Molecular differences may help explain why Black patients with breast cancer have a higher risk of death than their White counterparts, according to research published in Therapeutic Advances in Medical Oncology.
Prior studies have shown a link between DNA damage repair (DDR) dysregulation and endocrine therapy (ET) resistance in patients with estrogen receptor (ER)-positive breast cancer.
With the current study, researchers set out to determine if a higher frequency of DDR gene dysregulation leading to ET resistance contributes to disparities in outcomes between Black and White patients with ER+ breast cancer.
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The researchers assessed RNA levels of 104 DDR genes from 6 principal DDR pathways in 3 different datasets. The analysis revealed 67 DDR genes that were upregulated or downregulated in Black patients’ tumors, compared with White patients’ tumors.
Single strand break repair (SSBR) genes, particularly genes from the NER and BER pathways, were enriched in the Black patients. Similarly, genes from double strand break repair (DSBR) pathways were predominantly upregulated in the Black patients. The DSBR upregulation was not limited to tumor samples; it was also found in samples of normal breast tissue.
Overall, 16% of Black patients’ tumors had mutations in at least 1 DDR gene, compared with 3% of White patients’ tumors (P <.001). Mutations in any DDR gene were associated with significantly worse disease-free survival in Black patients (P =.02).
The researchers also identified 8 DDR genes — XRCC1, PARP1, XRCC4, NEIL3, MNAT1, FANCE, NBN, and BRCA1 — that were differentially regulated in tumors from Black patients.
To assess whether differential regulation of these genes is associated with cell-cycle dysregulation, the researchers analyzed RNA levels of cyclin-dependent kinases (CDKs) in tumors with differential regulation of the 8 genes.
The results showed significant upregulation of CDK1, CDK4, and CDK6. This suggests that Black patients may benefit from earlier treatment with CDK inhibitors, according to the researchers.
The team noted that, across the 3 datasets analyzed, 45% to 60% of ER+ tumors from Black patients had detectable dysregulation of at least 1 of the 8 DDR genes, compared with 25% to 30% of tumors from White patients.
The researchers also noted consistent enrichment for coincident upregulation of 1 of 2 homologous recombination (HR) genes — NBN or BRCA1 — with upregulation or downregulation of SSBR genes in the Black patients’ tumors. The HR/SSBR tumor subset was significantly associated with worse disease-specific survival, relapse-free survival, and overall survival.
“Overall, this study presents a roadmap for developing more effectively personalized biomarkers to predict and perhaps prevent poor outcomes for underserved patient populations,” the researchers concluded.
Disclosures: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Reference
Mazumder A, Jimenez A, Ellsworth RE, et al. The DNA damage repair landscape in Black women with breast cancer. Ther Adv Med Oncol. Published online February 8, 2022. doi:10.1177/17588359221075458
