Approximately one in 150 Nigerian women harbored inherited mutations in BRCA1, BRCA2, PALB2 or TP53, and one of eight invasive breast cancers in this population were associated with these mutations, according to findings from the Nigerian Breast Cancer Study.
“Based on state-of-the-art genomic technologies, two things were clear,” Mary-Claire King, PhD, American Cancer Society professor of medicine and genome sciences at University of Washington School of Medicine, said in a press release. “Risks to Nigerian women who carry mutations in breast cancer genes are higher than risks to women in the U.S. with mutations in the same genes. And inherited breast cancer plays a bigger role in the total occurrence of breast cancer in Nigeria compared to the U.S.”
Nigerian women tend to be diagnosed with breast cancer at more advanced stages, and triple-negative breast cancer occurs more frequently in this population than among patients of European descent.
Nigerian patients with breast cancer have undergone screening for a few specific alleles of BRCA1 and BRCA2; however, no African population has been evaluated for all known and candidate breast cancer genes.
Thus, King and colleagues sought to determine the proportion of inherited breast cancers among Nigerian women, the most common pathogenic mutations in this population, and the breast cancer risks associated with mutations in these genes.
The analysis included 1,136 women (mean age at diagnosis, 47.5 ± 11.5 years) with invasive breast cancer from Ibadan, Nigeria, as well as 997 women without cancer (mean age at interview, 47 ± 12.4 years) from the same communities.
Researchers used BROCA panel sequencing to identify loss-of-function mutations in known and candidate breast cancer genes, and they used immunohistochemistry to evaluate tumors among a subset of patients for ER, PR and HER-2 status.
Six percent of patients and 2% of controls reported a family history of breast cancer; however, a majority of participants had no information on family medical history available.
Among 577 patients with available data, 86.1% showed a diagnosis of breast cancer at stage III (n = 241) or stage IV (n = 256). Among 290 patients with available data on tumor hormone receptor status and HER-2, 45.9% had triple-negative breast cancer.
Among all cases, 14.7% carried a loss-of-function mutation in the following breast cancer genes: BRCA1 (7%), BRCA2 (4.1%), PALB2 (1%), TP53 (0.4%) or any of 10 other genes (2.1%).
Researchers noted the breast cancer risk associated with BRCA1 (OR = 23.4; 95% CI, 7.4-73.9) and BRCA2 (OR = 10.3; 95% CI, 3.7-28.5) mutations was “extremely high.”
PALB2 (11 cases, zero controls; P = .002) and TP53 (five cases, zero controls; P = .036) also were associated with significantly greater breast cancer risk.
Women with BRCA1 mutation (42.63 years vs. 47.9 years; P < .001) and TP53 mutation (32.8 years vs. 47.6 years; P = .023) tended to be younger than other patients.
BRCA1 mutations appeared more common among triple-negative breast cancers than those known to be positive for ER, PR or HER-2 (8.3% vs. 2.5%; OR = 3.45; 95% CI, 1.07-11.1).
Little data on histopathologic features of tumors was a major limitation.
“Lack of this information constrained efforts to characterize the high prevalence of triple-negative breast cancer in this population,” the researchers wrote. “These issues reflect resource-limited settings generally and support the importance of developing independent, inexpensive approaches to the identification of high-risk women.”
Researchers have developed a risk prediction model for breast cancer among Nigerian and other sub-Saharan African women to identify those at high risk for breast cancer, ensure proper surveillance and suggest risk reduction strategies, according to the release.
Addressing disparities in breast cancer mortality among women of African ancestry should be a priority, according to the researchers.
“We suggest that genomic sequencing to identify women at extremely high risk of breast cancer could be a highly innovative approach to tailored risk management and life-saving interventions,” they wrote. “An urgent need exists to address widening global disparities in breast cancer mortality that disproportionately affect women of African ancestry both in Africa and throughout the diaspora.
“It may seem paradoxical to apply the most recent technology in severely resource-limited settings, but the solution fits the problem well,” they added. “More than 20 years after the first extended family of African ancestry with a BRCA1 mutation was published, the critical genes and classes of mutations responsible for the high risk of inherited breast cancer among Nigerian women are now clear. On the basis of our results, the critical genes for inherited breast cancer in this population are BRCA1, BRCA2, PALB2 and TP53, and the critical mutations in these genes are those that lead to loss of function. Nigeria now has data to prioritize the integration of genetic testing into its cancer control plan.”
The findings raise questions about the practical implications of adopting a high-risk approach to reduce breast cancer incidence and mortality in Nigeria, Ophira Ginsburg, MD, MSc, director of the high-risk cancer program at Perlmutter Cancer Center of NYU Langone Health, and Paul Brennan, PhD, from the International Agency for Research on Cancer in Lyon, France, wrote in a related editorial.
Because 11% to 12% of the estimated 40,983 women in Nigeria aged younger than 65 years who will be diagnosed with breast cancer in 2030 will harbor a high-risk mutation, approximately 5,000 women with breast cancer each year could benefit directly from tailored risk-reducing strategies presented by Zheng and colleagues.
“The infrastructure and resources required for such an effort are unprecedented and clearly beyond the scope of most countries,” Ginsburg and Brennan wrote.
“Furthermore, women with pathogenic variants would require intensive follow-up and intervention strategies to reduce their risk of developing breast, ovarian/fallopian tube, and potentially other cancers depending on the gene involved,” they wrote, adding that the bigger problem of high breast cancer mortality among the vast majority of women without a pathogenic variant — but who make up approximately 85% of the breast cancer burden — would not be addressed.
“We commend Zheng [and colleagues] for stimulating this discussion,” Ginsburg and Brennan wrote. “In a research context, the program they have developed is an important step that can potentially leverage the necessary infrastructure, public and provider education, and other systems elements necessary to improve outcomes from breast and other cancers.” – by Melinda Stevens
Disclosures: King reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Ginsburg and Brennan report no relevant financial disclosures.