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A neu view of invasive lobular breast cancer
1Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. rbose@dom.wustl.edu
Abstract:
Genome sequencing of relapsed, invasive lobular breast cancer identified actionable mutations in 86% of the cases. HER2 alterations occur in 27% of the cases, including 4 cases with activating HER2 mutations and 1 with a novel HER2-GRB7 gene fusion. This fusion links the HER2 tyrosine kinase domain to the GRB7 src homology 2 (SH2) domain.
Insights
Genome sequencing of invasive lobular breast cancer revealed actionable mutations in 86% of cases. Notably, 27% had HER2 alterations, including activating mutations and a novel HER2-GRB7 gene fusion, offering potential therapeutic targets.
Area of Science:
- Genomics and Molecular Biology
- Oncology
- Breast Cancer Research
Background:
- Invasive lobular breast cancer (ILC) is the second most common type of breast cancer.
- Understanding the genomic landscape of relapsed ILC is crucial for identifying new therapeutic strategies.
- Hormone receptor-positive (HR+) ILC often develops resistance to endocrine therapy, necessitating alternative treatment options.
Purpose of the Study:
- To identify actionable genomic alterations in relapsed, invasive lobular breast cancer.
- To characterize the spectrum of HER2 alterations in this patient cohort.
- To explore potential therapeutic targets based on identified mutations and gene fusions.
Main Methods:
- Whole-genome sequencing was performed on tumor samples from patients with relapsed ILC.
- Bioinformatic analyses were used to identify somatic mutations, copy number alterations, and gene fusions.
- HER2 protein expression and activity were assessed through immunohistochemistry and functional assays.
Main Results:
- Actionable mutations were identified in 86% of the analyzed relapsed ILC cases.
- HER2 alterations were present in 27% of cases, including activating HER2 mutations and a novel HER2-GRB7 gene fusion.
- The HER2-GRB7 fusion involves the linkage of the HER2 tyrosine kinase domain to the GRB7 SH2 domain, suggesting potential oncogenic activity.
Conclusions:
- Genome sequencing reveals a high prevalence of actionable mutations in relapsed ILC, highlighting the potential for targeted therapies.
- HER2 alterations, including the novel HER2-GRB7 fusion, represent a significant subset of alterations in ILC and may be targetable.
- These findings support the utility of comprehensive genomic profiling for guiding treatment decisions in advanced ILC.
