AAT C-Terminal Peptides Show Independent Prognostic Value in Early-Stage NSCLC

Risk assessment in resected non–small cell lung cancer continues to rely heavily on clinicopathologic features. While helpful, these markers cannot fully account for individual biology. Protease activity, a process central to tumor invasion and tissue remodeling, may offer a more nuanced window into prognosis. The ability to measure this biology directly in serum through peptide fragments of alpha-1 antitrypsin (AAT) could refine how clinicians identify patients at higher risk after surgery.

Researchers in Germany analyzed preoperative serum from 222 patients with stage I to III non-small cell lung cancer. They quantified nine proteolytic fragments of AAT using LC-MS/MS, focusing on three peptides—C36, C37, and C42—that were consistently measurable. Associations with overall survival were assessed using multivariable models that adjusted for age, sex, performance status, stage, histology, and smoking history. A smaller subset also provided samples after surgery to explore postoperative dynamics.

Signals that Stood Out

Baseline peptide levels were strongly intercorrelated and moderately linked to full-length AAT, but not to tumor size or systemic inflammatory markers. Smoking status emerged as an important modifier; current smokers and those who had quit within six months showed higher peptide concentrations than never-smokers or long-term quitters.

Clinically, the most notable finding was survival discrimination. Elevated C37 and C42 independently predicted shorter overall survival, even after adjustment for standard covariates. C36 showed a weaker but still suggestive trend. These associations paralleled those seen with full-length AAT, strengthening the link between protease-related biology and outcome.

C-terminal AAT peptides act less as broad inflammatory signals and more as readouts of protease activity. C36 likely reflects serine protease cleavage, while C37 and C42 map to metalloproteinase activity. Importantly, their prognostic associations appear tied to enzyme activity rather than gene expression, underscoring the advantage of functional biomarkers over transcriptional surrogates. For clinicians, the potential lies in integrating serum C37 and C42 levels into preoperative workups as an additional dimension of risk alongside established clinicopathologic features.

Unexpectedly, peptide levels rose after surgery, with both absolute concentrations and peptide-to-AAT ratios increasing in the months following resection. This pattern likely reflects tissue remodeling and wound healing rather than tumor burden. From a practical perspective, it highlights the importance of timing; preoperative baselines or later, steady-state samples may provide more reliable prognostic information than early postoperative draws.

These findings stem from a retrospective, single-cohort analysis. External validation is essential, and cutoffs were derived within the study population. While biologically plausible, the protease activity hypothesis remains indirect, as serum enzyme activity was not measured. Smoking may still confound results despite statistical adjustment. Finally, broader adoption will require assay harmonization, since LC-MS/MS quantification can vary across laboratories.

Clinical Takeaways

Serum-derived AAT peptides—particularly C37 and C42—appear to reflect a protease-driven biology that carries prognostic weight in resected non-small cell lung cancer. While not yet ready for routine use, they add dimension to how clinicians might think about risk beyond stage and histology.

If validated in larger, prospective settings, these peptides could support more individualized surveillance or treatment planning and contribute to a broader biomarker toolkit in early-stage lung cancer.

Reference
Schneider MA, Boerner FR, Kiehntopf M, Muley T, Janciauskiene S. Serum levels of C-terminal peptides of alpha-1 antitrypsin as potential biomarkers in non-small cell lung cancer. Transl Lung Cancer Res. 2025;14(6):2113-2124. doi:10.21037/tlcr-2025-178