Study: Mutations in BRCA1 or BRCA2 may increase risk for endometrial cancer

IN-DEPTH REVIEW OF RESEARCH

Study background

BRCA1 and BRCA2 mutations are known to put women at greater risk for breast, ovarian and pancreatic cancer. Scientists have speculated that these gene mutations may put women at greater risk for other cancers as well, including endometrial cancer.

Research linking BRCA mutations to endometrial cancer has been inconclusive. Some studies have suggested that BRCA mutations increase the risk for an aggressive but rare form of endometrial cancer. Other studies have suggested that BRCA mutations do not increase endometrial cancer risk but that women with BRCA mutations who previously took tamoxifen to prevent or treat breast cancer may have increased endometrial cancer risk. More studies are needed to determine the level of endometrial cancer risk in people with a BRCA1 or BRCA2 mutation.

Researchers of this study wanted to know

The researchers wanted to know if people with inherited BRCA1 or BRCA2 mutations are at greater risk for endometrial cancer.

Populations looked at in this study

The study looked at 5,980 women with inherited BRCA mutations:

• 3,788 had a BRCA1 mutation
• 2,151 had a BRCA2 mutation
• 41 had both a BRCA1 and BRCA2 mutation

The study compared women with BRCA mutations to 8,451 women from BRCA-positive families who had tested negative for their family's BRCA gene mutation, as well as the general population of Dutch women.

Participants were identified from the Dutch cohort (HEBON) of the Hereditary Breast and Ovarian cancer study. Women without a BRCA gene mutation were required to have a family member with a known BRCA mutation. All participants were at least age 25 (the age at which women are considered at risk for endometrial cancer) when they enrolled in the study. Women diagnosed with endometrial cancer before the start of the study or before the age of 25 were excluded.

Study design

The frequency of endometrial cancer in women with a BRCA mutation was compared to two populations:

• The general population of Dutch women (derived from data from the Netherland Cancer Registry).
• Study participants without BRCA mutations who were from families with BRCA gene mutations.

Women with a BRCA mutation were followed from January 1, 1989, or the date they turned 25, to January 1, 2016. Women without BRCA mutations were followed from January 1, 1989, to January 1, 2012. Follow-ups were concluded due to death or an endometrial cancer diagnosis.

Tissue samples from women with an endometrial cancer diagnosis were evaluated by a pathologist to determine the subtype of cancer. Researchers then performed a statistical analysis to compare the rates of endometrial cancer in study groups and the rates of each subtype of endometrial cancer.

Study findings

Study findings showed that the estimated lifetime risk (by age 75) for developing endometrial cancer in women with an inherited BRCA mutation was low. A total of 3.4 percent women with BRCA1 mutations were likely to develop endometrial cancer in their lifetime compared to women with BRCA2 mutations, who had a 2 percent chance of developing endometrial cancer in their lifetime.

Comparison analyses showed that:

• Compared with the women in the general Dutch population, women with a BRCA1 mutation were three times more likely to develop any form of endometrial cancer.
  • Endometrial cancer in women with a BRCA1 mutation was 12 times more likely to be a subtype called serous-like (an aggressive form of cancer with poor prognosis) compared to women in the general population.
• Compared with women in the general population, women with a BRCA2 mutation were almost twice as likely to develop endometrial cancer. However, this result was barely significant and does not differ much from the estimated risk for women in the general Dutch population (1.0%-1.4%).
• The overall risk for endometrial cancer was greatest in women with a BRCA mutation who were between the ages 25 to 40 compared with the general population of women.
• The risk for a serous-like endometrial cancer was most prevalent in women from ages 60 to 80.
• Compared with women without a BRCA mutation who came from families with a known BRCA mutation, women with a BRCA1 mutation were approximately three times more likely to develop endometrial cancer in their lifetime.
  • Endometrial cancer in women with BRCA1 mutation was 8 times more likely to be diagnosed as serous-like cancer and 11 times more likely to be diagnosed as p53-abnormal cancer (another aggressive cancer subtype), compared to women without a BRCA mutation.

• Women with a BRCA2 mutation did not have a greater risk for any form of endometrial cancer compared to women without a BRCA2 mutation whose family had a known BRCA2 mutation.

Tamoxifen and endometrial cancer risk

Tamoxifen and aromatase inhibitors are a type of hormone therapy (HT) used to treat some breast cancers. However, using HT is believed to increase the risk of endometrial cancer. To test this belief, researchers looked at endometrial cancer among women with an inherited BRCA mutation who had any type of HT compared to those who did not have HT.

• Women with an inherited BRCA1 or BRCA2 mutation had a similar risk of endometrial cancer whether or not they had hormone therapy.

Strengths and limitations

Strengths

• The study followed participants over a long period (average follow-up was 22.5 years), allowing researchers to evaluate long-term trends.
• This study compares people with BRCA mutations to family members without BRCA mutations. This is a stronger comparison than to the general population in which the portion of people with a BRCA mutation is unknown. The families of people with BRCA mutations are expected to share many genetic and environmental features (more than with the general population).
• Researchers were able to account for the possible role of breast cancer treatment on endometrial cancer risk.

Limitations

• While the study included over 5,000 participants, only 58 endometrial cancers were observed.
• The study only looked at mutations in BRCA1 and BRCA2. It did not include other cancer risk genes (e.g., ATM, BRIP1, PALB2, RAD51C, RAD51D).
• The researchers did not have access to participants’ risk factors for endometrial cancer or additional health information, making it impossible to account for these factors in the statistical analysis.
• The study only included women in the Netherlands, limiting its generalizability to women of other nationalities or racial backgrounds.

Context

Endometrial cancer is the most common gynecologic malignancy worldwide. Although BRCA1 and BRCA2 mutations have been associated with increased risk for breast and ovarian cancer, previous studies were unable to determine whether these mutations also increase endometrial cancer risk. Like this study, some (but not all) studies have shown an increased risk for endometrial cancer, mainly in BRCA1 carriers, with the highest risk observed for serous-like endometrial cancer.

Conclusions

Similar to some studies, this study showed that an inherited BRCA1 mutation may be a risk factor for endometrial cancer. Although the lifetime risk for endometrial cancer in this study was low, women with a BRCA mutation had a two- or three-fold higher rate of endometrial cancer compared with women without a BRCA mutation. Women with a BRCA1 mutation had a 3.4 percent chance of developing endometrial cancer by age 75 compared to 2.0 percent (in the general Dutch population). Among women with a BRCA2 mutation, the risk of endometrial cancer was similar from that of women without a BRCA2 mutation. Endometrial cancer in people with a BRCA1 mutation is more likely to be an aggressive type that is linked to poorer outcomes.

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posted 11/30/21