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HAGE in Triple-Negative Breast Cancer Is a Novel Prognostic, Predictive, and Actionable Biomarker: A Transcriptomic and Protein Expression Analysis

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Abdel-Fatah, Tarek M.A., McArdle, Stephanie E.B., Agarwal, Devika, Moseley, Paul M., Green, Andrew R., Ball, Graham R., Pockley, A. Graham, Ellis, Ian O., Rees, Robert C., Chan, Stephen Y.T.·2016·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-15-0610

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Abstract

Purpose: The expression of HAGE as a novel prognostic and predictive tool was assessed in 1,079 triple-negative breast cancers (TNBC). Experimental Design: HAGE protein expression was investigated in an early primary TNBC (EP-TNBC; n = 520) cohort who received adjuvant chemotherapy (ACT) and in a locally advanced primary TNBC cohort who received anthracycline combination Neo-ACT (n = 110; AC-Neo-ACT). HAGE-mRNA expression was evaluated in the METABRIC-TNBC cohort (n = 311) who received ACT and in a cohort of patients with TNBC who received doxorubicin/cyclophosphamide Neo-ACT, followed by 1:1 randomization to ixabepilone (n = 68) or paclitaxel (n = 64) as part of a phase II clinical trial. Furthermore, a cohort of 128 tumors with integrated HAGE gene copy number changes, mRNA, and protein levels were analyzed. Results: In patients with EP-TNBC, who were chemotherapy-naïve, high HAGE protein expression (HAGE+) was associated with a higher risk of death [HR, 1.3; 95% confidence interval (CI), 1.2–1.5; P = 0.000005] when compared with HAGE− cases. Patients who received ACT and expressed mRNA-HAGE+ were at a lower risk of death than those who were mRNA–HAGE− (P = 0.004). The expression of HAGE was linked to the presence of tumor-infiltrating lymphocytes (TIL), and both features were found to be independent predictors for pathologic complete response (pCR, P < 0.001) and associated with prolonged survival (P < 0.01), following AC-Neo-ACT. In patients with residual disease, HAGE+ had a 2-fold death risk increase (P = 0.018) compared with HAGE−. Conclusions: HAGE expression is a potential prognostic marker and a predictor of response to anthracycline treatment in TNBC. A prospective clinical trial to examine the therapeutic value of HAGE for TNBC cases is warranted. Clin Cancer Res; 22(4); 905–14. ©2015 AACR.

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Metadata

Authors
Abdel-Fatah, T. M. A., McArdle, S. E. B., Agarwal, D., Moseley, P. M., Green, A. R., Ball, G. R., Pockley, A. G., Ellis, I. O., Rees, R. C., & Chan, S. Y. T.
Affiliations
  • Nottingham University Hospitals NHS Trust (GB)
  • 2John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, United Kingdom.
  • Nottingham Trent University (GB)
  • University of Nottingham (GB)
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2016-02-14
Volume
22
Issue
4
Pages
905-914
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-15-0610
OpenAlex
W1838159278
Cited by
20
References
3
Citations by year
2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 5 · 2017: 4 · 2016: 2
FWCI
1.21
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
  • Nottingham Trent University's Institutional Repository (Nottingham Trent Repository) (submittedVersion)
  • Repository@Nottingham (University of Nottingham) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Breast Lesions and Carcinomas
  • Health Sciences › Medicine › Oncology › Gastric Cancer Management and Outcomes
Keywords
Hage, triple-negative breast cancer, prognostic factors, predictive biomarkers, anthracycline response, adjuvant chemotherapy, neoadjuvant chemotherapy, tumor-infiltrating lymphocytes, pathological complete response, gene copy number, ixabepilone, paclitaxel, overall survival
MeSH terms
Adult, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Middle Aged, Neoplasm Proteins, Prognosis, Biomarkers, Tumor, Multivariate Analysis, Lymphocytes, Tumor-Infiltrating, Treatment Outcome, Chemotherapy, Adjuvant, Carcinoma, Ductal, Breast, Disease-Free Survival, Neoadjuvant Therapy, Gene Expression Profiling, Kaplan-Meier Estimate, DEAD-box RNA Helicases, Comparative Genomic Hybridization, DNA Copy Number Variations, Transcriptome, Triple Negative Breast Neoplasms

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