. 2025 Feb 14;27(1):22.

doi: 10.1186/s13058-025-01969-z.

HER2-low status as a distinct breast cancer subtype: myth or truth? Analysis of the WSG trials WSG-ADAPT-HR+/HER2-, WSG-PlanB, and WSG-ADAPT-TN

Gilda Schmidt¹, Oleg Gluz^{2

3

4}, Matthias Christgen⁵, Mattea Reinisch^{6

7}, Sherko Kümmel^{2

6

8}, Ulrike Nitz^{2

3}, Michael Braun⁹, Bahriye Aktas^{10

11}, Kerstin Lüdtke-Heckenkamp¹², Helmut Forstbauer¹³, Eva-Maria Grischke¹⁴, Claudia Schumacher¹⁵, Rolf Mahlberg¹⁶, Wolfram Malter¹⁷, Toralf Reimer¹⁸, Benno Nuding¹⁹, Andrea Stefek²⁰, Rachel Wuerstlein^{2

21}, Monika Graeser^{2

3

22}, Katarzyna Jóźwiak²³, Sandy Burmeister²³, Christine Zu Eulenburg^{2

24}, Michael Lauseker²⁵, Cornelia Kolberg-Liedtke^{26

27}, Aleix Prat^{28

29

30

31}, Peter Schmid³², Rick Baehner³³, Hans Heinrich Kreipe⁵, Erich-Franz Solomayer³⁴, Nadia Harbeck^{2

21}; West German Stud y Group investigators

Affiliations

¹ Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Medical Center, Homburg, Germany. gilda.schmidt@uks.eu.
² West German Study Group, Moenchengladbach, Germany.
³ Breast Center Niederrhein, Ev. Hospital Bethesda, Moenchengladbach, Germany.
⁴ University Clinics Cologne, Cologne, Germany.
⁵ Institute of Pathology, Hannover Medical School, Hannover, Germany.
⁶ Department of Gynecology with Breast Center, Charité - University Medicine Berlin, Berlin, Germany.
⁷ Interdisciplinary Breast Center, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
⁸ Breast Unit, Clinics Essen-Mitte, Essen, Germany.
⁹ Breast Center, Rotkreuz Clinics Munich, Munich, Germany.
¹⁰ University Clinics Leipzig, Women's Clinic, Leipzig, Germany.
¹¹ Breast Center, Department of Gynecology and Obstetrics, University Hospital of Essen, Essen, Germany.
¹² Department of Oncology and Hematology, Niels Stensen-Kliniken, Georgsmarienhütte, Germany.
¹³ Praxis Dr. H. Forstbauer, C. Ziske, R. Reihs, E. Rodermann, A. Diel, Troisdorf, Germany.
¹⁴ University Clinics Tübingen, Women's Clinic, Tuebingen, Germany.
¹⁵ . Elisabeth Hospital, Cologne, Germany.
¹⁶ Klinikum Mutterhaus Der Borromäerinnen, Trier, Germany.
¹⁷ Women's Clinic and Breast Center, University Clinics Cologne, Cologne, Germany.
¹⁸ University Hospital Gynecology and Policlinic Rostock, Rostock, Germany.
¹⁹ Ev. Hospital Bergisch Gladbach, Bergisch Gladbach, Germany.
²⁰ Johanniter Women's Clinic Stendal, Stendal, Germany.
²¹ Breast Center, Department of Gynecology and Obstetrics and CCCMunich, LMU University Hospital Munich, BZKF, Munich, Germany.
²² Department of Gynecology, University Medical Center Hamburg, Hamburg, Germany.
²³ Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany.
²⁴ Department of Medical Biometry and Epidemiology, University Medical Center Hamburg, Hamburg, Germany.
²⁵ LMU University Hospital Munich, Munich, Germany.
²⁶ Charité, Women's Clinic, Berlin, Berlin, Germany.
²⁷ Women's Clinic, University Clinics Essen, Essen, Germany.
²⁸ Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
²⁹ Reveal Genomics, Barcelona, Spain.
³⁰ Medicine Department, University of Barcelona, Barcelona, Spain.
³¹ Breast Cancer Unit, IOB-QuirónSalud, Barcelona, Spain.
³² Queen Mary University of London, London, UK.
³³ Exact Sciences, Redwood City, CA, USA.
³⁴ Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Medical Center, Homburg, Germany.

PMID: 39953511
PMCID: PMC11827153
DOI: 10.1186/s13058-025-01969-z

HER2-low status as a distinct breast cancer subtype: myth or truth? Analysis of the WSG trials WSG-ADAPT-HR+/HER2-, WSG-PlanB, and WSG-ADAPT-TN

Gilda Schmidt et al. Breast Cancer Res. 2025.

. 2025 Feb 14;27(1):22.

doi: 10.1186/s13058-025-01969-z.

Authors

Affiliations

¹ Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Medical Center, Homburg, Germany. gilda.schmidt@uks.eu.
² West German Study Group, Moenchengladbach, Germany.
³ Breast Center Niederrhein, Ev. Hospital Bethesda, Moenchengladbach, Germany.
⁴ University Clinics Cologne, Cologne, Germany.
⁵ Institute of Pathology, Hannover Medical School, Hannover, Germany.
⁶ Department of Gynecology with Breast Center, Charité - University Medicine Berlin, Berlin, Germany.
⁷ Interdisciplinary Breast Center, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
⁸ Breast Unit, Clinics Essen-Mitte, Essen, Germany.
⁹ Breast Center, Rotkreuz Clinics Munich, Munich, Germany.
¹⁰ University Clinics Leipzig, Women's Clinic, Leipzig, Germany.
¹¹ Breast Center, Department of Gynecology and Obstetrics, University Hospital of Essen, Essen, Germany.
¹² Department of Oncology and Hematology, Niels Stensen-Kliniken, Georgsmarienhütte, Germany.
¹³ Praxis Dr. H. Forstbauer, C. Ziske, R. Reihs, E. Rodermann, A. Diel, Troisdorf, Germany.
¹⁴ University Clinics Tübingen, Women's Clinic, Tuebingen, Germany.
¹⁵ . Elisabeth Hospital, Cologne, Germany.
¹⁶ Klinikum Mutterhaus Der Borromäerinnen, Trier, Germany.
¹⁷ Women's Clinic and Breast Center, University Clinics Cologne, Cologne, Germany.
¹⁸ University Hospital Gynecology and Policlinic Rostock, Rostock, Germany.
¹⁹ Ev. Hospital Bergisch Gladbach, Bergisch Gladbach, Germany.
²⁰ Johanniter Women's Clinic Stendal, Stendal, Germany.
²¹ Breast Center, Department of Gynecology and Obstetrics and CCCMunich, LMU University Hospital Munich, BZKF, Munich, Germany.
²² Department of Gynecology, University Medical Center Hamburg, Hamburg, Germany.
²³ Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany.
²⁴ Department of Medical Biometry and Epidemiology, University Medical Center Hamburg, Hamburg, Germany.
²⁵ LMU University Hospital Munich, Munich, Germany.
²⁶ Charité, Women's Clinic, Berlin, Berlin, Germany.
²⁷ Women's Clinic, University Clinics Essen, Essen, Germany.
²⁸ Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
²⁹ Reveal Genomics, Barcelona, Spain.
³⁰ Medicine Department, University of Barcelona, Barcelona, Spain.
³¹ Breast Cancer Unit, IOB-QuirónSalud, Barcelona, Spain.
³² Queen Mary University of London, London, UK.
³³ Exact Sciences, Redwood City, CA, USA.
³⁴ Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Medical Center, Homburg, Germany.

PMID: 39953511
PMCID: PMC11827153
DOI: 10.1186/s13058-025-01969-z

Abstract

Background: New data show that not only HER2-overexpressing breast cancer (BC) tumors but also HER2-low tumors, classically considered as HER2-negative, respond to HER2-targeting antibody-drug-conjugates. Our objective was to analyze the prevalence of HER2-low BC in a pooled analysis of contemporary early BC trials and to evaluate its role as a prognostic factor in terms of survival in comparison to HER2-zero BC.

Methods: We evaluated 5598 patients with locally HR + /HER2- BC from the screening cohort of WSG-ADAPT-HR + /HER2-, 2592 patients with HR + /HER2- or HR-/HER2- from the adjuvant WSG-PlanB trial, and 336 patients from the WSG-ADAPT-TN trial. Central HER2 testing was performed prospectively in WSG-ADAPT and retrospectively in WSG-PlanB. Following ASCO/CAP guidelines, HER2-low status was defined as immunohistochemistry (IHC) 1 + or 2 + and in situ hybridization (ISH)-negative, and HER2-zero was defined as IHC 0. Agreement between HER2 assessments was evaluated with Cohen's kappa coefficient, and effects of HER2 status on pathological complete response (pCR) and on survival were analyzed with logistic regression and Cox proportional hazards models, respectively.

Findings: In WSG-ADAPT-HR + /HER2-, 3198 (64.6%) tumors were HER2-low by the central and 3096 (55.6%) by the local histology (agreement for HER2-low status was 61.0%). In HR + /HER2- cases from WSG-PlanB, 601 tumors (28.7%) were HER2-low. In both cohorts, HER2-low status was significantly associated with higher ERBB2 mRNA expression by Oncotype DX test in comparison to HER2-zero: mean 9.3 vs. 9.1 (p < .001) by local HER2 assessment in WSG-ADAPT and mean 9.2 vs. 8.8 (p < .001) in WSG-PlanB. Furthermore, patients with HER2-low tumors in WSG-ADAPT-HR + /HER2- significantly less often had a pCR compared to the HER2-zero tumors (p = .015). No significant difference was observed in (invasive and/or distant) disease-free survival (DFS) between centrally HER2-low and HER2-zero tumors in both HR + /HER2- cohorts (WSG-ADAPT-HR + /HER2- distant DFS: unadjusted HR = 1.06, 95%CI 0.83-1.36, similar results for local assessment; WSG-PlanB DFS: unadjusted HR = 1.28, 95%CI 0.91-1.82). In the HR-/HER2- WSG-PlanB cohort, centrally HER2-low tumors (10.5%) were associated with better DFS (unadjusted HR = 0.21, 95%CI 0.05-0.83), this association was not observed in the WSG-ADAPT-TN.

Conclusion: The prevalence of HER2-low status varied between the analyzed trials. Our results show that survival does not differ between HER2-low and HER2-zero tumors in HR + /HER2- cohorts; however, HER2-low status appears to have an inconsistent impact on survival in TNBC. Therefore, our findings do not support the characterization of HER2-low status as a distinct BC subtype.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: WSG-ADAPT und PlanB trials were approved by institutional ethic boards and ethic committees, and national authorities and were conducted according to Declaration of Helsinki. All patients have signed consent to participate. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.Supplementary

Figures

**Fig. 1**
A HER2 assessment by local and the first and second central assessment and B changes in HER2 status between the first and the second central assessment in the WSG-ADAPT-HR + /HER2- trial

**Fig. 2**
A HER2 assessment by local and the first and second central assessment and B changes in HER2 status between the first and the second central assessment in the WSG-ADAPT-TN trial

**Fig. 3**
iDFS according to changes in HER2 status between the first and the second central IHC assessment in patients from the WSG-ADAPT-TN trial

See this image and copyright information in PMC

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HER2-low status as a distinct breast cancer subtype: myth or truth? Analysis of the WSG trials WSG-ADAPT-HR+/HER2-, WSG-PlanB, and WSG-ADAPT-TN

Affiliations

HER2-low status as a distinct breast cancer subtype: myth or truth? Analysis of the WSG trials WSG-ADAPT-HR+/HER2-, WSG-PlanB, and WSG-ADAPT-TN

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous