Not One Diagnosis: How Midlife Diseases Change Cancer Risk - 20-Year Follow-Up of 129,000 People

Oncological risks in middle-aged and older people are formed not only by genetics and lifestyle (smoking, nutrition, activity), but also by the “background” of chronic diseases. By the age of 55–70, most people already have comorbidities — cardiovascular, metabolic, respiratory, liver and gastrointestinal diseases. Biologically, these are not neutral conditions: systemic inflammation, hormonal and metabolic shifts, oxidative stress, changes in the immune response and tissue microenvironment can both accelerate carcinogenesis and — paradoxically — reduce the risk of individual tumors through behavioral factors or diagnostic features.

Short

The authors analyzed data from the famous American screening project PLCO (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial). The sample included 128,999 people aged 55–74 years without a history of cancer. The median follow-up was 20 years. The study was published in the journal JAMA Network Open.

• Comorbidities in midlife are associated with cancer risk—but differently for different cancer types.
• In general, for “any” tumors, the risk is higher in lung diseases and cardiovascular diseases.
• When looking at specific locations, the links become much stronger: from a fivefold increase in the risk of liver cancer in hepatitis/cirrhosis to a reduced risk of a number of tumors against the background of metabolic disorders.
• Even after an oncological diagnosis, the presence of chronic diseases is associated with higher cancer mortality.

What was known until now

• Metabolic disorders (obesity, T2DM, NAFLD) are associated with a higher risk of a number of solid tumors - liver, endometrium, colon, kidney, pancreas. At the mechanistic level, hyperinsulinemia/IGF-1, adipokines, chronic inflammation and steatohepatitis are involved.
• Chronic liver diseases (hepatitis B/C, cirrhosis of any etiology) are one of the strongest known risk factors for hepatocellular carcinoma.
• Respiratory diseases (COPD, chronic bronchitis, emphysema) are associated with lung cancer and probably with some extra-lung tumors through common inflammatory pathways and smoking.
• Cardiovascular diseases are more often considered as prognostic factors in already established cancer (cardiotoxicity of therapy, “frailty”, competing mortality), and their contribution to the risk of primary tumor development has been studied unequally by localization.
• There are also paradoxes. For example, obese people are often found to have a lower risk of lung cancer and some "smoking" tumors - the effect is partly explained by the residual effect of smoking, reverse causality (weight loss before diagnosis) and diagnostic features. Similarly, clinically significant prostate cancer is detected less often in obesity (PSA hemodilution, difficulty of palpation/biopsy).

What kind of research was this?

At the start, participants filled out a questionnaire about chronic diseases. They were grouped into five blocks:

1. Cardiovascular: coronary heart disease/heart attack, stroke, hypertension.
2. GI conditions: inflammatory bowel disease, diverticulosis/diverticulitis, gallstones/gallbladder inflammation.
3. Respiratory: chronic bronchitis or emphysema.
4. Liver: hepatitis or cirrhosis.
5. Metabolic: obesity (BMI ≥30) or type 2 diabetes.

The researchers then tracked first cancer cases (overall and across 19 types) and cancer deaths. Risks were calculated using Cox models with adjustments for age, sex, race/ethnicity, smoking history, and other factors.

How to read the results: HR (hazard ratio) is the ratio of risks.
HR 1.30 = risk is 30% higher; HR 0.70 = risk is 30% lower.

Key findings

"Any cancer" (pan-analysis)

• Lung diseases: HR 1.07 (1.02–1.12) – moderate increase in the overall risk of cancer.
• Cardiovascular: HR 1.02 (1.00–1.05) – small but statistically significant contribution.

When we look at specific types of cancer

• Liver diseases → liver cancer: HR 5.57 (4.03–7.71). The strongest signal of the entire study.
• Metabolic conditions (obesity/T2DM):
  • Increased risk: liver 2.04; endometrium 1.87; kidney 1.54; bile ducts 1.48; thyroid 1.31; rectum 1.28; colon 1.22; pancreas 1.20; hematological 1.14.
  • Risk reduction: lungs 0.75; head and neck 0.82; melanoma 0.88; prostate 0.91.
• Cardiovascular:
  • ↑ risk: kidney 1.47; bile ducts 1.42; upper gastrointestinal tract 1.28; prostate 1.07.
  • ↓ risk: mammary gland 0.93.
• Gastrointestinal conditions:
  • ↑ risk: thyroid 1.50; mammary gland 1.46; kidney 1.39; ovary 1.25.
  • ↓ risk: prostate 0.60.
• Respiratory:
  • ↑ risk: lungs 1.80; pancreas 1.33.
  • ↓ risk: prostate 0.70.

Mortality after cancer diagnosis

• For "any cancer," the risk of dying from cancer was higher with:
  • lung diseases - HR 1.19 (1.11–1.28),
  • cardiovascular - 1.08 (1.04–1.13),
  • metabolic - 1.09 (1.05–1.14).
• By localization, for example, metabolic disorders worsened survival in endometrial cancer (1.45), upper gastrointestinal tract (1.29), hematological tumors (1.23) and prostate cancer (1.16); cardiovascular disorders worsened survival in hematological (1.18) and lung cancer (1.10).

Why is that?

There are several layers of explanation:

• Biology: chronic inflammation, hormonal and metabolic changes, impact on the tumor microenvironment. For example, obesity and T2DM alter insulin/IGF-1, cytokine and adipokine levels — all of which can accelerate carcinogenesis in the liver, endometrium, colon, etc.
• Drugs and behavior: People with metabolic disorders are more likely to use statins/metformin, and less likely to use intense sun exposure and certain types of activity; this may explain the reduced risk of melanoma and some other tumors.
• Diagnostic considerations: Some tumours are more difficult/later to detect in the obese setting; in PLCO this is partly mitigated by standardised screening, but not entirely.

What does this mean for practice?

For doctors

• Consider comorbidity in personalized screening trajectories: for metabolic disorders, pay special attention to the liver, endometrium, intestines, kidney; for respiratory disorders, to the lungs and pancreas, etc.
• If cancer has already been identified, expect more complex management and the need for close coordination with cardiologists, pulmonologists and endocrinologists; work in advance on treatment tolerance (control of blood pressure, glycemia, rehabilitation).

For middle-aged people with chronic diseases

• Basic things work in several directions at once: weight, sugar, pressure, lipids, movement, smoking cessation - this is about the heart and about the prevention of a number of cancers.
• Don't skip screening: colonoscopy/FIT, mammogram, liver evaluation if indicated, talk to your family doctor about the risks.

Important Disclaimers

• Chronic diseases were recorded based on self-report at the start; some conditions were not taken into account.
• This is an observational study: even with correct adjustments, there may be confounding factors (lifestyle, treatment of specific cancers, etc.).
• Participants were volunteers for a screening trial; some groups were limited in representation, meaning generalizability is not absolute.

Why is this work important?

Long-term (≈20 years) follow-up, a very large cohort, uniform screening approaches, and detailed analysis by localization show that “background” chronic disease is not just background. It changes the map of cancer risks and outcomes. The next step is to build comorbidity into risk calculators and clinical pathways, and at the population level, to invest in the prevention of metabolic, cardiovascular, and respiratory diseases as an anti-cancer strategy.