Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer

• Published in: Scientific reports Vol. 10; no. 1; p. 1288
• Main Authors: Pantano, Francesco, Rossi, Elisabetta, Iuliani, Michele, Facchinetti, Antonella, Simonetti, Sonia, Ribelli, Giulia, Zoccoli, Alice, Vincenzi, Bruno, Tonini, Giuseppe, Zamarchi, Rita, Santini, Daniele
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.01.2020; Nature Publishing Group
• Subjects: 13/31; 14; 631/67/322/803; 692/4028/67/1347; Adult; Aged; Aged, 80 and over; Bone cancer; Breast cancer; Breast Neoplasms - blood; Breast Neoplasms - drug therapy; Denosumab - administration & dosage; Female; Gene Expression Regulation, Neoplastic - drug effects; Humanities and Social Sciences; Humans; Immunotherapy; Metastases; Metastasis; Middle Aged; Monoclonal antibodies; multidisciplinary; Neoplasm Metastasis; Neoplasm Proteins - blood; Neoplastic Cells, Circulating - metabolism; Pilot Projects; RANK Ligand - blood; Science; Science (multidisciplinary); Targeted cancer therapy; TRANCE protein; Tumor cells
• DOI: 10.1038/s41598-020-58339-2
• ISSN: 2045-2322

Receptor-activator of nuclear-factor –κB-ligand (RANKL) and its receptor RANK have been recently identified as key players in breast cancer bone metastases. Since Circulating Tumor Cells (CTCs) are considered a crucial step of metastatic process, we explored RANK expression on CTCs in metastatic breast cancer (MBC), and the predictive value of RANK-positive CTCs in monitoring patients during treatment with denosumab (anti-RANKL antibody). To this purpose, we developed a novel CTC assay to quantify RANK-positive CTCs in forty-two bone MBC patients, candidates to denosumab treatment. Companion algorithms ΔAUC and Slope were developed, and correlated with time to first skeletal-related-events (SRE), time to bone metastasis progression and time to visceral metastasis progression. Twenty-seven patients had at least one CTC at baseline and, among these, nineteen (70%) had one or more RANK–positive CTCs. Notably, the baseline total CTCs, but not the RANK-positive, were associated with Time-to-first-SRE, Time-to-Bone-Metastasis-Progression and Time-to-Visceral-Metastasis-Progression. Conversely, during treatment monitoring, positive ΔAUC value, expression of RANK-positive CTCs persistence, correlated with longer Time-to-first-SRE (p = 0.0002) and Time-to-Bone-Metastasis-Progression (p = 0.0012). Furthermore, the early increase at second day, in RANK-positive CTCs (Positive-Slope) was associated with delay in time-to-first-SRE (p = 0.0038) and Time-to-Bone-Metastasis-Progression (p = 0.0024). We demonstrate, for the first time, the expression of RANK on CTCs in MBC patients and that the persistence of RANK expression determines denosumab effectiveness.