Chemotherapy, radiation and surgery may accelerate aging among people with breast cancer
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Common treatments for breast cancer — including chemotherapy, radiation and surgery — may accelerate biological aging among breast cancer survivors, according to results of a longitudinal, observational study.
The analysis included 186 women (mean age, 55.5 years) diagnosed with stage 0 to stage III breast cancer, of whom 73 received chemotherapy with or without radiation, 76 received radiation alone and 37 underwent surgery alone.
Investigators used RNA sequencing to evaluate peripheral blood mononuclear cell gene expression on quality-verified RNA. They focused on markers of biological aging, including cellular senescence, which can damage nearby healthy cells and lead to aging and inflammation.
Researchers collected blood specimens from women before they began treatment, and then at 6, 12 and 18 months after treatment completion to assess acute and lasting changes.
Women who received chemotherapy with or without radiation therapy more often had detectable levels of p16INK4a — a biomarker of senescence — after treatment than those who received radiation alone or surgery alone (OR= 2.97; 95% CI, 1.52-5.8).
Over the course of follow-up, the percentage of women with detectable expression of p16INK4a increased in all treatment groups (P < .001). Additionally, all groups demonstrated increases in DNA damage response (P < .001), SenMayo senescence gene set (P < .001) and senescence-related secretory phenotype (P < .001).
All treatment approaches demonstrated these increases in aging biomarkers; however, women treated with chemotherapy showed ongoing increases, whereas increases observed with radiotherapy slowed over time.
“We don’t know all the factors and outcomes of these systemic treatments and, given the growing population of survivors with lasting symptoms and health complications, this work highlights possible avenues for remedying this,” Judith A. Carroll, PhD, associate professor of psychiatry and biobehavioral sciences at UCLA, told Healio. “We might be able to identify specific biological targets to alleviate symptoms after treatment to help identify behavioral factors that help some women recover and others struggle with lasting treatment effects.”
Healio spoke with Carroll about the findings and how they may help inform strategies to improve quality of life for breast cancer survivors.
Healio: Prior to your study, what evidence had been discovered about the effect of breast cancer treatments — specifically chemotherapy — on biological aging?
Carroll: A few studies suggested there may be an increase in some markers of biological aging, including the results we saw with p16INK4a — an indicator of cellular senescence. Our findings highlight that there is also an inflammatory signal and increases in DNA damage signal in immune cells. Both contribute to biological aging pathways. Interestingly, we saw this among women who did not receive chemotherapy as well as those who did.
Healio: Why did you conduct the study?
Carroll: We wanted to better understand what types of biological shifts occur in the immune cells that might contribute to accelerating aging, and see if this was different in women receiving chemotherapy compared with other women who did not receive chemotherapy. Our hope was to help identify potential targets for future therapies.
Healio: What did you find?
Carroll: We found changes in key genes related to biological aging pathways with patterns of change similar across treatment groups. Although women with chemotherapy had a different acute response, their gene expression profile over time looked similar to women who did not get chemotherapy, suggesting other factors may be contributing to these changes we observed.
Healio: What did you think about the finding that surgery and radiation may have the same effect on biological aging as chemotherapy?
Carroll: I was surprised but also curious as to what we were seeing. Although gene expression patterns capture some of the pathways involved in biological aging, they don't capture all aspects. There are also several caveats we can't rule out — that our findings have not been replicated, our sample of women with surgery alone was small, and we couldn't really disentangle other treatment effects like mastectomy or hormonal blocking agents. We need more research to really understand what is happening. There are also other studies that suggest chemotherapy has a stronger effect on some biological markers of aging, so we have to understand that our one study doesn't answer all these possible factors nor give us definitive answers.
Healio: How might these findings inform future research that could benefit breast cancer survivors in terms of survival and quality of life?
Carroll: This is really important part of why we are doing this work. We think there may be new treatments we could develop to be delivered after the initial cancer is gone to help alleviate symptoms and improve quality of life. We know from preclinical studies that many of these aging processes can be slowed down or even reversed. That would be remarkable if we could also deliver these types of treatments to survivors so they go on to live a healthier life.
Is there anything else you’d like to mention?
Healio: Our next steps will be to better identify resilience factors or protective factors that could be implemented right away. Factors like exercise, good sleep and stress management are all modifiers of aging in other research, so we are keenly focused on if these behaviors and psychological factors could be protective for cancer survivors.
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For more information:
Judith A. Carroll, PhD, can be reached at jcarroll@mednet.ucla.edu.
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