Investigators Seek to Resolve the “Obesity Paradox” in Lung Cancer

Smoking is associated with the most widely known cancer causing carcinogen across the world. However, a second, more insidious factor has been increasingly recognized for its role in promoting cancer growth: obesity.

Authors of a 2016 manuscript from the International Agency for Research on Cancer looked at data on several different cancer types and were the first to publish findings that prominently identified obesity as an important risk factor, as well as a prognostic factor, in at least 13 types of human cancer.¹ Six years later, that observation has become even more important in the context of the obesity epidemic, which has the United States firmly in its grip. Americans are becoming overweight at an increasingly alarming rate, creating an urgent need to understand how obesity affects cancer risk, progression, and treatment.

Analyses by our group at Roswell Park Comprehensive Cancer Center in Buffalo, New York, have demonstrated that in lung cancer, the relationship between obesity and either carcinogenesis or cancer progression is more nuanced. Most studies that have examined this relationship use body mass index (BMI) as a measure of obesity. Notably, many investigators have observed a positive relationship between high BMI and better outcomes in patients with lung cancer, as well as a decreased risk in the incidence of lung cancer. These observations are at odds with preclinical experiments that have for years shown an association between a high-fat diet, obesity, and, ultimately, increased rates of cancer development and progression. The discrepancy between these lines of evidence is known as the obesity paradox.

Visceral Fat, Related Immunosuppression Are Drivers of Lung Cancer

Recent investigations at Roswell Park have helped to unravel this paradox. Understanding that BMI may not accurately depict visceral obesity, which is known to be the main culprit behind many obesity-related negative health effects, for the same reason we sought to measure obesity differently in patients with lung cancer.

As most patients with lung cancer in the United States have a PET scan performed as part of their diagnostics and treatment planning, the CT component of the PET scan was chosen to identify and measure visceral fat. Using images obtained at the third lumbar level, investigators measured visceral fat using analysis software and normalized this readout against total body fat at that level. Armed with this new measure, called the visceral fat index, investigators sought to recalibrate the relationship between visceral fat and lung cancer. Consistent with the hypothesis and the wealth of available preclinical data, we saw clear indications that patients with a high visceral fat index had a higher recurrence rate after treatment for lung cancer.

Investigations strongly suggest that this relationship is mediated by the immunosuppression that is a by-product of visceral obesity.² Recent findings from our group suggest that in patients, as well as in preclinical models, obesity leads to a rewiring of the metabolic processes and immune cells that form the basis of these observations. We are focused specifically on understanding the role of regulatory T cells in the tumor microenvironment of patients who are obese because these suppressor cells are enhanced in both their frequency and activation status by obesity. Ongoing studies implicate these cells as an unappreciated link between obesity’s effects on metabolism and the immune response. We believe, though, that these data are just the tip of the iceberg.

Studies Are Underway With Widely Prescribed Diabetes Drug

Although the resolution of the obesity paradox and lung cancer is exciting, the implications of these observations in the therapeutic space hold the potential for an even greater effect. In both retrospective clinical data sets and carefully controlled preclinical experiments, we have found that the anticancer effect of the widely used antidiabetic drug metformin is accentuated in the context of obesity.

Testing the notion that specific patient characteristics such as obesity may affect the relative potency of metformin on lung cancer survival, we analyzed the patient outcomes of 756 non–small cell lung cancer (NSCLC) cases with early-stage (stage I/II; n = 490) or latestage disease (stage III/IV; n = 266) who either did or did not use metformin (n = 121 and n = 635, respectively) and did not receive neoadjuvant therapy.

Results showed that metformin use is associated with improved overall and recurrence-free survival only in patients who are overweight or obese, defined as a BMI greater than 25 kg/m². A manuscript is in preparation. These results expand on the finding of a previous study from our group³ and another large-scale study using data obtained from the Veterans Association Cancer Database.⁴ Corroborative findings obtained from immunocompetent preclinical lung cancer models aligned with these observations.

Results of preclinical studies suggest that metformin significantly reduces tumor development in the obese context but has little to no effect on tumor burden in normal-weight controls. Furthermore, flow cytometric evaluation of tumors in the cohort with obesity identified several previously described obesity-associated mediators of immune dysfunction (eg, widespread upregulation of the immune checkpoint factors PD-1 and LAG3, elevated myeloid-derived suppressor cell proportions and activity), metformin treatment was associated with their reversal specifically in obese models. Interestingly, the drug had little effect on the tumor immune contexture of normal-weight controls, and gene-expression analysis failed to reveal considerable alterations in canonical cancer pathways. A manuscript on these data is also in production.

Findings Should Inform Design of Lung Cancer Clinical Trials

Results of preclinical and clinical studies in this area suggest that metformin has an anticancer effect in NSCLC that is restricted to overweight individuals, highlighting the potential to improve treatment outcomes by applying favorable, context-specific immune reprogramming. This work also provides the rationale for using high BMI as a predictive biomarker of the anticancer effect of metformin in lung cancer. A proof-of-principle study in the prevention space is underway at 3 centers nationally, based on our extensive preliminary data and supported by a $3.1 million R01 award from the National Cancer Institute.⁵

Although further study is needed to fully realize the implications of these findings for physicians and patients, these observations should inform the design of future clinical trials exploring obesity’s effects on lung cancer outcomes and the potential use of drugs like metformin for anticancer benefit. They also demonstrate the unappreciated value of repurposing long-studied agents—in this case, an inexpensive, well-tolerated, and widely used diabetes drug—in specific sets of patients with cancer.

For more information on the ongoing research at Roswell Park, visit roswellpark.org.

References

1. Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K; International Agency for Research on Cancer Handbook Working Group. Body fatness and cancer—viewpoint of the IARC Working Group. N Engl J Med. 2016;375(8):794-798. doi:10.1056/ NEJMsr1606602
2. Barbi J, Patnaik SK, Pabla S, et al. Visceral obesity promotes lung cancer progression-toward resolution of the obesity paradox in lung cancer. J Thorac Oncol. 2021;16(8):1333-1348. doi:10.1016/j. jtho.2021.04.020
3. Yendamuri S, Barbi J, Pabla S, Petrucci C, et al. Body mass index influences the salutary effects of metformin on survival after lobectomy for stage I NSCLC. J Thorac Oncol. 2019;14(12):2181-2187. doi:10.1016/j.jtho.2019.07.020
4. Elkin PL, Mullin S, Tetewsky S, et al. Identification of patient characteristics associated with survival benefit from metformin treatment in patients with stage I non-small cell lung cancer. J Thorac Cardiovasc Surg. Published online March 10, 2022. doi: 10.1016/j. jtcvs.2022.02.046
5. Metformin for chemoprevention of lung cancer in obese subjects at high risk. National Institutes of Health. Accessed September 15, 2022. bit.ly/3QGr9Wd