NET Blood Transcript Analysis Defines the Crossing of the Clinical Rubicon: When Stable Disease Becomes Progressive

Abstract

Background/Aims: A key issue in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is early identification and prediction of disease progression. Clinical evaluation and imaging are limited due to the lack of sensitivity and disease indolence. We assessed the NETest as a predictive and prognostic marker of progression in a long-term follow-up study. Methods: GEP-NETs (n = 34) followed for a median 4 years (2.2-5.4) were evaluated. WHO tumor grade/stage grade 1: n = 17, grade 2: n = 14, grade 3: n = 1 (for 2, no grade was available); 31 (91%) were stage IV. Baseline and longitudinal imaging and blood biomarkers were available in all, and progression was defined per standard clinical protocols (RECIST 1.0). The NETest was measured by quantitative PCR of blood and multianalyte algorithmic analysis (disease activity scaled 0-100% with low <40% and high activity risk cutoffs >80%); chromogranin A (CgA) was measured by radioimmunoassay (normal <150 µg/l); progression-free survival (PFS) was analyzed by Cox proportional-hazard regression and Kaplan-Meier analysis. Results: At baseline, 100% were NETest positive, and CgA was elevated in 50%. The only baseline variable (Cox modeling) associated with PFS was NETest (hazard ratio = 1.022, 95% confidence interval = 1.005-1.04; p < 0.012). Using Kaplan-Meier analyses, the baseline NETest (>80%) was significantly associated (p = 0.01) with disease progression (median PFS 0.68 vs. 2.78 years with <40% levels). The NETest was more informative (96%) than CgA changes (<under>></under>25%) in consistently predicting disease alterations (40%, p < 2 × 10^-5, χ² = 18). The NETest had an earlier time point change than imaging (1.02 ± 0.15 years). Baseline NETest levels >40% in stable disease were 100% prognostic of disease progression versus CgA (χ² = 5, p < 0.03). Baseline NETest values <40% accurately (100%) predicted stability over 5 years (p = 0.05, χ² = 3.8 vs. CgA). Conclusion: The NETest correlated with a well-differentiated GEP-NET clinical status. The NETest has predictive and prognostic utility for GEP-NETs identifying clinically actionable alterations ∼1 year before image-based evidence of progression.

NETest Liquid Biopsy Is Diagnostic of Lung Neuroendocrine Tumors and Identifies Progressive Disease

“…NETest levels have been reported to be of value in defining SD and PD [18, 19]. In this study, we identified significantly ( p < 0.0001) higher levels in PD (mean: 61) than SD (mean: 35).…”

“…It has been suggested that measurement of transcript levels before and after BPC surgery will facilitate early identification of residual or recurrent disease prior to imaging. This has been demonstrated to be the case in gastroenteropancreatic NET disease [18]. …”

“…Tubes were coded and stored at –80°C within 2 h of collection per standard molecular diagnostics protocols for PCR-based studies [18]. Randomly selected coded blood samples were sent in mixed batches, blinded, and deidentified to Wren Laboratories, Connecticut, USA.…”

Current Concepts in 68Ga-DOTATATE Imaging of Neuroendocrine Neoplasms: Interpretation, Biodistribution, Dosimetry, and Molecular Strategies

“…To better reflect not only the mere secretory activity but also the complex biologic activities of an evolving neoplasm (cell proliferation, growth factor signaling, and others) that constitute the hallmarks of cancer, and to provide more relevant information on tumor behavior, new approaches have been introduced, including whole-genome sequencing, circulating micro-RNA, and tumor transcripts (60). Evaluation of circulating messenger RNA (transcript analysis) has provided information on disease status that is of substantial clinical utility in the management of NENs (61,62). This strategy uses simultaneous polymerase chain reaction-based analyses of multiple neuroendocrine tumor genes measurable in the blood and algorhythmic transformation into a mathematic index of disease activity (60,63).…”

WOMEN IN CANCER PROFILE: Neuroendocrine tumors: moving from the land of small tumors to an expanding universe

“…I am not only concerned and interested in making novel drugs possible for patients but also interested in clinical research related to prognostic factors in NET including novel biomarkers to predict disease progression (Hilfenhaus et al 2013, Pavel et al 2016. One of my research projects supported by the DKTK (Deutsches Konsortium für Translationale Krebsforschung, German Cancer Foundation, Heidelberg) focuses on the evaluation of a mutational panel for prognostic purpose.…”