Clinical Implications of Serum Matrix Metalloproteinase-12 and Tumor Cadherin-13 for Molecular Subtyping and Personalized Therapy in Lung Cancer.

Lung cancer remains a leading cause of cancer-related mortality worldwide, largely due to its biological heterogeneity, frequent late-stage diagnosis, and limitations in comprehensive molecular testing. Single biomarkers are often insufficient for guiding clinical decision-making, highlighting the need for complementary and clinically feasible indicators that integrate systemic and tumor-specific biology. In this single-center cohort study, 262 patients with lung cancer were enrolled. Serum matrix metalloproteinase-12 (MMP-12) levels were measured using enzyme-linked immunosorbent assay (ELISA), and tumor cadherin-13 (CDH13) expression was assessed by immunohistochemistry (IHC) using a validated immunoreactive score (IRS). Molecular subtyping was obtained from routine clinical testing, and associations with treatment response and survival outcomes were evaluated using multivariable logistic and Cox regression models. MMP-12 and CDH13 showed inverse distributions across molecular subtypes (P < 0.001), such that epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-altered tumors exhibited lower MMP-12 and higher CDH13, whereas Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant and wild-type tumors demonstrated the opposite pattern. Higher programmed death-ligand 1 (PD-L1) expression was consistently associated with increased MMP-12 and reduced CDH13 (all P < 0.05). Elevated MMP-12 was independently associated with reduced objective response rate (ORR) (adjusted odds ratio [OR] = 0.662, P < 0.001) and poorer survival (progression-free survival [PFS] hazard ratio [HR] = 1.382; overall survival [OS] HR = 1.421; both P < 0.001), while higher CDH13 predicted improved response (adjusted OR = 1.201, P < 0.001) and survival (PFS HR = 0.884; OS HR = 0.862; both P < 0.001). The combined high MMP-12/low CDH13 signature identified a subgroup with significantly worse outcomes (PFS HR = 2.281; OS HR = 2.506; P < 0.001). These findings suggest that serum MMP-12 and tumor CDH13 may serve as complementary biomarkers for molecular subtyping, therapeutic stratification, and prognostic assessment in lung cancer.