Epidermal growth factor receptor expression in breast cancer association with biologic phenotype and clinical outcomes

Abstract

Background: Epidermal growth factor receptor (EGFR) expression is associated with aggressive phenotypes in preclinical breast cancer models, but in clinical studies, EGFR has been inconsistently linked to poor outcome. We hypothesized that EGFR expression in human breast tumors, when centrally and uniformly assessed, is associated with an aggressive phenotype and resistance to systemic therapy.

Methods: In a database of 47,286 patients with breast cancer, EGFR status was known on 2567 tumors. EGFR levels were measured centrally by ligand binding assay, and tumors with > or =10 fmol/mg were prospectively deemed positive. Clinical and biological features of EGFR-positive and EGFR-negative tumors were compared. Clinical outcomes were assessed by systemic therapy status.

Results: Of 2567 tumors, 475 (18%) were EGFR positive. EGFR-positive tumors were more common in younger and in black women, were larger, had a higher S-phase fraction, and were more likely to be aneuploid. EGFR-positive tumors were more likely to be HER2-positive (26% vs 16%, P < .0001), but less likely to be estrogen receptor-positive (60% vs 88%, P < .0001) or progesterone receptor-positive (26% vs 65%, P < .0001). In multivariate analyses, EGFR expression independently correlated with worse disease-free survival (hazard ratio [HR] = 1.66; 95% confidence interval [CI], 1.4-2.41, P = .007) and overall survival (HR = 1.98, 95% CI, 1.36-2.88, P = .0004) in treated patients, but not in untreated patients.

Conclusions: EGFR expression is more common in breast tumors in younger and black women. It is associated with lower hormone receptor levels, higher proliferation, genomic instability, and HER2 overexpression. It is correlated with higher risk of relapse in patients receiving adjuvant treatment. Blocking EGFR may improve outcome in selected patients.

Figure 1

EGFR concentration histogram: EGFR concentration was determined using ligand binding assay. Tumors with protein concentration of ≥10fmol/mg membrane protein were prospectively deemed positive. Of the tumors with known EGFR status, 18% (n=475) were EGFR positive and 82% (n=2092) were EGFR negative. EGFR levels of EGFR-positive tumors varied widely (10–11084 fmol/mg) but 90% had concentrations less than 100 fmol/mg.

Figure 2

Kaplan-Meier curves for disease-free survival by EGFR status. A) In patients who did not receive any adjuvant systemic therapy (untreated patients), HR = 1.37, 95% CI (0.85 – 2.21), (p=0.20). B) In patients who received any form of adjuvant systemic therapy: chemotherapy, hormonal therapy, or both (treated patients), HR = 1.77, 95% CI (1.36 – 2.29), (p<0.0001).

Figure 2

Kaplan-Meier curves for disease-free survival by EGFR status. A) In patients who did not receive any adjuvant systemic therapy (untreated patients), HR = 1.37, 95% CI (0.85 – 2.21), (p=0.20). B) In patients who received any form of adjuvant systemic therapy: chemotherapy, hormonal therapy, or both (treated patients), HR = 1.77, 95% CI (1.36 – 2.29), (p<0.0001).

Figure 3

Kaplan-Meier curves for disease-free survival by EGFR status. A) In patients who received any adjuvant chemotherapy, HR = 1.30, 95% CI (0.91 – 1.86), (p=0.15). B) In patients who received adjuvant hormonal therapy, HR = 1.99, 95% CI (1.13 – 3.49), (p=0.015). C) In patients who received both chemotherapy and hormonal therapy, HR = 2.20, 95% CI (1.30 – 3.71), (p=0.003).

Figure 3

Kaplan-Meier curves for disease-free survival by EGFR status. A) In patients who received any adjuvant chemotherapy, HR = 1.30, 95% CI (0.91 – 1.86), (p=0.15). B) In patients who received adjuvant hormonal therapy, HR = 1.99, 95% CI (1.13 – 3.49), (p=0.015). C) In patients who received both chemotherapy and hormonal therapy, HR = 2.20, 95% CI (1.30 – 3.71), (p=0.003).

Figure 3

Kaplan-Meier curves for disease-free survival by EGFR status. A) In patients who received any adjuvant chemotherapy, HR = 1.30, 95% CI (0.91 – 1.86), (p=0.15). B) In patients who received adjuvant hormonal therapy, HR = 1.99, 95% CI (1.13 – 3.49), (p=0.015). C) In patients who received both chemotherapy and hormonal therapy, HR = 2.20, 95% CI (1.30 – 3.71), (p=0.003).

Figure 4

Kaplan-Meier curves for post-relapse survival by EGFR status. In the subgroup that suffered tumor relapse (n=416), patients whose primary tumors were EGFR-positive had a significantly worse post-relapse survival than those with EGFR negative primary tumors, (HR = 1.72, 95% CI (1.34 – 2.20), p < 0.0001).