Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry

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Abstract

Background

About 50% of all primary breast cancers show a low-level expression of HER2 (HER2-low), defined as immunohistochemically 1+ or 2+ and lack of HER2 gene amplification measured by in situ hybridization. This low HER2 expression is a promising new target for antibody–drug conjugates (ADCs) currently under investigation. Until now, little is known about the frequency and the prognostic value of low HER2-expression in metastatic breast cancer (MBC).

Patients and methods

The MBC-Registry of the Austrian Study Group of Medical Tumor Therapy (AGMT) is a multicenter nationwide ongoing registry for MBC patients in Austria. Unadjusted, univariate survival probabilities of progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan–Meier method and compared by the log-rank test. Multivariable adjusted hazard ratios were estimated by Cox regression models. In this analysis, only patients with known HER2 status and available survival data were included.

Results

As of 11/15/2020, 1,973 patients were included in the AGMT-MBC-Registry. Out of 1,729 evaluable patients, 351 (20.3%) were HER2-positive, 608 (35.2%) were HER2-low and 770 (44.5%) were completely HER2-negative (HER2-0). Low HER2-expression was markedly more frequent in the hormone-receptor(HR)+ subgroup compared to the triple-negative subgroup (40% vs. 23%). In multivariable analysis, low HER2 expression did not significantly influence OS neither in the HR+ (HR 0.89; 95% CI 0.74–1.05; P = 0.171) nor in the triple-negative subgroup (HR 0.92; 95% CI 0.68–1.25; P = 0.585), when compared to completely HER2-negative disease. Similar results were observed when HER2 IHC 2+ patients were compared to IHC 1+ or 0 patients.

Conclusion

Low-HER2 expression did not have any impact on prognosis of metastatic breast cancer in this real-world population.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13058-021-01492-x.

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Most cited references 26

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Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update

Antonio Wolff, M. Hammond, Kimberly H. Allison … (2018)

Purpose To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists human epidermal growth factor receptor 2 (HER2) testing in breast cancer guideline. Methods Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations. Recommendations Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in > 10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended work-up for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 ( HER2/chromosome enumeration probe 17 [CEP17] ratio ≥ 2.0; average HER2 copy number < 4.0 signals per cell), ISH group 3 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 6.0 signals per cell), and ISH group 4 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 4.0 and < 6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays. The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results. Find additional information at www.asco.org/breast-cancer-guidelines .

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Strategies and challenges for the next generation of antibody–drug conjugates

Alain Beck, Liliane Goetsch, Charles Dumontet … (2017)

Antibody–drug conjugate (ADCs), which aim to target highly cytotoxic drugs specifically to cancer cells, are one of the fastest growing classes of anticancer therapeutics, with more than 50 such agents currently in clinical trials. This Review discusses lessons learned and emerging strategies in the development of ADCs, including aspects such as target selection, the development of warheads, the optimization of linkers and new conjugation chemistries, and provides an overview of agents that are currently in clinical trials.

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DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1.

Tetsuo Aida, Yusuke Ogitani, Shingo Arakawa … (2016)

An anti-HER2 antibody-drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed.

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Author and article information

Contributors

Richard Greil:

ORCID: http://orcid.org/0000-0002-4462-3694

r.greil@salk.at

Journal

Journal ID (nlm-ta): Breast Cancer Res

Journal ID (iso-abbrev): Breast Cancer Res

Title: Breast Cancer Research : BCR

Publisher: BioMed Central (London )

ISSN (Print): 1465-5411

ISSN (Electronic): 1465-542X

Publication date (Electronic): 14 December 2021

Publication date PMC-release: 14 December 2021

Publication date (Print): 2021

Volume: 23

Electronic Location Identifier: 112

Affiliations

[1 ]GRID grid.21604.31, ISNI 0000 0004 0523 5263, Department of Internal Medicine III With Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, , Paracelsus Medical University Salzburg, ; Müllner Hauptstraße 48, 5020 Salzburg, Austria

[2 ]Laboratory for Immunological and Molecular Cancer Research (LIMCR) and Center for Clinical Cancer and Immunology Trials (CCCIT), Salzburg Cancer Research Institute (SCRI), Salzburg, Austria

[3 ]Cancer Cluster Salzburg, Salzburg, Austria

[4 ]GRID grid.508273.b, Internal Medicine - Department for Haemato-Oncology, , LKH Hochsteiermark-Leoben, ; Leoben, Austria

[5 ]Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Barmherzige Schwestern – Elisabethinen, Linz, Austria

[6 ]GRID grid.11598.34, ISNI 0000 0000 8988 2476, Division of Oncology, Department for Internal Medicine, , Medical University Graz, ; Graz, Austria

[7 ]GRID grid.459707.8, ISNI 0000 0004 0522 7001, Department of Internal Medicine IV, , Klinikum Wels-Grieskirchen GmbH, ; Wels, Austria

[8 ]GRID grid.9970.7, ISNI 0000 0001 1941 5140, Department of Hematology and Internal Oncology, , Kepler University Hospital, Johannes Kepler University Linz, ; Linz, Austria

[9 ]Department of Internal Medicine, County Hospital Kufstein, Kufstein, Austria

[10 ]GRID grid.5361.1, ISNI 0000 0000 8853 2677, Department of Gynaecology, , Medical University Innsbruck, ; Innsbruck, Austria

[11 ]GRID grid.413250.1, ISNI 0000 0000 9585 4754, Department of Internal Medicine II, , Academic Teaching Hospital Feldkirch, ; Feldkirch, Austria

[12 ]GRID grid.22937.3d, ISNI 0000 0000 9259 8492, Department of Obstetrics and Gynecology and Comprehensive Cancer Center, , Medical University of Vienna, ; Vienna, Austria

[13 ]Department of Internal Medicine II, Hospital Braunau, Braunau, Austria

[14 ]Breast Center Dornbirn, Dornbirn, Austria

[15 ]Department of Internal Medicine II, Pyrn-Eisenwurzen Klinikum Steyr, Steyr, Austria

[16 ]Department of Gynecology, Breast Health Center Schwaz, Schwaz, Austria

[17 ]Breast Center Eastern Switzerland, St. Gallen, Switzerland

Author information

Richard Greil http://orcid.org/0000-0002-4462-3694

Article

Publisher ID: 1492

DOI: 10.1186/s13058-021-01492-x

PMC ID: 8670265

PubMed ID: 34906198

SO-VID: 9db0130a-4837-4e80-9f45-442ae56bbc12

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 20 July 2021

Date accepted : 28 November 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100004337, roche;

Funded by: FundRef http://dx.doi.org/10.13039/501100002973, daiichi-sankyo;

Funded by: FundRef http://dx.doi.org/10.13039/100004319, pfizer;

Funded by: FundRef http://dx.doi.org/10.13039/100004325, astrazeneca;

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: metastatic breast cancer,her2-low,her2-positive,her2-negative,os,pfs,registry,real-world data

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: metastatic breast cancer, her2-low, her2-positive, her2-negative, os, pfs, registry, real-world data

Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry

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Abstract

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Karger: Oncology

Most cited references 26

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update

Strategies and challenges for the next generation of antibody–drug conjugates

DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1.

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