Genome-wide biomarker analysis across the full spectrum of HER2-expressing breast cancers to reveal a clonal chromosome 17 imbalance defining unfavourable HER2-low disease

The full spectrum of HER2-expressing breast carcinomas (BCs) may be treated with antibody-drug conjugates (ADCs) targeting HER2. However, much remains to be learned for optimal ADC use with respect to BC heterogeneity. We here applied shallow whole-genome sequencing (CUTseq method) to detect genome-wide copy number alterations in 157 BC patients (19 HER2-null, 21 HER2-ultralow, 84 HER2-low and 33 HER2-positive). CUTseq accurately detected the ERBB2 status with respect to standard methods and identified ERBB2 copy number loss in 13/157 cases (8%). HER2-null and ultralow BCs showed ‘cold’ chr17 copy number profiles, whereas HER2-low BCs comprised three distinct clusters based on chr17 and genome-wide copy number profiles. Notably, 40% of these tumours harboured a chr17 imbalance (p-arm loss/q-arm gain), which was significantly associated with poor prognosis. On four HER2-low tumours we additionally performed single-cell copy number profiling revealing that the chr17 copy number imbalance is a clonal rearrangement. This first in class genome-wide characterization sheds light on the heterogeneity of somatic copy number alterations and chromosomal instability across the spectrum of HER2-expressing BCs and further defines the presence of a chr17 imbalance showing a prognostic genomic feature for a subgroup of HER2-low tumours. Further studies are warranted to confirm the prognostic relevance of this genomic trait and to define whether it has an impact on stratification of response to treatment.