Jae Yun Lim

Comparison of Surgery Plus Chemotherapy and Palliative Chemotherapy Alone for Advanced Gastric Cancer with Krukenberg Tumor

Purpose This study was conducted to validate the survival benefit of metastasectomy plus chemotherapy over chemotherapy alone for treatment of Krukenberg tumors from gastric cancer and to identify prognostic factors for survival. Materials and Methods Clinical data from 216 patients with Krukenberg tumors from gastric cancer were collected. Patients were divided into two arms according to treatment modality: arm A, metastasectomy plus chemotherapy and arm B, chemotherapy alone. Results Overall survival (OS) was significantly increased in arm A relative to arm B for patients initially diagnosed with stage IV gastric cancer (18.0 months vs. 8.0 months; p < 0.001) and those with recurrent Krukenberg tumors (19.0 months vs. 9.0 months; p=0.002), respectively. Metastasectomy (hazard ratio [HR], 0.458; 95% confidence interval [CI], 0.287 to 0.732; p=0.001), signet-ring cell pathology (HR, 1.583; 95% CI, 1.057 to 2.371; p=0.026), and peritoneal carcinomatosis (HR, 3.081; 95% CI, 1.610 to 5.895; p=0.001) were significant prognostic factors for survival. Conclusion Metastasectomy plus chemotherapy offers superior OS when compared to palliative chemotherapy alone in gastric cancer with Krukenberg tumor. Prolonged survival applies to all patients, regardless of gastric cancer stage. Metastasectomy, signet-ring cell pathology, and peritoneal carcinomatosis were prognostic factors for survival. Future prospective randomized trials are needed to confirm the optimal treatment strategy for Krukenberg tumors from gastric cancer.

Clinical and genomic landscape of gastric cancer with a mesenchymal phenotype

Gastric cancer is a heterogeneous cancer, making treatment responses difficult to predict. Here we show that we identify two distinct molecular subtypes, mesenchymal phenotype (MP) and epithelial phenotype (EP), by analyzing genomic and proteomic data. Molecularly, MP subtype tumors show high genomic integrity characterized by low mutation rates and microsatellite stability, whereas EP subtype tumors show low genomic integrity. Clinically, the MP subtype is associated with markedly poor survival and resistance to standard chemotherapy, whereas the EP subtype is associated with better survival rates and sensitivity to chemotherapy. Integrative analysis shows that signaling pathways driving epithelial-to-mesenchymal transition and insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1R) pathway are highly activated in MP subtype tumors. Importantly, MP subtype cancer cells are more sensitive to inhibition of IGF1/IGF1R pathway than EP subtype. Detailed characterization of these two subtypes could identify novel therapeutic targets and useful biomarkers for prognosis and therapy response.The prognosis and treatment of gastric cancer is complicated by heterogeneity. Here, the authors reveal two molecular subtypes, the mesenchymal subtype associated with poor survival and chemoresistance, and the epithelial phenotype associated with better survival and sensitivity to chemotherapy.

Pazopanib for the treatment of non-clear cell renal cell carcinoma: A single-arm, open-label, multicenter, phase II study

Purpose The optimal treatment strategy for patients with metastatic non-clear cell type renal cell carcinoma (nccRCC) remains unclear. Although several inhibitors of vascular endothelial growth factor have recently shown efficacy against nccRCC, the clinical benefit of pazopanib in nccRCC has not been analyzed. We therefore designed a single-arm, open-label, phase II study to determine the efficacy and safety of pazopanib in patients with nccRCC. Materials and Methods Patientswith locally advanced or metastatic nccRCC, exceptfor collecting duct or sarcomatoid type, received 800 mg/day of pazopanib daily until progression of disease or intolerable toxicity. One cyclewas defined as 4weeks and tumorresponsewas evaluated every two cycles. The primary objective was overall response rate (ORR). Results A total of 29 eligible patients were enrolled at nine centers in Korea from December 2012 and September 2014. The median age of the patients was 58 years (range, 27 to 76 years) and 21 patients (72%) were male. Regarding histology type, 19 patients had papillary, three had chromophobe, two had unclassified and five had unknown non-clear cell type. Of 28 evaluable patients, eight achieved a confirmed partial response with ORR of 28%. The median progression-free survival was 16.5 months (95% confidence interval, 10.9 to 22.1) and median overall survival was not reached. Sixteen patients (55%) experienced treatment-related toxicity of grade 3 or more, but most adverse events were overcome through dose reduction and delay. Conclusion In this prospective phase II study, pazopanib demonstrated promising activity and tolerable safety profile in patients with metastatic nccRCC.

Development and Validation of a Six-Gene Recurrence Risk Score Assay for Gastric Cancer

Purpose: This study was aimed at developing and validating a quantitative multigene assay for predicting tumor recurrence after gastric cancer surgery. Experimental Design: Gene expression data were generated from tumor tissues of patients who underwent surgery for gastric cancer (n = 267, training cohort). Genes whose expression was significantly associated with activation of YAP1 (a frequently activated oncogene in gastrointestinal cancer), 5-year recurrence-free survival, and 5-year overall survival were first identified as candidates for prognostic genes (156 genes, P < 0.001). We developed the recurrence risk score (RRS) by using quantitative RT-PCR to identify genes whose expression levels were significantly associated with YAP1 activation and patient survival in the training cohort. Results: We based the RRS assay on 6 genes, IGFBP4, SFRP4, SPOCK1, SULF1, THBS, and GADD45B, whose expression levels were significantly associated with YAP1 activation and prognosis in the training cohort. The RRS assay was further validated in an independent cohort of 317 patients. In multivariate analysis, the RRS was an independent predictor of recurrence [HR, 1.6; 95% confidence interval (CI), 1.02–2.4; P = 0.03]. In patients with stage II disease, the RRS had an HR of 2.9 (95% CI, 1.1–7.9; P = 0.03) and was the only significant independent predictor of recurrence. Conclusions: The RRS assay was a valid predictor of recurrence in the two cohorts of patients with gastric cancer. Independent prospective studies to assess the clinical utility of this assay are warranted. Clin Cancer Res; 22(24); 6228–35. ©2016 AACR.

Abstract 4718: ERO1L, a novel prognostic marker of gastric cancer patient survival, mediates cancer cell invasion and chemoresistance

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnGastric cancer is the second cause of cancer-related deaths worldwide. Even though within same stage, gastric cancer patients present diverse clinical manifestations and prognosis. Molecular markers will be important in predicting patients outcomes and tailoring personalized treatments according to individual biology. In this study, we analyzed the gene expression profile of human gastric cancer (published on CCR) to identify potential biomarkers. We found that TXN family genes and ERO1L were significantly overexpressed and related to prognosis. We evaluated ERO1L significantly overexpressed in gastric cancer and ERO1L was very highly expressed in hypoxic condition. The other study has identified ERO1L as included in the small group of eight genes predicting poor survival of patients with pulmonary adenocarcinoma. We show that ERO1L is a prognostic marker for overall survival among patients with gastric cancer. To investigate the function of ERO1L gene in gastric cancer cell line (AGS and MKN1), we tested the effect of ERO1L expression on gastric cancer cells. To determine the biologic role of ERO1L in regulating cancer cell proliferation, stable transfection of shRNA and expression vector for ERO1L in gastric cancer cells. Our results showed that shERO1L decrease cell proliferation. Next, we tested whether or not the ERO1L gene is involved in progression to metastatic disease in gastric cancer, especially in tumorigenesis, including migration and invasion. In Functional studies, ERO1L silencing decrease gastric cancer cell migaration and invasion, whereas EROL expression significantly increase cell migration and invasiveness. We examined whether ERO1L plays a role in chemoresistance in gastric cancer cells. After silencing or overexpressing ERO1L, we carried out cell viability assays in gastric cancer cells with a panel of chemotherapy agents used to treat gastric cancer patients: a microtubule stabilizer (paclitaxel) and an antimetabilite (5-FU). Surprisingly, Silencing ERO1L expression led gastric cancer cells to become more sensitive to paclitaxel and 5-FU. In conclusion, our findings show that a prognostic molecular signature that can predict the poor progression of gastric cancer tumors. Furthermore, unequal distribution of expression patterns reflecting activation of ERO1L with different survival rates supports a personalized target therapy in gastric cancer with biomarker gene signature driven patient selection.nnCitation Format: So-Young Seol, Jae Yun Lim, Sun Och Yoon, Soon Won Hong, Jong Won Kim, Seung Ho Choi, Jae Yong Cho. ERO1L, a novel prognostic marker of gastric cancer patient survival, mediates cancer cell invasion and chemoresistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4718. doi:10.1158/1538-7445.AM2014-4718

Abstract 1961: Overexpression of miR-196b and HOXA10 characterize a poor-prognosis gastric cancer subtype.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DCnnBackground: Gastric cancer is composed of disease subgroups with heterogeneous clinical and biological behaviors. A previous study identified two subgroups with distinct gene-expression profiles strongly associated with prognosis. To identify molecular biologic differences between these two subgroups, we performed an integrative analysis of mRNA, microRNA, and protein expression.nnMethods: Array technologies were used to generate microRNA and protein expression profiles of frozen tissue samples from 60 patients with gastric cancer. All patients underwent curative gastric resection in 2005 and distributed from stage I to IV and their clinical characteristics were collected. BRB-ArrayTools were used for microarray data analysis. Data was compared between gastric cancer tissue and normal gastric tissue and also between two different prognostic groups. Aberrantly expressed microRNA and associated mRNA in patients with poor-prognosis gastric cancer were validated by quantitative RT-PCR and tissue microarray, respectively.nnResults: Four microRNAs were aberrantly expressed in gastric cancer tissue, especially poor prognostic group (P < 0.05). In the poor-prognosis subgroup, miR-196b showed the most significantly high expression patterns and also miR-135b, miR-93. On the contrary, miR-29c* was down-regulated. MiR-196b expression was positively correlated with HOXA10 expression (r = 0.726; P < 0.001), which was significantly increased in poor-prognosis patients (P < 0.001). HOXA10 protein-positive expression was identified in 56 of 368 gastric cancer tissue microarray samples. In reverse-phase protein array, 46/124 proteins were expressed differently (P < 0.05); COX2 (P < 0.001) and cyclin B1 (P = 0.017) were clearly over-expressed in the poor-prognosis group.nnConclusion: Integrative analysis of RNA and protein expression profile facilitates interpretation of the molecular biologic heterogeneity of cancer. Co-activation of miR-196b and HOXA10 characterized a poor-prognosis subgroup of patients with gastric cancer. As HOXA10 is involved in the proliferation of hematopoietic stem cells and progenitor cells, the relevance of hematopoietic progenitor cell and gastric cancer development/progression should be further investigated.nnCitation Format: Jae Yun Lim, Sun Och Yoon, So-Young Seol, Soon Won Hong, Jong Won Kim, Seung Ho Choi, Ju-Seog Lee, Jae Yong Cho. Overexpression of miR-196b and HOXA10 characterize a poor-prognosis gastric cancer subtype. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1961. doi:10.1158/1538-7445.AM2013-1961

Abstract 1147: Expression of ERO1L gene is poor prognostic factor for gastric cancer.

Gastric cancer is the second cause of cancer-related deaths worldwide. Even though within same stage, gastric cancer patients present diverse clinical manifestations and prognosis. Molecular markers will be important in predicting patients’ outcomes and tailoring personalized treatments according to individual biology. In this study, we analyzed the gene expression profile of human gastric cancer (published on CCR) to identify potential biomarkers. We found that TXN family genes and ERO1L were significantly overexpressed and related to prognosis. We evaluated ERO1L significantly overexpressed in gastric cancer and ERO1L was very highly expressed in hypoxic condition. The other study has identified ERO1L as included in the small group of eight genes predicting poor survival of patients with pulmonary adenocarcinoma. To investigate the function of ERO1L gene in gastric cancer cell line (AGS, MKN1 and NCI-N87), we tested the effect of shRNA inhibition of ERO1L on gastric cancer cells. To determine the biologic role of ERO1L in regulating cancer cell proliferation, stable transfection of shRNA for ERO1L in gastric cancer cells. Our results showed that shERO1L decrease cell proliferation. Furthermore, Knock down expression by shERO1L have effects on regulating gastric cancer cell apoptosis. Next, we tested whether or not the ERO1L gene is involved in progression to metastatic disease in gastric cancer,especially in late tumorigenesis, including migration and invasion. As a results, Knock down expression for ERO1L significantly decreased the migration and invasiveness of gastric cancer cells. In conclusion, our findings show that a prognostic molecular signature that can predict the poor progression of gastric cancer tumors. Furthermore, unequal distribution of expression patterns reflecting activation of ERO1L with different survival rates supports a personalized target therapy in gastric cancer with biomarker gene signature driven patient selection. While further work is needed to elucidate the biological contributions of these markers in. in vivo, the results presented here provide a basis for future investigations of the functional and clinical effect of new target genes in gastric cancer. Citation Format: So-Young Seol, Jae Yun Lim, Sun Och Yoon, Soon Won Hong, Jong Won Kim, Seung Ho Choi, Jae Yong Cho. Expression of ERO1L gene is poor prognostic factor for gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1147. doi:10.1158/1538-7445.AM2013-1147

Abstract 4536: Identification of new prognostic biomarker of gastric cancer by systems analysis

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, ILnnGastric cancer is one of the most common and cancer-related deaths worldwide and accounts for an estimated 800,000 deaths annually. Prognosis depends on the stage of disease. Even though within same stage, gastric cancer patients present diverse clinical manifestations and prognosis. To differentiate the malignant potential appropriately, many efforts have been made to select prognostic markers. Molecular markers will be important in predicting patients’ outcomes and personalized treatments according to individual biology. In this study, we analyzed the gene expression profile of human gastric cancer (published on CCR) to identify potential biomarkers which could be used to classify patients according to prognosis and also become new therapeutic targets. We found that TXN family genes and ERO1L were significantly overexpressed and related to prognosis. qRT-PCR and tissue microarray validated TXN overexpression and ERO1L have poor prognosis in gastric cancer. Finally, systems analysis revealed TXN family genes are highly correlated with many oncogene and tumor suppressor functional genes and shown relationship on energy and protein synthesis. Survival analysis based on Hierarchical-clustering of TXN family correlated mRNA expression genes revealed that TXN and TXNIP are significantly influenced the patient survival. We evaluated ERO1L and find out also significantly overexpressed in gastric tumor and suggest TXN family members are actively involved in gastric cancer. In vitro hypoxic experiment ERO1L was very highly expressed in hypoxic condition and this also supports TXN high expressed cancer cells are in hypoxic condition. In conclusion, our findings show that a prognostic molecular signature that can predict the poor progression of gastric cancer tumors. Furthermore, unequal distribution of expression patterns reflecting activation of TXN family and ERO1L with different survival rates supports a personalized target therapy in gastric cancer with biomarker gene signature driven patient selection. While further work is needed to elucidate the biological contributions of these markers, the results presented here provide a basis for future investigations of the functional and clinical effect of new target genes in gastric cancer.nnCitation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4536. doi:1538-7445.AM2012-4536

Abstract 4540: Pyruvate kinase M2 (PKM2) associated with poor prognosis in gastric signet ring cell carcinoma

Background: PKM2 (M2 isoform of pyruvate kinase) was identified as a driver of aerobic glycolysis, leading to cell growth and tumor development. PKM2 is usually known to overexpress in cancer, however, there are still remaining questions about the function and the potential as anti-cancer treatment target. We investigated the expression status of PKM2 in gastric cancer tissues and evaluated the possibility of biomarker and anticancer target. Methods: Paraffin-embedded tissue microarray blocks of gastric adenocarcinoma tissue specimens were obtained from 363 gastric cancer patients. All patients underwent curative gastric resection from 1999 to 2007 and distributed from stage I to IV and their clinical characteristics were collected. IHC (Immunohistochemical) assay was performed to evaluate PKM2 expression levels. The correlation of PKM2 expression level with gastric cancer prognosis / stage / histology was evaluated. Results: In our previous microarray study using 60 gastric cancer tissues, we identified PKM2 mRNA overexpressed in cancer tissue than non-cancer tissue (P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4540. doi:1538-7445.AM2012-4540