Whole-exome sequencing of long-term, never relapse exceptional responders of trastuzumab-treated HER2+ metastatic breast cancer

Naomi Walsh, Charlotte Andrieu, Peter O'Donovan, Cecily Quinn, Alanna Maguire, Simon J Furney, Giuseppe Gullo, John Crown, Naomi Walsh, Charlotte Andrieu, Peter O'Donovan, Cecily Quinn, Alanna Maguire, Simon J Furney, Giuseppe Gullo, John Crown

Abstract

Trastuzumab has significantly improved the overall survival of patients with HER2+ metastatic breast cancer (MBC). However, outcomes can vary, with patients progressing within 1 year of treatment or exceptional cases of complete response to trastuzumab for ≥10 years. Identification of the underlying genomic aberrations of "exceptional responders (ExRs)" compared to "rapid non-responders (NRs)" increases our understanding of the mechanisms involved in MBC progression and identification of biomarkers of trastuzumab response and resistance. Whole-exome sequencing was performed on six ExRs compared to five NR. The overall fraction of genome copy number alteration (CNA) burden was higher in NR patients (P = 0.07), while more significantly pronounced in copy number gains (P = 0.03) in NR compared to ExRs. Delineation of the distribution of CNA burden across the genome identified a greater degree of CNA burden in NR within Chr8 (P = 0.02) and in Chr17 (P = 0.06) and conferred a statistically significant benefit in overall survival. Clinical trial number: NCT01722890 [ICORG 12/09].

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1. Results of CNA burden on…
Fig. 1. Results of CNA burden on ExRs and NRs and overall survival outcome.
a Total overall genome-wide CNA burden. b Fraction of genome gained. c Fraction of genome lost. d Individual chromosome CNA burden in Chr8 and Chr17 in non-responder (NR) and exceptional responder (ExRs) genomes. e Kaplan–Meier overall survival curves of cases dichotomised by exceptional responder and non-responder. f Total CNA burden, low CNA (total CNA burden < median) and high CNA (total CNA ≥ median). g Overall CNA burden on Chr8, low CNA (Chr8 total CNA burden < median) and high CNA (Chr8 total CNA burden ≥ median). h Overall CNA burden on Chr17, low CNA (Chr17 total CNA burden < median) and high CNA (Chr17 total CNA burden ≥ median).

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Source: PubMed

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