Abstract 3106: A blood-based neuroendocrine tumor multi-transcript test predicts and defines PRRT efficacy in neuroendocrine tumors
Authors: Bodei Lisa , Kidd Mark , Severi Stefano , Drozdov Ignat , Nicolini Silvia , Kwekkeboom Dik , Krenning Eric , Baum Richard , Paganelli Giovanni , Modlin Irvin 
Published: July 2016

Background: Peptide receptor radionuclide therapy (PRRT) is an effective treatment for neuroendocrine tumors (NETs). Somatostatin receptor expression defines suitability for therapy. Elevated somatostatin receptor uptake (Krenning scale grade 4) at baseline has ∼60% predictive accuracy for efficacy. Increased (&gt;600ng/ml) baseline levels of chromogranin A (CgA) are also considered as predictive. A blood-based 51 multigene NET transcript analysis (NETest) including gene clusters defining cell signaling and metabolism directly correlates with tumor activity. A multialgorithm-derived NETest scale 0-100% (low activity &lt;40%) defines clinical disease activity.

Aim: Assess the effectiveness of the NETest as a predictive biomarker in PRRT-treated NETs.

Methods: 177Lu-based-PRRT treated NETs (n = 54) were followed for 33 months. At baseline we evaluated: histological grade, somatostatin receptor imaging (SRI), CgA (ELISA, normal &lt;108ng/ml) and NETest (qRT-PCR with multianalyte algorithmic analyses). A mathematical genomic response index comprising NETest genes regulating metabolism and growth factor signaling integrated with grade was developed as a predictive quotient. RECIST criteria were used to evaluate disease control (responder vs non-responder). Statistical analyses: multiple regression, Kaplan-Meier survival, Chi2 analyses.

Results: PRRT demonstrated a 72% response with median PFS not achieved (median follow-up 16 months). The only baseline clinical characteristic associated with outcome was low grade (G1/G2 [Ki67&lt;20%] - coefficient 0.6±0.2, p&lt;0.005). Although 77% (36/47) low grade and 50% (4/8) high-grade tumors responded, grade alone was not predictive (p = 0.12). Neither baseline SRI measurements (p = 0.58) nor CgA were predictive (p = 0.53). A baseline NETest &gt;40% predicted treatment response and a longer PFS (HR 2.97, p = 0.05). NETest accurately (89%, χ2 = 27.4; p = 1.2×10−7) correlated with RECIST-determined treatment response. The baseline NETest decreased in 88% of responders; and increased in 90% of non-responders. Baseline gene expression for metabolism and growth factor signaling had 76% accuracy for predicting PRRT-response. The Predictive Quotient Index (NETest and grade) accurately predicted responders (97%) and non-responders (91%). This offered a significantly better prediction than elevated SRI uptake (94% vs. 38% accuracy: Chi2 = 31.8, p&lt;0.0001).

Conclusions: The blood-based NETest provided a predictive multi-molecular biomarker for PRRT. Alterations in levels correlate with RECIST responses and assess real time treatment efficacy. A predictive quotient index (NETest and grading) is highly accurate (94%) in predicting efficacy and significantly outperforms (p&lt;0.0001) SRI assessment. NET multigene measurement in blood can be used to predict patients responsive to PRRT.

Citation Format: Lisa Bodei, Mark Kidd, Stefano Severi, Ignat Drozdov, Silvia Nicolini, Dik Kwekkeboom, Eric Krenning, Richard Baum, Giovanni Paganelli, Irvin Modlin. A blood-based neuroendocrine tumor multi-transcript test predicts and defines PRRT efficacy in neuroendocrine tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3106.