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).
We performed whole exome sequencing (WES) on n = 6 never relapse ExRs (med RFS < 149 mo) and n = 5 corresponding NRs (median RFS < 14 mo). Both tumour and adjacent normal tissue (where available) was sequenced by BGI using the NGS illumina HiSeq PR100 (2 x 100 bp) at a mean depth of 56 x. Reads were aligned to the hg19 reference genome using BWA software. Two-sample t-test with unequal variances was used to evaluate total genome CNA burden. Median CNA burden was used to stratify patients into high and low CNA burden groups, binary CNA stratification groups were further assessed using Kaplan-Meier survival estimation.
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 = 0.07); while more significantly pronounced in the amplification of the whole genome (P = 0.03) 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 = 0.02). Kaplan Meier survival analysis revealed that low total CNA burden at Chr8 and Chr17 conferred a statistically significant benefit in overall survival (P = 0.009 and P = 0.016, log rank).
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.
The authors.
Cancer Clinical Research Trust.
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.