EGFR and EGFR ligands in serum in healthy women; reference intervals and age dependency

Abstract

Background The epidermal growth factor receptor (EGFR) system is involved in cancer pathogenesis and serves as an important target for multiple cancer treatments. EGFR and its ligands epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF), betacellulin (BTC), amphiregulin (AREG) and transforming growth factor α (TGF-α) have potential applications as prognostic or predictive serological biomarkers in cancer. The aim was to establish EGFR and EGFR ligand reference intervals in healthy women. Methods EGFR and EGFR ligands were measured in serum from 419 healthy women aged 26–78 years. The need for age partitioned reference intervals was evaluated using Lahti’s method. EGFR and EGF were analyzed using ELISA assays, whereas HB-EGF, BTC, AREG and TGF-α were analyzed using the highly sensitive automated single molecule array (Simoa) enabling detection below the lower reference limit for all six biomarkers. Results Reference intervals for EGFR and the EGFR ligands were determined as the 2.5th and 97.5th percentiles. All six biomarkers were detectable in all serum samples. For EGFR, EGF, HB-EGF and TGF-α, reference intervals were established for women <55 years and for women >55 years, whilst common reference intervals were established for AREG and BTC including women aged 26–78 years. Conclusions Age specific reference intervals were determined for EGFR, EGF, HB-EGF, BTC, AREG and TGF-α.

Dysregulated EGFR pathway in serum in early-stage breast cancer patients: A case control study

“…Figure 2 depicts the distributions of the concentrations of S-EGFR (2a), S-EGF (2b), S-HBEGF (2c), S-AREG (2d), S-TGFα (2e), and S-BTC (2f) in breast cancer patients and healthy controls, respectively. The number and fraction of breast cancer patients with levels above, within, and below the age-dependent 95% reference intervals 33 for each of the six biomarkers are presented in Table 3. Elevated S-EGFR was observed in 11.3% of the breast cancer patients, whereas decreased S-EGF was observed in 11.6% of the patients.…”

“…Robust standard errors were applied to all models to account for heteroscedasticity in data. Second, the number and fractions of breast cancer patients with biomarker levels above, within, and below the reference intervals were evaluated using the upper and lower limits of age-dependent 95% reference intervals as cutoffs 33 . Third, we evaluated associations between elevated S-EGFR and decreased S-EGF, respectively, in the breast cancer patients and baseline clinicopathological characteristics using Pearson's Chi square test.…”

“…The prognostic and predictive value of EGFR and EGFR ligands in blood in breast cancer is furthermore still unclear 31 . Highly sensitive methods for measuring EGFR ligands have recently been developed 32,33 which has enabled detection of EGFR ligands with low abundance in the blood. We have previously established age-dependent reference intervals for EGFR and EGFR ligands 33 which enables evaluation of disease related up-or downregulation of EGFR Assays.…”

“…Highly sensitive methods for measuring EGFR ligands have recently been developed 32,33 which has enabled detection of EGFR ligands with low abundance in the blood. We have previously established age-dependent reference intervals for EGFR and EGFR ligands 33 which enables evaluation of disease related up-or downregulation of EGFR Assays. Levels of EGFR and the ligands EGF, HBEGF, AREG, TGF-α, and BTC were measured in all serum samples.…”

“…Levels of EGFR and the ligands EGF, HBEGF, AREG, TGF-α, and BTC were measured in all serum samples. The assays used to analyse the serum samples in the present study have been described in detail in previous studies by Kjaer et al 33 and Olsen et al 32 . S-EGFR and S-EGF were analysed using ELISA tests, whereas S-HBEGF, S-AREG, S-TGFα, and S-BTC were analysed on the Simoa platform; A highly sensitive immunoassay, enabling quantification of very low concentrations of the biomarkers 35 .…”