BRCA1 Mutations Can Lead to Lethal Uterine Cancer

Researchers from the Duke Cancer Institute have discovered that mutations in the BRCA1 gene can dramatically increase the probability of a woman developing serous or serous-like endometrial carcinoma. The newly defined link can have a significant bearing on the treatment plan for these women.

To date, mutations in the BRCA genes have been linked to the development of breast and ovarian cancers. Women with a familial history of BRCA mutations have been choosing to undergo preventive surgeries to remove their breasts as well as their ovaries to reduce their risk of a cancer in those organs. Studies have documented the advantage of risk-reducing salpingo-oophorectomy (RRSO) in reducing the risk of developing breast and ovarian or fallopian tube cancer in women with BRCA1 mutations. This new study by scientists at Duke, published in JAMA Oncology, creates case for women to undergo a preventive hysterectomy to reduce their risk of uterine cancer.

“Our study presents the strongest evidence to date that women with this genetic mutation should at least discuss with their doctors the option of having a hysterectomy along with removal of their ovaries and fallopian tubes,” said Noah D. Kauff, MD, senior author on the current study and head of the Clinical Cancer Genetics Program at the Duke Cancer Institute.

The multicenter (9 academic medical centers in the United States and the United Kingdom) prospective cohort study followed 1083 women with a deleterious BRCA1 or BRCA2 mutation that was identified between January 1, 1995, and December 31, 2011. The women underwent RRSO without a hysterectomy. A majority (627) of study participants were BRCA1-positive, while most other (453) were BRCA2-positive. Three women had mutations in both genes. The women were followed for a median of 5.1 years (interquartile range, 3.0 to 8.4 years) after ascertainment, BRCA testing, or both, whichever was last.

The main outcome measure of the study was incidence of uterine corpus cancer in BRCA1-positive women who had RRSO without a hysterectomy.

The study documented 8 uterine cancers, 4.3 of which were expected; there was, however, no increased risk for endometrioid endometrial carcinoma or sarcoma. Between 7.2 and 12.9 years after RRSO, 5 serous and/or serous-like endometrial carcinomas were observed, 4 of which were in women who were BRCA1-positive. Subsequent analysis of the tumors confirmed the loss of expression of wild-type BRCA1.

“We were surprised when we saw the data,” according to Kauff. “This is an event that should not occur in the over 600 women with BRCA1 mutations in our study. Even if we followed these women for 25 years, you would only expect to see no more than 1 serous cancer.”

Kauff recommends that women who are BRCA1 positive should consider removing their uterus while they are undergoing surgery to remove their ovaries and fallopian tubes, “unless they are hoping to still have children using assisted reproductive methods or have other medical reasons.”