Background: Although, 40-60 % of HER2+ MBC pts obtain a clinical response to T, most develop de novo or acquired resistance after a median response duration of < 1 year. However, long-term durable complete response (dCR) MBC cases have been documented. We previously reported that 9 % of HER2+ MBC pts achieved dCR (median follow-up 7 years) following T and chemotherapy in Irish and Italian institutions. Understanding the mechanisms of exceptional responses to T may improve patient selection and treatment rationale to identify HER2+ MBC pts who are more likely to achieve dCR following T treatment. Methods: HER2+ MBC pts treated with T and chemotherapy in the metastatic setting were retrospectively identified. Cases (n = 3) with extraordinary responses to T dCR > 60 mo and controls (n = 2) NR (non-responder) or PR < 6 mo had sufficient FFPE material available for analysis. Flow cytometry was used to sort diploid and aneuploidy populations from the archived tissue. DNA from sorted tumour nuclei was extracted using QIAamp DNA Micro Kit and amplified using Ovation WGA FFPE System and aCGH were performed. Results: aCGH analysis of pure tumour DNA from dCR and NR identified distinct patterns of copy number alterations. HER2 amplicon was confirmed in all samples. Decreased copy number alterations were observed in the dCR group compared to the NR group (11±5.2 vs 19.5±3.5). Interestingly, no deletions were observed in the dCR group. Conclusions: Our preliminary data highlights distinct copy number alterations between dCR and NR suggesting that exceptional responder genomes are potentially more stable with overall less genomic aberrations. A larger study is ongoing to further validate genomic determinants of dCR following T therapy which could serve as the basis for a predictive assay for the risk stratification of pts.