Molecular Deconvolution of Circulating “Other Cells”: A Reliable Predictive Marker of Therapy Response and Survival in Neuroendocrine Tumor Patients Receiving 177 Lu ‐ DOTATATE PRRT

ABSTRACT Purpose To assess the prognostic impact of pre‐treatment circulating other cells on treatment response and survival in neuroendocrine tumor (NET) patients receiving Peptide Receptor Radionuclide Therapy (PRRT) with 177 Lu‐DOTATATE. Methods Healthy donors (HDs, n = 81) and NET patients ( n = 137) were analyzed. Baseline circulating other cells proportions (OC%) were deconvoluted from RNA‐Seq profiles using the Kassandra‐B algorithm. Associations of OC% with demographic and clinicopathologic characteristics, tumor response to PRRT, and survival outcomes were evaluated. Results NET patients had a significantly higher OC% compared to HDs (median = 0.26 vs. 0.18, p = 0.0018). A positive correlation was observed between OC% and the tumor grade (G3 tumors: median = 0.47, G1 tumors: median = 0.22, p = 0.029) or disease burden (high: median = 0.32, low: median = 0.23, p = 0.016). The OC% was negatively associated with 68 Ga‐DOTATATE avidity (high: median = 0.22, low: median = 0.32, p = 0.0026). Patients with progressive disease had high OC% (median = 0.41, IQR = 0.25–0.56), significantly higher than those with stable disease (median = 0.24, IQR = 0.12–0.36, p = 0.0024) or complete/partial response (median = 0.22, IQR = 0.08–0.32, p = 0.0067). NET patients in the OC Low group (OC% ≤ 0.18%) had > 90% disease control rate on PRRT, independent of tumor characteristics. Patients in the OC High group (OC% > 0.18%) had a significantly higher risk of early disease progression [HR = 3.2, 95% CI = 1.32–7.75, p = 0.01]. After adjusting for demographic and tumor characteristics, the association of OC% with progression‐free survival retained marginal significance [HR = 2.08, 95% CI = 0.78–5.54, p = 0.14], in a multivariate model. Integration of OC% with established risk variables identified a specific subgroup of NET patients at an increased risk of PRRT failure and poor prognosis. Conclusions Pre‐treatment OC%, in conjunction with critical risk factors, is predictive of treatment response and survival in NET patients receiving 177 Lu‐DOTATATE PRRT. This RNA‐Seq‐based test may evolve as a dependable adjunct for clinicians in the risk stratification of NET patients, in the PRRT setting.