Recently, mortality from breast cancer has decreased due to effective endocrine therapies;. However, many recovered patients have reported the development of type 2 diabetes mellitus (T2DM) following endocrine therapy.
A recent Nature Reviews Endocrinology study discusses the history of endocrine therapies, highlights their adverse metabolic effects, and emphasizes the need for better biomarkers of T2DM.
Study: Diabetes mellitus in breast cancer survivors: Metabolic effects of endocrine therapy. Image Credit: Pixel-Shot / Shutterstock.com
A brief history of endocrine therapies
Tamoxifen is a selective endocrine receptor (ER) modulator (SERM) that was first synthesized in 1963. Subsequently, research revealed that tamoxifen prolonged survival rates for patients with breast cancer, particularly among post-menopausal women.
In the mid-1900s, scientists used the aromatase enzyme (CYP19A1) to catalyze androgens to synthesize estrogens, which ultimately led to the development of aromatase inhibitors. Concurrently, others studying nonsteroidal aromatase inhibitors developed anastrozole and letrozole, both of which prolonged disease-free survival by the late 1990s and, as a result, emerged as the first line of treatment for breast cancer.
Recent approaches to treating breast cancer include ovarian function suppression by the recently approved elacestrant. Ovarian function suppression, coupled with aromatase inhibition, is currently considered standard treatment in high-risk premenopausal patients.
Breast cancer survivors and T2DM risk
A higher incidence of T2DM has been reported among breast cancer survivors with endocrine therapy. This could be explained by the fact that medical monitoring is higher following breast cancer diagnosis, which may increase the likelihood of detecting T2DM diagnosis. However, certain aspects of breast cancer or its treatment may also promote T2DM.
In many studies, the link between T2DM and breast cancer treatment is particularly strong with tamoxifen. Raloxifene has also been approved for treatment but less is known about its long-term metabolic complications.
There remains a lack of long-term studies on the combination of conjugated estrogens and bazedoxifene. The link between aromatase inhibitor use and T2DM is less clear, as evidence is mixed. This could be because aromatase inhibitors are newer, frequently prescribed to older women, and have less follow-up data.
Previous studies have shown that central or visceral adiposity is correlated with obesity complications that could lead to T2DM. Patients undergoing endocrine therapy have elevated levels of free fatty acids, which are often exacerbated by obesity or being overweight.
Another theory considers adipose tissue as an endocrine organ, rather than an energy storage device. This theory predicts that large adipocytes promote chronic inflammation and a change in the production of adiponectin and leptin could promote insulin resistance.
Targeting ER in breast cancer treatment
ER isoforms are expressed in various tissues including the liver, skeletal muscle, and adipose tissues, each of which exhibit different levels of gene expression. Estrogen replacement appears to mitigate hepatic steatosis, excess adiposity, and impaired glucose tolerance in female mice. In female mice, ER maintained glucose tolerance and insulin sensitivity.
ERs use central mechanisms to regulate metabolism. Key functions, such as locomotion, bone density, food intake, and energy, have been seen to be brought about by ER signaling in the mouse hypothalamus.
Endocrine therapy could significantly contribute to metabolic changes; however, there is a lack of data on the effects of aromatase inhibitors and SERMs on the eating patterns of patients. This is especially true for patients with short-term exposure.
The elevated risk of T2DM and long-term effects in breast cancer patients are not in line with tamoxifen being an ER agonist in all tissues. Notably, fulvestrant, tamoxifen, and raloxifene can act as agonists of GPER1, which is an isoform of ER.
Many therapies for breast cancer can successfully prolong the survival of patients; however, some of these treatments are associated with potential adverse effects, such as the development of T2DM. Thus, breast cancer patients should be treated by a team of endocrinologists and oncologists who can detect and minimize potential problems during the course of treatment.
Adipose tissue is a key target of endocrine therapy; therefore, disrupting estrogen production or ER function could lead to adipocyte hypertrophy and, ultimately, the attenuation of insulin sensitivity. In the future, more research is needed to identify the effects of breast cancer treatments on different parts of the body and potential remedies that can mitigate the risk of T2DM development.
- Thomas, N. S., Scalzo, R. L., & Wellberg, E. A. (2023) Diabetes mellitus in breast cancer survivors: Metabolic effects of endocrine therapy. Nature Reviews Endocrinology; 1-11. doi:10.1038/s41574-023-00899-0