Theranostics 2018; 8(22):6386-6399. doi:10.7150/thno.29164

Research Paper

Genomic Landscape and Endocrine-Resistant Subgroup in Estrogen Receptor-Positive, Progesterone Receptor-Negative, and HER2-Negative Breast Cancer

Xi-Yu Liu*, Ding Ma*, Xiao-En Xu, Xi Jin, Ke-Da Yu, Yi-Zhou Jiang, Zhi-Ming Shao

Department of Breast Surgery, Fudan University Shanghai Cancer Center; Cancer Institute, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, P.R. China
*These authors contributed equally to this work.


Estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2 (HER2)-negative (ER+PR-HER2-) breast cancer comprise a special type of breast cancer that constitutes ~10% of all breast cancer patients. ER+PR-HER2- tumor benefits less from endocrine therapy, while its genomic features remain elusive. In this study, we systematically assessed the multiomic landscape and endocrine responsiveness of ER+PR-HER2- breast cancer.

Methods: This study incorporated five cohorts. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n=130,856) and Molecular Taxonomy of Breast Cancer International Consortium (n=1,055) for analyzing survival outcomes and endocrine responsiveness. The third cohort was from The Cancer Genome Atlas (n=630) for multiomic analysis and endocrine-resistant subgroup exploration. The fourth cohort, from the MD Anderson database (n=92), was employed to assist gene selection. The fifth cohort was a prospective observational cohort from Fudan University Shanghai Cancer Center (n=245) that was utilized to validate the gene-defined subgroup by immunohistochemistry (IHC).

Results: Clinically, ER+PR-HER2- tumors showed lower endocrine responsiveness than did ER+PR+HER2- tumors. Genomically, copy number loss or promoter methylation of PR genes occurred in 75% of ER+PR-HER2- tumors, collectively explaining PR loss. ER+PR-HER2- tumors had higher TP53 (30.3% vs. 17.0%) and lower PIK3CA mutation rates (25.8% vs. 42.7%) and exhibited more ZNF703 (21.5% vs. 13.6%) and RPS6KB1 (18.5% vs. 7.8%) amplification events than ER+PR+HER2- tumors. Among ER+PR-HER2- tumors, nearly 20% were of the PAM50-defined non-luminal-like subgroup and manifested lower endocrine sensitivity scores and enriched biosynthesis, metabolism and DNA replication pathways. We further identified the non-luminal-like subgroup using three IHC markers, GATA3, CK5, and EGFR. These IHC-defined non-luminal-like (GATA3-negative, CK5-positive and/or EGFR-positive) tumors received limited benefit from adjuvant endocrine therapy.

Conclusion: ER+PR-HER2- breast cancer consists of clinically and genomically distinct groups that may require different treatment strategies. The non-luminal-like subgroup was associated with reduced benefit from endocrine therapy.

Keywords: ER+PR-HER2-, endocrine resistance, multiomic, non-luminal-like, breast cancer

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How to cite this article:
Liu XY, Ma D, Xu XE, Jin X, Yu KD, Jiang YZ, Shao ZM. Genomic Landscape and Endocrine-Resistant Subgroup in Estrogen Receptor-Positive, Progesterone Receptor-Negative, and HER2-Negative Breast Cancer. Theranostics 2018; 8(22):6386-6399. doi:10.7150/thno.29164. Available from