Ji-Won Kim

Amphiregulin confers trastuzumab resistance via AKT and ERK activation in HER2-positive breast cancer

PurposeHuman epidermal growth factor receptor 2 (HER2) heterodimerizes and shares common signaling pathways with epidermal growth factor receptor (EGFR). In this study, we investigated the clinical implication of amphiregulin, a ligand for EGFR, on trastuzumab therapy in HER2-positive breast cancer.MethodsSerum amphiregulin levels were quantified in 50 consecutive patients with HER2-positive metastatic breast cancer who received first-line trastuzumab plus taxane chemotherapy between October 2004 and July 2009. In addition, in vitro experiments were carried out to validate the results.ResultsThe median serum amphiregulin level was 1.0xa0ng/mL with a maximum level of 4.4xa0ng/mL. Patients with high serum amphiregulin levels (≥0.5xa0ng/mL) had significantly shorter progression-free survival (15.1xa0months vs. not reached; Pxa0=xa00.018). Colony-forming assays demonstrated that the addition of amphiregulin resulted in increased proliferation of cells. In addition, the anti-proliferative effect of trastuzumab was decreased in the presence of amphiregulin. Western blot analysis showed that amphiregulin activated AKT and ERK pathways. In addition, in the presence of amphiregulin, sustained phosphorylation of AKT and ERK pathways was observed after trastuzumab treatment.ConclusionsHigh serum amphiregulin levels were associated with early disease progression in these patients, possibly due to AKT and ERK signaling activation by amphiregulin.

Epidemiology and management of primary immune thrombocytopenia: A nationwide population-based study in Korea

INTRODUCTIONnThe epidemiology of immune thrombocytopenia (ITP) is not well characterized in an Asian population.nnnMATERIALS AND METHODSnFrom July 2010 to June 2014, ITP patients were identified using the Korean Health Insurance Review and Assessment Service database.nnnRESULTSnThe overall incidence rate of ITP was 5.3 per 100,000 person-years (95% CI: 5.1-5.5). The overall incidence rate ratios of children under 15years old to adults and females to males were 3.8 (95% CI: 3.7-3.9) and 1.3 (95% CI: 1.2-1.4), respectively. Of the total 10,814 patients, 3388 patients (31%) needed treatment for ITP; of these, 54% continued treatment for more than three months. First-line therapy consisted of corticosteroids (CS) in 42%, immunoglobulin (IVIg) in 35%, CS with IVIg in 19%, and other immunosuppressive agents (ISA) in 4%. Among treated patients, 75% of adults and 33% of children continued treatment for more than three months. After three months, the most frequently used drug was CS alone in 63% of patients. Only 104 patients underwent splenectomy; of these, 51% received salvage treatment after a median of one month after surgery (range: 0-27). The proportion of patients who received platelet transfusions of 12units or more per month for at least two consecutive months was significantly higher among patients treated for more than three months compared with patients who completed treatment within three months.nnnCONCLUSIONSnThis population-based study is the first to describe the incidence of ITP and its treatment reality for patients in Korea.

Efficacy and Safety of FOLFIRI Regimen in Elderly Versus Nonelderly Patients with Metastatic Colorectal or Gastric Cancer

BACKGROUNDnIrinotecan-based chemotherapy is a standard backbone of therapy in patients with metastatic colorectal cancer (CRC) or gastric cancer (GC). However, there is still a paucity of information concerning the efficacy and safety of irinotecan-based regimens in elderly patients.nnnPATIENTS AND METHODSnUsing the patient cohort (nu2009=u20091,545) from the UGT1A1 genotype study, we compared the efficacy and safety between elderly and nonelderly patients with metastatic CRC (nu2009=u2009934) or GC (nu2009=u2009611) who received first- or second-line FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy.nnnRESULTSnDespite lower relative dose intensity in elderly patients, progression-free survival and overall survival were similar between elderly (age ≥70 years) and nonelderly (<70 years) patients in the CRC cohort (hazard ratio [HR], 1.117; 95% confidence interval [CI], 0.927-1.345; pu2009=u2009.244, and HR, 0.989; 95% CI, 0.774-1.264; pu2009=u2009.931, respectively) and the GC cohort (HR, 1.093; 95% CI, 0.854-1.400; pu2009=u2009.479, and HR, 1.188; 95% CI, 0.891-1.585; pu2009=u2009.241, respectively). In both cohorts, febrile neutropenia (22.1% vs. 14.6% in CRC cohort and 35.2% vs. 22.5% in GC cohort) and asthenia (grade 3: 8.4% vs. 1.7% in CRC cohort and 5.5% vs. 2.9% in GC cohort) were more frequent in elderly patients. In the CRC cohort, mucositis and anorexia were more frequent in elderly patients. In the GC cohort, nausea and vomiting were less frequent in elderly patients.nnnCONCLUSIONnThe efficacy of the FOLFIRI regimen was similar between elderly and nonelderly patients in both the CRC and the GC cohorts. However, special attention should be paid to elderly patients because of increased risk for febrile neutropenia and asthenia. The Oncologist 2017;22:293-303 IMPLICATIONS FOR PRACTICE: The efficacy of FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy in elderly patients with metastatic colorectal cancer or gastric cancer was similar to that in nonelderly patients. However, special attention should be paid to elderly patients because of the increased risk for febrile neutropenia and asthenia. These data suggest that the FOLFIRI regimen could be considered as a standard backbone of therapy in elderly patients with metastatic colorectal cancer or gastric cancer and that the clinical decision between doublet and singlet chemotherapy may not be based solely on age. However, the data require further assessment of frailty and performance status.

Src as a Therapeutic Target in Biliary Tract Cancer

Src, a nonreceptor tyrosine kinase, is involved in a number of cancer-related signaling pathways and aberrantly activated in biliary tract cancer (BTC). This study aimed to elucidate the potential role of Src as a therapeutic target in BTC. We tested bosutinib, an orally active c-Src/Abl kinase inhibitor, alone or in combination with cytotoxic agents using 9 human BTC cell lines: SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079, SNU-1196, HuCCT1, TFK-1, and EGI-1. Of these, SNU-308 and SNU-478 were relatively sensitive to bosutinib. Bosutinib abrogated phosphorylation of Src and its downstream molecules, and significantly increased G1 cell-cycle arrest and apoptosis. Bosutinib significantly inhibited cell migration and invasion and decreased epithelial–mesenchymal transition markers. Bosutinib combined with gemcitabine or cisplatin showed synergistic antiproliferative and antimigratory effects. In addition, this combination further inhibited phosphorylation of Src and its downstream molecules and decreased epithelial–mesenchymal transition marker expression compared with bosutinib alone. We established a SNU-478 xenograft model for in vivo experiments, because SNU-478 was more tumorigenic than SNU-308. Bosutinib combined with gemcitabine or cisplatin showed significantly more potent antitumor effects than bosutinib alone. Bosutinib combined with gemcitabine further decreased Ki-67 expression and Src phosphorylation, and further increased TUNEL expression. Our data suggest that Src might be a potential therapeutic target in BTC. Bosutinib demonstrated promising antitumor activity alone or in combination with gemcitabine or cisplatin in BTC cells, which supports further clinical development in patients with advanced BTC. Mol Cancer Ther; 15(7); 1515–24. ©2016 AACR.

Effect of Early Adjuvant Chemotherapy on Survival of Advanced Gastric Cancer Patients: a Propensity Score-matched Analysis

Purpose Generally, adjuvant chemotherapy (AC) should be initiated as soon as possible after surgery to eradicate microscopic cancer cells. In this study, we investigated the effect of early AC on the survival of stage II/III gastric cancer patients. Materials and Methods Four hundred sixty patients who received AC (S-1 or XELOX) for pathologic stage II/III gastric cancer at Seoul National University Bundang Hospital between January 2008 and December 2014 were included. Patients were divided into 2 groups: early AC administration (within 4 weeks) and late AC administration (more than 4 weeks). Patients in the early AC group (n=174) were matched 1:1 with patients in the late AC group (n=174) by propensity scoring to adjust for clinical differences. Three-year relapse-free survival (RFS) was evaluated according to the timing of AC. Results Three-year RFS was 98.1% in stage IIA (n=109), 85.0% in stage IIB (n=83), 87.4% in stage IIIA (n=96), 83.5% in stage IIIB (n=91), and 62.5% in stage IIIC (n=81). After propensity score matching, RFS was similar between early and late AC groups (hazard ratio [HR],1.04; 95% confidence interval [CI], 0.62–1.74; P=0.889). Pathologic stage and histological type were independent prognostic factors of RFS (HR, 2.05; 95% CI, 1.06–3.96; P=0.033 and HR, 2.61; 95% CI, 1.42–4.80; P=0.002, respectively). Conclusions Early initiation of AC within 4 weeks does not affect survival rates in stage II/III gastric cancer.

Serum free light chain difference and beta-2 microglobulin levels are risk factors for thromboembolic events in patients with AL amyloidosis

&NA; AL amyloidosis might increase the risk of thromboembolism and other plasma cell dyscrasias. Therefore, we evaluated the features of thromboembolism in AL amyloidosis. The incidence of thromboembolism was substantial (12.3%); most events developed within the first year after the diagnosis, and arterial thromboembolism occurred frequently. In particular, patients with risk factors might require close monitoring for thromboembolism. Background: AL amyloidosis might increase the risk of thromboembolism and other plasma cell dyscrasias; however, only a few reports have described the clinical features of thromboembolism. The present study aimed to elucidate the clinical features of thromboembolic events and to identify the risk factors for these events. Materials and Methods: The medical records were retrospectively reviewed to define the clinically significant thromboembolic events. Results: A total of 106 patients with biopsy‐proven AL amyloidosis were included. During a median follow‐up of 18.1 months (range, 0.4‐166.9 months), 13 thromboembolism events were identified in 13 patients. Of the 13 patients, 9 (8.5%) experienced acute cerebral infarction, 2 (1.9%) experienced pulmonary embolism, and 2 (1.9%) experienced deep vein thrombosis. Patients with a higher serum free light chain (FLC) difference (≥ 172.4 mg/L) or &bgr;2‐microglobulin (&bgr;2MG) levels (≥ 2.78 mg/L) experienced significantly more thromboembolic events compared with those with a lower value according to multivariable analysis (for FLC difference: hazard ratio, 4.309; 95% confidence interval, 1.158‐16.032; P = .029; for &bgr;2MG: hazard ratio, 9.739; 95% confidence interval, 1.127‐84.174; P = .039). Most thromboembolic events (11 of 13; 84.6%) occurred within the first year after the AL amyloidosis diagnosis. Conclusion: The incidence of thromboembolism was substantial in those with AL amyloidosis. A greater FLC difference and for &bgr;2MG levels were risk factors for thromboembolic events.

Abstract 5136: HER2 or EGFR inhibition interacts with tumor microenvironment by downregulation of PD-L1 and chemokines

Background: Agents targeting HER2 or EGFR have been applied in several cancer types. Tumor microenvironment including tumor-infiltrating lymphocytes could be a predictive marker in HER2- or EGFR- targeted therapy, although there are some controversies. However, the effects of HER2 and EGFR inhibition on tumor microenvironment are unclear. Method: We screened HER2, EGFR, and PD-L1 expression in gastric cancer cell lines by western blot (SNU216, SNU668, SNU719, AGS, N87, YCC3, and YCC10). HER2 and EGFR was inhibited by using dual inhibitor (afatinib, lapatinib). After HER2 and EGFR inhibition, the change of PD-L1 expression was evaluated in HER2 overexpressed cell lines (SNU216, N87, SKBR3) at western blot, FACS, PCR, and qPCR. Selective blockade for down-steam molecules of HER2 and EGFR was conducted by using pictilisib (PI3K inhibitor) and trametinib (MEK inhibitor). The change of chemokines such as CXCL1, CCL2, and CCL21 was evaluated after HER2 and EGFR inhibition by PCR. In clinical data, PD-L1 expression and HER2 expression in resected gastric cancer were also evaluated by immunohistochemistry analysis. Results: EGFR-overexpressed or HER2-overexpressed gastric cancer cell lines (SNU216, SNU668, N87) showed higher protein expression of PD-L1. PD-L1 expression decreased with dose-dependent manner in afatinib- or lapatinib- treated cell lines (SNU216, N87, SKBR3). In pictilisib-treated cell lines, PD-L1 was also down-regulated. However, trametinib-treated cell lines did not show down-regulation of PD-L1. After lapatinib treatment in HER2 overexpressed cell lines, CXCL1, CCL21, and CCL2 decreased with dose-dependent manner. In 289 patients with resected gastric cancer, there was a significant association between HER2 and PD-L1 expression (p = 0.03). Conclusions: PD-L1 is associated with HER2 and EGFR expression. PD-L1 is regulated by inhibition of PI3K pathway. Therefore, HER2 or EGFR inhibition could interact with tumor microenvironment by down-regulation of expression of PD-L1 and chemokines. Citation Format: Jin Won Kim, Ji Hea Sung, Mi Hyun Kang, Ji-Won Kim, Se-Hyun Kim, Keun-Wook Lee, Hye Seung Lee, Jee Hyun Kim. HER2 or EGFR inhibition interacts with tumor microenvironment by downregulation of PD-L1 and chemokines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5136.

Antitumorigenic effect of plumbagin by induction of SHP1 in human gastric carcinoma cell lines.

74 Background: Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a plant-drived natural agent extracted from the root of Plumbago zeylanic. A recent study reported that plumbagin down-regulated the activity of Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway to show various anti-tumor effects. We aimed in this in vitrostudy to demonstrate the inhibition of JAK2-STAT3 pathway by plumbagin through inducing SH2-containing protein tyrosine phosphatase 1 (SHP1) expression in gastric cancer cell line. Methods: We performed Wetern blot to measure SHP1, phospho-JAK2/STAT3 level, and reverse transcriptase-polymerase chain reaction (RT-PCR) to evaluate target gene expression of STAT3. Several functional studies such as water soluble tetrazolium-1 (WST-1) assay, wound closure assay and matrigel invasion assay were also performed. Results: Plumbagin induced SHP1 expression and simultaneously down-regulated phospho-JAK2/STAT3 level via dose-and time-dependant manner in MKN28 ...

Methylenetetrahydrofolate reductase gene polymorphisms in Korean gastric cancer patients: Relationship with in vitro chemosensitivity assay and clinical response to 5-fluorouracil containing regimen

4186 Background: Fluorouracil(5-FU) is widely used in the treatment of gastric cancer. The folate pool in cancer tissue is essential for the effect of 5-FU-based chemotherapy. Many enzymes includin...