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

Carolin Hartung; Martin Porsch; Kathrin Stückrath; Sandy Kaufhold; Martin S Staege; Volker Hanf; Tilmann Lantzsch; Christoph Uleer; Susanne Peschel; Jutta John; Marleen Pöhler; Edith Weigert; Jörg Buchmann; Karl-Friedrich Bürrig; Kathleen Schüler; Daniel Bethmann; Ivo Große; Eva Johanna Kantelhardt; Christoph Thomssen; Martina Vetter

doi:10.1159/000519255

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

Breast Care (Basel). 2021 Dec;16(6):637-647. doi: 10.1159/000519255. Epub 2021 Oct 19.

Authors

Carolin Hartung¹, Martin Porsch², Kathrin Stückrath¹, Sandy Kaufhold¹, Martin S Staege³, Volker Hanf⁴, Tilmann Lantzsch⁵, Christoph Uleer⁶, Susanne Peschel⁷, Jutta John⁸, Marleen Pöhler⁹, Edith Weigert¹⁰, Jörg Buchmann¹¹, Karl-Friedrich Bürrig¹², Kathleen Schüler¹, Daniel Bethmann¹³, Ivo Große^{2

14}, Eva Johanna Kantelhardt¹, Christoph Thomssen¹, Martina Vetter¹

Affiliations

¹ Department of Gynecology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
² Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
³ Department of Surgical and Conservative Pediatrics and Adolescent Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
⁴ Department of Gynecology, Nathanstift, Hospital Fürth, Fürth, Germany.
⁵ Department of Gynecology, Hospital St. Elisabeth and St. Barbara, Halle (Saale), Germany.
⁶ Gynäkologisch-Onkologische Praxis, Hildesheim, Germany.
⁷ Department of Gynecology, St. Bernward Hospital, Hildesheim, Germany.
⁸ Department of Gynecology, Helios Hospital Hildesheim, Hildesheim, Germany.
⁹ Department of Gynecology, Asklepios Hospital Goslar, Goslar, Germany.
¹⁰ Institute of Pathology, Hospital Fürth, Fürth, Germany.
¹¹ Institute of Pathology, Hospital Martha-Maria, Halle (Saale), Germany.
¹² Institute of Pathology Hildesheim, Hildesheim, Germany.
¹³ Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
¹⁴ German Centre for Integrative Biodiversity Research (iDiv), Halle-Jena-Leipzig, Germany.

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.