Body mass index and fasting insulin predict survival and EGFR-TKI benefit in Stage IV lung adenocarcinoma

Obesity, hyperinsulinemia, and type 2 diabetes mellitus (T2DM) are considered adverse metabolic conditions in cancer, although exceptions like the "obesity paradox" have been reported. Their prognostic significance in advanced lung adenocarcinoma (LUAD), particularly in patients receiving tyrosine kinase inhibitor (TKI) therapy, remains unclear.

We prospectively analyzed 133 consecutive patients with newly diagnosed stage IV LUAD and ECOG performance status 0-1 enrolled between 2020 and 2024. All had ≥3 months of follow-up and T2DM status. BMI was available in 104 patients, glucose and fasting insulin in 46 patients. Primary endpoint was overall survival (OS), assessed using Kaplan-Meier and multivariable Cox regression. Propensity score and interaction analyses evaluated TKI, immune checkpoint inhibitor (ICI), and anti-VEGF therapies.

High BMI, hyperglycemia, hyperinsulinemia, and T2DM were not associated with worse outcomes. In contrast, low BMI (<22.1 kg/m²; P = 0.007, HR 2.56, 95%CI 1.29 - 5.08) and low fasting insulin (≤34 pmol/L; P < 0.001, HR 10.02, 95%CI 2.73-36.8) were independently associated with shorter OS, while EGFR-TKI therapy was associated with improved survival (P = 0.02, HR 0.52). Patients with combined BMI <22.1 kg/m² and insulin <34 pmol/L also derived survival benefit from EGFR-TKI therapy; however, absence of EGFR-TKI in this subgroup was associated with very poor 3-year OS (35%). ICI and anti-VEGF outcomes were not significantly affected.

Low BMI and low fasting insulin identify a metabolically depleted subgroup with poor prognosis in stage IV LUAD, with worse outcomes observed in patients not receiving EGFR-TKI therapy. These parameters may improve risk stratification and support early nutritional and exercise-based interventions.