IN-DEPTH REVIEW OF RESEARCH

Study background

Understanding the frequency of inherited mutations in genes that predispose people to cancer is helpful for guiding genetic screening. People with an inherited mutation have different surveillance and preventive options to consider with their doctors. For those who develop cancer, an inherited mutation may alter treatment choices and the risk of recurrence.

The Cancer Risk Estimates Related to Susceptibility (CARRIERS) study looked at a group of 32,247 women with breast cancer to determine the frequency of harmful (pathogenic or likely pathogenic) mutations compared to 32,544 women without breast cancer. The women were enrolled regardless of whether they had a family history of cancer or not. The researchers found that 5.03 percent of women with breast cancer had an inherited mutation that was associated with breast cancer risk while only 1.63 percent of women without breast cancer had one of these mutations. This is a comprehensive and definitive study.

Inherited mutations in the BRCA1 and BRCA2 genes were linked to a high chance of breast cancer—more than seven times that of people without inherited mutations in these genes. Mutations in PALB2 were linked to four times the risk of breast cancer compared to women without PALB2 mutations. Mutations in the BARD1, RAD51C and RAD51D genes were linked to a higher risk of ER-negative and triple-negative breast cancer, while mutations in the ATM, CHD1 and CHEK2 genes were linked to a higher risk of ER-positive breast cancer.

Black women in the United States are more likely to be diagnosed with breast cancer at an early age (before 50) or with estrogen receptor-negative (ER-negative) or triple-negative breast cancer (TNBC) than non-Hispanic white women. It was not known whether these differences were due to varying rates of inherited mutations or to other factors.

Research shows that Black women are less likely to have genetic testing, are less likely to be referred for genetic testing and have less access to care among other barriers such as different rates of insurance access, longer intervals between screening and lower rates of follow up

A remaining question in this study was whether the frequency of inherited mutations varies between different racial groups.

Because the CARRIERS study enrolled a large number of participants, including a substantial number of Black women, it was possible to ask this question and have statistical confidence in the result. Researchers looked at the self-reported race of the women with breast cancer who participated in the study and then determined the frequency of harmful mutations in Black and white women.

Researchers of this study wanted to know

Researchers wanted to know whether there was a difference in the frequency of inherited mutations linked to increased breast cancer risk among Black and white women.

Populations looked at in this study

This study evaluated information about 3,946 Black women and 25,287 non-Hispanic white women with breast cancer from the CARRIERS study. These women were enrolled between June 1993 and June 2020 regardless of their family history or age at breast cancer diagnosis, and self-reported their race and ethnicity. Among participants, the average age of Black women was 56 and of white women was 62. Black women and white women who were included in this study were not Hispanic.

All of the women participated in one of 12 studies that were included in the CARRIERS study [the Black Women's Health Study (HBWS), the Cancer Prevention Study II (CPSII), the California Teachers Study (CTS), the Multiethnic Cohort Study (MEC), the Nurses' Health Study (NHS), the Nurses' Health Study II (NHSII), the Women's Health Initiative (WHI), the Cancer Prevention Study (CPS3), Mayo Mammography Health Study (MMHS), the Mayo Clinic Breast Cancer Study (MCBCS), the Women's Circle of Health Study (WCHS) and the Wisconsin Women's Health Study (WWHS)].

Study design

Researchers looked at the DNA from each participant for the presence of inherited mutations in any of 37 known or potential cancer risk genes. Twelve genes that are linked to elevated breast cancer risk were evaluated, including ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53.

Researchers first compared the frequency of all Black women with an inherited mutation in a breast cancer gene to the frequency of all white women with an inherited mutation. They then looked for any difference in frequency of inherited mutations in the two groups based on age or estrogen-receptor status of the breast cancer.

Study findings

• Black women and white women have a similar chance of having an inherited mutation in a gene that increases breast cancer risk.
  • 223 of 3,946 Black women (5.65%) had an inherited mutation in a high-risk breast cancer gene. 
  • 1,279 of 25,287 white women (5.06%) had an inherited mutation in a high-risk breast cancer gene.
  • These frequencies are statistically similar.
     
• The chance of having an inherited mutation in a particular gene that increases breast cancer risk differed between Black women and white women. Black women were less likely to have a CHEK2 mutation and more likely to have a BRCA2 or PALB2 mutation than non-Hispanic white women.
  • 0.35% of Black women had a mutation in CHEK2.
  • 1.29% of white women had a mutation in CHEK2.
     
  • 1.8% of Black women had a mutation in BRCA2.
  • 1.24% of white women had a mutation in BRCA2.
     
  • 1.1% of Black women had a mutation in PALB2.
  • 0.4% of white women had a mutation in PALB2.
     
  • Black and white women had a similar chance of having a mutation in ATM, BRCA1, BARD, CDH1, NBN, NF1, RAD51C, RAD51D or TP53.
     
• There was no difference in the frequency of inherited mutations between Black and white women based on estrogen-receptor status.
  • Among women with ER-positive breast cancer:
    • 4.38% of Black women had an inherited mutation.
    • 4.38% of white women had an inherited mutation.
  • Among women with ER-negative breast cancer:
    • 9.28% of Black women had an inherited mutation.
    • 8.08% of white women had an inherited mutation.
       
• There was no difference in the frequency of inherited mutations between Black and non-Hispanic white women who were diagnosed before age 50.
  • 8.83% of Black women had an inherited mutation.
  • 10.04% of white women had an inherited mutation.
     

This study indicates that there is no difference in the rate of inherited mutations among Black and white women. While overall mutation rates were the same, differences in the rate of mutations of a few individual genes were seen; BRCA2 and PALB2 mutations were seen more often in Black women and CHEK2 mutations were seen less often.

Strengths and Limitations

Strengths

• This was a large study involving 29,233 women (3,946 non-Hispanic Black women and 25,287 non-Hispanic white women). This enables researchers to be confident in their conclusions.
• Participants were not selected based on their family history of cancer or age at diagnosis. In other words, they may or may not have had a family history of cancer and they could have been diagnosed at any age. This is a good approach for reducing selection bias. (Selection bias occurs when groups differ due to factors other than the ones being studied.)
• A careful statistical analysis was done to determine whether any differences existed between the groups.

Limitations

• Information on family history and receptor status of breast cancers was missing for some participants.
• The number of women with mutations in some genes (e.g., RAD51C and RAD51D) was small, limiting the conclusions that could be made.
• This study focused only on Black women and white women. No information about Hispanic, Indigenous, Pacific Islander or Asian American women was provided.
• This study looked only at women with breast cancer. It did not look at the frequency of mutations among women without breast cancer in the original CARRIERS study. The comparison between Black women with and without breast cancer and white women with and without breast cancer may be informative.

Context

This study further analyzes the findings of the CARRIERS study by looking at inherited mutations among Black women and white women. It builds on the prior observation that about 5 percent of women in the U.S. with breast cancer have an inherited mutation in a cancer gene. Black women are diagnosed at younger ages, and more often with ER-negative breast cancer. It is known that referral for genetic testing and access to care is reduced among Black women compared to white women. The contribution of genetic differences among Black women to this disparity was not known. This study indicates that race is not helpful for determining who should have genetic testing. Instead, other factors like family history, age at diagnosis (both well-described predictors of inherited mutations) should guide genetic testing referral.

Conclusions

No difference in the rate of inherited mutations was seen among Black and white women in this study. Black and white women did have a different frequency of mutations in a few individual genes: BRCA2 and PALB2 mutations occurred more often in Black women and CHEK2 mutations occurred less often.

The study researchers concluded that race should not be an independent consideration for genetic testing. Furthermore, they suggested that systemic racism rather than genetic differences may account for racial disparities in breast cancer diagnoses in Black women.

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posted 8/13/21