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

Neuroendocrinology - Tập 104 Số 2 - Trang 170-182 - 2017
Marianne Pavel1, Henning Jann1, Vikas Prasad2, Ignat Drozdov3, Irvin M. Modlin3, Mark Kidd3
1Department of Hepatology and Gastroenterology, Campus-Virchow-Klinikum, and
2Department of Nuclear Medicine, Charité Universitätsmedizin, Berlin, Germany
3Wren Laboratories, Branford, Conn., USA

Tóm tắt

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.

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10.1016/S1470-2045(15)00186-2

10.1159/000335629

10.1159/000335597

10.1016/S1470-2045(13)70362-0

10.1093/jnci/djn275

10.1097/MED.0000000000000033

10.1530/ERC-13-0365

10.1016/j.ejca.2008.10.026

10.4329/wjr.v5.i6.241

10.1016/j.ejrad.2013.06.017

10.1159/000358727

10.1159/000350418

10.1007/s00259-010-1512-3

10.1158/1078-0432.CCR-09-1759

10.1007/s10555-013-9465-1

10.1007/s11523-012-0216-y

10.1038/nbt0510-431

10.1159/000368363

10.3109/1354750X.2012.654511

10.1007/978-1-4614-8778-4_2

10.1016/B978-0-12-387718-5.00011-0

10.1038/nm.3600

10.1038/modpathol.2012.216

10.1371/journal.pone.0063364

10.1530/ERC-14-0190

10.1530/ERC-15-0092

10.1530/ERC-14-0106

10.1515/cclm-2013-0496

10.1210/jc.2015-2792

10.1126/science.1136800

10.1016/j.ejca.2015.04.005

10.1530/ERC-12-0340

10.3109/00365521.2012.733953

10.1177/0284185115579932

10.1007/s00259-014-2836-1

10.1016/j.cell.2011.02.013

10.1038/ajg.2010.154

10.1159/000369818

10.1007/s00259-015-3041-6

10.3109/1354750X.2012.654511

10.1200/JCO.2010.33.2056

10.1038/nrc3721

10.1038/bjc.2014.339

10.1002/ijc.24910

10.1111/j.1747-0803.2012.00632.x

10.4137/CIN.S7135

10.3748/wjg.v17.i41.4581

10.1371/journal.pmed.1001453

10.1016/j.eururo.2013.07.006

10.1038/ajg.2015.160

10.1016/j.surg.2015.06.056

10.1007/s00259-015-3075-9

10.1136/gutjnl-2014-308859

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Neuroendocrinology

Tập 104 Số 2

170-182

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