Roxanne Nelson

March 25, 2014

TAMPA, Florida — Women with BRCA1 mutations could be at increased risk of developing rare types of aggressive uterine cancer, in addition to their already well-known increased risk for breast and ovarian cancer, a new study shows.

Patients who plan to undergo a prophylactic salpingo-oophorectomy to avoid ovarian cancer should discuss the potential advantages and disadvantages of having a hysterectomy during the same procedure, according to data presented here at the Society of Gynecologic Oncology 45th Annual Meeting on Women's Cancer.

Researchers followed 525 women for an average of 6 years. All had a BRCA1 or BRCA2 mutation and had undergone risk-reducing salpingo-oophorectomy (RRSO). During follow-up, 4 uterine cancers were diagnosed — all in women with a BRCA1 mutation.

None of the women with a BRCA2 mutation developed uterine cancer.

There were also no cases of low-risk disease (although 1.95 cases would be expected; P = .14). All 4 uterine cancers were high risk (1 serous, 1 high-grade serous with undifferentiated components, 1 carcinosarcoma, 1 leiomyosarcoma).

"Up to this time, we have thought it reasonable, but not required, to remove the uterus," said senior author Noah D. Kauff, MD, director of ovarian cancer screening and prevention for the gynecology service at Memorial Sloan-Kettering Cancer Center in New York City. "But it appears that women with BRCA1 mutations may have an increased incidence of high-risk uterine cancer after risk-reducing salpingo-oophorectomy that approaches 2.1% over 10 years," or an increase that is approximately 26-fold higher than in the general population.

In this group, 2.2 uterine cancers would be expected, but instead there were 4.0, which is a doubling of the risk. "This was slightly higher when compared with the general population, but it was not statistically significant," Dr. Kauff reported.

Dr. Kauff emphasized that it is too early to suggest any changes to current practice. "Given the study limitations, these data should be considered preliminary," he said. "They require confirmation before any changes in clinical recommendations can be made."

RRSO is associated with a decrease in risk for ovarian cancer of about 80% to 90% in women harboring BRCA mutations, and a decrease in risk for breast cancer of 40% to 70%. The effect of concomitant hysterectomy has not been established.

Hysterectomy has its advantages and disadvantages, Dr. Kauff explained. "It ensures complete removal of the fallopian tubes and can simplify hormone replacement therapy. It also eliminates a baseline risk of uterine cancer."

On the downside, there is a higher risk for complications, higher cost, and longer surgical time. There have been no reported cases of cancer in the cornual portion of the fallopian tube after RRSO, he noted.

High-Risk Disease With BRCA1 Mutations

Dr. Kauff and his colleagues prospectively analyzed the risk for uterine cancer after RRSO.

Of the 525 women evaluated, 296 (56%) had a BRCA1 mutation, 226 (43%) had a BRCA2 mutation, and 3 (0.6%) had both mutations. All had undergone RRSO but had an intact uterus. The women were followed with an annual questionnaire and medical record review. The researchers used age- and race-specific SEER data to determine the expected cancer incidence, and adjusted it for the prevalence of hysterectomy.

Uterine cancer was categorized as low risk (endometrioid, mucinous, adenocarcinoma not otherwise specified) or high risk (serous, clear cell, sarcoma).

The expected number of high-risk cases was 0.28. "Instead, it was 4, and that was highly statistically significant," Dr. Kauff said. They occurred 1.4 to 12.9 years after surgery.

One of the women had no history of breast cancer; the number expected would be 0.06 (P = .06). Three of the women had a history of breast cancer; the number expected would be 0.22 (P = .001).

The researchers also looked at previous tamoxifen use, which is associated with an increased risk for endometrial cancer and endometrial changes.

Two of the women with uterine cancer had previously used tamoxifen (expected, 0.092; P = .004), and 2 had not (expected, 0.184; P = .015). "Women exposed to tamoxifen had a 22% increased risk," said Dr. Kauff.

Table. Characteristics of the 4 Women With Uterine Cancer

Characteristic Patient A Patient B Patient C Patient D
Age at RRSO 43.8 59.5 40.5 54.4
History of breast cancer no yes yes yes
Previous tamoxifen use no no yes yes
Uterine cancer histology Carcinosarcoma Leiomyosarcoma High-grade serous Serous
FIGO stage ll llB lA lA
Time from RRSO to diagnosis (yr) 7.4 1.4 12.9 7.2


Routine Hysterectomy Not Recommended Yet

This is "definitely something that should be discussed with patients considering RRSO," said Stacey N. Akers, MD, from the Department of Gynecologic Oncology at Roswell Park Cancer Institute in Buffalo, New York. However, "we need further studies to determine risks so that we can counsel patients appropriately."

The women in this study who developed endometrial cancer had type 2 endometrial cancers, which are more aggressive than type 1 endometrial cancers, she pointed out. "Women with known BRCA1/2 mutations who opt for uterine preservation need to be aware of this," she told Medscape Medical News. They should "be sure report any signs of bleeding to their care team."

This "is a good study," noted Steven Narod, MD, director of the familial breast cancer research unit at Women's College Research Institute in Toronto. "The 4 cancers seen are interesting, but it is a small sample and is insufficient to guide practice," he said.

However, several previous studies have suggested that tamoxifen causes these serous endometrial cancers.

In fact, in a study 10 times larger than this one, Dr. Narod and his colleagues followed 4456 women with a BRCA1 or a BRCA2 mutation (Gynecol Oncol. 2013;130:127-131). They found that the risk for endometrial cancer was similar in women with a BRCA1 or BRCA2 mutation and in those in the general population. There was a significant increase in women who had breast cancer, but this was restricted to those who had used tamoxifen.

Dr. Narod agrees that a hysterectomy should not routinely be recommended as a part of prophylactic surgery for BRCA1 and BRCA2 mutation carriers. "However, women should be made aware that they face a non-negligible risk of cervical and endometrial cancer, and that this can be eliminated through hysterectomy," he said.

Society of Gynecologic Oncology (SGO) 45th Annual Meeting on Women's Cancer. Presented March 24, 2014.


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