• Retrospective evidence shows GLP-1s may protect against several cancers, including some not linked to obesity.
• A prospective study will assess their impact on breast cancer incidence among women at high risk.

The inflection point has arrived.

More than a dozen studies presented at ASCO Annual Meeting added to a growing volume of research that suggests GLP-1 receptor agonists may protect against several types of cancer.

However, as evidence mounts, so do reminders that findings have emerged entirely from database-driven retrospective cohort studies, which are prone to systematic biases and cannot prove causality.

“The signal is as strong as it has ever been — and probably as strong as it will ever be — but we are still talking about associations,” Colton Frisco Jones, MD, a hematology/oncology fellow at Mays Cancer Center at UT Health San Antonio and coauthor on several of the ASCO abstracts, told Healio. “The results need to be validated in clinical trials, and now is the time to act.”

Elizabeth S. McDonald, MD, PhD, could not agree more.

McDonald — a breast radiologist at University of Pennsylvania’s Abramson Cancer Center and professor of radiology at Penn’s Perelman School of Medicine — presented data at ASCO that showed 30% lower breast cancer incidence among women who used GLP-1s than nonusers.

Her research group is now poised to launch a multisite prospective study to assess the impact of GLP-1s on women at high risk for breast cancer, including those with history of the disease.

“There have been such great gains in mortality reduction through screening and early detection, but there haven’t really been gains in prevention,” McDonald said in an interview. “If these agents are shown to be causal for prevention with an effect of that magnitude, and we finally have something women can do beyond lifestyle modifications to reduce their risk, it would have transformational impact. We would be talking about thousands of women who would not develop breast cancer.

“Of course, we’re not there yet,” she added. “We need considerable investment from industry, the U.S. government and foundations so the research community can proceed in an evidence-based fashion and determine if the effect against breast cancer — and other cancer types — is real.”

GLP-1 receptor agonists have been approved to treat diabetes since 2005. They have been approved since 2014 to treat obesity, which is linked to 13 malignancies and soon may surpass tobacco as the leading modifiable risk factor for cancer.

The medications reduce glucose, decrease inflammation and improve insulin resistance, three factors linked to cancer development and progression.

As Healio previously reported, studies presented at major conferences last year showed GLP-1s may improve outcomes among people with certain blood cancers or breast cancer and help reduce risk for colorectal cancer.

This year’s ASCO program added multiple new chapters to the rapidly evolving story.

One study showed people with certain stage I to stage III cancers who used GLP-1s had significantly lower risk for metastatic disease than those who used dipeptidyl peptidase-4 (DPP-4) inhibitors, another class of type 2 diabetes medications. Others suggested the agents may extend survival among people diagnosed with multiple cancer types and help prevent postmastectomy lymphedema among people with breast cancer.

Seven additional abstracts highlighted the potential role of GLP-1s for primary prevention of specific cancer types.

“Some reported on cancers for which obesity is a known risk factor, but others showed benefits in malignancies that are not classically thought to be associated with weight,” McDonald said. “It is exciting to see a conglomerate body of work building that appears to show protective benefits across the cancer continuum.”

Many studies to date that linked GLP-1s to reductions in cancer risk focused on solid tumors.

Jones and colleagues aimed to extend that work to blood cancers, conducting the first real-world study of the effects of GLP-1s on risk for leukemia among high-risk individuals independent of diabetes status.

Investigators used TriNetX — a global health research network that aggregates deidentified data from 300 million people — to identify those with risk factors such as obesity, family history, prior radiation or chemotherapy, or diagnosis of myelodysplastic syndrome or polycythemia vera.

They used propensity score matching to establish one cohort with GLP-1 users and another with nonusers (n = 313,099 each).

Results showed 51% lower risk for acute myeloid leukemia among GLP-1 users (HR = 0.49; 95% CI, 0.34-0.7).

“AML is the leukemia subtype most associated with obesity, so reduction in obesity could be a major driver,” Jones said. “However, preclinical data suggest GLP-1s have an anticancer effect in leukemia cell lines, so there may be a multifactorial mechanism.”

GLP-1s exhibited the strongest effect among individuals who received prior chemotherapy. In that subgroup, results showed significant reductions in risk for AML (HR = 0.26; 95% CI, 0.17-0.4), acute lymphoblastic leukemia (HR = 0.29; 95% CI, 0.18-0.47) and chronic myeloid leukemia (HR = 0.5; 95% CI, 0.3-0.82).

Results showed higher rates of gastrointestinal adverse events — known side effects of GLP-1s — among those who used the agents, but no new safety concerns emerged.

Researchers applied “rigorous confounder adjustment,” Jones said, utilizing a clinical trial emulation design that included a 6-month landmark analysis and sensitivity analyses. They also controlled for more than 100 covariates and healthcare utilization to minimize selection bias.

However, the potential for residual confounding exists, Jones said. He also noted the short duration of GLP-1 treatment (mean, 84 to 94 days) and short follow-up for GLP-1 users (median, 1,080 days).

“Typically, 10 to 20 years is needed for primary prevention studies, and we were far off from this,” he said. “However, our data provide a reassuring signal that the protective benefits that have been reported in solid tumors can be extrapolated to liquid cancers.”

Ariana N. Neely, MD, a third-year internal medicine resident at Jefferson Einstein Philadelphia Hospital, presented findings from a multicenter retrospective study that assessed the impact of GLP-1 use on lung cancer incidence among high-risk individuals.

“As a medical community, we recommend smoking cessation for risk reduction but there is no pharmacological agent for prevention,” Neely told Healio. “The metabolic benefits of GLP-1s are well established, but preclinical data show they also have anti-inflammatory, anti-immunomodulatory and antiproliferative effects in the tumor microenvironment. Despite emerging evidence about the benefits of these agents for cancer risk, data about lung cancer are limited. We wanted to fill that gap.”

Researchers used TriNetX to identify adults with no lung cancer history who had high-risk characteristics, such as tobacco use, chronic lung disease, prior radiation, and environmental or occupational exposures.

They performed propensity score matching for demographics, comorbidities and medications, establishing one cohort with GLP-1 users and another with nonusers (n = 34,187 each).

Median follow-up reached 6.3 years. After that time, 2% of GLP-1 users and 2.4% of nonusers developed lung cancer, equating to a relative risk reduction of 31% (HR = 0.687; 95% CI, 0.62-0.76).

“The absolute risk reduction is quite modest but if we extrapolate this — understanding that lung cancer is the leading cause of cancer mortality — the population-level impact could be quite significant,” Neely said.

The findings are biologically plausible given the established effects of GLP-1s and warrant prospective evaluation for lung cancer prevention in high-risk populations, Neely said.

“For now, these data are hypothesis generating, not practice changing, though we hope one day they may be,” she said.

Neely and Jones collaborated with a dozen other investigators to evaluate GLP-1s for primary prevention of hepatocellular carcinoma among high-risk individuals.

Researchers used TriNetX to identify individuals with at least one risk factor, such as chronic viral hepatitis, cirrhosis or alcohol use disorder. They used propensity score matching to establish one cohort with GLP-1 users and one with nonusers (n = 296,359 each). Median follow-up exceeded 5.75 years in both groups.

Results showed a 73% reduction in HCC among GLP-1 users (HR = 0.27; 95% CI, 0.22-0.33), with particularly pronounced protective effects among individuals without diabetes (HR = 0.18; 95% CI, 0.14-0.23) and those with BMI less than 29 kg/m² (HR = 0.16; 95% CI, 0.1-0.25).

“We know GLP-1s can reduce risk for metabolic-associated steatohepatitis, and that is an independent risk factor for liver cancer among people with type 2 diabetes,” Jones said. “It was unclear whether they also may benefit people with other risk factors or genetic liver conditions that predispose them to HCC, and the signal was very clear.”

GLP-1 users more often experienced nausea, vomiting, abdominal pain and diarrhea. However, they exhibited significantly lower risk for pancreatitis (HR = 0.44; 95% CI, 0.41-0.47) — potentially due to reduction in inflammation — and acute kidney injury (OR = 0.64; 95% CI, 0.62-0.66), possibly due to improvements in glomerular filtration rate.

Study participants lost about 4.8% of body weight at 1 year.

“This very mild weight loss suggests weight reduction is not the primary driver,” Jones said. “We think the explanation is multifactorial, with reduction in chronic inflammation and a direct anticancer effect driving much of the signal.”

Two studies examined GLP-1s for prevention of breast cancer.

Gotera and colleagues used TriNetX to identify women with at least one high-risk characteristic, including genetic predisposition, family history or dense breasts. All had BMI of 30 kg/m² or higher.

Researchers used propensity score matching to establish one cohort of GLP-1 users and one with nonusers (n = 46,581 each). Median follow-up exceeded 7 years in each group.

Results showed lower breast cancer incidence in the GLP-1 group (2.95% vs. 3.01%; HR = 0.84; 95% CI, 0.78-0.92).

McDonald presented findings from a separate retrospective analysis of women aged 45 to 80 years who underwent breast imaging from 2022 through mid-2025. All had BMI of 25 kg/m² or higher, 26.3% had Charlson risk scores of 3 or higher, and 8.8% had a breast cancer history.

Researchers established 15,264 matched pairs of GLP-1 users and nonusers based on age, race, ethnicity, breast density, BMI and type 2 diabetes.

Results showed 30% lower breast cancer incidence among GLP-1 users (1.62% vs. 2.31%; OR = 0.695; 95% CI, 0.59-0.82). An unmatched analysis yielded a similar result (OR = 0.649; 95% CI, 0.57-0.74), leading investigators to conclude the association is not entirely explained by differences in key baseline characteristics.

“People have asked if I am surprised by the magnitude of effect,” McDonald said. “Meta-analyses of women who have undergone bariatric surgery have shown risk reductions of that amount, but that intervention is not scalable at a population level. Our findings are clearly hypothesis generating, but they show these drugs have potential and that is why we need to proceed with a clinical trial.”

McDonald and colleagues are in the final stages of securing funding for a prospective international trial to examine if GLP-1s reduce breast cancer incidence among women at high risk, including breast cancer survivors.

The INSPIRE study — which also will assess cardiovascular disease risk — will follow women enrolled in ECOG-ACRIN’s randomized TMIST trial (n = 108,000+), designed to compare screening with standard 2-D vs. 3-D mammograms. Once INSPIRE is fully funded, it could be initiated in 6 months.

“A clinical trial is essential — there is no other path to understanding whether the benefits of these drugs are truly causal,” McDonald said. “We can do bigger observational studies but, as you get into bigger datasets, you have more missing data fields. A trial can establish benefits vs. risks, as well as magnitude of effect, and provide the evidence that the FDA needs to determine whether these drugs should be taken for a cancer prevention indication.”

Although the mechanisms for cancer-protective benefits observed in the retrospective analyses are not fully understood, lower estrogen production due to weight loss, improved insulin sensitivity and reduced inflammation all may contribute, McDonald said.

INSPIRE has been designed in a way to ensure blood- and tissue-based biomarkers of effect can be extracted.

The trial also will allow for mechanistic studies that could assess impact on immune cells in the surrounding tumor microenvironment, as well as impact on gene expression, estrogen signaling, metabolism and cell cycle pathways.

One in eight U.S. women develop breast cancer in their lifetime. The high expected number of events should ensure a measurable effect size, making it an appropriate setting for the first prospective study of GLP-1s for a cancer indication, Jones said.

“We need to focus on cancers where incidence is higher and, if the signal is broad, then we can think about how to expand this to other cancers,” Jones said. “A lot of work has gone into treating cancer, with very little work focusing on how to prevent it. If prospective trials pan out, we may be talking about a next wonder drug for cancer prevention that could potentially impact billions of people around the world.”

In late June, an article published in Science raised concerns about the increasing volume of research based on data from TriNetX.

Critics contend the publications tout impressive effects with a litany of drugs on a broad range of outcomes but often fail to mention key biases that can skew results. The article referenced prior research about GLP-1 use and cancer risk but did not cite any of the studies presented at ASCO.

“TriNetX is a powerful database but propensity score matching can only balance what we can measure, and there’s always potential for residual confounding from variables not reliably captured in electronic health records,” Neely said. “Every retrospective cohort study using electronic health data has those limitations, and it is important to name them upfront, which is why findings from these studies are best treated as hypothesis-generating rather than causal.”

Rayjean J. Hung, PhD, FCAHS, head of Prosserman Centre for Population Health Research at Sinai Health in Canada, served as discussant for an ASCO session in which multiple GLP-1 abstracts were presented.

Hung noted the strong biologic rationale supporting a role for GLP-1s in cancer prevention but also emphasized important caveats, such as the potential for selection bias and time-related bias, as well as relatively short follow-up time.

During a panel discussion, researchers acknowledged these concerns and reiterated the need for prospective studies.

The tale of another type 2 diabetes treatment once heralded for potential anticancer effects underscores why that next step is essential.

“Ten years ago, early data from retrospective observational studies suggested metformin could reduce cancer incidence, but that didn’t pan out in prospective studies,” Jones said. “Now, it’s almost like déjà vu. The question is, will GLP-1s pan out or will it be another metformin situation? All we can do right now is report what the observational studies show. The signal in terms of pan-cancer risk reduction is clear, but we must await confirmation from clinical trials.”

Colton Frisco Jones, MD, can be reached at jonesc17@uthscsa.edu or on X @theglpman.

Elizabeth S. McDonald, MD, PhD, can be reached at elizabeth.mcdonald@pennmedicine.upenn.edu.

Ariana N. Neely, MD, can be reached at ariana.neely@jefferson.edu.