A new understanding of the origins of ovarian cancer is driving efforts to determine whether the removal of the fallopian tubes alone can enable women who have BRCA1 or BRCA2 mutations to reduce their cancer risk while avoiding early menopause and maintaining their quality of life.
“We’ve come to understand that many genetic ovarian cancers appear to start in the fallopian tubes. So removing these tubes may greatly reduce risk,” said Denise Nebgen, M.D., Ph.D., an associate professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center.
Removing only the fallopian tubes and leaving the ovaries to be removed at a later date may avoid the side effects stemming from early menopause in women who have BRCA1/2 mutations and desire prophylactic surgery to reduce their risk of ovarian cancer, a recent clinical trial by physicians at The University of Texas MD Anderson Cancer Center has demonstrated.
Imperfect risk management options
More than 60% of ovarian cancers are not diagnosed until the disease has metastasized, and the 5-year overall survival rate of patients with metastatic ovarian cancer is less than 50%. Although women in the general population have only a 1.4% risk of ovarian cancer, BRCA1 and BRCA2 mutations increase the risk to 46% and 27%, respectively.
Strategies to mitigate the risk of ovarian cancer for women with BRCA1/2 mutations include regular screening, oral contraceptives, and bilateral salpingo-oophorectomy. Unfortunately, none of these strategies is ideal.
Oral contraceptives decrease the risk of ovarian cancer in women with BRCA1/2 mutations by only 50%. And the screening methods for ovarian cancer—transvaginal ultrasonography and the CA-125 (carbohydrate antigen 125) blood test—lack the sensitivity and specificity to reliably detect early-stage disease. For this reason, screening guidelines vary for women with increased risk of the disease.
Bilateral salpingo-oophorectomy between the ages of 40 and 45 years in women with BRCA1/2 mutations reduces the risk of ovarian cancer by 80%–90% and may reduce the risk of breast cancer by 50%. However, removing the ovaries causes premature menopause, which can increase the risk of cardiovascular disease, osteoporosis, and symptoms that can reduce quality of life (including hot flashes and sexual and cognitive dysfunction). Moreover, hormone replacement therapy to ameliorate these symptoms is controversial in this group of patients because such therapy may increase the risk of breast cancer.
The understanding of the origins of ovarian cancer has changed substantially in the past 5 years. Previously, ovarian cancer was thought to originate exclusively in the ovarian surface epithelium, but recent research indicates that many ovarian cancers originate in the fallopian tubes. The origin of ovarian cancer in the fallopian tubes is further supported by the fact that bilateral tubal ligation, a procedure often used for permanent birth control, reduces ovarian cancer risk by 50%. In addition, researchers have identified serous tubal intraepithelial carcinomas and occult invasive serous carcinomas of the fallopian tubes, but no ovarian lesions, in women with BRCA1/2 mutations who undergo prophylactic salpingo-oophorectomies.
The refined understanding of the origins of ovarian cancer has led to the emergence of bilateral salpingectomy, or removal of just the fallopian tubes, as an alternative to salpingo-oophorectomy for women 30–40 years old who have BRCA1/2 mutations. Salpingectomy enables women to reduce their risk of ovarian cancer while retaining their ovaries for several years. Sparing the ovaries helps patients maintain their quality of life and avoid the health risks posed by premature menopause. “We do not know, however, to what extent the risk of ovarian cancer is reduced by salpingectomy,” Dr. Nebgen said.
The disadvantage of salpingectomy is that patients later must undergo a second surgery—an oophorectomy—to further reduce their risk of ovarian and breast cancers. In accordance with national guidelines, the oophorectomy is performed at ages 40 and 45 years, respectively, for women with BRCA1 and BRCA2 mutations.
“I tell women that salpingectomy is an interim measure we can take,” Dr. Nebgen said. “Eventually these women will also want their ovaries removed to decrease not only ovarian cancer risk but also breast cancer risk. But having the tubes out early, and then the ovaries out later, can be a stop-gap that reduces risk in this window without initiating menopause.”
Beginning in 2014, Dr. Nebgen was the principal investigator for the first clinical trial (No. 2013-0340) in the United States to offer salpingectomy to women with BRCA1/2 mutations to see if this group would be interested in the option. Forty-four patients participated in the trial. The participants were allowed to choose their interventions: 20 patients chose salpingectomy, 12 chose screening at 6-month intervals, and 12 chose salpingo-oophorectomy. The trial closed in 2016, but it will take many years to determine the long-term effects of salpingectomy and whether the patients who chose this option will follow up and have their ovaries removed at a later time. So far, one patient has.
After the success of the first study, Karen Lu, M.D., a professor in and chair of the Department of Gynecologic Oncology and Reproductive Medicine, designed a phase II trial, the Women Choosing Surgical Prevention (WISP) trial (No. 2015-0814). “Dr. Nebgen’s proof-of-concept study confirmed that women are interested in salpingectomy to reduce cancer risk and stave off menopause,” Dr. Lu said. “Now we’re ready to build on that initial research with larger studies that give us data on salpingectomy’s safety and effectiveness.”
The WISP trial opened in May 2016 at six United States sites and will enroll 270 women who have mutations in BRCA1, BRCA2, or other genes linked to increased ovarian cancer risk. So far, 13 patients have enrolled. These patients will choose between salpingo-oophorectomy and salpingectomy followed by delayed oophorectomy.
The primary objective of the WISP trial is to compare sexual function and quality of life between the two treatment groups. Other objectives include comparing the incidence of ovarian cancer in the two groups and determining whether patients who undergo salpingectomy later undergo oophorectomy. Dr. Nebgen is confident that the study will show that salpingectomy, like tubal ligation, reduces ovarian cancer risk by at least 50%.
Recommendations for patients at risk
Dr. Nebgen urges women who have a family history of breast or ovarian cancer at a young age in first- or second-degree relatives (i.e., sisters, mothers, aunts, or grandmothers) to participate in genetic counseling and screening. Women who have confirmed BRCA1/2 mutations or Lynch syndrome are advised to consider undergoing recommended cancer screening at a clinic with experience in screening high-risk patients and to consider surgical prophylaxis.
“Women and their doctors should be aware that there are several preventive methods for ovarian cancer, but the timing of these procedures is crucial,” Dr. Nebgen said. “Sometimes risk-reducing salpingo-oophorectomy can be performed too soon, leading to other health problems. Salpingectomy allows women to reduce their risk while postponing menopause.” She added that patients who choose to undergo salpingectomy should be encouraged to follow up with cancer screening and eventual ovary removal.
For more information, call Dr. Karen Lu at 713-745-8902 or Dr. Denise Nebgen at 713-792-8507. To learn more about the WISP trial, visit www.clinicaltrials.org.
OncoLog, February 2017, Volume 62, Issue 2