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Neuroendocrine tumors (NETs) are a group of malignancies arising from neuroendocrine cells and frequently originate in the gastrointestinal tract and pancreas. Although curative resection is the main treatment for localized disease, systemic therapy is needed for relapsed or metastatic/unresectable gastroenteropancreatic NETs (GEP-NETs). Although there are several NET treatment guidelines from various countries, the geographical discrepancies between patient clinical characteristics, the regulatory approval status for therapeutic agents, and medical practices necessitate specific guidelines for Korean patients. We here provide a consensus review of the diagnosis, staging and systemic treatment of Korean GEP-NET patients. Systemic therapy options and the current Korean expert consensus on these treatments, including somatostatin analogs, targeted therapies such as everolimus and sunitinib, peptide receptor radionuclide treatments, and cytotoxic chemotherapies are addressed.

461 Background: In localized gastric cancer (GC), deficient mismatch repair (dMMR) tumors reportedly have a favorable prognosis. However, a potentially detrimental effect of the dMMR status was suggested in patients treated with adjuvant chemotherapy. It remains unclear whether the mismatch repair (MMR) status can impact clinical outcomes in patients with metastatic GC (mGC) receiving palliative chemotherapy. We examined the impact of the MMR status on survival outcomes of patients with HER2-negative mGC receiving first-line fluoropyrimidine plus platinum (FP) chemotherapy. Methods: We reviewed patients with histologically confirmed metastatic, recurrent, or locally advanced unresectable adenocarcinoma of the stomach or gastroesophageal junction receiving first-line FP chemotherapy between January 2015 and August 2018 at Asan Medical Center, Korea. MMR status was correlated with clinical characteristics and survival outcomes for patients with available MMR immunohistochemistry results. Results: Of 895 patients, we analyzed 543 with available MMR protein expression results, and dMMR was detected in 4.4% (n=24). Patients with dMMR exhibited a significantly higher median age than those with proficient MMR (pMMR) (64 vs. 58 years, p=0.044). No signet ring cell carcinoma (SRCC) was detected among dMMR tumors, whereas SRCC was found in 17.5% of pMMR tumors. Based on our prognostic model (Koo DH et al, 2011), only 4.2% of patients with dMMR were classified as the poor-risk group (vs. 16.8% of patients with pMMR, p=0.097). No significant difference in progression-free survival (PFS) was noted between patients with dMMR and pMMR tumors (median, 5.6 vs. 5.8 months, p=0.266). Patients with dMMR tumors tended to have better overall survival than those with pMMR tumors; this difference was not statistically significant (median, 17.9 vs. 12.2 months, p=0.183). In the good-risk subgroup, patients with dMMR tumors had a significantly worse PFS than those with pMMR tumors (median, 5.6 vs. 9.2 months, p=0.009); multivariate analysis revealed that MMR status was an independent factor for poor PFS in this subgroup. Conclusions: Survival outcomes of dMMR mGC did not differ from pMMR in patients who received first-line FP chemotherapy. However, in the good-risk subgroup, patients with dMMR tumors had a significantly shorter PFS than those with pMMR, suggesting a potentially reduced efficacy of cytotoxic chemotherapy in these patients.

The aim of our study is to evaluate the clinical efficacy of durvalumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) or polymerase epsilon (POLE)-mutated metastatic or unresectable colorectal cancer (mCRC) who had disease progression after standard chemotherapy. This prospective, open-label, multicenter, phase II study enrolled patients with mCRC harboring MSI-H/dMMR or POLE mutations treated with at least one prior line of therapy. The participants received durvalumab (1500 mg) every 4 weeks intravenously. The primary endpoint was the objective response rate (ORR). Of the 33 patients, 30 had MSI-H/dMMR and 3 had POLE-mutated microsatellite stable (MSS) CRC. With a median follow-up duration of 11.2 months (95% confidence interval [CI]: 7.3-15.0), the ORR was 42.4% (95% CI: 25.5-60.8). Among three patients with POLE-mutated CRC, one patient who had an exonuclease domain mutation (EDM) achieved an objective response, but the others with mutations in the non-exonuclease domain had progressive disease. Overall, the median duration of response was not reached and 85.7% of the responses were ongoing at data cutoff. The progression-free survival rate of 12 months was 58.2% (95% CI: 39.0-73.1) and the 12-month overall survival rate was 68.3% (95% CI: 48.8-81.7). Grade 3 treatment-related adverse events occurred in 36.4% of the patients and were manageable. In conclusion, durvalumab showed promising clinical activity with encouraging response rates and satisfactory survival outcomes in mCRC patients with MSI-H/dMMR or POLE EDM. In patients with POLE-mutated mCRC, clinical response to durvalumab may be restricted to those with EDM.

BackgroundWe evaluated the clinical implications of epithelial–mesenchymal transition (EMT) markers and peritumoral immune cell infiltration in patients with biliary tract cancer (BTC) treated with gemcitabine plus cisplatin (GemCis).MethodsForty-five patients with advanced BTC who received GemCis were included as the study population. We conducted multiplex immunohistochemistry and examined EMT markers and their correlations with immune cell infiltrate at the invasive tumor margin. Study population was subdivided into two groups: twenty-four patients with overall survival (OS) less than 10 months (short-term survivor group, SS) and 21 with OS of 20 months or longer (long-term survivor group, LS).ResultsThe density of tumor cells expressing epithelial marker E-cadherin (E-cadherin+ CK+) at the invasive tumor margin tended to be higher in the LS group than in the SS group (p = 0.065). The density of tumor cells expressing mesenchymal marker vimentin (vimentin+ CK+) was significantly higher in the SS group than in the LS group (p = 0.021). Accordingly, the density of E-cadherin- vimentin+ CK+ cells was also significantly higher in the SS group (p = 0.020). The density of OX40 expressing cells (OX40+) was significantly higher in the SS group than in the LS group (p = 0.006). The density of vimentin+ CK+ cells was positively correlated with FoxP3+ CD4+ regulatory T-cells (r = 0.29, p = 0.047) and OX40+ cells (r = 0.48, p < 0.001).ConclusionsEMT-related features were enriched in BTC patients with poor survival outcomes and were associated with the immunosuppressive tumor microenvironment.

Pazopanib is the only tyrosine kinase inhibitor approved for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy, but there have been limited real-world data on pazopanib for the treatment of advanced STS. We aimed to evaluate clinical outcomes of pazopanib in patients with multiple histologic STS types in real-world settings. We retrospectively analyzed clinical data of Korean patients with advanced STS treated with pazopanib between 2008 and 2019. Outcomes of interest included treatment response, survival according to histologic subtypes, and adverse events. The analysis included 347 STS patients. The disease control rate for all pazopanib-treated patients was 54.8% (95% confidence interval (CI) 49.5–60.0); 54 patients (15.6%) achieved a partial response and 136 (39.2%) had stable disease. Patients with alveolar soft-part sarcoma (ASPS; 90%), solitary fibrous tumor (SFT; 88.2%), synovial sarcoma (66.7%), leiomyosarcoma (61.1%), and undifferentiated pleomorphic sarcoma (59.6%) showed higher disease control rates than those with other STS subtypes. Overall, median progression-free survival (PFS) and overall survival (OS) were 5.3 months (95% CI 4.5–6.0) and 12 months (95% CI 10–14), respectively. Noticeable survival outcomes occurred in patients with ASPS and SFT, with a median PFS of 24.5 (95% CI 2.5–30.0) and 13.0 (95% CI 3.0–21.3) months, respectively. The median OS of patients with ASPS and SFT was 48 (95% CI 17–52) and 32 (95% CI 19–66) months, respectively. Adverse drug reactions occurred in 170 patients (49.0%) but were not life-threatening. This real-world data analysis showed acceptable efficacy and tolerability of pazopanib in patients pretreated with cytotoxic chemotherapy for advanced STS, with favorable treatment outcomes for ASPS and SFT.

Background We investigated whether the microsatellite instability (MSI) status affects the survival outcomes in patients with stage II/III rectal cancer who have undergone an upfront curative resection. Patients and Methods A total of 1103 patients with curatively resected stage II/III rectal cancer who had available polymerase chain reaction-based MSI results were included in the final analysis. Results Twenty-four (2.2%) patients in the total cohort were found to be MSI-high (MSI-H). In univariate analysis, neither disease-free survival (DFS) nor overall survival (OS) demonstrated significant differences between patients with MSI-H tumors and those with MSI-low (MSI-L) or microsatellite stable (MSS) tumors. The 5-year DFS rate was 78.0% in MSI-H patients and 69.9% in MSI-L/MSS patients (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.35-2.02; P = .689). The 5-year OS rates for MSI-H and MSI-L/MSS patients were 84.0% and 83.1%, respectively (HR, 0.86; 95% CI, 0.27-2.69; P = .790). By multivariate analysis, the MSI status did not affect either the DFS (HR, 1.00; 95% CI, 0.40-2.47; P = .994) or OS (HR, 0.85; 95% CI, 0.26-2.73; P = .778). Conclusions MSI-H tumors are rarely observed in rectal adenocarcinoma, and the MSI status may not affect the survival outcome in patients with a resected rectal cancer.

Purpose: We evaluated the potential role of Vascular Endothelial Growth Factor-A (VEGFA) amplification and genome-wide copy number variations (CNVs) using circulating cell-free DNA (cfDNA) as predictors of treatment outcome in hepatocellular carcinoma (HCC) patients treated with first-line sorafenib. Methods: Among 184 patients from a prospective biomarker cohort, who had started sorafenib between April 2015 and May 2016, 151 eligible patients were included in the analysis. Plasma cfDNA was extracted from peripheral blood in patients before starting sorafenib or healthy donors. Plasma VEGFA-to-EIF2C1 ratios (the VEGFA ratios) were determined using droplet digital polymerase chain reaction. We applied low depth whole genome sequencing in cfDNA to find CNVs and developed I-score to express genomic instability, which was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. Results: The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; p Citation Format: Sook Ryun Park, Chung Ryul Oh, Sun-Young Kong, Min Kyeong Kim, Kyong-Ah Yoon, Eun-Hae Cho, Junnam Lee, Jihoon Kang, Baek-Yeol Ryoo. Biomarker analysis in circulating cell-free DNA in patients treated with sorafenib for advanced hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4600.