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Genomic Landscape and Endocrine-Resistant Subgroup in Estrogen Receptor-Positive, Progesterone Receptor-Negative, and HER2-Negative Breast Cancer.
- Source :
-
Theranostics [Theranostics] 2018 Dec 08; Vol. 8 (22), pp. 6386-6399. Date of Electronic Publication: 2018 Dec 08 (Print Publication: 2018). - Publication Year :
- 2018
-
Abstract
- 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.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
- Subjects :
- Adolescent
Adult
Aged
Aged, 80 and over
Breast Neoplasms classification
Breast Neoplasms drug therapy
Female
Humans
Middle Aged
Prospective Studies
Receptor, ErbB-2 analysis
Receptors, Estrogen analysis
Receptors, Progesterone analysis
Treatment Outcome
Young Adult
Antineoplastic Agents, Hormonal administration & dosage
Breast Neoplasms pathology
Drug Resistance, Neoplasm
Genotype
Receptor, ErbB-2 genetics
Receptors, Estrogen genetics
Receptors, Progesterone genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1838-7640
- Volume :
- 8
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Theranostics
- Publication Type :
- Academic Journal
- Accession number :
- 30613307
- Full Text :
- https://doi.org/10.7150/thno.29164