Investigators Explore Metformin to Prevent Cancers in Li-Fraumeni Syndrome Carriers

Payal Khincha, MBBS, MSHS

Individuals with Li-Fraumeni Syndrome (LFS), a rare hereditary condition, are at increased risk for a wide spectrum of malignancies, including breast cancer and sarcomas. Investigators are working to determine whether metformin, a drug indicated for diabetes and infertility caused by polycystic ovarian syndrome, can prevent cancers in LFS carriers.

LFS is a highly penetrant autosomal dominant cancer predisposition disorder caused by germline TP53pathogenic variants. The syndrome is associated with a 24-times higher incidence of any cancer compared with the general population (standardized incidence ratio, 23.9; 95% CI, 21.9-26.0), according to findings from the National Cancer Institute’s referral-based longitudinal study of 480 carriers of pathogenic or likely pathogenic germline TP53 variants.¹ The risk was greatest from childhood to 30 years of age, but the overall cancer incidence remained 10.3 times (95% CI, 7.9-13.2) higher than in the general population after age 50.

According to the National Organization for Rare Diseases, people with LFS have a roughly 50% chance of developing cancer by age 40, and up to a 90% chance by age 60. Women with LFS have nearly a 100% lifetime risk of developing cancer, with a particularly high risk for developing early-onset breast cancer. LFS also increases the risk that carriers will develop 2 or more primary cancers over their lifetimes.²

While LFS is associated with several different cancer types, the most frequently occurring are premenopausal breast cancer, bone and soft tissue sarcomas, brain cancer, adrenal cancers, and hematological cancers, among others. There are no symptoms associated with LFS; the condition is usually identified when someone has a personal or family history of cancers associated with LFS. Practitioners working with patients and families that have a history of multiple cancers or LFS-associated cancers should screen for the presence of LFS.

“There is genetic testing for a gene called TP53, the gene that is associated with LFS,” said Payal Khincha, MBBS, MSHS, a physician-scientist early investigator in the National Cancer Institute’s clinical genetics branch. “Damaging germline variants in that gene are known to be associated with Li-Fraumeni syndrome. Those are the individuals who would come to our attention, and then we would recommend further screening for them.”

Currently, the only prevention strategies for individuals with LFS are risk-reducing mastectomy, a major invasive surgery, or regular colonoscopy. Cancer screening can only monitor individuals with LFS and hope to detect cancer in its earliest stages. However, work has begun to determine whether metformin stops cancers from developing in this population.

Christina M. Annunziata, MD, PhD, head of the translational genomics section and a senior investigator with the Women’s Malignancies Branch at the National Cancer Institute, was a coauthor on a pilot study (NCT01981525) examining safety and tolerability of metformin in 26 nondiabetic adults with LFS and measuring changes in metabolic profiles.³

Investigators obtained blood samples for measurement of serum insulin-like growth factor–1 (IGF-1), insulin, and insulin-like growth factor binding protein 3 (IGFBP-3). Hepatic mitochondrial function was assessed with fasting exhaled CO2 after ingestion of 13C-labeled methionine. Changes in serum metabolome were measured. All statistical tests were 2-sided.

Metformin was associated with a statistically significantly suppressed cumulative mean 13C exhalation (P = .001). The drug also significantly lowered mean levels of IGF-1 and IGFBP-3 (P = .02). Investigators did not observe any lactic acidosis or changes in fasting glucose, and the most common adverse events (AEs) were grade 1 diarrhea (50.0%) and nausea (46.2%). There were no grade 3 to 5 AEs.

“There have been retrospective studies that have shown that people on metformin developed fewer of a number of cancers,” Annunziata said. “There have been, for example, studies in ovarian cancer showing that patients on metformin had less frequent ovarian cancers and did better when they were diagnosed with ovarian cancer if they had previously been on metformin. Those are hypothesis-generating studies, but this evidence suggests that there is something about metformin and the way it potentially affects the cellular metabolism that is important in in preventing cancers from developing or progressing.”

Metformin Goes to Trial as a Treatment

Khincha is leading the development of an upcoming phase 2 clinical trial of metformin in participants with LFS in North America. “The overarching question is: Is metformin a pharmacological intervention that can potentially reduce the risk of cancer in individuals who have LFS?” she said. “The best way to scientifically answer that is through a clinical trial where we will be comparing occurrence of cancer 2 groups of people: one group who receive cancer screening per current standard of care to another group who will receive cancer screening and metformin.”

Individuals diagnosed with LFS already undergo extensive screening including yearly whole-body and brain MRIs, bloodwork, and endoscopy and colonoscopy every 2 to 5 years starting at age 25. Female patients undergo breast MRIs starting at age 20 and pediatric patients undergo regular abdominal ultrasounds to screen for adrenal cancers.

The phase 2 study is based on biological findings described by Annunziata. Participants would be randomly assigned to a control group that would undergo screening as usual, while the intervention group will receive screening plus metformin. Khincha and her team will evaluate patients to see if there is a statistically significant difference in incidence of cancer between the 2 groups at 5 years.

There has been international collaboration with the metformin trial. Investigators at University of Oxford will be launching a randomized, phase 2 Metformin in Li Fraumeni trial evaluating whether metformin can prevent or delay the emergence of cancer in people in the United Kingdom with LFS; 200 adult participants in this regimen are planned to be recruited.⁴ This trial will have the same study design as the North American trial, a product of collaborative discussions between the 2 study teams. Primary outcomes are expected in 2028.

“The intention is that while the trials in each country will be an independent study that will be analyzed within itself, at the end we will have the ability to pool the data from all the sites and analyze them together,” she said. “This will give us much more power to delve into the results and effects of metformin.

“The collaboration was in coming up with the study design, statistical methods, and outcomes to be studied, and will continue with sharing of data and samples to further research while the trials are ongoing.”

There are several teams of investigators currently exploring metformin as a cancer treatment or preventive. Marijo Bilusic, MD, PhD, leader of the Genitourinary Cancers Site Disease Group at Sylvester Comprehensive Cancer Center in Miami, Florida, recently published findings evaluating metformin alone or in combination with bicalutamide (Casodex) for patients with prostate cancer (NCT02614859). The study failed to meet its primary end point—metformin did not induce significant difference in the percent of patients who reached an undetectable prostate-specific antigen level—but he said there is a reason this diabetes drug that has been available for decades is having a moment in cancer research.⁵

“Metformin has some immune modulating effect, which then kind of brings additional excitement [that it] should be combined with immunotherapy,” he said in an interview with OncLive®. “It's safe. It's been around for a while. It seems to have some effect. It’s not expensive. Financial toxicity has been a big deal for [patients with] cancer, so we [could] have a treatment that costs a penny a day or $1 a month. That would be fascinating and great.”

References

1. de Andrade KC, Khincha PP, Hatton JN, et al. Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. Lancet Oncol. 2021;22(12):1787-1798. doi:10.1016/S1470-2045(21)00580-5
2. National Organization for Rare Diseases. Li-Fraumeni syndrome. Accessed February 2, 2022. https://rarediseases.org/rare-diseases/li-fraumeni-syndrome/
3. Walcott FL, Wang PY, Bryla CM, et al. pilot study assessing tolerability and metabolic effects of metformin in patients with Li-Fraumeni syndrome. JNCI Cancer Spectr. 2020;4(6):pkaa063. doi:10.1093/jncics/pkaa063
4. University of Oxford. World’s first cancer prevention trial to test diabetes drug in patients with high-risk genetic condition. November 24, 2021. Accessed February 3, 2022. https://bit.ly/3ooEh6V
5. Bilusic M, Toney NJ, Donahue RN, et al. A randomized phase 2 study of bicalutamide with or without metformin for biochemical recurrence in overweight or obese prostate cancer patients (BIMET-1). Prostate Cancer Prostatic Dis. Published online January 25, 2022. doi:10.1038/s41391-022-00492-y