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Multicenter Study
. 2025 Jan;209(1):27-38.
doi: 10.1007/s10549-024-07444-1. Epub 2024 Aug 17.

Prognostic and predictive impact of NOTCH1 in early breast cancer

Julia Engel  1 , Vanessa Wieder  1 , Marcus Bauer  2 , Sandy Kaufhold  1 , Kathrin Stückrath  1 , Jochen Wilke  3 , Volker Hanf  4 , Christoph Uleer  5   6 , Tilmann Lantzsch  7 , Susanne Peschel  8 , Jutta John  9 , Marleen Pöhler  10   11 , Edith Weigert  12   13 , Karl-Friedrich Bürrig  14 , Jörg Buchmann  15 , Pablo Santos  16 , Eva Johanna Kantelhardt  1   16 , Christoph Thomssen #  1 , Martina Vetter #  17
Affiliations
Multicenter Study

Prognostic and predictive impact of NOTCH1 in early breast cancer

Julia Engel et al. Breast Cancer Res Treat. 2025 Jan.

Erratum in

  • Correction: Prognostic and predictive impact of NOTCH1 in early breast cancer.
    Engel J, Wieder V, Bauer M, Kaufhold S, Stückrath K, Wilke J, Hanf V, Uleer C, Lantzsch T, Peschel S, John J, Pöhler M, Weigert E, Bürrig KF, Buchmann J, Santos P, Kantelhardt EJ, Thomssen C, Vetter M. Engel J, et al. Breast Cancer Res Treat. 2025 Jan;209(1):209-210. doi: 10.1007/s10549-024-07520-6. Breast Cancer Res Treat. 2025. PMID: 39565513 Free PMC article. No abstract available.

Abstract

Purpose: Systemic therapy plays a major part in the cure of patients with early breast cancer (eBC). However, personalized treatment concepts are required to avoid potentially harmful overtreatment. Biomarkers are pivotal for individualized therapy. The Notch signalling pathway is widely considered as a suitable prognostic or predictive marker in eBC. This study aimed primarily at assessing the relationship between NOTCH1 mRNA expression levels and histopathological features of breast cancer tumors, as well as clinical characteristics of the correspondent eBC patients. As a secondary aim, we investigated the prognostic and predictive value of NOTCH1 by assessing possible associations between NOTCH1 mRNA expression and recurrence-free interval (RFI) and overall survival after five years of observation.

Patients and methods: The relative NOTCH1 mRNA expression was determined in 414 tumour samples, using quantitative PCR in a prospective, multicenter cohort (Prognostic Assessment in Routine Application (PiA), 2009-2011, NCT01592825) of 1,270 female eBC patients.

Results: High NOTCH1 mRNA expression was detected in one-third of the tumours and was associated with negative hormone receptor status and high uPA/PAI-1 status. In addition, high NOTCH1 mRNA expression was found to be associated with more RFI related events (adjusted hazard ratio 2.1, 95% CI 1.077-4.118). Patients who received adjuvant chemotherapy and had high NOTCH1 mRNA expression in the tumour (n = 86) were three times more likely to have an RFI event (adjusted hazard ratio 3.1, 95% CI 1.321-7.245, p = 0.009).

Conclusion: In this cohort, NOTCH1 mRNA expression had a prognostic and predictive impact. Tumours with high NOTCH1 mRNA expression may be less sensitive to cytotoxic treatment and downregulation of the Notch signalling pathway (e.g. by γ-secretase inhibitors) may be valuable for eBC therapy as an individualised treatment option.

Keywords: Chemotherapy resistance; Early breast cancer; Notch; Prediction; Prognosis.

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Conflict of interest statement

Declarations. Conflict of interest: C.T. resports support from Amgen, AstraZeneca, Aurikamed, Daichi-Synkyo, Forum Sanitas, Gilead, Jörg Eickeler, Hexal, Lilly, Medupdate, MSD, Nanostring, Novartis, Onkowissen, Pfizer, Roche, Seagen, Vifor. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. All other authors have no relevant financial or non-financial interests to disclose. Ethical approval: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of the Medical Faculty of the Martin Luther University Halle-Wittenberg (#214/16.12.09/11). Informed consent: Informed consent was obtained from all subjects involved in the study.

Figures

Fig. 1
Fig. 1
Consort diagram: patients of the PiA-cohort (n = 1270) and groups that were used for multivariate NOTCH1 mRNA expression analyses (n = 414). HR hormone receptor, HER2 human epidermal growth factor receptor 2, NACT neoadjuvant chemotherapy, TNBC triple-negative breast cancer
Fig. 2
Fig. 2
Survival estimates for patients of the Notch-cohort for total Notch-cohort considering NOTCH1 RFI (A) and OS (B); total Notch-cohort considering NOTCH1 and uPA/PAI-1 RFI (C); total Notch-cohort considering NOTCH1 and CT RFI (D), HR positive, HER2 negative, CT-treated RFI (E); HER2 positive, irrespective HR, CT-treated RFI (F); the tables present the effective sample size for each interval (No. at Risk). uPA urokinase-type plasminogen activator, PAI-1 plasminogen activator inhibitor type 1, uPA/PAI-1 low uPA and PAI-1 low, uPA/PAI-1 high uPA and/or PAI-1 high, CT chemotherapy, HR hormone receptor, HER2 human epidermal growth factor receptor 2
Fig. 3
Fig. 3
Benefit of chemotherapy by NOTCH1 low expression visualised as stacked bar graph (blue) Hazard ratios for CT by high and low NOTCH1 expression (no CT as reference) CT chemotherapy, CI confidence interval
See this image and copyright information in PMC

References

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