Molecular Deconvolution of Circulating "Other Cells": A Reliable Predictive Marker of Therapy Response and Survival...

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 ¹⁷⁷Lu-DOTATATE.

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.

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 ⁶⁸Ga-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.

Pre-treatment OC%, in conjunction with critical risk factors, is predictive of treatment response and survival in NET patients receiving ¹⁷⁷Lu-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.