Genomic Characterization and Prognostic Significance of Human Epidermal Growth Factor Receptor 2-Low, Hormone Receptor-Positive, Early Breast Cancers From the BIG 1-98 and SOFT Clinical Trials

Stephen J Luen ^1,2, Lauren C Brown ^1,2, Courtney T van Geelen ²

¹Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
²Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
³International Breast Cancer Study Group, Coordinating Center, Central Pathology Office, Bern, Switzerland.
⁴International Breast Cancer Study Group Central Pathology Office, Milan, Italy.
⁵Department of Pathology and Laboratory Medicine, IEO European Institute of Oncology IRCCS, Milan, Italy.
⁶International Breast Cancer Study Group and University of Sydney, Sydney, Australia.
⁷Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Harvard T.H. Chan School of Public Health, and Frontier Science and Technology Research Foundation, Boston, MA.
⁸SwissBreastCare, Zürich, Switzerland.
⁹Swiss Group for Clinical Cancer Research SAKK, Berne, Switzerland.
¹⁰Division of Medical Senology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
¹¹Department of Medicine, The University of Chicago, Chicago, IL.
¹²Division of Biostatistics, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

⁰Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Jco Precision Oncology +

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January 24, 2025

View abstract on PubMed

Summary

Hormone receptor-positive, human epidermal growth factor receptor 2-low (HER2-low) early breast cancers do not appear to be a distinct clinical or biologic entity compared to HER2-zero tumors. Genomic profiles and recurrence risks were similar across both groups in large clinical trials.

Area Of Science

Oncology
Genomics
Clinical Trials

Background

Hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) early breast cancer is a common subtype.
The clinical and biologic significance of HER2-low expression in this subtype remains under investigation.

Purpose Of The Study

To determine if HR+HER2-low early breast cancers exhibit distinct genomic and clinical characteristics compared to HR+HER2-zero early breast cancers.
To analyze differences in recurrence risk and somatic genomic profiles between these two groups.

Main Methods

Analysis of HR+, HER2-negative early breast cancers from the BIG 1-98 and SOFT phase III clinical trials.
Tumors classified as HER2-low (HER2 IHC 1+ or 2+ with negative ISH) or HER2-zero (HER2 IHC 0) based on central review.
Somatic genomic profiling and clinicopathologic variable assessment.

Main Results

No significant differences in clinicopathologic variables or distant recurrence risk were observed between HER2-low and HER2-zero groups.
Somatic genomic profiles were largely similar, with a higher frequency of MAP3K1 mutations in HER2-zero tumors.
While ERBB2 copy number and gene expression were higher in HER2-low tumors, the absolute differences were small and of unclear biologic relevance.

Conclusions

Findings from two large clinical trials do not support HER2-low breast cancer as a distinct clinical or biologic entity within the HR+HER2- early breast cancer population.
The observed small differences in ERBB2 metrics between HER2-low and HER2-zero tumors lack clear biologic significance.