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Updated: Jul 11, 2025
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Integrative whole-genome and transcriptome analysis of HER2-amplified metastatic breast cancer
Noortje Verschoor1, Marcel Smid2, Agnes Jager2
1Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands. n.verschoor@erasmusmc.nl.
Background:
In breast cancer, the advent of anti-HER2 therapies has made HER2+ tumors a highly relevant subgroup. However, the exact characteristics which prohibit clinical response to anti-HER2 therapies and drive disease progression are not yet fully known. Integrative whole-genome and transcriptomic sequencing data from both primary and metastatic HER2-positive breast cancer will enhance our understanding of underlying biological processes.
Methods:
Here, we used WGS and RNA sequencing data of 700 metastatic breast tumors, of which 68 being HER2+, to search for specific genomic features of HER2+ disease and therapy resistance. Furthermore, we integrated results with transcriptomic data to associate tumors exhibiting a HER2+-specific gene expression profile with ERBB2 mutation status, prior therapy and relevant gene expression signatures.
Results:
Overall genomic profiles of primary and metastatic HER2+ breast cancers were similar, and no specific acquired genomics traits connected to prior anti-HER2 treatment were observed. However, specific genomic features were predictive of progression-free survival on post-biopsy anti-HER2 treatment. Furthermore, a HER2-driven expression profile grouped HER2-amplified tumors with ERBB2-mutated cases and cases without HER2 alterations. The latter were reported as ER positive in primary disease, but the metastatic biopsy showed low ESR1 expression and upregulation of the MAPK pathway, suggesting transformation to ER independence.
Conclusions:
In summary, although the quantity of variants increased throughout HER2-positive breast cancer progression, the genomic composition remained largely consistent, thus yielding no new major processes beside those already operational in primary disease. Our results suggest that integrated genomic and transcriptomic analyses may be key in establishing therapeutic options.
Insights
Genomic analysis of HER2-positive breast cancer reveals consistent profiles from primary to metastatic stages, with specific genomic features predicting treatment response and potential ER independence. Integrated genomic and transcriptomic data are key for future therapies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Anti-HER2 therapies have significantly impacted HER2-positive breast cancer, yet resistance mechanisms and progression drivers remain incompletely understood.
- Identifying specific genomic characteristics associated with treatment failure is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the genomic and transcriptomic features of HER2-positive breast cancer in metastatic settings.
- To identify genomic markers predictive of response to anti-HER2 therapies and understand mechanisms of resistance or transformation.
Main Methods:
- Whole-genome sequencing (WGS) and RNA sequencing were performed on 700 metastatic breast tumors, including 68 HER2-positive cases.
- Integrated analysis correlated genomic profiles with gene expression, ERBB2 mutation status, and prior treatment history.
Main Results:
- Genomic profiles of primary and metastatic HER2-positive breast cancers were largely similar, with no acquired resistance traits identified post-anti-HER2 treatment.
- Specific genomic features predicted progression-free survival in patients receiving anti-HER2 therapy.
- A HER2-driven expression profile linked HER2-amplified tumors with ERBB2-mutated and HER2-altered cases, some showing ER independence via MAPK pathway upregulation.
Conclusions:
- Genomic composition in HER2-positive breast cancer remains consistent during progression, with no novel major processes emerging.
- Integrated genomic and transcriptomic analyses are essential for developing effective therapeutic strategies for HER2-positive breast cancer.
