Estrogen Receptor–Positive, Progesterone Receptor–Negative Breast Cancer: Association With Growth Factor Receptor Expression and Tamoxifen Resistance

Abstract

Background: Clinical data indicate that estrogen receptor–positive/progesterone receptor–negative (ER ⁺ /PR ⁻ ) breast cancers are less sensitive to tamoxifen than are ER ⁺ /PR ⁺ tumors. It has also been reported that tamoxifen may be less effective in tumors that overexpress either HER-2 or HER-1 (epidermal growth factor receptor) and that signaling through these receptors reduces PR expression in experimental models. We hypothesized that ER ⁺ /PR ⁻ breast tumors are more likely than ER ⁺ /PR ⁺ breast tumors to have an aggressive phenotype, to express HER-1 and overexpress HER-2, and are less likely to benefit from tamoxifen adjuvant therapy. Methods: Clinical and biological features of 31 415 patients with ER ⁺ /PR ⁺ tumors were compared with those of 13 404 patients with ER ⁺ /PR ⁻ tumors. Association between disease-free survival (DFS) and HER-1 and HER-2 status was analyzed in a subset of 11 399 patients receiving adjuvant tamoxifen therapy. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression or Kaplan–Meier analyses, and all statistical tests were two-sided. Results: ER ⁺ /PR ⁻ tumors were more frequent in older patients, were larger in size, had a higher S-phase fraction, and were more likely to be aneuploid than ER ⁺ /PR ⁺ tumors. Furthermore, three times as many ER ⁺ /PR ⁻ tumors as ER ⁺ /PR ⁺ tumors expressed HER-1 (25% versus 8%; P <.001) and 50% more overexpressed HER-2 (21% versus 14%; P <.001). Among all tamoxifen-treated women, recurrence was higher among women with HER-1–expressing tumors than with HER-1–negative tumors (HR = 1.9, 95% CI = 1.0 to 3.5; P = .05); a stronger association between worse DFS and HER-2 overexpression was observed (HR = 2.3, 95% CI = 1.2 to 4.3; P = .006). However, results varied by PR status. Among tamoxifen-treated women with ER ⁺ /PR ⁺ tumors, HER-1 or HER-2 status was not associated with worse DFS. Among women with ER ⁺ /PR ⁻ tumors, however, both HER-1 expression (HR = 2.4, 95% CI = 1.0 to 5.4; P = .036) and HER-2 overexpression (HR = 2.6, 95% CI = 1.1 to 6.0; P = .022) were associated with a higher likelihood of recurrence. Conclusions: ER ⁺ /PR ⁻ tumors express higher levels of HER-1 and HER-2 and display more aggressive features than ER ⁺ /PR ⁺ tumors. As in laboratory models, lack of PR expression in ER ⁺ tumors may be a surrogate marker of aberrant growth factor signaling that could contribute to the tamoxifen resistance observed in these tumors.