SLNB identifies micrometastasis in one-third of early-stage patients. Negative SLNB may predict for improved but not necessarily favorable outcome. Initial tumor size and clinical nodal disease predict for poor outcome. High recurrence rates warrant the development of more effective adjuvant therapies, and better markers of recurrence and treatment response for MCC are needed.

Purpose Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor, often metastatic at presentation, for which current chemotherapeutic regimens are largely ineffective. As its pathogenesis is still unknown, we hypothesized that deregulation of signaling pathways commonly activated in cancer may contribute to MCC tumorigenesis and may provide insights into targeted therapy approaches for this malignancy. Experimental Design We retrospectively profiled 60 primary MCC samples using a SNaPshot-based tumor genotyping assay to screen for common mutations in 13 cancer genes. Results We identified mutations in 9 (15%) MCC primary tumors, including mutations in TP53 (3/60) and activating mutations in the PIK3CA gene (6/60). Sanger sequencing of the primary MCC tumors detected one additional PIK3CA mutation (R19K) that had not been previously described in cancer. Merkel cell polyoma virus (MCPyV) was detected in 38 (66%) MCC cases and patients with MCPyV-positive cancers showed a trend toward better survival. With one exception, the presence of MCPyV and of activating mutations in PIK3CA appeared mutually exclusive. We observed that signaling through the PI3K/pAKT pathway was active in one MCPyV-positive and in all MCPyV-negative MCC cell lines, as evidenced by AKT phosphorylation. Importantly, the presence of a PIK3CA activating mutation was associated with sensitivity to treatment with ZST474, a specific PI3K inhibitor and to NVP-BEZ235, a dual PI3K-mTOR inhibitor, targeted agents under active clinical development. Conclusions PI3K pathway activation may drive tumorigenesis in a subset of MCC and screening these tumors for PIK3CA mutations could help identify patients who may respond to treatment with PI3K pathway inhibitors.

Objective To compare outcomes for patients with hepatocellular carcinoma (HCC) treated with either liver resection or transplantation. Methods A retrospective, single institution analysis of 413 HCC patients from 1999–2009. Results 413 patients with HCC underwent surgical resection (n=106), transplantation (n=270), or were listed without receiving transplantation (n=37). Excluding transplanted patients with incidental tumors (n=50), 257 patients with suspected HCC were listed with the intent to transplant (ITT). The median diameter of the largest tumor by radiography was 6.0 cm in resected, 3.0 cm in transplanted, and 3.4 cm in the listed-but-not-transplanted patients. Median time to transplant was 48 days. Recurrence rates were 19.8% for resection and 12.1% for all ITT patients. Overall, patient survival for resection vs. ITT patients was similar (5-year survival of 53.0% vs. 52.0%, NS). However, for HCC patients with MELD scores <10 and who radiologically met Milan or UCSF criteria, 1-year and 5-year survival rates were significantly improved in resected patients. For patients with MELD <10 and who met Milan criteria, 1-year and 5-year survival were 92.0% and 63.0% for resection (n=26) vs. 83.0% and 41.0% for ITT (n=73, p=0.036). For those with MELD <10 and met UCSF criteria, 1-year and 5-year survival was 94.0% and 62.0% for resection (n=33) vs. 81.0% and 40.0% for ITT (n=78, p=0.027). Conclusions Among known HCC patients with preserved liver function, resection was associated with superior patient survival versus transplantation. These results suggest surgical resection should remain the first line therapy for patients with HCC and compensated liver function who are candidates for resection.

Tyrosine kinase inhibition of gastrointestinal stromal tumors (GIST) is effective but typically culminates in resistance and is rarely curative. Immunotherapy has potential application to GIST, as we previously showed that T-cell checkpoint blockade increases the antitumor effects of imatinib. Here, we showed that ligation of CD40 using an agonistic antibody (anti-CD40) activated tumor-associated macrophages (TAMs) in vivo in a knock-in mouse model of GIST harboring a germline mutation in Kit exon 11. Activated TAMs had greater TNF production and NFκB signaling and directly inhibited tumor cells in vitro. Anti-CD40 required concomitant therapy with imatinib for efficacy and depended on TAMs, and to a lesser extent CD8+ T cells, but not on CD4+ T cells or B cells. In an analysis of 50 human GIST specimens by flow cytometry, we found that CD40 was expressed on human TAMs and tumor cells yet was downregulated after response to imatinib. CD40 ligation did not have a direct inhibitory effect on human GIST cells. Our findings provide the rationale for combining anti-CD40 and tyrosine kinase inhibition to treat human GIST.

Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. While GIST are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Lastly, cabozantinib, a dual MET and KIT small molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment.

Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a KIT or PDGFRA mutation. However, the molecular basis for tumor malignancy is not well defined. While the Wnt/β-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed β-catenin and contained active, dephosphorylated nuclear β-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4. Accordingly, in human GIST T1 cells, Wnt stimulation increased β-catenin–mediated transcriptional activity in a reporter assay as well as transcription of the downstream target genes axin2 and cyclin D1. In contrast, DKK4 overexpression in GIST T1 cells reduced Wnt/β-catenin signaling. Additionally, we showed that nuclear β-catenin stability was partially regulated by the E3 ligase COP1, as demonstrated with co-immunoprecipitation and COP1 knockdown. Three molecular inhibitors of the Wnt/β-catenin pathway demonstrated anti-tumor efficacy in various GIST models, both in vitro and in vivo. Notably, the tankyrase inhibitor G007-LK alone had substantial activity against tumors of genetically engineered KitV558Δ/+ mice, and the effect was increased by the addition of the Kit inhibitor imatinib mesylate. Collectively, our findings demonstrate that Wnt/β-catenin signaling is a novel therapeutic target for selected untreated or imatinib-resistant GISTs.

Background Given the survival advantage of neoadjuvant treatment for locally advanced esophageal cancer, accurate clinical staging is necessary. The aim of this study was to assess the clinical (c) and pathologic (p) staging concordance rates for presumably early stage esophageal adenocarcinoma patients that had upfront esophagectomy (UFE) and evaluate if survival (OS) was negatively affected by inaccurate preoperative staging and subsequent treatment selection. Methods An NCDB retrospective review of nonmetastatic esophageal adenocarcinoma patients that had UFE. The rates of concordance between c and p staging system and OS were calculated. Results Of 2775 patients, most patients presented with cN0 (82.8%) and cT1 tumors (53.6%). The overall concordance between c and p staging was 78.8% for T‐classification (moderate agreement; weighted κ = 0.729; P < .001) and 78.8% for N‐classification (weak agreement; weighted κ = 0.448; P < .001). Patients that were upstaged due to a lack of concordance between T‐classification had decreased 5‐ and 10‐year OS (30% and 16%, P < .001) and those upstaged due to discordant N‐classification had decreased 5‐ and 10‐year OS (28% and 23%, P < .001).” Conclusions Preoperative staging of esophageal adenocarcinoma has moderate reliability and accuracy for predicting pT and pN classification. Up to 25% of patients have discordant clinical and pathological staging, which impacts OS.

Background and Objectives Most breast cancer (BC) patients present with early disease and clinically negative lymph nodes (cN0). Timing of surgery has not been standardized. We hypothesized that surgical delay results in an increased likelihood of nodal metastasis. Methods Patients diagnosed with cN0 BC undergoing surgery with sentinel lymph node biopsy as initial therapy between 2006 and 2014 were identified in the NCDB and divided into four groups based on time intervals between diagnosis and surgery (<4 weeks, 4–8 weeks, 8–12 weeks, and >12 weeks). Regression analysis evaluated the independent impact of surgical timing on axillary upstaging and survival. Results Of 355,443 patients with cN0 BC, 39.6% had surgery within 4 weeks and 5.4% more than 12 weeks from diagnosis. After controlling for relevant factors, a month delay in surgery was associated with an increased likelihood of nodal positivity (odds ratio: 1.04; 95% confidence interval [CI]: 1.04–1.05; p < .001) and decreased overall survival (hazard ratio: 1.03; 95% CI: 1.02–1.04; p < .001). When compared to patients who underwent surgery less than 4 weeks from diagnosis, the absolute increase in nodal positivity and relative risks were 5.3% (95% CI: 0.047–0.059) and 1.34 (95% CI: 1.30–1.38), respectively, in the more than 12 weeks group. Conclusions Delay in BC surgery in cN0 patients was associated with an increased likelihood of axillary upstaging and decreased survival.