African American women are more likely to be diagnosed with triple negative breast cancer (TNBC)

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Two gene variants found in African American women may explain why they are more likely to be diagnosed with triple negative breast cancer (TNBC) than white women of European ancestry, according to Weill Cornell Medicine and NewYork-Presbyterian investigators.

The study findings may have implications for developing better risk assessment tools for TNBC in African American women and for understanding why they have poorer TNBC outcomes.

In a study, published April 29 in Scientific Reports, the investigators found that a version of the ANKLE1 gene that can be protective against TNBC is less likely to be found in African American women than white women of European ancestry. In addition, African American women with a mutation in the Duffy gene, which plays a role in inflammation, have a higher risk of TNBC.

“While more white women are diagnosed with breast cancer, African American women are more likely to die from the disease,” said Dr. Melissa B. Davis, who was recruited to Weill Cornell Medicine as an associate professor of cell and developmental biology research in surgery, and is scientific director of the International Center for the Study of Breast Cancer Subtypes (ICSBCS). Moreover, African American women have twice the risk of developing TNBC than white women of European ancestry.

Historically, genetic studies of breast cancer have not included enough information about people of African descent, Dr. Davis said. This lack of data contributes to problems with understanding some of the less common versions of genes, or genetic mutations that are found in populations that are not of European descent.

To help address this problem, Dr. Davis and her research team analyzed genetic information from the ICSBCS cohort. The scientists collected DNA from saliva samples in 120 breast cancer patients from Ghana and Ethiopia. Additional samples were collected from 193 African American and 184 European American women with breast cancer. Dr. Davis’s team also collected data from 271 healthy controls in the United States and Ghana. The team then assessed the effect in these patients of different gene versions, known as alleles, that had been previously associated with breast cancer risk.

“We have this African-enriched cohort where we’ve assessed genetic ancestry, and this includes patients and case controls of African ancestry, which is unlike any other study,” said Dr. Davis, acknowledging the work of her research partners in Ghana and Ethiopia over the last 17 years, as part of the ICSBCS. The center was founded by co-author Dr. Lisa Newman, chief of the Section of Breast Surgery at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, who was recruited to Weill Cornell Medicine as a professor of surgery.

The researchers found two risk alleles previously defined by the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium were replicated in the ICSBCS study group of patients. Dr. Davis’s team validated that an ANKLE1 variant is protective against TNBC but that African American women are more likely to have a version that may be oncogenic, or cancer causing.

ANKLE1 has not been thoroughly studied in cancer yet. “Part of the reason would be that it’s under the radar,” Dr. Davis said. “It’s a risk allele that was only identified when looking at African-Americans and Africans.”

ANKLE1 appears to have DNA repair properties like the BRCA gene. BRCA has enzymatic activity that helps to correct mistakes in DNA leading to cancer. Mutations in the gene increase breast cancer risk and physicians often recommend screening for mutations in BRCA in the Ashkenazi Jewish population in which it appears at higher rates.

The researchers’ current findings on ANKLE1 should inform breast cancer risk models in African American women, Dr. Davis said.

The researchers also verified that a mutation in the Duffy gene, known for its role in inflammation and tumor biology, was associated with an increased risk of TNBC in African American women. The mutation causes the gene to lose function and is what researchers call a null allele.

“I would like women to be more informed about their Duffy-null status,” Dr. Davis. “If you have that status, you have a higher likelihood of developing triple negative breast cancer, if you get breast cancer,” she said.

A better genetic understanding of breast cancer in African American women can help to inform treatment. “Genetic signature tests can predict whether or not patients have a high risk of recurrence or high risk of having a refractory tumor,” Dr. Davis said. “Doctors can then determine whether the current standard of care is going to be effective or if they need to adjust the treatment plan for better outcomes.”


Breast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of cancer death among women in the United States [American Cancer Society. Cancer Facts and Figures 2017]. Approximately 268,600 women will be diagnosed with BC, and nearly 41,760 will die with this malignancy in 2019 [American Cancer Society. Cancer Facts and Figures 2019].

Breast cancer is a heterogeneous disease consisting of distinct biological subtypes with a range of clinical, pathological, molecular, and genetic features and differing therapeutic responses and outcomes including the Black-White disparities in outcome (1). These differences have been demonstrated by molecular classification based on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).

Using this approach, at least four intrinsic subtypes of breast cancer have been identified. These include luminal A [ER+ and/or PR+, HER2- and low Ki67 (<14%)], luminal B [ER+ and/or PR+, HER2-, and high Ki67 (>14%) or ER+ and/or PR+, HER2+], HER2 [ER-, PR-, HER2 amplification], triple negative [ER-, PR-, HER2-, basal markers, such as cytokeratin (CK) 5/6, CK 14, CK 17, and epidermal growth factor receptor].

While the terms basal-like subtype (characterized as ER−/PR−/HER2−, basal-markers+) and triple negative breast cancer (TNBC) have been used interchangeably in some studies, evidence has shown that although most TNBCs are basal-like, up to 20–30% of them are not; additionally, not all basal-like breast cancers are TNBCs (2–4).

A recent population study in the United States has described four molecular breast cancer subtypes as mentioned above, based on the expression of three tumor markers, namely estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) (5, 6). Luminal A subtype constituted the majority (72.6%), TNBC 13%, luminal B 5% and HER2-enriched constituted 10% of all breast cancers diagnosed in 2011 (7). The presence of these four breast cancer subtypes varied notably with age and race. But we do not know whether it also varied with healthcare variables such as access to healthcare resources.

Prominent racial differences have been noted in the incidence of and mortality from breast cancer between African American (AA) and Non-Hispanic White (NHW) women. The 2017 CDC and NCI review of trends in population-based BC incidence and mortality rates in 1999–2014 by age and race in 2014 indicates that although the incidence rates are comparable for AA and NHW women for all ages and stages of diagnosis the mortality rates are very different (8).

AA patients have an ~2-fold higher mortality incidence compared with the NHW women, resulting in a disproportionately higher (>65%) risk of death (United States Cancer Statistics: 1999–2014 Incidence and Mortality Web-based Report at: http://www.cdc.gov/USCS). In addition, a greater proportion of five-year breast cancer-specific survival rates are significantly lower in AAs (78.9%) compared with NHWs (88.6%) (9). The mortality disparity is especially noteworthy in light of the similar incidence rates of breast cancer among AA and NHW women.

The reasons underlying the health disparities in breast cancer outcome are multifactorial and complex. Many biological and non-biological factors are perceived to contribute to these disparities. Significant molecular differences have been identified in the biological properties between AA women and NH White women. The present review is undertaken to provide a comprehensive view of how these factors contribute to marked differences in age of onset, stage of presentation and survival between AA and NH White women and eventually the development and outcome of the TNBC disparity.

An understanding of these factors and how do they contribute to disparities is critical in defining an in depth understanding of the marked differences in development, presentation, and outcome of breast cancer between Caucasian and AA women. To address inequities, we begin the article with a description of the pattern of TNBC disparities among AA and NH White women. Because obesity is a well-documented factor exerting a significant effect on the development of breast cancer, in the second section we addressed the potential link between obesity and TNBC in AA women.

Several studies have suggested that tumor biology may contribute to the outcome disparities with TNBC in AA women. Therefore, in the third section of the article, we address the biological mechanisms of TNBC risk in AA women. There is increasing evidence that lower socioeconomic status disproportionately promotes aggressive biology in AA patients with TNBC. Thus, the fourth section encompasses the social determinants of TNBC risk in AA women.

The article will provide comprehensive view of the relationship between biological and non-biological factors to facilitate our understanding of disparities in the risk of TNBC, and to guide future efforts to eliminate such disparities.

reference link : https://www.frontiersin.org/articles/10.3389/fpubh.2020.576964/full


More information: Rachel Martini et al, Investigation of triple-negative breast cancer risk alleles in an International African-enriched cohort, Scientific Reports (2021). DOI: 10.1038/s41598-021-88613-w

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