STAT3 inhibition for gastroenteropancreatic neuroendocrine tumors: Potential for a new therapeutic target?

340 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly vascular tumors with similar treatments applied to all sites. The expression of pro-angiogenic factors (STAT3, VEGF, and HIF-1α) and their association with known adverse pathologic factors and disease recurrence after resection is not known. Methods: All pts with non-metastatic primary GEP-NETs who underwent curative-intent resection at a single institution from 2000-2013 were included. Immunohistochemistry was performed for STAT3, VEGF, HIF-1α, Ki-67 index, and CD31 using tissue microarrays made in triplicate by a pathologist blinded to other clinicopathologic variables. STAT3, VEGF, and HIF-1α were categorized into high vs low expression; CD31 was dichotomized at the median value. Primary outcome was 3-yr recurrence-free survival (3-yr RFS); secondary outcomes were correlation of STAT3, VEGF, and HIF-1α expression with Ki-67 index, adverse pathologic factors, and CD31 expression, a marker of microvascular density. Results: Of 265 GEP-NETs resected, 144 had tissue for analysis. STAT3 expression was high in 12 (8%) and low in 132 (92%). VEGF expression was high in 19 (13%) and low in 125 (87%), and HIF-1α was high in 1 (1%) and low in 143 (99%). High STAT3 expression was associated with worse 3-yr RFS compared to low expression (55% vs 84%; p = 0.003). High VEGF expression had a 3-yr RFS of 76% compared to 82% for low expression (p = 0.098); HIF-1α expression was not associated with RFS. Ki-67 ≥3% was associated with worse 3-yr RFS (≥3%: 51% vs < 3%: 84%; p < 0.001), as was the presence of lymphovascular invasion (LVI: 72% vs 95%; p = 0.001) and increased microvascular density per µm2 (CD31 > median: 75% vs CD31 < median: 86%; p = 0.043). High STAT3 expressing tumors were more likely to have a Ki-67≥3% (42% vs 7%; p < 0.001). LVI was present in 82% of high STAT3 tumors compared to only 50% with low STAT3 (p = 0.058). CD31 overexpression was similar between groups (58% vs 49%; p = 0.5). Conclusions: In resected GEP-NETs, high STAT3 expression is associated with an increased Ki-67 index, presence of lymphovascular invasion, and worse 3-yr RFS. STAT3 inhibition may be a novel therapeutic option for patients undergoing resection of high-risk tumors.