Comorbidities in midlife have distinct associations with cancer development
Key takeaways:
- Respiratory, cardiovascular and metabolic conditions increased risk for cancer incidence.
- All comorbidity types increased risk for at least one cancer type, but some seemed to lower the risk for certain cancers.
Comorbid conditions in midlife may significantly increase or decrease an individual’s risk for developing cancer or specific malignancies, according to results of a retrospective analysis.
Researchers found that people with respiratory, cardiovascular and metabolic conditions had higher risk for developing any cancer. However, individuals with certain comorbidity types had lower risk for some malignancies, such as prostate cancer.
“It’d be easy for me to say, in general, individuals [in midlife with comorbidities] appear to be at higher risk [for developing cancer],’” Lee W. Jones, PhD, study author and head of the exercise oncology program at Memorial Sloan Kettering Cancer Center, told Healio. “That certainly reflects some of the data, but not all the data. ... What this is saying is we need a better understanding. These conditions that we think are distinct are talking to one another, whether that’s in a bad way or maybe even a positive way.”
Cross-disease communication
As an exercise scientist, Jones has dedicated his career to examining how exercise can affect cancer outcomes.
“I’ve always been interested in this intersection between host tumor microenvironment and cancer cell biology,” he said. “I think exercise is one of those interventions that can significantly regulate that interaction.”
That research led Jones and colleagues to begin investigating other cross-disease communications.
Their early work showed heart attacks may have an association with breast cancer growth.
Other mechanistic work showed immune factors that are released to deal with the heart attack also targeted the tumor.
“It’s almost like the breast cancer was a bystander,” he said. “It benefited from all these proinflammatory tumor suppressive immune factors that were released, and that made it grow faster.”
An observational study showed that women with breast cancer had about a 30% higher risk for recurrence if they had experienced a heart attack compared with those who had not.
“When we think about someone who’s been diagnosed with cancer, we’re not thinking about trying to manage these other comorbidities,” Jones said. “I think the focus has been that we need to manage the cancer, but the reality is that all these things are talking to one another.”
Investigating the interactions
Jones and colleagues investigated those interactions using the Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial.
The PLCO, designed to evaluate how screening affects cancer mortality, enrolled individuals aged 55 to 74 years without a history of cancer between 1993 and 2001. Participants self-reported on numerous comorbidities.
Jones and colleagues included 128,999 participants (median age at enrollment, 62 years; interquartile range, 58-66; 50.3% women; 88.4% white) in their study.
They grouped 12 comorbidities into five categories — cardiovascular, metabolic, gastrointestinal, respiratory and liver.
Associations of overall cancer incidence and specific cancer types with comorbidities served as the primary endpoint.
‘This is the starting point’
In all, 38.4% of patients had cardiovascular conditions, 27.6% had metabolic conditions, 16.4% had gastrointestinal conditions, 6.2% had respiratory conditions and 3.5% had liver conditions.
After median follow-up of 20 years, 32,857 cancer cases got diagnosed across 20 malignancy types.
Any cancer incidence occurred significantly more often among patients with respiratory conditions (HR = 1.07; 95% CI, 1.02-1.12), cardiovascular conditions (HR = 1.02; 95% CI, 1-1.05) and metabolic conditions (HR = 1.02; 95% CI, 1-1.05).
Each comorbidity classification significantly increased the risk for at least one specific cancer type.
The highest associations included liver conditions with liver cancer (HR = 5.57; 95% CI, 4.03-7.71); metabolic conditions with liver cancer (HR = 2.04; 95% CI, 1.58-2.65), endometrial cancer (HR = 1.87; 95% CI, 1.62-2.17) and kidney cancer (HR = 1.54; 95% CI, 1.33-1.79); respiratory conditions with lung cancer (HR = 1.8; 95% CI, 1.63-1.98); gastrointestinal conditions with thyroid cancer (HR = 1.5; 95% CI, 1.13-1.99) and breast cancer (HR = 1.46; 95% CI, 1.37-1.57); and cardiovascular conditions with kidney cancer (HR = 1.47; 95% CI, 1.27-1.7) and biliary cancer (HR = 1.42; 95% CI, 1.04-1.94).
“There were some slam dunks,” Jones said.
However, Jones and colleagues also observed associations that surprised them, particularly cancer types that had lower associations with certain comorbidities.
For example, prostate cancer occurred significantly less often among men with respiratory conditions (HR = 0.7; 95% CI, 0.63-0.78), gastrointestinal conditions (HR = 0.6; 95% CI, 0.56-0.64) and metabolic conditions (HR = 0.91; 95% CI, 0.86-0.95).
“It’s fascinating,” Jones said. “[The data are] suggesting that men who basically are sicker are protected from prostate cancer.”
Jones highlighted previous research that showed exercise had associations with higher risk for prostate cancer.
“I think there’s something to that,” he said. “I don’t think this comes down to a screening bias or something else. Maybe there’s something to that that we don’t quite understand.”
Individuals with metabolic conditions also had lower risk for lung cancer (HR = 0.75; 95% CI, 0.69-0.81), head and neck cancer (HR = 0.82; 95% CI, 0.68-0.98) and melanoma (HR = 0.88; 95% CI, 0.79-0.98).
“The type or combination of comorbidities is important,” Jones said. “This is not just the more you have, the worse it is. It’s very specific combinations here that appear to be to influencing the risk.”
Researchers acknowledged study limitations, including self-reporting of comorbidities.
“This is the starting point — it’s not the end point,” Jones said. “It’s hopefully the start of a new wave of research looking at these different cross-disease communications. Hopefully that will lead to some beneficial therapies in the future that can prevent cancer in a large number of individuals.”
‘What is going on here?’
Jones highlighted the need for future investigations to “replicate or validate” the data.
“I want to emphasize that these [data] are hypothesis-generating. They’re not hypothesis-testing,” he said.
Research into the mechanisms behind the associations interested him more, though.
“What’s the message here: If you’re overweight, you’re at low risk of prostate cancer? That’s probably not the message we want,” Jones said. “What is going on there? Why are these individuals seemingly protected?”
Siran M. Koroukian, PhD, professor in the department of population and quantitative health sciences and the Center for Community Health Integration at Case Western Reserve University’s School of Medicine, and colleagues wrote in an accompanying editorial that individual factors also must be considered when investigating these cross-disease associations.
“Multimorbidity is not simply a pathophysiological phenomenon, but it manifests differently depending on the multifaceted context in which it presents,” they said. “Future studies must therefore contextualize these chronic conditions in individuals’ socioeconomic status, social drivers of health, health-related social needs, psychosocial support, access to care, behavioral risk factors, environmental exposures and polypharmacy. Only by accounting for the interconnectedness of these factors can we obtain a comprehensive assessment of individuals’ cancer risk and subsequently personalize treatment strategies.”
References:
- Koelwyn GJ, et al. Nat Med. 2020;doi:10.1038/s41591-020-0964-7.
- Koroukian SM, et al. JAMA Netw Open. 2025;doi:10.1001/jamanetworkopen.2025.3476.
- Lavery JA, et al. JAMA Netw Open. 2025;doi:10.1001/jamanetworkopen.2025.3469.
For more information:
Lee W. Jones, PhD, can be reached at jonesl3@mskcc.org.
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