Abstract 40P
Background
About half of all breast cancers (BCs) harbor HER2-low expression, which can be targeted with the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd), leading to a relevant survival benefit in about 50% of advanced BC patients. Whether these carcinomas constitute a discrete BC entity remains debated. Recently, we and others have provided evidence of genomic heterogeneity within the HER2-low spectrum of BC. Of note, chromosome 17 (chr17) often displays copy number (CN) alterations in BC and HER2-low BCs often show increased HER2 and CEP17 CN in diagnostic in situ hybridization tests.
Methods
We performed shallow whole-genome sequencing (CUTseq method) on 84 HER2-low carcinomas [28 cases with HER2 immunohistochemistry (IHC) score 1+(1), 15 HER2 not-amplified cases with score 2+ (2N), 41 2+ cases with HER2 copy number in the equivocal range (2E)]. A control group of 40 HER2-negative (score 0) and 30 HER2-positive (score 3+ or score 2+ harboring HER2 amplification) was also analysed. To further dissect HER2-low heterogeneity, we also subjected four 2E samples to single-cell DNA sequencing (single-cell CUTseq).
Results
By applying k-means clustering on either genome-wide or chr17 (mapping site of the HER2 locus) CN profiles, 3 distinct CN clusters emerged. The clusters were partially independent from IHC classes and HER2-low BCs were split between different clusters. Among HER2-low cases, a cluster enriched in 2E samples (71%) and characterized by a conserved unbalancing of chr17 (loss of p-arm and gain of the whole q-arm) was associated with a significantly shorter progression-free survival (PFS) compared to the other HER2-low subgroups subjected to comparable adjuvant treatment. Single-cell analysis from 3,200 cells isolated from four 2E samples recapitulated bulk genome-wide copy number profiles, corroborating the chr17 CN unbalance as a clonalnrearrangement of a subset of 2E lesions.
Conclusions
HER2-low BCs harbour heterogenous copy number landscapes. Notably, a characteristic chr17 CN profile identifies a specific subgroup of HER2-low carcinomas with dismal prognosis, suggesting this might be used as a novel risk biomarker in this subset of breast neoplasms.
Legal entity responsible for the study
C. Marchio.
Funding
Italian Association of Cancer Research, AIRC, IG 2019 id 22850.
Disclosure
A. Botticelli: Financial Interests, Personal and Institutional, Invited Speaker: Lilly, Novartis, Pfizer, MSD, Pierre Fabre, Daiichi Sankyo, AstraZeneca, Amgen; Financial Interests, Personal and Institutional, Principal Investigator: Gilead, Daiichi Sankyo, AstraZeneca, Roche, MSD. C. Marchiò: Financial Interests, Personal, Invited Speaker: Veracyte, Illumina, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Bayer, Menarini, Roche. All other authors have declared no conflicts of interest.