Abstract 2310: Tumor macrophage fusion cells detected in the circulation of metastatic breast cancer patients is prognostic for rapid progression and death
Authors: Adams Daniel L. , Alpaugh R. Katherine , Lapidus Rena G. , Chumsri Saranya , Reduzzi Carolina , Gardner Kirby P. , Tang Cha-Mei , Priore Giuseppe Del , Williams William V. , Cristofanilli Massimo 
Published: June 2023

Abstract
Background: Recently, it was described that macrophages and tumor cells can fuse to form tumor macrophage fusion cells (TMFs) which are detectable within primary tumors and patient’s (pts) circulation. However, there are multiple pathways and subsequent subtypes of TMFs, with limited data on the various TMF types, commonality in blood, and clinical relevance. Here we evaluated n=120 metastatic breast cancer (mBC) blood samples for CTCs & TMFs. We describe numerous types of TMFs with vastly different fusion phenotypes, including partial (i.e. some membrane interaction & both cells retaining their original phenotypes), homodimeric (i.e. both cells with fused membranes & sharing cytoplasm), cannibalistic (i.e. CTC within a CD14+ macrophage & cells retaining their individual phenotypes), binucleated (i.e. both cells completely merge & becoming one cell with dual expression phenotypes), and hyperploidy (i.e. multiple cells merge to form a large polyploid cell). As CTCs & TMFs are isolated in conjunction from a single blood sample, we evaluated both CTCs & all TMF subtypes to determine their prognostic and predictive values for aggressiveness of disease.
Methods: We categorized and enumerated the 5 forms of TMFs from a prospective pilot study using n=120 mBC pts that were starting new lines of treatment. Whole peripheral blood (7.5mL) was procured, filtered and stained using cytokeratin & CD45/CD14 to identify CTCs & TMFs. We compared the presence of the various types of TMFs & CTCs to pt’s progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs), analyzed by censored univariate analysis based on RECIST v1.1 over 24 months.
Results: CTCs were found in 39% (n=47/120), with partial fusion TMFs in 26% (n=31/120), homodimeric 2% (n=2/120), cannibalistic 0% (n=0/120), binucleated 2% (n=2/120), hyperploidy 93% (n=113/120). Presence of CTCs alone, binucleated, or hyperploidy TMFs were not prognostic for PFS (p=0.0988, p=0.4120, & p=0.7615 respectively), or OS (p=0.2015, p=0.0845, p=0.1121 respectively). However, TMFs with partial or homodimeric fusion were prognostic for worse PFS (HR=2.2, p=0.0063 and HR=6.0, p=0.0305, respectively) and for worse OS (HR=2.8, p=0.0037 and HR=8.8, p=0.0271, respectively). Furthermore, combining pts with any TMFs into one group, minus hyperploidy, was highly significant for worse PFS (HR=2.9, 95%CI 1.7-5.0, p=0.0002) and worse OS (HR=3.8, 95%CI 2.0-7.5, p=0.0002), though certain subtypes of hyperploidy were also indicative of worse outcomes.
Conclusion: The study of TMFs is relativity limited and their existence is new in oncology. Here we detected and described TMFs in the blood of mBC pts while demonstrating an association with poor clinical outcomes. These data suggest TMF involvement in the pathogenic cascade of cancer and further understanding of their biology may be important in the study of tumorigenesis.
Citation Format: Daniel L. Adams, R. Katherine Alpaugh, Rena G. Lapidus, Saranya Chumsri, Carolina Reduzzi, Kirby P. Gardner, Cha-Mei Tang, Giuseppe Del Priore, William V. Williams, Massimo Cristofanilli. Tumor macrophage fusion cells detected in the circulation of metastatic breast cancer patients is prognostic for rapid progression and death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2310.