Adler (4) di B i d (5) Handley (8) Kaufmann (7) Kettle (8) Krumbhaar (9) Paget (10) Reichelman (11) Taylor (12) 374 2422 422 1078 240 930 735 670 677
Background: The biological characteristics conferring Inflammatory BC's (IBC) distinctive and aggressive clinical features are currently not fully clarified. The aim of this study is to dissect IBC's biology through the integration of DNA and CTC-based circulating biomarkers. Methods: This study retrospectively analyzed 251 Advanced BC (ABC) patients (pts) treated and longitudinally characterized for CTCs and circulating tumor DNA (ctDNA) at Thomas Jefferson University (Philadephia, PA) and Northwestern University (Chicago, IL). CTCs were enumerated through CellSearch (Menarini Silicon Biosystems), and characterized for HER2 expression using the CellSearch CXC Kit, while ctDNA was analyzed using the Guardant360 NGS assay (Guardant Health) and its percentage (%ctDNA) was classified based on the previously reported cut-off of 5.7% (Gerratana et al 2018). A subset of 117 pts was further characterized for circulating cell-free DNA (ccfDNA) through Qubit® dsDNA HS quantitation Assay (Thermo Fisher Scientific) and quantitative real-time PCR assay for ALU DNA repeats on chromosome 1.Associations between clinical characteristics, CTCs-derived biomarkers and IBC were explored through Fisher's exact test; survival was tested though Cox regression and log-rank test. Results: Of the total 251 pts, 115 were diagnosed with IBC. Among the 117 patients characterized for ccfDNA, 70 had IBC. Median ccfDNA was 1.59 for IBC (IQR 1.02-3.19) and 2.37 for non-IBC (nIBC) (IQR 1.13-3.52), P=0.27. Consistent results were observed for %ctDNA levels (median value: 2 vs 1.6). The impact on OS of ccfDNA after log transformation was significant for the total population (HR 1.73 95%CI: 1.11-2.69) but not in IBC pts (HR 1.40 95%CI: 0.84-2.34). On the other hand, ctDNA high pts had a significantly worse OS (nIBC: HR 5.34 95%CI: 1.70-18.81 P=0.004; IBC: HR 4.05 95%CI: 1.91-8.58 P< 0.001). In the ctDNA high subgroup no differences in total number of CTCs were observed between IBC and nIBC, while significantly lower CTCs were observed in ctDNA low IBC pts (P=0.0097). The ctDNA low IBC subgroup had a higher incidence of HER2 positive BC (P=0.003) and a significantly lower incidence of CTCs clusters (P=0.006), HER2 positive CTCs (P=0.041). Notably, no associations were observed with stage at baseline, number of metastatic sites, liver, lung and visceral involvement. On the other hand, the ctDNA_high IBC subgroup was characterized by a lower incidence in liver, bone and visceral involvement (P=0.017, P=0.014 and P=0.03 respectively) and a marginally high incidence in soft tissue involvement (0.084). Moreover, IBC diagnosis conferred a significantly worse prognosis only in the ctDNA low subgroup (OS at 12 months nIBC: 100% vs IBC: 70%; P=0.049), while no differences were observed in the ctDNA_high subgroup (OS at 12 months nIBC: 29% vs IBC: 26%; P=0.767). Conclusion: ctDNA is able to stratify BC according to aggressiveness independently from the sites and type of metastases, both in the IBC and nIBC subgroups. IBC has a distinctive CTCs/ctDNA-based signature, in particular ctDNAlow pts have a lower incidence of HER2 positive CTCs and CTC clusters. This signature is probably due to predominant lymphatic metastatic spread and aggressive phenotype. Citation Format: Gerratana L, Zhang Q, Wang C, Shah A, Davis AA, Ye Z, Zhang Y, Abu-Khalaf M, Flaum L, Strickland K, Rossi G, Behdad A, Gradishar W, Platanias L, Yang H, Cristofanilli M. Dissecting the biology of inflammatory breast cancer (BC) through cell free DNA and a circulating tumor cells (CTC)-derived signature [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 P5-17-02.
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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.
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