Epidermal Growth Factor Expression Prognostic Significance

Numerous studies (16,18,46-48) have been conducted to determine if EGFR can serve as a prognostic factor. In part, conflicting data has resulted from variability in methods used to assay the EGFR protein and the heterogeneity of clinical studies.

Unlike ErbB2 (HER2), which has a Food and Drug Administration approved testing assay [immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH)], no defined analysis exists for the expression of EGFR. EGFR can be evaluated at the DNA, RNA, and protein level (49-52). Several techniques have included IHC (49), Western blotting (49), or enzyme immunoassay (ElA) (53). EGFR protein levels in serum, from breast cancer patients, have been examined using EIA and have been reported to be elevated in 67.5% of patients (53). Radioimmunohistochemistry (RIHC) has also been used to determine EGFR expression and has yielded an overall higher positive rate of EGFR expression (54). Northern analysis and reverse transcriptase polymerase chain reaction can be utilized to detect levels of the EGFR RNA transcript (55). However, as noted by Rampaul et al. (56), such levels may not reflect the levels of protein produced. Kersting et al. (51) studied the correlation between EGFR gene amplification and protein expression in breast cancer utilizing variable technology. The majority of cases that reported EGFR protein overexpression lacked amplifications.

In addition to the variable data that surrounds EGFR testing, clinical studies have not yielded any comforting data regarding the prognostic and predicative value of this marker. A large meta-analysis by Klijn et al. (16) examined EGFR expression in breast cancer from 1984 to 1992 and reported on over 5000 patients. The authors found univariate significance in five studies. EGFR expression correlated with tumor grade in 10 of 18 studies, tumor size in 2 of 17 studies, nodal status in 5 to 9 of 20 studies and proliferative index in 3 of 9 studies. Associations between relapse-free survival and EGFR expression were dependent on time of follow-up with more significant correlations found for short-term follow-up than for long-term follow-up. Fox et al. (57) examined 370 patients with a median follow-up of 18 months. No correlation was reported with size, stage, or grade. Rampaul et al. (58) examined a cohort of patients with primary breast cancer (median follow-up of 222 months) who did not receive adjuvant treatment. Twenty percent of the cases (56; n = 255) were positive for EGFR by IHC. Univariate analysis showed a significant correlation among grade (P < 0.004), Nottingham Prognostic Index (NPI) (P < 0.001), tumor type (P < 0.037), and patient age (P < 0.006) and a highly significant inverse correlation was noted between EGFR and estrogen receptor (ER) (P < 0.001). Multivariate analysis showed significance for only NPI and grade (58).

As illustrated by the studies described, larger scale studies are warranted to strengthen correlations between EGFR and prognosis, metastatic potential and survival.

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