Related Experiment Video
Updated: Apr 10, 2026
Validated Immunochemical Assay for Comprehensive Determination of the Human Epidermal Growth Factor Receptor 2 Released from and Bound to Cells
Published on: May 9, 2025
Patterns of HER2 Gene Amplification and Response to Anti-HER2 Therapies
Rocio Vicario1, Vicente Peg2, Beatriz Morancho3
1Preclinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Campus de la UAB, 08193, Bellaterra, Spain.
Abstract:
A chromosomal region that includes the gene encoding HER2, a receptor tyrosine kinase (RTK), is amplified in 20% of breast cancers. Although these tumors tend to respond to drugs directed against HER2, they frequently become resistant and resume their malignant progression. Gene amplification in double minutes (DMs), which are extrachromosomal entities whose number can be dynamically regulated, has been suggested to facilitate the acquisition of resistance to therapies targeting RTKs. Here we show that ~30% of HER2-positive tumors show amplification in DMs. However, these tumors respond to trastuzumab in a similar fashion than those with amplification of the HER2 gene within chromosomes. Furthermore, in different models of resistance to anti-HER2 therapies, the number of DMs containing HER2 is maintained, even when the acquisition of resistance is concomitant with loss of HER2 protein expression. Thus, both clinical and preclinical data show that, despite expectations, loss of HER2 protein expression due to loss of DMs containing HER2 is not a likely mechanism of resistance to anti-HER2 therapies.
Insights
Double minutes (DMs) containing HER2 are found in ~30% of HER2-positive breast cancers. Loss of HER2 protein expression from DMs is not a likely cause of resistance to HER2-targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- HER2 gene amplification occurs in 20% of breast cancers, driving response to HER2-targeted therapies.
- Tumors often develop resistance to HER2-targeted treatments, leading to disease progression.
- Double minutes (DMs) are extrachromosomal elements that can amplify genes and have been implicated in therapy resistance.
Purpose of the Study:
- To investigate the role of HER2 amplification in double minutes (DMs) in HER2-positive breast cancers.
- To determine if DM-mediated HER2 amplification influences response to HER2-targeted therapies.
- To assess the contribution of DM-associated HER2 loss to resistance mechanisms against anti-HER2 therapies.
Main Methods:
- Analysis of HER2 amplification status in double minutes (DMs) in clinical tumor samples.
- Evaluation of treatment response to trastuzumab in patients with HER2-positive tumors, comparing chromosomal vs. DM amplification.
- Assessment of DM dynamics and HER2 expression in preclinical models of acquired resistance to anti-HER2 therapies.
Main Results:
- Approximately 30% of HER2-positive breast tumors exhibit HER2 amplification within DMs.
- Tumors with HER2 amplification in DMs responded similarly to trastuzumab as those with chromosomal HER2 amplification.
- In models of acquired resistance, the number of HER2-containing DMs remained stable, even with decreased HER2 protein expression.
Conclusions:
- HER2 amplification in double minutes (DMs) is present in a significant subset of HER2-positive breast cancers.
- DM-mediated HER2 amplification does not appear to alter initial response to HER2-targeted therapy.
- Loss of HER2 protein expression due to loss of DMs is unlikely to be a primary mechanism of resistance to anti-HER2 therapies.
More Related Videos
Related Concept Videos
02:38Mitogens and the Cell Cycle
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...