Estrogen receptor-positive, progesterone receptor-negative breast cancer: Association with growth factor receptor expression and tamoxifen resistance

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.