Abstract P2-05-07: Whole Exome Sequencing of Extreme Responders Reveals Low Mutation Burden in Metastatic Breast Cancer

Abstract Background: Extreme responders to anticancer therapy are rarely encountered in the treatment of advanced breast cancer patients, but their treatment response have not been investigated on the whole exome level. We performed whole exome analysis to characterize genomic landscape of extreme responders in metastatic breast cancer patients. Methods: Clinical samples were obtained from patients who showed exceptional response to anti-HER2 therapy or hormonal therapy. Non-responders were selected among those who did not respond. Matched breast tumor tissue (somatic DNA) and blood samples (germline DNA) were collected from a total of 18 responders (12 ER+, 6 HER2+) and 8 non-responders (6 ER+, 1 HER2+, 1 TNBC). Whole exome sequencing using Illumina HiSeq2500 was performed on the 26 patients (52 samples). Somatic single nucleotide variants (SNVs), indels and copy number variants (CNVs) were identified for each patient genome. Group specific somatic variants and mutation burden were statistically analyzed. Findings: Cancer exomes were characterized by 1,455 somatic single-nucleotide variants (1,327 missense, 80 nonsense, 36 splice-site, 12 start/stop-lost), 149 insertions/deletions (108 frameshift, 41 inframe), with a median of 1 mutations per Mb (0.2 to 2.7 mutations per Mb) in all patients. Responders harbored a significantly lower non-synonymous mutation burden than non-responders (median, 27 vs. 90.5, P=0.01), and copy number variation burden was also lower (median 23 vs. 31, P=0.14). Multivariate analyses of factors influencing progression-free survival showed that high mutation burden and visceral metastases were significantly related with progression. Interpretation: Extreme responders of metastatic breast cancer are characterized by low nonsynonymous mutational burden. Citation Format: Sohn J, Lim SM, Kim E, Kim S, Koo JS, Kim SI, Park S, Park HS, Kwon N-J, Kim GM, Kim S. Whole exome sequencing of extreme responders reveals low mutation burden in metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-05-07.