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DNA damage repair may be key to higher breast cancer mortality in Black women

Therapeutic Advances in Medical Oncology
Reuters Health - 14/02/2022 - Black women's cells respond differently than whites' to damage from breast cancer and its therapy, and these molecular differences could impact mortality, researchers say.

"Our results are immediately actionable for clinicians, because they suggest that Black women may not even need different therapies, just different timing for the drugs we already have," Dr. Svasti Haricharan of Sanford Burnham Prebys Medical Discovery Institute in La Jolla told Reuters Health by email.

"More broadly," she said, "the findings show us that our lived experiences can absolutely change the molecular biology of our cells, and that those changes need to be considered when we're tailoring precision medicine for different patients."

Recent studies identify DNA damage repair (DDR) genes as drivers of endocrine therapy resistance that contribute to poor survival among ER+ breast cancer patients, Dr. Haricharan and colleagues note in Therapeutic Advances in Medical Oncology.

Further, they suggest, "DDR pathways make an attractive starting point for understanding how molecular factors that translate environmental stressors into cellular phenotypes may differ by race/ethnicity."

In the current study, the team analyzed mutations and up/downregulation of 104 DDR genes in breast tumor and normal samples from Black and white patients. They found that Black patients' tumors upregulate or downregulate RNA levels of a wide array of single strand break repair (SSBR) genes relative to whites, and uniformly upregulate double strand break repair (DSBR) genes. This upregulation was also seen in normal breast tissue samples from Black women.

Specifically, eight candidate DDR genes were regulated differently in tumors from Black women compared to whites, and were associated with poor survival. Three were downregulated (XRCC1, PARP1, XRCC4), and the others were upregulated (NEIL3, MNAT1, FANCE, NBN, BRCA1).

Overall, 45%-60% of ER+ tumors from Black women had detectable dysregulation of at least one of these eight DDR genes, compared to 25-30% of tumors from white women - a significant difference.

Further investigation showed that a unique DDR signature comprised of simultaneous upregulation of homologous recombination gene expression and downregulation of SSBR genes was enriched in Black patients. This signature associated with cell cycle dysregulation, a hallmark of endocrine therapy resistance, and significantly worse survival outcomes (hazard ratio 9.5).

The authors note that upregulation of CDK2, a cyclin-dependent kinase instrumental in disease progression, suggests that at least a subset of Black ER+ breast cancer patients may benefit from earlier intervention with CDK inhibitors in combination with endocrine therapy.

Dr. Haricharan said, "The next steps are to create a much larger dataset that better represents breast cancer in Black women, and to use that data to test our hypothesis that some Black women may benefit from earlier treatment with CDK inhibitors."

"Moving forward," she added, "the medical field should look to develop more meaningful diagnostic tests that address the individual molecular signature of each patient's breast cancer--potentially including demographic information such as whether patients are Black, Asian, Hispanic, white or other."

Dr. Carmen Perez, Director, Diversity Equity and Inclusion in the Department of Radiation Oncology at the Perlmutter Cancer Center, NYU Langone Health, commented on the study in an email to Reuters Health. "It is important to highlight that race is a social construct and that the patients classified as Black women in the study's datasets existed in the context of social determinants of health (e.g., socioeconomics, access to care, structural racism) that can also affect biology, including expression levels of the DDR genes addressed in the study."

Study limitations included the inability to test the effect of these social determinants of health and other variables on gene expression, and the effect of treatments on survival, she said.

"Another limitation," she added, "is the small sample size of tumors from Black women (17% in tumor datasets, 11%-21% in normal tissue datasets) and the lack of formal experimental testing to confirm the hypothesis that the signature of altered DNA damage repair gene expression indeed results in resistance to therapy."

"Since the DNA damage repair signature includes genes involved in one of the major repair pathways that cells use following radiation therapy, I would like to see research evaluating the effect of this new gene signature biomarker on radiation therapy responses," Dr. Perez said. "I would also like to see (validation of its effect) on cyclin-dependent kinases, which are part of the downstream cellular machinery and for which there are drugs in current clinical use."

SOURCE: https://bit.ly/3rMqM38 Therapeutic Advances in Medical Oncology, online February 8, 2022.

By Marilynn Larkin

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