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

J Natl Cancer Inst. 2005 Sep 7;97(17):1254-61. doi: 10.1093/jnci/dji249.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Biomarkers, Tumor / analysis*
  • Breast Neoplasms / chemistry
  • Breast Neoplasms / drug therapy*
  • Chemotherapy, Adjuvant
  • Confidence Intervals
  • Disease-Free Survival
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / analysis*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Middle Aged
  • Odds Ratio
  • Proportional Hazards Models
  • Receptor, ErbB-2 / analysis
  • Receptors, Estrogen / analysis*
  • Receptors, Progesterone / analysis*
  • Tamoxifen / pharmacology*
  • Treatment Outcome
  • Up-Regulation


  • Antineoplastic Agents, Hormonal
  • Biomarkers, Tumor
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Tamoxifen
  • ErbB Receptors
  • Receptor, ErbB-2