STAT3 activation in HER2-positive breast cancers: Analysis of data from a large prospective trial

Int J Cancer. 2021 Mar 15;148(6):1529-1535. doi: 10.1002/ijc.33385. Epub 2020 Nov 23.


The JAK/STAT3 signaling pathway may be aberrantly activated and have various and conflicting roles in breast cancer. The current study explored prognostic implications of activated STAT3 in human epidermal growth factor receptor 2 (HER2)-positive primary breast cancers in the context of a large prospective study (ALTTO). Activated STAT3 was determined by immunohistochemical analysis of STAT3 phosphorylation (Y705) performed on the primary tumors. This analysis evaluated whether patients with activated STAT3 had disease-free survival (DFS) and overall survival (OS) different from patients without activated STAT3. A total of 5694 patients out of the 8381 patients enrolled in ALTTO were included in this analysis (67.9%), and 2634 of them (46%) had evidence of STAT3 activation (minimum tumor Allred score ≥2). The median follow-up was 6.93 years (6.85-6.97 years), at the end of which 1035 (18.18%) and 520 (9.13%) patients experienced DFS and OS events, respectively. Patients with STAT3 activation experienced improved DFS compared to those without it (multivariable hazard ratio [HR], 0.84; 95% confidence interval [CI] 0.74-0.95; P = .006). There were no group differences in OS (multivariable HR, 0.92; 95% CI 0.78-1.10; P = .37). This effect was limited to ER-positive tumors. In conclusion, these findings support the role of STAT3 activation as a marker of favorable outcome in ER-positive/HER2-positive breast cancer patients.

Trial registration: NCT00490139.

Keywords: ALTTO; HER2; STAT3; breast cancer; estrogen receptor.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Immunological / therapeutic use
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Disease-Free Survival
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Female
  • Humans
  • Middle Aged
  • Receptor, ErbB-2 / metabolism
  • Receptors, Estrogen / metabolism
  • STAT3 Transcription Factor / metabolism*
  • Trastuzumab / therapeutic use


  • Antineoplastic Agents, Immunological
  • Biomarkers, Tumor
  • Receptors, Estrogen
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab

Associated data