Gastrointestinal Neuroendocrine Carcinoma Research Articles

Case Report: Gastrointestinal neuroendocrine carcinoma with SMARCA4 deficiency: a clinicopathological report of two rare cases

BackgroundGastrointestinal neuroendocrine carcinoma (GI NEC) is a rare but highly malignant neoplasm with an aggressive clinical course. SMARCA4 is one of the subunits of the SWI/SNF chromatin remodeling complex. SMARCA4 deficiency can occur rarely in subsets of NECs. Reports of the clinicopathological features of GI NECs with SMARCA4 deficiency are limited.MethodsIn this study, we retrospectively reported two rare cases of GI NEC with SMARCA4 deficiency and described the clinicopathological, radiographic and histopathological features.ResultsCase 1 was a 43-year-old male with a stage cT3NxM1, IV tumor. Case 2 was a 64-year-old female with a stage cT4aN1M0, IIIA tumor. Both tumors presented as ulcerated masses with infiltration. Pathological examination indicated a solid architecture with poorly differentiated morphology, and complete loss of SMARCA4 (BRG1) was found. Immunohistochemical staining showed positivity for Syn, CgA and CD56. The Ki-67 index was 90% and 70%, respectively. None of the cases had mismatch repair (MMR) deficiency. Case 1 received treatment with chemotherapy and anti-PD-1 immunotherapy. He did not respond to treatment, and died 9 months later. Case 2 received neoadjuvant chemotherapy before surgical treatment, and the tumor showed TRG3 in response to neoadjuvant chemotherapy, chemotherapy and anti-PD-1 immunotherapy were continued after surgical resection. There was no evidence of disease for 10 months.ConclusionsGI NEC with SMARCA4 deficiency is a rare entity of gastric NEC. SMARCA4 may be a promising targetable and prognostic biomarker. BRG1 immunohistochemical staining could be performed for GI NECs. Further studies with a larger cohort will be needed.

P-118 Clinical significance of primary tumor sites and epithelial tumor markers in patients with unresectable/recurrent gastrointestinal neuroendocrine carcinoma treated with combined chemotherapy with irinotecan and cisplatin

P-118 Clinical significance of primary tumor sites and epithelial tumor markers in patients with unresectable/recurrent gastrointestinal neuroendocrine carcinoma treated with combined chemotherapy with irinotecan and cisplatin

Primary tumor resection improves survival of gastrointestinal neuroendocrine carcinoma patients with nonresected liver metastases.

The role of primary tumor resection (PTR) in the survival of gastrointestinal neuroendocrine carcinoma (GI-NEC) patients with liver metastases only remains poorly defined. Therefore, we investigated the impact of PTR on the survival of GI-NEC patients with nonresected liver metastases. GI-NEC patients with a liver-confined metastatic disease diagnosed between 2016 and 2018 were identified in the National Cancer Database. Multiple imputations by chained equations were used to account for missing data, and the inverse probability of treatment weighting (IPTW) method was used to eliminate selection bias. Overall survival (OS) was compared by adjusted Kaplan-Meier curves and log-rank test with IPTW. A total of 767 GI-NEC patients with nonresected liver metastases were identified. Among all patients, 177 (23.1%) received PTR and had a significantly favorable OS before (median: 43.6 months [interquartile range,IQR, 10.3-64.4] vs. 8.8 months [IQR, 2.1-23.1], p < 0.001 in log-rank test) and after (median: 25.7 months [IQR, 10.0-64.4] vs. 9.3 months [IQR, 2.2-26.4], p < 0.001 in IPTW-adjusted log-rank test) the IPTW adjustment. Additionally, this survival advantage persisted in an adjusted Cox model (IPTW adjusted hazard ratio = 0.431, 95% confidence interval: 0.332-0.560; p < 0.001). The improved survival persisted in subgroups stratified by primary tumor site, tumor grade, and N stage, even in the complete cohort (excluding patients with missing data). PTR led to improved survival for GI-NEC patients with nonresected liver metastases regardless of primary tumor site, tumor grade, and N stage. However, the decision for PTR should be made on an individualized basis following multidisciplinary evaluation.

P373 An Unusual Occurrence of Right-sided Colonic Neuroendocrine Carcinoma in Ulcerative Colitis – A case report

Abstract Background It's estimated that inflammatory bowel disease (IBD) accounts for 1-2% of all colorectal cancer (CRC) cases. However, the mere presence of IBD increases the risk by 2 folds compared with the general population. It's been established that the most prevalent epithelial colonic malignancy linked to IBD is adenocarcinoma. Neuroendocrine neoplasms arising in the large intestines are extremely rare (rate &amp;lt;1%), even less common in association with IBD.(1) Herein, we report a 49 years-old male with a longstanding history of ulcerative pancolitis, who was found to have a metastatic right-sided colorectal neuroendocrine carcinoma (NEC). Methods Case Presentation A 49-years-old male patient, with a 13-years history of ulcerative pancolitis underwent a colonoscopy. It revealed a large ulcerated mass extending from the ileocecal valve into the proximal ascending colon highly suspicious for malignancy. Biopsy showed a large cell poorly differentiated NEC in the ascending colon. Tumor cells were positive for Synaptophysin and cytokeratin AE1/3, and a high Ki67. Serum Chromogranin A (CgA) and urine 5-hydroxyindoleacetic acid were high. Imaging was evident for a short segment circumferential wall thickening at the ascending colon and hepatic metastasis. The patient was planned to receive chemotherapy, but died before treatment. Results Discussion Risk of CRC increments linearly approximately 7 years following diagnosis of IBD. After 30 years of colitis, the incidence is estimated to be around 18%. NECs in particular are not frequently encountered in association with IBD, much less right-sided.(1) Colonic NECs are usually aggressive with a Ki67 typically greater than 20%, often present with metastasis with absence of a characteristic hormonal secretion picture.(2, 3) The incidence of NECs in association with Ulcerative Colitis (UC) is twice more frequent in males, with a mean age of 49.36, and development after a median of 15 years of UC first diagnosis. Majority of NECs were found in the left side of the colon, in the contrary to our patient. Prognosis was dismal in most cases, as most demonstrated a higher malignant potential compared to adenocarcinomas.(3) Early diagnosis of gastrointestinal NECs poses a challenge since it lacks a specific clinical presentation. Serum CgA level correlates with the tumor burden and overall survival. Additionally, studies demonstrating the role of endoscopic surveillance in colonic NECs early detection is scarce.(1,4) Conclusion Thorough understanding of the condition and its risk factors is crucial for a timely diagnosis, which maximizes the likelihood of a favorable prognosis. By reporting this case, we emphasize the importance of considering NEC as a differential diagnosis of CRC in IBD, particularly in UC patients.

O12-1 Ramucirumab-containing chemotherapy for gastrointestinal neuroendocrine carcinoma: RAM-NEC study (WJOG13420G)

Second-line chemotherapy (CTx) for advanced gastrointestinal neuroendocrine carcinoma (GI-NEC) after platinum-based CTx is adopted according to the guidelines of GI adenocarcinoma or small cell lung cancer in daily practice. Recently, some reports suggested that vascular endothelial growth factor receptor-2 highly expressed in tumor vessels of GI-NEC. In this study, we evaluated the efficacy of ramucirumab (RAM)-containing CTx.

Multicenter retrospective study of ramucirumab-containing chemotherapy for gastrointestinal neuroendocrine carcinoma patients previously treated with platinum-based chemotherapy: RAM-NEC study (WJOG13420G).

511 Background: Platinum-based systemic chemotherapy (CTx) is recommended for poorly differentiated advanced gastrointestinal neuroendocrine carcinoma (GI-NEC). As second-line CTx various regimens are adopted according to the guidelines of GI adenocarcinoma or small cell lung cancer in daily practice. Recently, some clinical and preclinical reports suggest that vascular endothelial growth factor (VEGF) inhibitors are effective against NEC. In this study, we evaluated the efficacy of ramucirumab (RAM, anti-VEGF receptor 2 antibody)-containing CTx. Methods: We retrospectively evaluated gastric (G-) or colorectal (C-) NEC patients previously treated with first-line platinum-based CTx followed by second-line CTx between March 2015 and June 2020 (G-NEC) or between May 2016 and June 2020 (C-NEC). The main inclusion criteria were ECOG performance status (PS) of 0–2, pathologically diagnosed as G or C- NEC or mixed adenoneuroendocrine carcinoma. We compared the efficacy of RAM-containing CTx as second- or later-line treatment (Group A) with that of CTx without RAM as second-line treatment (Group B). A Cox proportional hazard model and inverse probability weighting of propensity scores were used to adjust the background factors between the two groups. Results: From 25 facilities, 139 patients were included in this study. Group A and B contained 50 (G/C, 43/7 patients) and 89 (G/C, 58/31 patients) patients, respectively. Patient characteristics were as follows (Group A/Group B): median age (range), 70 (28–83)/68 (39–86); ECOG PS 1–2, 66/69%, more than two prior regimens, 46/0%; response to previous platinum-based CTx, 46/38%. The regimen in combination with RAM in Group A was paclitaxel/nab-paclitaxel/FOLFIRI (62/26/12%). Second-line CTx in Group B were commonly amrubicin (58%) and irinotecan (11%). The efficacy (Group A/Group B) after a median follow-up time of 7.5/5.5 months were as follows: median overall survival (mOS), 8.6/5.8 months (HR, 0.68; 95% CI, 0.45–1.01; p = 0.058); median progression-free survival, 4.3/1.9 months (HR, 0.57; 95% CI, 0.39–0.84; p = 0.004); objective response rate, 50/8% ( p &lt; 0.0001); disease control rate, 70/24% ( p &lt; 0.0001); mOS in G-NEC, 8.6/5.3 months (HR, 0.62; 95% CI, 0.39–0.99; p = 0.047); and mOS in C-NEC, 5.4/6.8 months (HR, 0.66; 95% CI, 0.26–1.66; p = 0.378). The most common grade 3 or higher treatment-related adverse event that occurred in more than 5% of patients in Group A was neutropenia (32%). Conclusions: This study suggests that RAM-containing CTx as second- or later-line treatment is effective for GI-NEC patients, especially for G-NEC. Central pathological review and biomarker analyses using pretreated tissue specimens are ongoing. We will present updated data in the congress. Clinical trial information: UMIN000043200.

Survival Analysis in Gastrointestinal Neuroendocrine Carcinoma With Bone Metastasis at Diagnosis.

PurposeGastrointestinal neuroendocrine carcinoma (NEC) with bone metastasis is rarely reported. The purpose of this study is to explore the prognosis and risk factors of such patients.Patients and MethodsWe retrospectively reviewed patients diagnosed as gastrointestinal NECs with bone metastasis at diagnosis from 2010 to 2016 by using the Surveillance, Epidemiology and End Results (SEER) database. Predictors of overall survival (OS) and cancer-specific survival (CSS) were analyzed by univariable and multivariable Cox analyses. Kaplan–Meier plots were constructed to show the correlation between independent predictors and survival.ResultsA total of 330 gastrointestinal NEC patients with bone metastasis at diagnosis were included for analysis. Over half of patients were male and older than 60 years old. The most common primary site of gastrointestinal NEC with bone metastasis was the pancreas. The prognosis of gastrointestinal NEC with bone metastasis (3-year OS and CSS rates: 16.7 and 17.0%) was very poor. On Cox multivariable analysis, age over 60 years old, no surgery, and lung metastasis were independent predictors of decreased OS and CSS.ConclusionsWe identified three independent factors associated with prognosis among gastrointestinal NEC patients with bone metastasis, namely age, surgery, and lung metastasis. For younger gastrointestinal NEC patients with bone metastasis, surgical resection of primary tumors as well as actively treating lung metastasis might be useful for prolonging survival.

Risk Factors and Predictive Score Model for Early Recurrence After Curative Surgery in Patients With Poorly Differentiated Gastrointestinal Neuroendocrine Neoplasms.

Purpose: Studies on early recurrence in gastrointestinal neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma (MANEC) are lacking and risk factors related to early recurrence are not clear. We evaluated risk factors for early recurrence in such patients and developed a predictive scoring model.Methods: Patients undergoing curative surgery for GI-NEC or MANEC between January 2010 and January 2019 were included. Early recurrence was defined as recurrence within 12 months after surgery. Risk factors for early recurrence were identified using logistic regression.Results: Of the 80 included patients, 27 developed early recurrence and 53 had no early recurrence. Independent risk factors associated with early recurrence included tumor location in the midgut/hindgut [odds ratio (OR) = 5.077, 95% confidence interval (CI) 1.058–24.352, p = 0.042], alkaline phosphatase (ALP) >80 (OR = 5.331, 95% CI 1.557–18.258, p = 0.008), and lymph node ratio (LNR) >0.25 (OR = 6.578, 95% CI 1.971–21.951, p = 0.002). Risk scores were assigned to tumor location (foregut, 0; midgut/hindgut, 1), ALP (≤80, 0; >80, 1), and LNR (≤0.25, 0; >0.25, 1). Patients with a high risk (score 2–3) for early recurrence had significantly shorter disease-free survival and overall survival than those with low- (score 0) and intermediate risks (score 1) (both p < 0.001). The novel scoring model had superior predictive efficiency for early recurrence over TNM staging (area under the curve 0.795 vs. 0.614, p = 0.003).Conclusion: Tumor location, preoperative ALP, and LNR were independent factors associated with early recurrence after curative surgery for GI-NEC or MANEC. The risk scoring model developed based on these three factors shows superior predictive efficiency.

Exploration of Novel Prognostic Markers in Grade 3 Neuroendocrine Neoplasia.

Simple SummaryHigh grade neuroendocrine tumours and carcinomas (NETs/NECs) behave aggressively and have limited survival outcomes. The mainstay of therapy is systemic therapy, in which the associated side-effects are a key consideration in a palliative population. We have conducted a retrospective review of patients with high grade NETs and NECs to determine possible tests that will predict survival before patients start treatment. This will allow patients to avoid potentially toxic treatment that is unlikely to be of benefit.Background: High-grade neuroendocrine tumours and carcinomas (NET/NECs) behave aggressively, typically presenting at an advanced stage. Prognosis is poor, with median survival between 5 and 34 months. The mainstay of treatment is palliative systemic therapy. However, therapy carries a risk of toxicity, which can reduce quality of life. Therefore, accurate prognostic scores for risk stratification of patients with high-grade NET/NECs are needed to help guide patient management to decide whether active treatment is likely to improve overall survival (OS). We aimed to compare the prognostic ability of published prognostic scores to predict OS in a cohort of patients with high-grade NET/NECs of any primary site. Methods: Treatment, biochemical and clinicopathological data were collected retrospectively from 77 patients with high-grade NET/NECs across three hospitals between 2016 and 2020. Variables including performance status (PS), Ki-67, age at diagnosis, previous treatment and presence of liver metastases were recorded. Pre-treatment neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, modified Glasgow prognostic score (mGPS), and gastrointestinal neuroendocrine carcinoma (GI-NEC) score were derived. Univariable and multivariable survival analyses were used to assess prognostic ability. Results: The median age of the cohort was 63 years (range: 31–85); 53% of subjects were female. Grade 3 NETs (G3-NETs) were identified in 32 patients and NECs in 45 patients. The median OS was 13.45 months (range: 0.87–65.37) with no difference observed between G3-NETs and NECs. Univariable analysis revealed that NLR (n = 72, p = 0.049), mGPS (n = 56, p = 0.003), GI-NEC score (n = 27, p = 0.0007) and Ki-67 (n = 66, p = 0.007) were significantly associated with OS. Multivariable analysis confirmed that elevated mGPS (p = 0.046), GI-NEC score (p = 0.036), and Ki-67 (p = 0.02) were independently prognostic for reduced OS across the entire cohort. mGPS was identified as an independent prognostic factor in G3-NETs. Independent predictors of OS in NECs were PS and Ki-67. Conclusions: mGPS, PS and Ki-67 are independent prognostic markers in high-grade NET/NEC patients. Our study supports the use of these prognostic scores for risk stratification of patients with high grade cancers and as useful tools to guide treatment decisions.

Salvage Chemotherapy by FOLFIRI Regimen for Poorly Differentiated Gastrointestinal Neuroendocrine Carcinoma.

Chemotherapy is the mainstay treatment for advanced poorly differentiated gastrointestinal neuroendocrine carcinoma (GI-NEC), with platinum-containing regimens being the optimal first-line regimen. However, the role and efficacy of second-line chemotherapy for GI-NEC are unclear. This study aimed to evaluate the feasibility and efficacy of fluorouracil, leucovorin, and irinotecan (FOLFIRI) as second-line therapy in patients with relapsed or recurrent GI-NEC after first-line platinum plus etoposide therapy. We retrospectively evaluated eight consecutive patients with unresectable GI-NEC treated between 2017 and 2020. The inclusion criteria were pre-treatment with platinum doublet therapy, performance status (PS) 0-2, having measurable lesions, and treatment with FOLFIRI as second-line therapy. The overall response rate, progression-free survival (PFS), overall survival (OS), safety, and relative dose intensity were evaluated. Five patients met the inclusion criteria. Overall, 37 cycles of FOLFIRI were administered. The relative dose intensities for irinotecan, continuous infusion of 5-FU, and a bolus injection of 5-FU were 76%, 72%, and 54%, respectively. Overall, 2 of the 5 patients achieved partial response (40%), and the duration of response (DOR) was 4.0 months. The PFS and OS rates were 5.8 (95% CI, 1.5-NA) and 11 (95% CI, 6.3-NA) months, respectively. Overall, 4 of the 5 patients (80%) proceeded with further chemotherapy. Grade ≥ 3 adverse events except hematological toxicity included febrile neutropenia (n = 2), anorexia (n = 2), and fatigue (n = 1). Treatment discontinuation due to treatment-related adverse events was not observed. FOLFIRI showed modest efficacy and feasibility for GI-NEC patients and has thus potential for patients who fail the first-line treatment.

Combined use of albumin and neutrophil-to-lymphocyte ratio as new prognostic and predictive factor in patients with poorly differentiated neuroendocrine carcinomas.

e15543 Background: Outcomes of patients affected by advanced neuroendocrine carcinomas (NEC) with Ki-67 labeling index &gt; 55% are heterogeneous regardless of the primary tumor site. We explored baseline inflammatory indexes and serum albumin levels to identify markers of response to standard first line chemotherapy. Methods: We retrospectively identified patients with advanced NEC treated with cisplatin (CP) or carboplatin (CB) and etoposide between 2015 and 2019 at the National Cancer Institute of Milan. Linear and Cox regressions were used to investigate, respectively, numeric and time-to-event outcomes. Maximization of log-rank statistics was used for optimal cutoffs finding. An artificial intelligence algorithm, random forest, was used to rank the impact of different clinical features on OS and PFS. Results: A total of 81 consecutive patients with different primary tumors (53 small cell lung carcinoma, 12 large cell neuroendocrine carcinoma, 10 gastrointestinal neuroendocrine carcinoma and 6 Merkel cell carcinoma) either treated with CP (n = 39) or CB (n = 42) were analyzed. Overall response rate (ORR), median progression free survival (PFS) and median overall survival (OS) were, respectively, 50.6%, 5.5 months (m) and 9.1m. Considered together, high serum albumin (SA &gt; 3.5 g/dl) and low neutrophile-to-lymphocyte ratio (NLR &lt; 3.59) identified a group of patients (n = 42) with longer median PFS and OS compared to the rest of the cohort (8.3m vs 1.5m, HR 3.58, CI 2.14-6.02, p &lt; 0.001 for PFS and 12.6m vs 4.4m, HR 3.11, CI 1.88-5.18, p &lt; 0.001 for OS); within this group a higher ORR (74% vs 36%, OR 5.01, CI 1.83-14.64, p = 0.002) was observed. Two multivariate models showed statistically significant associations of SA and NLR with PFS ( p = 0.017 and p = 0.005) and OS ( p = 0.016 and p = 0.036), independent of baseline ECOG performance status, age, sex, body mass index, smoking status, stage, hepatic tumor burden, primary site, histology, lactate dehydrogenase (LDH) serum levels, type of platinating agent and number of cycles. Two random forest models ranked SA, NLR and LDH as the most important factors for PFS and OS prediction. Conclusions: In the setting of advanced NEC with Ki-67 &gt; 55% the combined use of SA and NLR identified two groups of patients with remarkably different outcomes, suggesting that these serum markers at baseline may have prognostic implications and be predictive of response to platinating agents. Prospective studies should validate these preliminary findings.

Capecitabine, Oxaliplatin, Irinotecan, and Bevacizumab Combination Followed by Pazopanib Plus Capecitabine Maintenance for High-Grade Gastrointestinal Neuroendocrine Carcinomas

Gastrointestinal neuroendocrine carcinoma (NEC) is a lethal, uncommon, and understudied neoplasm. We present the efficacy and safety of first-line capecitabine (CP), oxaliplatin, irinotecan, and bevacizumab (CAPOXIRI-BEV) combination followed by pazopanib plus CP maintenance therapy in patients with advanced high-grade poorly differentiated gastrointestinal NEC. This was a two-stage phase II study conducted at multiple institutions. Patients were consecutively enrolled and had advanced NEC of the colon or small bowel. Patients received irinotecan 125 mg/m, oxaliplatin 80 mg/m on day 1, CP 1000 mg/m twice daily on days 1 to 14, plus bevacizumab 8 mg/kg on day 1 for six 21-day cycles. Maintenance therapy was given to those who responded (complete response/partial response) or had stable disease after 6 cycles with CAPOXIRI-BEV with pazopanib 800 mg daily plus CP 1600 mg/m daily on days 1 to 14 every 3 weeks until disease progression or unacceptable toxicity. Patients who progressed on CAPOXIRI-BEV received standard etoposide-carboplatin. The primary endpoint was overall response rate. Twenty-two patients were enrolled of whom 19 were evaluable. The median age was 60 years. The overall response rate (3 complete response/6 partial response) was 47.4% (95% confidence interval: 29.5-76.1), the overall disease control rate was 78.9% (95% confidence interval: 62.6-99.6), and, at median 30 (11 to 41 mo) months' follow-up, 5 patients (26.3%) were still alive. Median progression-free survival was 13 months, and the 1-year progression-free survival rate was 52.6%. The median overall survival was 29 months. The median overall survival of the 9 patients who responded versus those with stable disease/progressive disease was 30.5 versus 14 months, respectively. The median duration of response was 16 months. Predictable toxicity was observed. First-line CAPOXIRI-BEV followed by pazopanib plus CP maintenance therapy for advanced NEC demonstrates promising efficacy and predictable toxicity. Further investigation is warranted.

Delta-like 3 localizes to neuroendocrine cells and plays a pivotal role in gastrointestinal neuroendocrine malignancy.

Delta‐like 3 (DLL3) is a member of the Delta/Serrate/Lag2 (DSL) group of Notch receptor ligands. Five DSL ligands are known in mammals, among which DLL3 has a unique structure. In the last few years, DLL3 has attracted attention as a novel molecular targeting gene in neuroendocrine carcinoma of the lung due to its high expression. However, the expression pattern and functions of DLL3 in the gastrointestinal tract and gastrointestinal neuroendocrine carcinoma remain unclear. In this study, we examined the expression and role of DLL3 in the gastrointestinal tract, as well as in gastrointestinal neuroendocrine carcinoma. Immunohistochemical staining of the human normal gastrointestinal tract revealed that DLL3 localized in neuroendocrine cells. DLL3 showed intense staining in chromogranin A‐positive gastric cancer specimens. Real‐time quantitative RT‐PCR and western blotting analyses showed considerable upregulation of DLL3 in gastrointestinal neuroendocrine carcinoma cell lines. Immuno‐electron microscopy demonstrated abundant expression of DLL3 in neurosecretory granules in these cells. Furthermore, gene silencing of DLL3 caused significant growth inhibition through the induction of intrinsic apoptosis. Our findings suggest that DLL3 is expressed in neuroendocrine cells of the gastrointestinal tract and that it has a pivotal role in gastrointestinal neuroendocrine carcinoma cells. Based on these findings, further investigations are required to achieve a breakthrough in developing therapeutic strategies for gastrointestinal neuroendocrine carcinoma.

Safety and efficacy of amrubicin monotherapy in patients with platinum-refractory metastatic neuroendocrine carcinoma of the gastrointestinal tract: a single cancer center retrospective study.

PurposePatients with gastrointestinal neuroendocrine carcinoma (GI-NEC) have poor prognoses. Although platinum-based combination chemotherapy is commonly used as first-line treatment, the benefit of amrubicin (AMR) and salvage chemotherapy in those who develop platinum-refractory GI-NEC remains unknown. This study aimed to evaluate the efficacy and safety of AMR monotherapy in patients with platinum-refractory GI-NEC.Patients and methodsPlatinum-refractory GI-NEC patients who received AMR monotherapy between April 2012 and September 2017 were retrospectively analyzed. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events were evaluated. PFS and OS were estimated using Kaplan-Meier methods and compared using log-rank tests.ResultsIn total, 16 patients were enrolled. Of them, 13 (81.3%), 1 (6.2%), and 2 (12.5%) received cisplatin plus irinotecan, cisplatin plus etoposide, and fluoropyrimidine plus platinum, respectively, before AMR monotherapy. The primary sites of NEC included the esophagus (N=3, 18.8%), stomach (N=10, 62.5%), duodenum (N=1, 6.2%) and colorectum (N=2, 12.5%). Patients were administered a median of 3 (range, 1–15) cycles of AMR. The ORR was 6.3%, and the median PFS and OS were 2.9 months (95% CI: 1.7–7.4) and 13.8 months (95% CI: 7.9–23.5), respectively. Neutropenia was the most serious adverse event. Grade 3 or higher neutropenia and febrile neutropenia occurred in 50.0% and 6.2% of patients, respectively. Other nonhematological toxicities were not severe, and no treatment-related deaths occurred. The 10 patients who received subsequent chemotherapy after AMR had significantly longer OS than those who did not (17.3 months vs 8.9 months; p=0.018). The median PFS of those who received organ-specific subsequent chemotherapy after AMR was 3.8 months, which was longer than that of those who received prior AMR.ConclusionAMR is feasible with minimal side effects for platinum-refractory GI-NEC. Organ-specific subsequent chemotherapy after AMR may improve patient survival.

Therapy alteration of solid tumors based on FoundationOne comprehensive genome profiling assay.

e14742 Background: Molecular profiling assays are becoming widely available and provide valuable information on tumor characteristics, which can identify targeted therapies or immunotherapies for cancer patients. However, the clinical utility of such tests remains unclear. Within our institution, we analyzed the clinical utility and subsequent treatment alterations of the FoundationOne Comprehensive Genome Profiling Test (FOne). Methods: We conducted a retrospective cohort review (2017 - 2018) of patients with solid tumors under standard diagnostic care who received FOne testing. We reviewed the therapies that were proposed by FOne and studied whether they led to a therapeutic alteration. Results: 71 patients were identified, of which the majority presented a progressive disease state (80%). Among the cancer types most frequently tested were adenocarcinoma of the colon (14%), prostate (8%), lung (4%), intrahepatic cholangiocarcinoma (8%) and breast invasive ductal carcinoma (4%). In 16 cases (22%), therapies suggested by FOne were approved in patient’s tumor type while in 30 cases (42%) therapies were approved in another tumor type. For an additional 13 cases (18%) only therapies tested in clinical trials were reported. 4 patients (6%) received a new therapy based on the FOne result: cancer of unknown primary (Everolimus due to a TSC1 mutation), cutaneous angiosarcoma (Pembrolizumab due to a high tumor mutational burden (TMB)), gastrointestinal neuroendocrine carcinoma (Ipilimumab and Nivolumab due to an intermediate TMB) and mucinous adenocarcinoma of the appendix (Talazoparib due to an ATM mutation). For 11 cases (15%), a new therapy option was identified by FOne, which due to the current treatment plan might be considered for later use. 3 cases (4%) were evaluated for potential clinical trial enrollment. Note that for an additional 6 patients (8%), the therapies proposed by FOne were already established on the basis of previous testing (e.g. smaller genomic panels, IHC, FISH). Conclusions: Overall, 18 (25%) patients received a new therapy option by FOne after standard of care diagnostics. Therapeutic alterations were observed particularly in patients with a rare or unknown tumor type.

Development of a nomogram to predict overall survival in patients presenting with gastrointestinal neuroendocrine carcinoma (WHO G3).

197 Background: To evaluate the prognostic factors in patients with gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) and develop a nomogram to predict 1-year overall survival (OS). Methods: We performed a retrospective analysis of 122 patients with GI-NEC. Nomogram for 1-year OS was created as visualizations of Cox proportional hazards regression models and internally validated by use of bootstrap and cross-validation. We assessed nomogram model performance by examining overall accuracy (Brier score), calibration (calibration plot), and discrimination (Harrell C index). Results: The median survival was 9 months in 122 patients, and 51 (41.8%) patients died in the development cohort. A 1-year OS was chosen because 82% of the patients who died from disease did so within 1 year. Multivariable analysis identified prognostic factors including performance status, stage, Ki-67 index and LDH, all of which were included in the final model. In the development cohort, the Harrell C index for overall survival was 0·887 (95% CI 0·810-0·964), and calibration curves showed adequate calibration (judged by eye) of the observed and predicted probabilities. Conclusions: Prognostic factors were used to develop nomograms for 1-year OS for GI-NEC. The nomogram can be offered to clinicians to improve their abilities to assess patient prognosis, strengthen the prognosis-based decision making, enhance patient stratification, and inform patients in the clinic.

First-line irinotecan combined with 5-fluorouracil and leucovorin for high-grade metastatic gastrointestinal neuroendocrine carcinoma.

High-grade gastrointestinal neuroendocrine neoplasms, ie, poorly differentiated neuroendocrine carcinomas, with no effective therapeutic approaches, have a high ability to metastasize. A review of the hospital information system was performed. Patients with histologically proven gastrointestinal neuroendocrine carcinoma who were treated with irinotecan combined with 5-fluorouracil and leucovorin in a first-line setting were eligible for analysis. We extracted information on age, sex, disease stage, laboratory findings, radiological findings, pathological findings, chemotherapy, effectiveness and adverse events of therapy, and outcomes. Eleven patients were included in the study. Partial response was observed in 7 patients. Median progression-free survival and overall survival were 6.5 (95% CI, 5.1-7.9) and 13.0 (95% CI, 9.8-16.2) months, respectively. No treatment-related deaths occurred. The results demonstrated that irinotecan combined with 5-fluorouracil and leucovorin is an active regimen with acceptable toxicity for patients with metastatic high-grade gastointestinal neuroendocrine carcinoma that merits further investigation in prospective trials.

Diagnosis and therapy of primary hepatic neuroendocrine carcinoma: clinical analysis of 10 cases.

Primary hepatic neuroendocrine carcinoma (PHNEC) is rarer than extrahepatic gastrointestinal neuroendocrine carcinoma (NEC). It is difficult to make a correct diagnosis and poses a challenge for management. Ten PHNEC patients were admitted to our hospital from June 2006 to June 2011. Laboratory tests and imaging scans were performed for diagnosis and exclusion of extrahepatic NEC. All patients were AFP - and CA199- . Seven patients had solid tumors with cystic changes on ultrasonography, CT and/or MRI. For the initial treatment, four patients received combined-therapy and six monotherapy. Considering overall treatment, six patients received combined-therapy and four patients monotherapy. Staging criteria of primary hepatocellular carcinoma (PHC, AJCC 7th edition) were used to differentiate the stage of all patients: 3 patients were stage I, 2 stage II, 4 patients stage III and 1 stage IV. All patients were followed up and clinical data were gathered. The median follow-up duration was 38.5 months. The 1-year, 2-year, 3-year and 6-year disease-free survival was 80.0%, 46.2% and 46.2% and 0% respectively. The overall survival rates were 100%, 67.1%, 67.1% and 33.6% respectively. Patients in early-stages (I/II) had similar disease-free and overall survival as those in advanced-stages (III/IV). Patients with monotherapy had significant shorter disease-free and overall survival than the patients with combination-therapy. PHNEC has a unique specificity during its occurrence and development. The staging criteria of PHC might not be suitable for the PHENT. More convenient and effective features need to be found in imaging and laboratory detection. Surgical resection, TACE, chemotherapy and radiofrequency ablation should be performed in combination and actively for patients with PHNEC or recurrence to get the best effectiveness; they might extend the disease-free and overall survival.

Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): The NORDIC NEC study

As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.

First-Line Irinotecan Combined with 5-Fluorouracil and Leucovorin for High-Grade Metastatic Gastrointestinal Neuroendocrine Carcinoma

High-grade gastrointestinal neuroendocrine neoplasms, ie, poorly differentiated neuroendocrine carcinomas, with no effective therapeutic approaches, have a high ability to metastasize. A review of the hospital information system was performed. Patients with histologically proven gastrointestinal neuroendocrine carcinoma who were treated with irinotecan combined with 5-fluorouracil and leucovorin in a first-line setting were eligible for analysis. We extracted information on age, sex, disease stage, laboratory findings, radiological findings, pathological findings, chemotherapy, effectiveness and adverse events of therapy, and outcomes. Eleven patients were included in the study. Partial response was observed in 7 patients. Median progression-free survival and overall survival were 6.5 (95% CI, 5.1-7.9) and 13.0 (95% CI, 9.8-16.2) months, respectively. No treatment-related deaths occurred. The results demonstrated that irinotecan combined with 5-fluorouracil and leucovorin is an active regimen with acceptable toxicity for patients with metastatic high-grade gastointestinal neuroendocrine carcinoma that merits further investigation in prospective trials.