Obesity may increase risk for breast cancer among BRCA mutation carriers
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Key takeaways:
- Evidence suggests lifestyle and environment can impact breast cancer risk among women with genetic predispositions to cancer.
- Exposure to metformin could mitigate the DNA damage associated with obesity.
Obesity may cause DNA damage in the breast tissue of BRCA mutation carriers and may increase breast cancer risk in this already high-risk population, according to multi-institutional research led by investigators at Weill Cornell Medicine.
“It’s important to understand the role of metabolic health in cancer risk in these women, as well as anyone else who has a genetic predisposition to cancer,” senior study author Kristy A. Brown, PhD, the Emilie Lippmann and Janice Jacobs McCarthy research scholar in breast cancer and an associate professor of biochemistry at Weill Cornell Medicine, told Healio. “There has been more and more evidence suggesting that lifestyle and environment can modulate risk in women with genetic predispositions to cancer. With this knowledge, we can potentially provide better guidance to these women once they’re diagnosed with a BRCA mutation.”
Brown discussed the study’s findings on obesity-related risk for cancer, the potential role of metformin in mitigating this risk and her future research in this area.
Healio: What inspired you to conduct this study?
Brown: We had been studying the relationship between obesity and breast cancer in the general population for quite some time. There is strong evidence linking obesity to the development of breast cancer after menopause, especially hormone receptor-positive cancers. What wasn’t clear was whether this also applied to BRCA mutation carriers. The epidemiologic data in that space was very mixed, and we felt that it was difficult from a clinical standpoint to make strong recommendations one way or another for this population. Because we study the biology of the breast, we wanted to take a slightly different approach to those epidemiologic studies and look at what was happening locally within the breast tissue of the women. The goal was to see whether we could gain some insights and some signals that might have been missed in population studies.
Healio: You and your colleagues evaluated noncancerous breast tissue samples from patients with BRCA1 or BRCA2 mutations. What did you find?
Brown: We hypothesized that if obesity or poor metabolic health impacted the risk for cancer, there would be an effect on the DNA of the cells where tumors originate. So, we decided to look at damage to the DNA of normal glandular tissue of the breast. We measured a marker of double-strand breaks in the DNA called gamma-H2AX. We were able to access samples from 69 women, and the BMI of those women ranged from 19, which is considered healthy, to nearly 45, considered obese. We were able to show that not only was BMI associated with more damage in that breast tissue, but so were other markers of poor metabolic health, such as insulin.
Healio: What did you find when you exposed this damaged tissue to metformin?
Brown: We became interested in metformin, which is used to treat diabetes, for a few reasons. It is a relatively safe and affordable drug, and my laboratory had previously shown that it was able to suppress the expression of aromatase in the breast. We know that aromatase is a key driver of estrogen production and required for the growth of hormone receptor-positive cancers. Because we had a signal that estrogens may be involved in the DNA damage that we saw, we decided to test the effects of metformin. Not only did we see a reduction in estrogen production, but also in DNA damage in the breast tissues. It’s important to keep in mind that this study was conducted ex vivo in a laboratory setting. We hope to be able to do those studies in a clinical setting to determine the effectiveness of metformin at reducing breast cancer risk.
Healio: Do you plan to conduct future studies on metformin in this patient population?
Brown: Yes. Metformin has gotten a bad rap over the past few years, in part due to the results of the MA.32 study, a phase 3 study that looked at the effect of metformin on DFS in women with breast cancer, in addition to best practices. Results showed no improvement in outcomes for an unselected population. We still believe that there may be benefit in using this drug, with few adverse effects, in the risk-reduction setting. Showing an effect on DNA damage and, more importantly, cancer risk would be a big deal for this population of women with relatively few options available to them beyond surgery and active surveillance.
Healio Do these findings warrant advising women with BRCA mutations to maintain a normal BMI?
Brown: I think our findings further support advocating for a healthy lifestyle. Few people are aware of the strong evidence linking obesity and poor metabolic health to the development of cancer in the general population. Our study demonstrates that this may also be an important factor for cancer development in individuals who are already at high risk due to genetic predispositions. Maintaining a healthy weight will have beneficial effects that go beyond a cancer diagnosis, largely preventing many of the comorbidities associated with excess body weight.
References:
- Bhardwaj P, et al. Sci Transl Med. 2023:doi: 10.1126/scitranslmed.ade1857.
- Goodwin PJ, et al. JAMA. 2022; doi:10.1001/jama.2022.6147.
For more information:
Kristy A. Brown, PhD, can be reached at Brown Laboratory, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065; email: kab2060@med.cornell.edu.
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