Recurrent ERBB2 alterations are associated with esophageal adenocarcinoma brain metastases

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. HighlightsO_LIERBB2 is an early recurrent and targetable oncogene alteration in EAC-BM C_LIO_LIHigh T cell infiltration in JAK2-deleted tumor links to immunotherapy response C_LIO_LIGenomic instability of EAC-BM is marked by presence of micronuclei and ecDNA C_LIO_LIEAC brain metastasis resembles monoclonal seeding events C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/25322558v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1f08458org.highwire.dtl.DTLVardef@180c0ddorg.highwire.dtl.DTLVardef@1f616f8org.highwire.dtl.DTLVardef@15e22f2_HPS_FORMAT_FIGEXP M_FIG C_FIG