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Recurrent ERBB2 alterations are associated with esophageal adenocarcinoma brain metastases
Nora M Lawson1, Lingqun Ye1, Chae Yun Cho1
1Department of Neurosurgery, MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
Brain metastases in esophageal adenocarcinoma (EAC) patients are associated with poor prognosis and remain understudied. We performed multi-omics analysis with whole-genome sequencing and single-cell spatial transcriptomics on the brain metastases and matched primary tumors. Our analysis identified ERBB2 as a recurrent oncogene in EAC brain metastases, with 9 out of 10 cases harboring amplifications. Single-cell whole-genome and multi-region sequencing revealed that ERBB2 alterations, occur early during disease progression and are associated with monoclonal seeding. Although the median survival in our cohort was 13 months, one patient on HER2 antibody-drug conjugate therapy remains a long-term survivor beyond 34 months. Interestingly, the sole patient without an ERBB2 alteration had JAK2 deletion, high T cell infiltration in the brain lesion, and survived 35 months after immune checkpoint therapy. Our findings have significant clinical implications for the treatment and management of EAC brain metastases.
Insights
ERBB2 amplifications are common in esophageal adenocarcinoma brain metastases and may occur early. Targeted therapies show promise, with one patient surviving over 34 months on HER2-targeted treatment.
Area of Science:
- Oncology
- Genomics
- Translational Research
Background:
- Brain metastases in esophageal adenocarcinoma (EAC) significantly worsen patient prognosis.
- The molecular drivers and therapeutic targets for EAC brain metastases are not well understood.
Purpose of the Study:
- To investigate the genomic landscape of EAC brain metastases using multi-omics analysis.
- To identify potential therapeutic targets for EAC brain metastases.
Main Methods:
- Whole-genome sequencing and single-cell spatial transcriptomics were performed on brain metastases and matched primary tumors from EAC patients.
- Analysis included single-cell whole-genome and multi-region sequencing.
Main Results:
- ERBB2 amplification was identified as a recurrent oncogenic driver in 9 out of 10 EAC brain metastases.
- ERBB2 alterations were found to occur early in disease progression and were linked to monoclonal tumor seeding.
- One patient with ERBB2 amplification achieved long-term survival (>34 months) with HER2-targeted therapy.
- A patient without ERBB2 alteration, but with JAK2 deletion and high T cell infiltration, survived 35 months with immune checkpoint therapy.
Conclusions:
- ERBB2 is a key oncogene in EAC brain metastases, suggesting potential for HER2-targeted therapies.
- Early detection of ERBB2 alterations may guide treatment strategies for EAC brain metastases.
- Alternative molecular alterations (e.g., JAK2 deletion) and immune profiles may inform immunotherapy approaches in EAC brain metastases.
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