ERBB2/HOXB13co-amplification with interstitial deletion ofBRCA1defines a unique subset of breast cancers

Abstract

AbstractBackgroundTheHOXB13/IL17BRgene expression biomarker has been shown to predict response to adjuvant and extended endocrine therapy in patients with early-stage ER+ HER2- breast tumors.HOXB13gene expression is the primary determinant driving the prognostic and endocrine treatment-predictive performance of the biomarker. Currently, there is limited data onHOXB13expression in HER2+ and ER- breast cancers. Herein, we studied the expression ofHOXB13in large cohorts of HER2+ and ER- breast cancers.MethodsWe investigated gene expression, genomic copy number, mutational signatures, and clinical outcome data in the TGGA and METABRIC breast cancer cohorts. Genomic-based gene amplification data was validated with tri-colored fluorescencein situhybridization.ResultsIn the TCGA breast cancer cohort,HOXB13gene expression was significantly higher in HER2+ versus HER2- breast cancers, and its expression was also significantly higher in the ER- versus ER+ breast cancers.HOXB13is frequently co-gained or co-amplified withERBB2. Joint copy gains ofHOXB13andERBB2occurred with low-level co-gains or high-level co-amplifications (co-amp), the latter of which is associated with an interstitial deletion that includes the tumor suppressorBRCA1.ERBB2/HOXB13co-amp tumors with interstitialBRCA1loss exhibit a mutational signature associated with APOBEC deaminase activity, and copy number signatures associated with chromothripsis and genomic instability. AmongERBB2-amplified tumors of different tissue origins,ERBB2/HOXB13co-amp with aBRCA1loss appeared to be unique to breast cancer. Lastly, patients withERBB2/HOXB13co-amplified andBRCA1lost tumors displayed a significantly shorter progression-free survival (PFS) than those withERBB2-only amplifications. The difference in PFS was restricted to the ER- subset patients and this difference in PFS was not solely driven byHOXB13gene expression.ConclusionsHOXB13is frequently co-gained withERBB2at both low-copy number level or as complex high-level amplification with relativeBRCA1loss.ERBB2/HOXB13amplified,BRCA1-lost tumors are strongly enriched in breast cancer, and patients with such breast tumors experience a shortened PFS.