BRCA+ Patients May Have Higher Risk of Serous Uterine Cancers After RRSO

Noah D. Kauff, MD

Hysterectomy, in addition to standard risk-reducing salpingo-oophorectomy (RRSO) measures, should be considered in women who are BRCA-positive to reduce the risk of serous uterine cancers, particularly in patients with BRCA1-positive mutations, according to a prospective study presented earlier this year at the 2015 ASCO Annual Meeting.

The study, which looked at 1083 BRCA-positive women for a median of 5.2 years after RRSO, found eight incidents of uterine cancer. When the uterine cancers were stratified by subtype into endometrioid endometrial cancers, serous endometrial cancers, and sarcoma, there was no increase risk found in endometrioid endometrial cancers or sarcoma, but five serous endometrial cancers identified after RRSO (0.33 expected [Exp]; observed/Exp = 15.2, P <.0001). When the data were furthered stratified in BRCA1 and BRCA2, a small absolute increased risk of serous endometrial cancers of 1.1% at 10 years was identified.

OncLive: What were the goals in conducting this study?

To better understand what these results could mean for women with BRCA-positive mutations, OncLive spoke with lead study author Noah D. Kauff, MD, gynecologist and geneticist, director, Ovarian Cancer Screening and Prevention, Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center.Dr Kauff: RRSO is a standard of care for woman with BRCA1 and BRCA2 mutations. RRSO is a preventative removal of the ovaries and the fallopian tubes. This has been shown to reduce the risk of ovarian cancer by 85% to 90% in women with BRCA1 and BRCA2 mutations. If the procedure is done premenopausal, it will also reduce the risk of subsequent breast cancer by 40% to 70%. It has been controversial whether or not to include hysterectomy in RRSO because it has not been clear whether or not uterine cancer is part of the tumor spectrum seen with BRCA-mutations.

How was the study conducted?

What were the most significant findings?

Serous ovarian cancers account for only about 10% of uterine cancers, however they are more aggressive and account for 40% of the uterine cancer deaths. There has been a question as to whether or not uterine serous tumors are associated with BRCA mutations. The data on this have been controversial. Two studies from 2000 and 2001 that looked at a series of women with serous uterine cancer did not find an overrepresentation of BRCA mutations. However, more recent research found a higher rate of BRCA mutations than would be expected.Our study was a prospective study from nine centers encompassing 1083 patients. These were all women with documented deleterious mutations in BRCA1 or BRCA2 who had undergone RRSO with their uterus being left in situ. These women were followed for a median of 5.2 years prospectively, through a combination of a structured questionnaire and medical record review. We compared what was observed versus what we expected from SEER and we used age- and race-adjusted rates. We also needed to adjust SEER for the prevalence of hysterectomy, as 31% of women in the US over the age of 60 have had a hysterectomy and SEER does not account for this. We further stratified by the subtypes of cancer that were seen, breaking it up into carcinomas and sarcomas as well as breaking it up by endometrioid and serous carcinomas.From this prospective study, we saw eight uterine cancers; we would have expected around four. This is about a 1.9% higher rate of uterine cancer than what we would have expected. This was of borderline statistical significance. However, when we looked at the specific subtypes of uterine cancer, we saw that of the eight, five were serous cancers. We would have expected just over 0.3 serous cancers, and we saw five.

This was a 15-fold increased risk of serous uterine cancer and it was highly statistically significant. We had tumor specimens available on four of the eight cancers, including three of the serous carcinomas. We did immunohistochemical analysis on the tumors for expression of the BRCA protein. All three of the serous cancers, showed loss of expression of BRCA, while the sarcoma maintained expression, suggesting that there was loss of function of BRCA1 in the tumor. The most common mechanism of loss of BRCA1 function is through loss of heterozygosity. What has happened in women who have BRCA mutations is that they have inherited one abnormal copy of BRCA and they have one normal copy. In order for a cancer to develop by loss of BRCA function, the patient has to lose the other working copy.

We looked at the three serous cancers and two of them showed a loss of heterozygosity at BRCA1. In the third serous cancer, we did not see loss of heterozygosity, but interestingly, data from the Cancer Genome Atlas (TCGA) in BRCA-associated ovarian and fallopian tube cancers show that about 19% of BRCA-associated ovarian and fallopian tube cancers also do not show loss of heterozygosity.

In the serous cancers, we stratified by BRCA1 and BRCA2. In women with BRCA1-associated disease, there was a 22—fold increased incidence of serous cancer. Additionally, we calculated the 10-year absolute risk that this would translate into, which was a 1.1% absolute 10-year risk of serous cancers. These do have a mortality of 45% to 50%. In fact, of the five serous cancers that developed with a mean follow-up of 3.5 years, two have recurred and one had lead to the death of the patient. This risk was irrespective of prior history of breast cancer or tamoxifen use.

What impact will these findings have?

In terms of BRCA2, there was about a 6-fold increased risk of serous, but this did not reach statistical significance.We think this is going to be important information for those with BRCA mutations who are considering risk-reducing surgery. They will need to consider the pros and cons of hysterectomy and include the risk of serous uterine cancer in that thought process.

Up until this point, we thought it was reasonable but not required to remove the uterus at the time of risk-reducing surgery. While a 1.1% 10-year risk may not seem like a large amount, since the average age of women removing their ovaries and fallopian tubes is in their late 30s, early 40s, most of these women will have a life expectancy exceeding 4 decades from that point. If the risk is constant, this will translate into a 4% to 5% lifetime risk of serous uterine cancer, with approximately half of those resulting in death. Given that these are women who are already at increased genetic risk of both breast and ovarian cancers, it is something that women with this mutation really need to think about.

Shu C, Pike M, Jotwani A et. all Uterine cancer (Ut Ca) following risk-reducing salpingo-oophorectomy (RRSO) in women with BRCA mutations (BRCA+): a multicenter, prospective study. J Clin Oncol 33, 2015 (suppl; abstr 1504).