Women with BRCA1 mutations who undergo risk-reducing ovary and fallopian tube removal without concomitant hysterectomy appear to be at increased risk for serous or serous-like endometrial carcinoma, results of a long-term prospective study suggest.

Among 1,083 women with deleterious mutations in BRCA1, BRCA2, or both who underwent risk-reducing salpingo-oophorectomy (RRSO) without hysterectomy, there was no overall increase in the incidence of uterine corpus cancers, compared with the background population. But among women with BRCA1 mutations, however, there was increased risk for serous/serous-like endometrial carcinomas, which comprise only 10% of endometrial cancers, but account for about 40% of endometrial cancer deaths, reported Catherine A. Shu, MD , of Columbia University, New York, and her colleagues (JAMA Oncol. 2016 Jun 30. doi: 10.1001/jamaoncol.2016.1820).

“Our results suggest that BRCA1+ women are at increased risk for serous/serous-like endometrial carcinoma. Although instability in the estimated magnitude of this risk remains, we believe that the possibility of this cancer should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1+ women,” they wrote.

Salpingo-oophorectomy to reduce risk for breast, ovarian, and fallopian-tube cancers is a standard option for women with BRCA mutations, but it’s unclear whether concomitant hysterectomy offers additional benefit, or adds only morbidity.

To help clarify the issue, investigators at nine comprehensive cancer centers enrolled 627 women with BRCA1 mutations, 453 with BRCA2 mutations, and 3 with mutations in both genes who underwent RRSO without either prior or concomitant hysterectomy. They then followed the patients for a median of 5.1 years after the date of ascertainment, receipt of BRCA testing results, or RRSO.

There were a total of 8 incident uterine cancers over the course of follow-up, compared with 4.3 that would be expected based on Surveillance, Epidemiology, and End Results (SEER) data. The observed-to-expected incidence ratio was 1.9, and was not statistically significant.

In addition, when the investigators stratified by subtype, there was no increased risk for endometrioid endometrial carcinoma or sarcoma.

However, there were five cases of serous/serous-like endometrial carcinomas occurring from 7.2 to 12, 9 years after surgery. The patients included four women positive for BRCA1 mutations, and one positive for BRCA2.

In the SEER population, 0.18 incident cases would be expected, translating into an observed-to-expected ratio for women with BRCA1 of 22.2 (P less than .001). For BRCA2, however, the ratio was 6.4, and was not statistically significant.

In the three serous/serous-like tumors from women positive for BRCA1, tumor analysis showed loss of the wild-type BRCA1 gene and/or loss of protein expression.

Finally to see whether the results could have been confounded by a history of breast cancer or exposure to tamoxifen, which is associated with a small but significant increase in risk for endometrial cancer, the investigators looked at the serous/serous-like subtype tumors, 4 of which occurred among 727 women with history of breast cancer, compared with 0.26 expected (observed-to-expected ratio 15.5, P less than .001). Among 356 women with no history of breast cancer, the expected incidence was 0.08, and the observed-to-expected ratio was 12.6 (not significant).

There were 3 serous/serous-like carcinomas among 273 women with tamoxifen exposure (expected rate 0.12, observed-to-expected ratio, 24.4, P less than .001) and two occurring in 655 women without tamoxifen exposure (expected 0.18, observed-to-expected ratio 11.3, P = .01).

The authors noted that with minimally invasive approaches, the additional surgical risks, mortality rates, and costs of adding concomitant hysterectomy to RRSO are relatively modest and may be an acceptable trade-off for some high-risk patients.

“[I]f the present results are confirmed by future studies, hysterectomy with bilateral salpingo-oophorectomy may become the preferred risk-reducing surgical approach for BRCA1+ women. However, even if these results are confirmed, RRSO alone may still have a role for BRCA1+ women if strong reasons exist for uterine retention, such as dense pelvic adhesions or desire for future pregnancy using assisted reproductive approaches,” they wrote.


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