Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Dec;16(6):637-647.
doi: 10.1159/000519255. Epub 2021 Oct 19.

Identifying High-Risk Triple-Negative Breast Cancer Patients by Molecular Subtyping

Carolin Hartung  1 , Martin Porsch  2 , Kathrin Stückrath  1 , Sandy Kaufhold  1 , Martin S Staege  3 , Volker Hanf  4 , Tilmann Lantzsch  5 , Christoph Uleer  6 , Susanne Peschel  7 , Jutta John  8 , Marleen Pöhler  9 , Edith Weigert  10 , Jörg Buchmann  11 , Karl-Friedrich Bürrig  12 , Kathleen Schüler  1 , Daniel Bethmann  13 , Ivo Große  2   14 , Eva Johanna Kantelhardt  1 , Christoph Thomssen  1 , Martina Vetter  1
Affiliations

Identifying High-Risk Triple-Negative Breast Cancer Patients by Molecular Subtyping

Carolin Hartung et al. Breast Care (Basel). 2021 Dec.

Abstract

Introduction: Triple-negative breast cancer (TNBC) is considered the most aggressive type of breast cancer (BC) with limited options for therapy. TNBC is a heterogeneous disease and tumors have been classified into TNBC subtypes using gene expression profiling to distinguish basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor (LAR), and one nonclassifiable group (called unstable).

Objectives: The aim of this study was to verify the clinical relevance of molecular subtyping of TNBCs to improve the individual indication of systemic therapy.

Patients and methods: Molecular subtyping was performed in 124 (82%) of 152 TNBC tumors that were obtained from a prospective, multicenter cohort including 1,270 histopathologically confirmed invasive, nonmetastatic BCs (NCT01592825). Treatment was guideline-based. TNBC subtypes were correlated with recurrence-free interval (RFI) and overall survival (OS) after 5 years of observation.

Results: Using PAM50 analysis, 87% of the tumors were typed as basal with an inferior clinical outcome compared to patients with nonbasal tumors. Using the TNBCtype-6 classifier, we identified 23 (15%) of TNBCs as LAR subtype. After standard adjuvant or neoadjuvant chemotherapy, patients with LAR subtype showed the most events for 5-year RFI (66.7 vs. 80.6%) and the poorest probability of 5-year OS (60.0 vs. 84.4%) compared to patients with non-LAR disease (RFI: adjusted hazard ratio [aHR] = 1.87, 95% confidence interval [CI] 0.69-5.05, p = 0.211; OS: aHR = 2.74, 95% CI 1.06-7.10, p = 0.037).

Conclusion: Molecular analysis and subtyping of TNBC may be relevant to identify patients with LAR subtype. These cancers seem to be less sensitive to conventional chemotherapy, and new treatment options, including androgen receptor-blocking agents and immune checkpoint inhibitors, have to be explored.

Keywords: Early breast cancer; Luminal androgen receptor; Molecular triple-negative breast cancer subtypes; Prognosis; Triple-negative breast cancer.

PubMed Disclaimer

Conflict of interest statement

C. Hartung, M. Porsch, K. Stückrath, S. Kaufhold, M.S. Staege, V. Hanf, S. Peschel, J. John, M. Pöhler, E. Weigert, J. Buchmann, K.-F. Bürrig, K. Schüler, D. Bethmann, I. Große, and E.J. Kantelhardt have no conflicts of interest to declare. T. Lantzsch reports personal honoraria from Pfizer, Astra Zeneca, Lilly, Roche, and Novartis, all outside the submitted work. C. Uleer reports personal honoraria from Astra Zeneca, Novartis, Onkowis, Pierre Fabre, Roche, and Seagen, all outside the submitted work. C. Thomssen reports personal honoraria from Amgen, Astra Zeneca, Celgene, Daiichi-Sankyo, Eisai, Lilly, MEDA-Pharma, MSD, Novartis, Pfizer, Pierre-Fabre, Roche, and Vifor, all outside the submitted work. M. Vetter got travel support from NanoString.

Figures

Fig. 1
Fig. 1
Enrolment of TNBC patients (n = 152) of the PiA cohort (n = 1,270) and RNA samples for molecular subtyping (n = 124). TNBC, triple-negative breast cancer.
Fig. 2
Fig. 2
TNBC subtypes correlated with PAM50 intrinsic molecular types (n = 124). TNBC, triple-negative breast cancer.
Fig. 3
Fig. 3
TNBCtype-6 Kaplan-Meier plots. The tables present the effective sample size for each interval (number at risk). A, B All subdivided stable subtypes RFI (A) and OS (B). C, D Summarized groups LAR versus non-LAR subtypes RFI (C) and OS (D). LAR, luminal androgen receptor; OS, overall survival; RFI, recurrence-free interval.
Fig. 4
Fig. 4
Correlation of androgen receptor (A) and MKI67 (Ki-67) (B) RNA expression to LAR subtype (n = 124). LAR, luminal androgen receptor.
See this image and copyright information in PMC

References

    1. Metzger-Filho O, Tutt A, de Azambuja E, Saini KS, Viale G, Loi S, et al. Dissecting the heterogeneity of triple-negative breast cancer. J Clin Oncol. 2012;30:1879–87. - PubMed
    1. Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol. 2016;13:674–90. - PMC - PubMed
    1. Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486:395–9. - PMC - PubMed
    1. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164–72. - PubMed
    1. Rida P, Ogden A, Ellis IO, Varga Z, Wolff AC, Traina TA, et al. First international TNBC conference meeting report. Breast Cancer Res Treat. 2018;169:407–12. - PMC - PubMed

LinkOut - more resources