Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials

Carsten Denkert ¹, Fenja Seither ², Andreas Schneeweiss ³

¹Institute of Pathology, Philipps-Universität Marburg and University Hospital of Giessen and Marburg, Marburg, Germany; German Breast Group, Neu-Isenburg, Germany.
²German Breast Group, Neu-Isenburg, Germany.
³Nationales Centrum für Tumorerkrankungen, Universitätsklinikum und Deutsches Krebsforschungszentrum, Heidelberg, Germany.
⁴Department of Gynecology and Obstetrics, Universitätsklinikum Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany.
⁵Breast Cancer Center, Charité Universitätsmedizin Berlin, Berlin, Germany.
⁶Onkologische Schwerpunktpraxis Bielefeld, Bielefeld, Germany.
⁷Institut für Pathologie, Universitätsklinikum Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany.
⁸Onkologie Bethanien Krankenhaus Frankfurt, Frankfurt, Germany.
⁹Department of Gynecology, Sana Klinikum Offenbach, Offenbach, Germany.
¹⁰Brustzentrum Kassel, Elisabeth Krankenhaus, Kassel, Germany.
¹¹Interdisciplinary Breast Unit, Kliniken Essen Mitte, Essen, Germany.
¹²Department of Gynecology, University of Saarland, Homburg, Germany.
¹³Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany.
¹⁴Frauenklinik München, Rotkreuzklinikum München, München, Germany.
¹⁵Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
¹⁶DIAKOVERE Henriettenstift Gynäkologie, Hannover, Germany.
¹⁷Department of Gynecology and Obstetrics, University Hospital Frankfurt, Frankfurt, Germany.
¹⁸Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
¹⁹Medizinische Fakultät Mannheim, Universität Heidelberg, Universitätsfrauenklinik Mannheim, Germany.
²⁰Department of Obstetrics and Gynecology, University of Rostock, Rostock, Germany.
²¹Department of Obstetrics and Gynecology, Universitätsmedizin Mainz, Mainz, Germany.
²²Department of Gynecology and Obstetrics, University Hospital Ulm, University of Ulm, Ulm, Germany.
²³Clinics for Gynaecology and Obstetrica, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
²⁴Hämatoonkologische Schwerpunktpraxis, München, Germany.
²⁵Breast Cancer Center, Department of Gynecology and Obstetrics, Helios-Klinikum Berlin Buch, Germany.
²⁶German Breast Group, Neu-Isenburg, Germany; Goethe University of Frankfurt, Frankfurt, Germany.

⁰Institute of Pathology, Philipps-Universität Marburg and University Hospital of Giessen and Marburg, Marburg, Germany; German Breast Group, Neu-Isenburg, Germany.

The Lancet. Oncology +

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July 12, 2021

View abstract on PubMed

Summary

HER2-low-positive breast cancer, a new subtype identified by immunohistochemistry (IHC), shows distinct clinical and molecular characteristics compared to HER2-zero breast cancer. This finding impacts treatment strategies and prognosis, particularly for hormone receptor-negative tumors.

Area Of Science

Oncology
Genetics
Pathology

Background

The emergence of anti-HER2 antibody-drug conjugates has created new therapeutic avenues for breast cancer patients, including those with low HER2 expression.
Characterizing HER2-low-positive breast cancer is crucial for understanding its distinct clinical and molecular features and optimizing treatment strategies.

Purpose Of The Study

To compare the clinical and molecular characteristics of HER2-low-positive and HER2-zero breast cancer.
To evaluate the response to neoadjuvant chemotherapy and prognosis in these distinct breast cancer subtypes.

Main Methods

A pooled analysis of 2310 patients with HER2-non-amplified primary breast cancer from four prospective neoadjuvant clinical trials.
HER2 status was determined by central immunohistochemistry (IHC) and in-situ hybridization, defining HER2-low-positive as IHC 1+ or IHC2+/in-situ hybridisation negative, and HER2-zero as IHC0.
Disease-free survival and overall survival data were analyzed using logistic regression and Cox-proportional hazards models.

Main Results

47.5% of tumors were HER2-low-positive, and 52.5% were HER2-zero. HER2-low-positive tumors were more frequently hormone receptor-positive (64.0% vs 36.7%).
HER2-low-positive tumors exhibited a significantly lower pathological complete response rate (29.2% vs 39.0%) compared to HER2-zero tumors, particularly in the hormone receptor-positive subgroup.
Patients with HER2-low-positive tumors demonstrated significantly longer disease-free survival (3-year DFS: 83.4% vs 76.1%) and overall survival (3-year OS: 91.6% vs 85.8%) than those with HER2-zero tumors, especially in the hormone receptor-negative subgroup.

Conclusions

HER2-low-positive breast cancer represents a distinct subtype identifiable by standardized IHC, with unique biological characteristics, therapeutic responses, and prognostic implications.
These findings are particularly relevant for therapy-resistant, hormone receptor-negative tumors, suggesting a need for refined diagnostic and therapeutic strategies.
The study provides a foundation for better understanding breast cancer subtypes and advancing future treatment approaches.