In the Journals

BRCA1 mutations linked to increased risk for serous, serous-like endometrial carcinoma

Women who harbored a BRCA1 mutation had increased risk for serous and serous-like endometrial carcinoma following risk-reducing salpingo-oophorectomy, according to the results of a prospective cohort study.

Although risk-reducing salpingo-oophorectomy is standard for women who harbor BRCA mutations, the role of concomitant hysterectomy is controversial because the risk for uterine cancer in this cohort had been unclear. Some studies had suggested that the risk for uterine corpus cancer in these women was linked to tamoxifen citrate use.

Noah Kauff, MD

Noah D. Kauff

“Serous uterine cancer generally only accounts for about 10% of all uterine cancer diagnosed compared with the much more common endometrioid cancer, which accounts for 80% to 85% of uterine cancers,” Noah D. Kauff, MD, director of clinical cancer genetics program at Duke Cancer Institute of Duke Medicine, told HemOnc Today. “However, serous cancer is associated with a much worse outcome — it accounts for approximately 40% of all uterine cancer-related mortality.”

Researchers evaluated data from 1,083 BRCA–positive women (median age at surgery, 45.6 years; interquartile range [IQR], 40.8-52.2; 94.6% white) who underwent risk-reducing salpingo- oophorectomy without a prior or concomitant hysterectomy at one of nine academic medical centers in the United States and United Kingdom. The cohort included 627 women with a BRCA1 mutation, 453 with a BRCA2 mutation and three with both mutations.

Overall, 67.1% of the women had a prior history of breast cancer, 25.2% had previous tamoxifen exposure and 14.3% had unknown tamoxifen history.

Researchers evaluated the observed incidence of uterine corpus cancer among women in this cohort compared with SEER database–expected incidence.

Follow-up continued for a median of 5.1 years (IQR, 3-8.4) after ascertainment, BRCA testing or salpingo-oophorectomy.

Eight women developed uterine cancers in the population, which was not statistically significantly different from the 4.3 cases that were expected using SEER data. The observed–expected ratio was 1.9 (95% CI, 0.8-3.7).

In a secondary analysis that evaluated cancer incidence based on cancer subtype, researchers found no significant increased risk for endometrioid endometrial carcinoma or sarcoma in BRCA–positive women.

However, five of these women were diagnosed with serous or serous-like endometrial carcinomas 7.2 to 12.9 years after risk-reducing salpingo-oophorectomy, whereas 0.34 cases of this cancer type were expected.

When researchers stratified women based on BRCA mutation, the risk for serous and serous-like endometrial carcinoma was significantly greater among BRCA1 carriers than the 0.18 expected incidence (observed–expected ratio = 22.2; 95% CI, 6.1-56.9). The observed–expected ratio for BRCA2 carriers was not statistically significant (0.16 expected; observed–expected ratio = 6.4; 95% CI, 0.2-35.5).

“A cohort this size, followed for a little over 5 years, should experience less than one serous or serous-like diagnosis,” Kauff said. “Although five is a small number, for an event that should really not be occurring at all, it is a highly statistically significant result.”

Researchers also examined samples of four of the five tumors from BRCA1–positive women to evaluate the expression of the BRCA1 protein within the tumor. Three of these tumors were serous or serous-like and one was leiomyosarcoma.

“Interestingly, all three of the serous tumors showed loss of the normal BRCA1 protein expression,” Kauff said. “However, there were internal controls that showed that that nontumor cells retained [BRCA1 protein], suggesting that the loss of BRCA1 protein function may be important in tumor genesis.”

BRCA1 function also was lost in the leiomyosarcoma sample, Kauff said.

“Additionally, in two of the three serous tumor samples, the working copy of BRCA1 was lost in the tumor, further suggesting that the tumor cells had no functioning BRCA1 expression, which associates the loss of BRCA1 function with tumor development,” he said.

Researchers acknowledge that a history of breast cancer or exposure to tamoxifen may have confounded results. Research has suggested that women with serous cancer are more likely to have a personal or family history of breast cancer than women without cancer or women with endometrioid carcinoma.

These data add to existing literature that links BRCA mutations with risk — even though it may be small — for endometrial cancer, Charles A. Leath, MD, MSPH, associate professor in the division of gynecologic oncology at University of Alabama Birmingham School of Medicine, and colleagues wrote in an accompanying editorial.

“Perhaps it is time to consider that the line for risk-reducing gynecologic surgery in patients with BRCA mutations not stop at the ovaries and fallopian tubes,” Leath and colleagues wrote. “We would recommend that all women with a BRCA1/2 mutation undergoing risk-reducing salpingo-oophorectomy should be made aware of the potential risks and benefits of a concurrent hysterectomy and the limitations in the available studies on this issue prior to making an individualized decision.” by Nick Andrews

For more information:

Noah D. Kauff, MD, can be reached at noah.kauff@duke.edu.

Disclos ure: Kauff reports no relevant financial disclosures. One researcher reports consultant roles with and royalties from Cambridge University Press, Merck and Springer. Leath and colleagues report no financial disclosures pertaining to the published editorial. Please see the full article for a list of all their financial disclosures.

Women who harbored a BRCA1 mutation had increased risk for serous and serous-like endometrial carcinoma following risk-reducing salpingo-oophorectomy, according to the results of a prospective cohort study.

Although risk-reducing salpingo-oophorectomy is standard for women who harbor BRCA mutations, the role of concomitant hysterectomy is controversial because the risk for uterine cancer in this cohort had been unclear. Some studies had suggested that the risk for uterine corpus cancer in these women was linked to tamoxifen citrate use.

Noah Kauff, MD

Noah D. Kauff

“Serous uterine cancer generally only accounts for about 10% of all uterine cancer diagnosed compared with the much more common endometrioid cancer, which accounts for 80% to 85% of uterine cancers,” Noah D. Kauff, MD, director of clinical cancer genetics program at Duke Cancer Institute of Duke Medicine, told HemOnc Today. “However, serous cancer is associated with a much worse outcome — it accounts for approximately 40% of all uterine cancer-related mortality.”

Researchers evaluated data from 1,083 BRCA–positive women (median age at surgery, 45.6 years; interquartile range [IQR], 40.8-52.2; 94.6% white) who underwent risk-reducing salpingo- oophorectomy without a prior or concomitant hysterectomy at one of nine academic medical centers in the United States and United Kingdom. The cohort included 627 women with a BRCA1 mutation, 453 with a BRCA2 mutation and three with both mutations.

Overall, 67.1% of the women had a prior history of breast cancer, 25.2% had previous tamoxifen exposure and 14.3% had unknown tamoxifen history.

Researchers evaluated the observed incidence of uterine corpus cancer among women in this cohort compared with SEER database–expected incidence.

Follow-up continued for a median of 5.1 years (IQR, 3-8.4) after ascertainment, BRCA testing or salpingo-oophorectomy.

Eight women developed uterine cancers in the population, which was not statistically significantly different from the 4.3 cases that were expected using SEER data. The observed–expected ratio was 1.9 (95% CI, 0.8-3.7).

In a secondary analysis that evaluated cancer incidence based on cancer subtype, researchers found no significant increased risk for endometrioid endometrial carcinoma or sarcoma in BRCA–positive women.

However, five of these women were diagnosed with serous or serous-like endometrial carcinomas 7.2 to 12.9 years after risk-reducing salpingo-oophorectomy, whereas 0.34 cases of this cancer type were expected.

When researchers stratified women based on BRCA mutation, the risk for serous and serous-like endometrial carcinoma was significantly greater among BRCA1 carriers than the 0.18 expected incidence (observed–expected ratio = 22.2; 95% CI, 6.1-56.9). The observed–expected ratio for BRCA2 carriers was not statistically significant (0.16 expected; observed–expected ratio = 6.4; 95% CI, 0.2-35.5).

“A cohort this size, followed for a little over 5 years, should experience less than one serous or serous-like diagnosis,” Kauff said. “Although five is a small number, for an event that should really not be occurring at all, it is a highly statistically significant result.”

Researchers also examined samples of four of the five tumors from BRCA1–positive women to evaluate the expression of the BRCA1 protein within the tumor. Three of these tumors were serous or serous-like and one was leiomyosarcoma.

“Interestingly, all three of the serous tumors showed loss of the normal BRCA1 protein expression,” Kauff said. “However, there were internal controls that showed that that nontumor cells retained [BRCA1 protein], suggesting that the loss of BRCA1 protein function may be important in tumor genesis.”

BRCA1 function also was lost in the leiomyosarcoma sample, Kauff said.

“Additionally, in two of the three serous tumor samples, the working copy of BRCA1 was lost in the tumor, further suggesting that the tumor cells had no functioning BRCA1 expression, which associates the loss of BRCA1 function with tumor development,” he said.

Researchers acknowledge that a history of breast cancer or exposure to tamoxifen may have confounded results. Research has suggested that women with serous cancer are more likely to have a personal or family history of breast cancer than women without cancer or women with endometrioid carcinoma.

These data add to existing literature that links BRCA mutations with risk — even though it may be small — for endometrial cancer, Charles A. Leath, MD, MSPH, associate professor in the division of gynecologic oncology at University of Alabama Birmingham School of Medicine, and colleagues wrote in an accompanying editorial.

“Perhaps it is time to consider that the line for risk-reducing gynecologic surgery in patients with BRCA mutations not stop at the ovaries and fallopian tubes,” Leath and colleagues wrote. “We would recommend that all women with a BRCA1/2 mutation undergoing risk-reducing salpingo-oophorectomy should be made aware of the potential risks and benefits of a concurrent hysterectomy and the limitations in the available studies on this issue prior to making an individualized decision.” by Nick Andrews

For more information:

Noah D. Kauff, MD, can be reached at noah.kauff@duke.edu.

Disclos ure: Kauff reports no relevant financial disclosures. One researcher reports consultant roles with and royalties from Cambridge University Press, Merck and Springer. Leath and colleagues report no financial disclosures pertaining to the published editorial. Please see the full article for a list of all their financial disclosures.