Roswell Park Research Debunks Perceived Benefits of Overweight/Obesity in Lung Cancer Patients

BUFFALO, N.Y. —Obesity is associated with a higher risk of developing at least 13 types of cancer — and worse outcomes after diagnosis. But lung cancer seems to be an exception: Studies have shown that patients with a high body mass index (BMI) experience a lower risk of disease recurrence and longer survival after surgical treatment — an irregularity called “the obesity paradox.” In light of obesity’s detrimental effects in other cancers, what accounts for those unexpected outcomes? 

Research conducted at Roswell Park Comprehensive Cancer Center has identified two main “confounding factors” that help explain why previous studies reached the inaccurate conclusion that overweight and obesity are potentially beneficial for lung cancer patients. Sai Yendamuri, MD, MBA, FACS, Chair of Thoracic Surgery at Roswell Park, will discuss his team’s findings during a major symposium at the annual meeting of the American Association for Cancer Research (AACR) in San Diego, California, April 5-10, 2024. 

Dr. Yendamuri led a research team that included Santosh Patnaik, MD, PhD, Assistant Professor of Oncology, Department of Thoracic Surgery, and Joseph Barbi, PhD, Assistant Professor of Oncology, Department of Immunology.

He points to the use of BMI for measuring obesity as one of two factors that skewed the conclusions of previous studies. “Obesity is second only to smoking as a cause of cancer,” he says. “So it matters how you measure it.” 

While BMI is widely used to define obesity, Dr. Yendamuri and his colleagues have demonstrated that it is deeply flawed. BMI uses a mathematical equation involving height and weight, but it provides only a rough estimate of the percentage of fat in the body. Furthermore, it does not pinpoint where the fat is located or what types of fat are present. Using CT images in a case-control study, the Roswell Park team discovered that patients with early-stage lung cancer had more fat — but not a higher BMI — than those without lung cancer who were at high risk for the disease. 

They also recorded a higher risk of disease recurrence among lung cancer patients treated with surgery who did not have a high BMI but did have a high volume of dangerous visceral fat, which is found between organs in the abdominal cavity. The team’s complementary observations in laboratory studies suggested the reason: Rapidly growing lung tumors appeared to be protected by an obesity-enhanced pool of suppressor leukocytes capable of reining in the immune system’s anticancer response. 

The team confirmed that finding in patients at Roswell Park who were identified as obese by CT imaging rather than BMI. An analysis of leukocytes in their lungs confirmed the team’s hypothesis that the lung microenvironment suppressed the immune response, enabling cancer cells to proliferate.

The Roswell Park researchers emphasize the need for developing more accurate ways to measure obesity, to provide a clearer picture of its impact on lung cancer patients and to inform treatment. 

“When we use measures other than BMI, we find that obesity is harmful, even in lung cancer, underscoring how important it is to accurately identify and measure obesity,” says Dr. Yendamuri. 

“We are hoping that blood-based testing will be the path forward, because not all cancer patients typically get a CT scan. Over the next few years, we hope to identify blood-based biomarkers that will correlate with image-based fat measurements,” he adds. “That way you can actually measure obesity for patients and decide who is metabolically obese rather than relying on weight alone.”

The team also identified a second confounding factor in existing evidence that some commonly prescribed medications have a bonus anticancer effect in obese patients but not nonobese patients. For example, patients who took the drug metformin to control their diabetes had a lower risk of recurrence of early-stage lung cancer after surgical treatment, but only if they had a BMI over 25. At the same time, the tumors of obese patients with late-stage lung cancer who took metformin have been shown to express fewer immune checkpoint molecules — which can prevent the immune system’s T cells from attacking cancer cells — than the tumors of nonobese patients who also took metformin. 

The Roswell Park team has since reproduced these effects in laboratory studies, confirming the strong anticancer effect of metformin in obese cancer models only. Their findings led them to suspect that in obese individuals, the use of metformin could make lung carcinoma tumors more vulnerable to immune checkpoint inhibitors (ICIs), a type of immunotherapy that “releases the brakes” on the immune system to launch a stronger response against cancer cells.

In preclinical studies carried out in Dr. Barbi’s group, indeed, a combination of metformin and checkpoint inhibition stunted tumor growth substantially in obese cancer models. Under these conditions, metformin shifted the balance between effector T cells, which have tumor-killing potential, and suppressor T cells, which keep that response in check, in the tumor microenvironment, making it much less hospitable to cancer cells. 

The team observed the same context-specific benefits of metformin in a retrospective analysis of more than 500 patients treated with immunotherapy at Roswell Park for adenocarcinoma or squamous cell carcinoma — two subtypes that make up more than 90% of lung cancers. The study documented slower disease progression in overweight or obese patients who were treated with a combination of ICIs and metformin.

Dr. Yendamuri and his colleagues speculate that other commonly prescribed drugs, especially those that affect cellular metabolism, may have the same potential to slow cancer progression. A second retrospective study involving 600 patients with early-stage non-small cell lung cancer who underwent surgical treatment at Roswell Park concluded that overweight/obese patients who took statins — drugs given to lower cholesterol — experienced longer recurrence-free survival compared to non-obese patients who did not take statins. 

The Roswell Park team concludes that the design of future studies must account for both the shortcomings of BMI as a means of measuring obesity and for the obesity-specific effects of commonly used medications. 

“The obesity paradox is seen in a few cancers,” notes Dr. Yendamuri. “It confounds our ability to give recommendations to patients — for example, the need to lose weight. If we resolve the paradox, we can come up with clearer recommendations that can help support the most favorable patient outcomes, so these findings have broad implications.”

The investigators gratefully acknowledge support from both public and private funding organizations, including the Roswell Park Alliance Foundation and National Institutes of Health agencies, in making this work possible.
 

AACR 2024 Presentation Details

Abstract SY38-02, “Clinical investigations of obesity in cancer: BMI and other confounders,” Monday, April 8, 10:45-11:05 a.m. PDT, San Diego Conference Center — Room 30, upper level.

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From the world’s first chemotherapy research to the PSA prostate cancer biomarker, Roswell Park Comprehensive Cancer Center generates innovations that shape how cancer is detected, treated and prevented worldwide. Driven to eliminate cancer’s grip on humanity, the Roswell Park team of 4,000 makes compassionate, patient-centered cancer care and services accessible across New York State and beyond. Founded in 1898, Roswell Park was among the first three cancer centers nationwide to become a National Cancer Institute-designated comprehensive cancer center and is the only one to hold this designation in Upstate New York. To learn more about Roswell Park Comprehensive Cancer Center and the Roswell Park Care Network, visit www.roswellpark.org, call 1-800-ROSWELL (1-800-767-9355) or email ASKRoswell@RoswellPark.org.