Genome copy number alteration burden represents predictor of response in long-term, never relapse exceptional responders of trastuzumab-treated HER2+ metastatic breast cancer

Abstract

Abstract Background The introduction of anti-HER2 therapies such as trastuzumab for HER2+ metastatic breast cancer (MBC) has led to significant improvements to disease progression. We, and others have reported cases of long-term durable complete response to trastuzumab in HER2+ MBC. However, to-date only clinical and molecular analysis of this “exceptional” cohort exists. We hypothesise that genomic copy number alteration (CNA) burden can act as a prognostic measure of predicting response to trastuzumab in long-term never relapse exceptional responders (ExRs) from rapid non-responders (NR). Methods We performed whole exome sequencing (WES) on n\xa0=\xa06 never relapse ExRs (med RFS Results We analysed the DNA chromosome disruption (fraction of the genome amplified/deleted) and present CNA burden. We observed the overall fraction of genome CNA burden was more destructed (P\xa0=\xa00.07); while more significantly pronounced in the amplification of the whole genome (P\xa0=\xa00.03) in NR compared to ExRs. We further delineated the distribution of CNA burden in all genomes and identified chromosome 8 as significantly disrupted in NRs (P\xa0=\xa00.02). Kaplan Meier survival analysis revealed that low total CNA burden at Chr8 and Chr17 conferred a statistically significant benefit in overall survival (P\xa0=\xa00.009 and P\xa0=\xa00.016, log rank). Conclusions CNA burden in HER2+ MBC exceptional responders may represent a novel prognostic predictor to trastuzumab response. Our investigation of genome-wide CNA burden offers the potential to gain insight into the underlying genetic landscape of long-term, never relapse exceptional response to trastuzumab. Legal entity responsible for the study The authors. Funding Cancer Clinical Research Trust. Disclosure G. Gullo: Honoraria (self): Genomic Health; Travel / Accommodation / Expenses: Roche. J. Crown: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Shareholder / Stockholder / Stock options: OncoMark; Honoraria (self): Amgen; Honoraria (self), Research grant / Funding (institution): Puma Technology; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self): Vertex; Honoraria (self): Genomic Health; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self): MSD Oncology. All other authors have declared no conflicts of interest.