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Molecular Diagnostics

Copy number heterogeneity identifies ER+ breast cancer patients that do not benefit from adjuvant endocrine therapy

British Journal of Cancer volume 127, pages 1332–1339 (2022)Cite this article

Subjects

Abstract

Background

Endocrine therapy forms the backbone of adjuvant treatment for oestrogen-receptor-positive (ER+) breast cancer. However, it remains unclear whether adjuvant treatment improves survival rates in low-risk patients. Low intra-tumour heterogeneity (ITH) has been shown to confer low risk for recurrent disease. Here, it is studied if chromosomal copy-number ITH (CNH) can identify low-risk ER+, lymph-node-negative breast cancer patients who do not benefit from adjuvant endocrine therapy.

Methods

Lymph-node-negative ER+ patients from the observational METABRIC dataset were retrospectively analysed (n = 708). CNH was determined from a single bulk copy-number measurement for each patient. Survival rates were compared between patients that did or did not receive adjuvant endocrine therapy for CNH-low, middle and high groups with Cox proportional-hazards models, using propensity-score weights to correct for confounders.

Results

Adjuvant endocrine therapy improved the relapse-free survival (RFS) for CNH-high patients treatment (HR = 0.55), but not for CNH-low patients treatment (HR = 0.88). For CNH-low patients adjuvant endocrine therapy was associated with impaired OS (HR = 1.62).

Conclusions

This retrospective study of lymph-node-negative, ER+ breast cancer finds that patients identified as low risk using CNH do not benefit from adjuvant endocrine therapy.

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Fig. 1: Flowchart of patient selection for this study.
Fig. 2: Distribution of copy-number heterogeneity (CNH) and survival per CNH group and treatment.
Fig. 3: Forest plots and Kaplan–Meier curves of propensity-score-weighted patient groups.

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Data availability

CNH values for patients in METABRIC and other data related to this study are available upon request.

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Acknowledgements

We thank Dr. Erik van Dijk for useful discussions.

Funding

This work was supported by Amsterdam UMC and Oncode; a talent development grant of the AG&M institute of Amsterdam UMC and a Young Investigator Grant of KWF (12215) to DMM. The funders had no role in study design or manuscript submission.

Author information

Authors and Affiliations

  1. Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Tom van den Bosch, Louis Vermeulen & Daniël M. Miedema

  2. Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Tom van den Bosch, Louis Vermeulen & Daniël M. Miedema

  3. MRC Biostatistics Unit, University of Cambridge, Cambridge, UK

    Oscar M. Rueda

  4. Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK

    Carlos Caldas

  5. Department of Oncology, University of Cambridge, Cambridge, CB2 2QQ, 17, UK

    Carlos Caldas

  6. CRUK Cambridge Centre, Cambridge Experimental Cancer Medicine Centre (ECMC) and NIHR Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0RE, UK

    Carlos Caldas

Authors
  1. Tom van den Bosch
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  2. Oscar M. Rueda
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  3. Carlos Caldas
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  4. Louis Vermeulen
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  5. Daniël M. Miedema
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Contributions

TvdB, LV and DMM designed the study. TvdB, OMR, CC, LV and DMM analysed the data. TvdB, LV and DMM wrote the manuscript.

Corresponding author

Correspondence to Daniël M. Miedema.

Ethics declarations

Competing interests

LV and DMM are listed as inventors in a pending patent application (PCT/EP2021/04963) filed by Oncode Institute on behalf of the Academisch Medisch Centrum, describing CNH and the application of CNH to stratify the risk of cancer patients.

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This is a retrospective study of previously published data.

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van den Bosch, T., Rueda, O.M., Caldas, C. et al. Copy number heterogeneity identifies ER+ breast cancer patients that do not benefit from adjuvant endocrine therapy. Br J Cancer 127, 1332–1339 (2022). https://doi.org/10.1038/s41416-022-01906-3

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  • DOI: https://doi.org/10.1038/s41416-022-01906-3

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