Soluble Human Epidermal Growth Factor Receptor 2 (sHER2) as a Potential Risk Assessment, Screening, and Diagnostic Biomarker of Lung Adenocarcinoma

Abstract

Lung cancer is the leading cause of cancer-related death in the United States. Here, we evaluated the potential clinical utility of soluble human epidermal growth factor receptor 2 (sHER2) for the risk assessment, screening, and diagnosis of non-small cell lung cancer (NSCLC) using an unmatched case-control study design. Serum sHER2 concentrations were measured by immunoassay in 244 primary NSCLC cases and 218 healthy controls. Wilcoxon rank-sum tests, logistic regression models, and receiver operating characteristic plots were used to assess whether sHER2 is associated with lung cancer. Median serum sHER2 concentrations are higher in patients with adenocarcinoma than squamous cell carcinoma regardless of gender, and sHER2 is a weak, independent biomarker of adenocarcinoma, but not of squamous cell carcinoma, adjusted for age and gender. The age-adjusted relative risk (odds) of adenocarcinoma is 3.95 (95% CI: 1.22, 12.81) and 7.93 (95% CI: 2.26, 27.82) greater for women and men with high sHER2 concentrations (≥6.60 ng/mL) vs. low sHER2 concentrations (≤1.85 ng/mL), respectively. When adjusted for each other, sHER2, age, and gender discern healthy controls from patients with primary adenocarcinomas of the lung with 85.9% accuracy. We conclude that even though serum sHER2 is not a strong, stand-alone discriminatory biomarker of adenocarcinoma, sHER2 may be a useful, independent covariate in multivariate risk assessment, screening, and diagnostic models of lung cancer.

Keywords: adenocarcinoma; diagnosis; early detection; non-small cell lung cancer; risk assessment; screening; soluble human epidermal growth factor receptor 2 (sHER2); squamous cell carcinoma (SCC).

Figure 1

Log soluble human epidermal growth factor receptor 2 (sHER2) concentrations vs. age. Log-transformed serum sHER2 concentrations are plotted against age (years) with nonparametric regression curves for healthy men (a), men with non-small cell lung cancer (b), healthy women (c), and women with non-small cell lung cancer (d). Spearman correlations (rho) and p-values are given for each comparison.

Figure 2

Scattergrams of sHER2 concentrations in healthy controls and patients with lung cancer. Serum sHER2 concentrations are compared between healthy men vs. men with non-small cell lung cancer (a), healthy women vs. women with non-small cell lung cancer (b), men with squamous cell carcinoma (SCC) vs. adenocarcinoma (c), and women with SCC vs. adenocarcinoma (d). Each data point represents the median sHER2 concentration for one serum sample assayed in quadruplicate. The horizontal lines indicate the median serum sHER2 concentration for each group of participants. Horizontal lines in the box plot represent the first, second (median), and third quartiles; whiskers extend from the box to a distance of 1.5 interquartile ranges.

Figure 3

Receiver operating characteristic curves for log serum sHER2 concentrations of adenocarcinoma vs. squamous cell carcinoma.ROC curves for log-transformed sHER2 concentrations are shown comparing patients with adenocarcinoma vs. SCC for men (blue ROC curve labeled M) and women (red ROC curve labeled W), respectively.

Figure 4

Receiver operating characteristic curves of lung cancer cases vs. controls. ROC curves are shown comparing all cancer cases vs. healthy controls (a, d, g), SCC vs. healthy controls (b, e, h), and adenocarcinoma vs. healthy controls (c, f, i). ROC curves are shown for a reduced model of log-transformed sHER2 concentrations alone (a, b, c), a model of age alone (d, e, f), and a model including both age and log-transformed sHER2 concentrations (g, h, i) for both men and women combined (black ROC curves labeled C), men only (blue ROC curves labeled M), and women only (red ROC curves labeled W).