophorectomy (RRSO), a surgical procedure to remove ovaries and fallopian tubes by the age of 40 or after childbearing is complete. (1)However, this approach leads to early menopause and associated side effects. Interval salpingectomy with delayed oophorectomy (ISDO) may be a viable alternative risk-reducing strategy for these women, sparing them the adverse effects of early surgical menopause. The rationale behind this proposed strategy is strong; however, there are still many unanswered questions regarding efficacy and safety.

The Fallopian Tube Hypothesis

Over the past decade, the fimbriated end of the fallopian tube has become the primary suspect as the etiologic origin of hereditary ovarian high-grade serous carcinoma (HGSC). Molecular markers, gene expression, and, most notably, the identification of serous tubal intraepithelial carcinoma (STIC) — a precursor lesion of ovarian HGSC found in the fallopian tubes — have provided some of the most convincing evidence supporting the tubal hypothesis. See Figure 1.

STIC lesions have been identified in the fallopian tubes of up to 15 percent of BRCA mutation carriers undergoing RRSO, up to 80 percent of BRCA-associated HGSCs, and up to 60 percent of sporadic HGSCs. (2)(3)(4)

Back to top

Expanding the Definition of High Risk

As genetic testing becomes more accessible and widespread, we are finding an increasing number of women who have an inherited predisposition to ovarian cancer. Women with mutations in the BRCA1 and BRCA2 genes have a lifetime risk of ovarian cancer of 39 to 46 percent and 10 to 27 percent, respectively. (5)Mutations associated with Lynch syndrome (MSH2, MSH6, MLH1, or PMS2), as well as others including BRIP1, RAD51C, and RAD51D, have also been associated with an increased risk of ovarian cancer development.

An RRSO can reduce the risk of ovarian cancer and breast cancer by 75 to 90 percent and up to 50 percent, respectively. (6) However, early surgical menopause can have detrimental consequences. Hot flashes, vaginal dryness, sexual dysfunction, and sleep disturbances can negatively impact quality of life and ultimately deter women from proceeding with prophylactic surgery. (7)

Back to top

Interval Salpingectomy with Delayed Oophorectomy: A Valid Alternative?

Many researchers believe that ISDO can be a valid risk-reducing option for select women who want to avoid early surgical menopause. This approach is currently being studied in premenopausal women under the age of 50 who have completed childbearing. ISDO may fulfill an unmet clinical need, as only 60 to 70 percent of BRCA mutation carriers undergo RRSO by the recommended age. (8)The majority of occult cancers found during RRSO in BRCA mutation carriers are located in the fallopian tube; therefore, it is reasonable to hypothesize that ISDO would confer significant protection. ISDO would also provide an opportunity for an experienced clinician to inspect the peritoneal cavity and for early pathologic evaluation of the fallopian tubes, which may lead to the identification of STIC or occult HGSC.

A cost-effectiveness analysis published in 2013 compared RRSO and ISDO in a theoretical cohort of women with BRCA mutations. While RRSO provided the greatest protection against breast and ovarian cancer, ISDO was the preferred option when quality-adjusted life expectancy was considered. (9) In an online study of premenopausal women with BRCA mutations, 34 percent reported interest in a study of ISDO and would accept the associated risks. (10)

However, there are still unanswered questions regarding the safety and appropriateness of ISDO. RRSO is a proven strategy in these women, and the risks of deviating from this approach must be carefully evaluated. One concern is the impact on breast cancer risk reduction. RRSO reduces the risk of breast cancer by approximately 50 percent in women with BRCA mutations, likely due to endocrine ablation from oophorectomy. These women have an estimated 80 percent lifetime risk of developing the disease. Also, ISDO requires two separate surgical procedures, and while these would likely be minimally invasive, surgical morbidity would undoubtedly increase. Lastly, there are concerns that women may not proceed with delayed oophorectomy, and the impact of this is unknown.

Overall, ISDO represents an exciting possibility for the future management of women with inherited risk of ovarian cancer. As science moves forward, the hope is that strategies such as this can maximize protection while minimizing the impact on quality of life. 

Back to top

  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Genetic/familial high-risk assessment: breast and ovarian (Version 2.2016). Updated March 15, 2016. Accessed April 26, 2016.

  2. Crum CP, Drapkin R, Miron A, et al. The distal fallopian tube: a new model for pelvic serous carcinogenesis. Curr Opin Obstet Gynecol 2007; 19:3-9.

  3. Callahan MJ, Crum CP, Medeiros F, et al. Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J Clin Oncol 2007; 25:3985-90.

  4. Leeper K, Garcia R, Swisher E, et al. Pathologic findings in prophylactic oophorectomy specimens in high-risk women. Gynecol Oncol 2002; 87:52-6.

  5. King MC, Marks JH, Mandell JB; New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003; 302:643-6.

  6. Kauff ND, Domchek SM, Friebel TM, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 2008; 26:1331-7.

  7. Campfield Bonadies D, Moyer A, Matloff ET. What I wish I’d known before surgery: BRCA carriers’ perspectives after bilateral salpingo-oophorectomy. Fam Cancer 2011; 10:79-85.

  8. Greene MH, Piedmonte M, Alberts D, et al. A prospective study of risk-reducing salpingo-oophorectomy and longitudinal CA-125 screening among women at increased genetic risk of ovarian cancer: design and baseline characteristics: a Gynecologic Oncology Group study. Cancer Epidemiol Biomarkers Prev 2008; 17:594-604.

  9. Kwon JS, Tinker A, Pansegrau G, et al. Prophylactic salpingectomy and delayed oophorectomy as an alternative for BRCA mutation carriers. Obstet Gynecol 2013; 121:14-24.

  10. Holman LL, Friedman S, Daniels MS, et al. Acceptability of prophylactic salpingectomy with delayed oophorectomy as risk-reducing surgery among BRCA mutation carriers. Gynecol Oncol 2014; 133:283-6.