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Epigenetic Imprint of Chemotherapy Linked to Inflammation in Breast Cancer Survivors

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Key Points

  • Up to 30% breast cancer survivors experience persistent fatigue long after treatment has ended.
  • Women with breast cancer who had been treated with chemotherapy exhibited changes in the methylation of the DNA in their white blood cells, some of which were present 6 months after radiation.
  • These methylation changes correlated with increased levels of two inflammatory signaling proteins, IL-6 and sTNFR2, that have been associated with fatigue in breast cancer survivors.

 

Many breast cancer survivors experience fatigue and other debilitating symptoms that persist months to years after their course of treatment has ended. Now researchers at the Winship Cancer Institute of Emory University have found clues that may explain how these symptoms can linger. Chemotherapy can leave a long-lasting epigenetic imprint in the DNA of breast cancer patients’ blood cells. That imprint is associated with biologic signs of inflammation up to 6 months after the completion of treatment, which has been linked to symptoms such as fatigue. The findings by Smith et al are published in Brain, Behavior, and Immunity.

"Chemotherapy is a life-saving intervention, but for some women it comes at a cost," said Mylin Torres, MD, Assistant Professor of Radiation Oncology at Emory University School of Medicine and Winship Cancer Institute. "These results are the first to suggest a biologic mechanism by which treatment-related side effects can persist long after treatment completion in women with breast cancer."

Up to 30% breast cancer survivors experience persistent fatigue long after treatment has ended. In a previously published study by Dr. Torres and study author Andrew Miller, MD, of Winship Cancer Institute, chemotherapy was associated with increased markers of inflammation in the blood, which correlated with fatigue.

"We had found that increased fatigue was similar no matter whether patients received chemotherapy before or after surgery, indicating that the timing of chemotherapy was less important than whether you got it in the first place," Dr. Torres said.

Study Details

In the current study, researchers examined DNA methylation patterns in women with stage 0 to IIIA breast cancer who received partial mastectomy with or without chemotherapy. All patients received radiation therapy.

The investigators founds that women who had been treated with chemotherapy exhibited changes in the methylation of the DNA in their white blood cells, with some of these changes being present 6 months after radiation.

The researchers scanned hundreds of thousands of potential sites of methylation; only eight sites were reliably altered in women who received chemotherapy, and changes at half of those sites were visible 6 months later.

Correlation With Inflammatory Markers

The biology connecting this handful of sites to inflammation remains unclear; the eight sites were not in genes that encode inflammatory signaling proteins secreted into the blood, for example. However, the methylation changes did correlate with increased levels of two inflammatory signaling proteins, IL-6 and sTNFR2, that have been associated with fatigue in breast cancer survivors.

Many chemotherapeutic agents are effective precisely because they damage DNA in cancer cells. While it was well known that chemotherapy induces epigenetic changes in cancer cells, this is the first study to identify epigenetic changes induced by chemotherapy for breast cancer in noncancerous cells of the blood.

The authors hypothesized that chemotherapy may directly alter methylation status in the blood cells, or it may be a result of the inflammatory response to chemotherapy-related tissue injury.

"It may be something about the intensity or the repetitive nature of chemotherapy that makes it qualitatively different from acute inflammation," Dr. Miller said. "The more we know about this imprinting process, the better chance we have of getting to new therapies for chronic treatment-related problems, such as fatigue, in breast cancer survivors."

Dr. Torres is the corresponding author of the Brain, Behavior, and Immunity article.

The study was supported by the National Cancer Institute, the Cooper Family Foundation, and the Winship Cancer Institute.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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