Abstract P4-01-18: Correlation between circulating tumor DNA (ctDNA) alterations and circulating tumor cells (CTC) uncovers new mechanisms of metastasis for patients with metastatic breast carcinoma (MBC)

Abstract

Abstract Introduction:Novel molecular diagnostics including CTCs and ctDNA have been proved to predict disease metastasis and survival. However, the frequency of detection of actionable mutations using CTCs and ctDNA is variable based upon tumor related factors and diagnostic platform sensitivity. Herein, we evaluated a novel NGS technology in the ability of detecting driver and clonal genomic abnormalities in samples from MBC patients, and compared ctDNA alterations with CTCs and CTC-cluster. This study demonstrated several novel correlation between some specific ctDNA alterations and CTCs or CTCs related biomarkers, which opened new insight on mechanisms of metastasis for MBC. Methods: This study included 52 samples from 26 patients with stage III/IV BCa treated at NMH (2016-2017) and who received standard systemic treatments based on disease subtypes. Whole blood samples (7.5ml/each) were used for CTC enrichment and enumeration in FDA approved CELLTRACKS ANALYZERII® System (Menarini). ctDNA from clinical plasma samples was analyzed by using PredicinePLUS, a NGS-based assay (Predicine Inc) with a 180-gene panel for genomic alterations mutations. Results of CTCs and ctDNA alterations were linked to clinical database. Matched pairs variations between CTCs and ctDNA alterations was compared by Wilcoxon signed-ranks test and Kruskal-Wallis test. Results: Genomic Alterations (SNVs, Indels and copy number variations) were detected on 52 genes by PredicinePLUS assay. All samples (100%) demonstrated at least 1 somatic alterations. There were 75 mutations detected within 29 genes, and the variant frequency of mutated genes ranges from 0.11% to 68.56%. Increased CTCs were highly significantly correlated with genomic alterations in the genes (wild type vs alterations) including GATA3 (8vs 37), ESR1 ( 2.5 vs 41.3), CDH1 (3.5 vs 50.5) and CCND1 (4 vs 120) (P<0.01). Decreased CTCs were correlated with alterations of CDKN2A (20.5 vs 0) (P=0.025). CTC-cluster appear associated predominantly with alterations of CDH1 (P=0.0018), CCND1 (P=0.008) and BRCA1 (P=0.04). Furthermore, in HER positive CTCs group, ERBB2 mutations caused increased CTCs in compared with ERBB2 wild type (0 vs 5), when CCND1, CDKN2A, GATA3 and TP53 alterations were associated with increase of HER2 negative CTCs. Conclusions: By using the novel diagnostic platform with the ability to identify ctDNA mutation and copy number variation, this study demonstrated several novel genes alterations which were highly correlated with CTCs, CTC-cluster and HER2. Some genes (CCND1 and CDH1) got involved into the changes on both CTCs and CTC-cluster, when some genes (CCND1, CDKN2A, ESR1 and GATA3) were related with change of CTCs and HER2 expression. Correlation of CTCs and ctDNA can be reliably and routinely used as non-invasive method for monitoring disease metastasis and predict the prognosis in MBC in clinic. Citation Format: Davis A, Zhang Q, Gerratana L, Zhang Y, Flaum L, Shad A, Behdad A, Gradishar W, Platanias L, Cristofanilli M. Correlation between circulating tumor DNA (ctDNA) alterations and circulating tumor cells (CTC) uncovers new mechanisms of metastasis for patients with metastatic breast carcinoma (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-01-18.