GLP-1 Receptor Agonists, Endocrine Therapy, and Metabolic Health Comprise Holistic Breast Cancer Care

In part 1 and part 2 of an exclusive Breast Cancer Briefing podcast, host Sara Nunnery, MD, MSCI, sat down with Neil M. Iyengar, MD, to discuss frequently asked questions about the metabolic consequences of breast cancer therapy and the rapidly expanding role of glucagon-like peptide-1 (GLP-1) receptor agonists in oncology.

Nunnery is a breast medical oncologist and the director of breast cancer research at Tennessee Oncology in Nashville. Iyengar is an associate professor and codirector of Breast Medical Oncology in the Department of Hematology and Medical Oncology at the Emory University School of Medicine, as well as the director of Survivorship Services at the Winship Cancer Institute of Emory University in Atlanta, Georgia.

Q: How does endocrine therapy affect metabolic health beyond its anticancer effects?

A: Estrogen signaling is more nuanced than a single “on/off” switch, Iyengar explained. Estrone is a more proinflammatory estrogen, whereas estradiol is generally more protective; however, current antiestrogen therapies cannot selectively spare one over the other. The result is a “conglomerate effect” of estrogen blockade that, over time, contributes to cardiometabolic dysfunction, including a higher risk of cardiac disease, diabetes, and chronic inflammation, and adverse effects (AEs) affecting bone health and quality of life.

Since estrogen participates in energy homeostasis, blocking estrogen signaling can disrupt that balance and trigger compensatory changes, such as hyperinsulinemia, Iyengar said. Breast cancer survivors carry more than a doubling of the risk of developing diabetes and of mortality from cardiometabolic disease, he noted. Iyengar emphasized that this should not be considered evidence against the use of endocrine therapy; rather, this highlights an opportunity to develop adjunctive strategies that reverse the metabolic toll of treatment.

Q: Why does endocrine therapy lead to weight gain, and which patients are most at risk?

A: This mechanism is not fully understood, Iyengar acknowledged. In older randomized trials of antiestrogen therapy in both the prevention and treatment settings, patients gained weight in the investigational arms, as well as the control arms, reflecting the natural history of aging and the menopausal transition rather than a direct drug effect.

“It’s not so much that the antiestrogen therapy directly causes weight gain; it’s that we’re inducing a postmenopausal, estrogen-deprived state,” Iyengar said. “That goes along with all the mechanisms we were talking about, like inflammation, cardiometabolic dysfunction, and adipose tissue dysfunction. When you disrupt all those processes, that’s going to lead to weight gain and make it harder to lose weight.”

Risk stratification should move beyond body mass index (BMI) alone, he added. He noted that although a BMI of 30 or greater raises the risk of relapse and treatment resistance, body composition matters independently of BMI.

“Even in women who have a normal BMI but higher percentages of body fat, that’s a risk factor,” Iyengar noted. “That’s called normal-weight obesity. It’s a risk factor not for developing breast cancer, [and it] increases the risk of recurrence. Ultimately, what we need is a fat and metabolic signature to more precisely stratify who’s at risk.”

Q: How does obesity affect long-term breast cancer outcomes?

A: Patients with obesity, hyperinsulinemia, or high body-fat levels have a higher risk of breast cancer recurrence, and that association holds across triple-negative, HER2-positive, and estrogen receptor–positive disease, Iyengar said.

Nunnery framed the resulting clinical tension, saying, “It can be a struggle to feel like we’re giving [a patient] a drug to try to improve their outcome, but then we’re also potentially giving them AEs that might compromise that outcome.”

Iyengar reframed that tension as an opportunity, adding, “If you look at chemotherapy cohort studies, nearly every single metabolic parameter worsens after adjuvant or neoadjuvant chemotherapy, yet that chemotherapy is lifesaving, so I view it as an opportunity. If we can correct that metabolic dysfunction, perhaps the survival benefit of chemotherapy will be even more profound.”

Q: How should diet and exercise be prescribed as “medical therapy”?

A: Iyengar argued that lifestyle interventions should be developed for patients with the same rigor as drugs are prescribed, explaining, “We’ve taken a drug development paradigm to develop precision lifestyle interventions. I don’t think there is a one-size-fits-all approach; we should not be recommending the same diet for every single person.”

The first step in clinic, he said, is to define the indication for exercise, because modality and dose follow from it.

On the common objection that fatigued patients cannot exercise, Iyengar pointed to “activation energy,” explaining, “It is a huge struggle to get your fatigued self to get up and move, but the return on investment is huge. If you don’t feel the benefit the first day, you’ll likely feel it the next day. On the flip side, if you remain sedentary, that compounding effect is also huge.”

He favors a ramp-up period, involvement of exercise physiologists or therapists, and selecting a modality that brings the patient joy.

Q: What are GLP-1 receptor agonists?

A: GLP-1 receptor agonists are incretin mimetics that replicate endogenous hormone signaling to maintain glycemic homeostasis, Iyengar explained. They promote insulin secretion in a glucose-dependent manner (avoiding insulin release during hypoglycemia), slow gastric emptying to enhance satiety, and appear to centrally reduce hunger signaling, with emerging tissue-specific effects on brain and bone health.

Iyengar noted that these are not new molecules; the first GLP-1 receptor agonist was approved approximately 20 years ago for the management of type 2 diabetes. He also explained that the current surge of these agents in the health care space reflects recognition of obesity’s harms and the substantially greater weight loss seen with these agents vs older antidiabetic drugs.

Q: Do GLP-1 receptor agonists carry cancer risk?

A: This class of agents carries a boxed warning for thyroid cancer derived from early studies, Iyengar said, but subsequent large observational and population data sets have largely not confirmed an increased incidence, and the cases observed tended to be the less aggressive, more treatable thyroid cancers.

“The preponderance of evidence suggests that there may not be an increased risk of thyroid cancer,” he said, “and if there is, it’s probably low.”

Notably, he stated that the broader signal points the other way: Target-trial emulation and large observational analyses have reported that GLP-1 receptor agonists are associated with a lower incidence of several obesity-related cancers, without an accompanying increase in thyroid cancer. In one matched cohort study of 67,591 cancer survivors, GLP-1 receptor agonist use was associated with significantly lower all-cause mortality (HR, 0.36; 95% CI, 0.25-0.51) and no increase in recurrence risk (HR, 0.80; 95% CI, 0.50-1.30).¹

Q: What do the retrospective data show about the efficacy of GLP-1 receptor agonists in patients with breast cancer?

A: Most current evidence with this class of agents in patients with cancer is retrospective, Iyengar and Nunnery noted, and weight loss in patients with breast cancer has been more modest than in the nononcology phase 3 trials. For instance, in a single-center retrospective cohort of 75 patients with breast cancer treated at Memorial Sloan Kettering Cancer Center in New York, New York, GLP-1 receptor agonist use over a median of 20 months (range, 6-111) produced a mean relative weight loss rate of –5% (95% CI, –6% to –3%) at 12 months.²

Q: Can patients receiving endocrine therapy still succeed on a GLP-1 receptor agonist?

A: Yes, but dosing and monitoring matter, Iyengar said. Mixed data suggest that endocrine therapy can blunt weight loss, but he advises closely tracking the weight-loss trajectory and escalating the GLP-1 receptor agonist dose (as tolerated) if weight loss plateaus. Importantly, he cautioned against assuming that a patient who reached a target weight on a GLP-1 receptor agonist before starting endocrine therapy will continue along the same trajectory once endocrine therapy begins.

Q: Is it safe to use GLP-1 receptor agonists during active cancer treatment?

A: This is where Iyengar drew the firmest line. Based on observational data, GLP-1 receptor agonists appear safe and potentially beneficial during endocrine therapy and in survivorship after completion of cancer therapy, he said. He is far more cautious about active cytotoxic or immunotherapy treatment.

“I worry about initiating a GLP-1 receptor agonist in patients who are receiving or starting chemotherapy,” Iyengar said. “We don’t know about the interactions; we don’t know if the adverse effects [AEs] will compound. The last thing I want to do is cause a patient more AEs, like gastric or gastrointestinal toxicities, that will decrease our ability to deliver chemotherapy effectively.”

He also flagged a quality-of-life caveat: “We have to remember that [GLP-1 receptor agonists] reduce the joy of eating. In the vulnerable setting of a cancer diagnosis, the last thing we want to do is pull away sources of joy for our patients. It’s a complex discussion, and we need to be transparent about what we know and what we don’t know.”

Finally, Iyengar stressed that GLP-1 receptor agonists do not replace lifestyle interventions. Because rapid weight loss can reduce skeletal muscle, “strength training and exercise are important for maintaining that muscle mass, especially in patients with cancer,” he said. He also urged a deliberate approach to GLP-1 receptor agonist discontinuation, emphasizing, “If you’ve hit that target weight loss and you’re ready to consider stopping the GLP-1, taper it slowly over 20 weeks. If you’re seeing weight gain creep up to 5% or greater, start to increase the dose again or prolong the taper, because we need to be slow and methodical about weight loss.”

References

1. Xande JG, del Giglio A. GLP-1 receptor agonists in breast cancer: a new frontier in obesity and prognosis management. Int J Mol Sci. 2025;26(16):7744. doi:10.3390/ijms26167744
2. Shen S, Liu B, Fanti C, et al. GLP-1 receptor agonist use and weight change in patients with breast cancer. Oncology (Williston Park). 2025;39(7):294-296. doi:10.46883/2025.25921046