Serum Biomarkers May Prognosticate Recurrence in Node-Negative, Non-Small Cell Lung Cancers Less Than 4 Centimeters

Ann Thorac Surg. 2017 Nov;104(5):1637-1643. doi: 10.1016/j.athoracsur.2017.06.036. Epub 2017 Sep 28.


Background: A significant proportion of patients who undergo lung resection for less than 4 cm non-small cell lung cancer (NSCLC) will die of disease recurrence within 5 years. The ability to identify patients at greatest risk for recurrence may help individualize treatment and surveillance regimens and improve outcomes. We hypothesized that a serum-based biomarker panel could help risk stratify patients with node-negative NSCLC less than 4 cm for recurrence after lung resection.

Methods: An institutional biorepository of more than 1,800 cases was used to identify patients with resected, node-negative NSCLC less than 4 cm in size. Clinical and radiographic data were collected. Preoperative serum specimens were evaluated in a blinded manner for 47 biomarkers that sampled biological processes associated with metastatic progression, including angiogenesis, energy metabolism, apoptosis, and inflammation. Receiver-operating characteristics curves and log rank tests were used to evaluate individual biomarkers with respect to recurrence, followed by random forest analysis to generate and cross validate a multiple-analyte panel to risk stratify patients for recurrence.

Results: The cohort included 123 patients with a median follow-up of 58.2 months; 23 patients had recurrences. A seven-analyte panel consisting of human epididymis protein 4, insulinlike growth factor-binding protein 1, beta-human chorionic gonadotropin, follistatin, prolactin, angiopoietin-2, and hepatocyte growth factor optimally identified patients with disease recurrence with a cross-validated specificity of 91%, sensitivity of 22%, negative predictive value of 83%, positive predictive value of 36%, and accuracy of 78%, providing an area under the receiver-operating characteristics curve of 0.70.

Conclusions: Serum-based biomarkers may be useful for risk stratifying patients with node-negative NSCLC less than 4 cm for recurrence after lung resection.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • Carcinoma, Non-Small-Cell Lung / blood*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Carcinoma, Non-Small-Cell Lung / surgery
  • Cohort Studies
  • Disease-Free Survival
  • Female
  • Humans
  • Lung Neoplasms / blood
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / surgery
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Neoplasm Invasiveness / pathology
  • Neoplasm Recurrence, Local / mortality*
  • Neoplasm Recurrence, Local / pathology*
  • Neoplasm Staging
  • Pneumonectomy / methods
  • Pneumonectomy / mortality
  • Prognosis
  • Retrospective Studies
  • Risk Assessment
  • Survival Analysis
  • Treatment Outcome


  • Biomarkers