Metastatic breast cancer (MBC) is generally an incurable neoplasm. A small cohort of patients with HER2-positive MBC, however, achieve such prolonged remission without relapse following anti-HER2 therapy and chemotherapy, that it is speculated they might be cured. The genomes of these patients might provide insights into the underlying mechanisms for their successful treatment. Here, a total of 243 HER2-positive patients diagnosed with MBC between 2000 and 2015 were studied. Of these, 29 patients were identified as exceptional responders (ExR) with an overall survival (OS) > 60 months and no evidence of relapse, 54 patients with an OS > 60 months but who relapsed or developed progressive disease were defined as exceptional survivors (ExS), and 160 patients with an OS < 60 months were identified as short-term responders (STR). Whole-Genome Sequencing and centromere copy number (CCN) analysis was performed on 27 patients (12 ExR; 4 ExS; 11 STR). A significant amplification was observed in the centromeric regions of ExR, exhibiting higher CCN compared to the ExS and STR. Digital PCR validation of chromosome 4 centromere region D4Z1 copy number was not associated with ExR OS. Our results suggest that the amplification of centromere regions are associated with very prolonged remission and survival in patients with HER2-positive MBC.