Taekyu Lim

Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma

Erlotinib, in combination with gemcitabine, has shown clinical benefits in pancreatic adenocarcinoma patients. The presence of EGFR mutations and increased EGFR copy numbers in pancreatic adenocarcinoma was explored.

Impact of KRAS Mutations on Clinical Outcomes in Pancreatic Cancer Patients Treated with First-line Gemcitabine-Based Chemotherapy

Although erlotinib has become an important therapeutic option in addition to gemcitabine, the high frequency of KRAS mutations in pancreatic cancer probably limits the benefits. We retrospectively studied 136 pancreatic cancer patients with available formalin-fixed paraffin-embedded tumor blocks from 2003 to 2009 to understand the clinical significance of KRAS mutations in pancreatic cancer patients treated with gemcitabine-based chemotherapy. KRAS mutations were analyzed by sequencing codons 12, 13, and 61. In this study, 71 (52.2%) of the 136 pancreatic adenocarcinomas examined harbored a point mutation in codons 12 (n = 70) and 61 (n = 1) of KRAS. KRAS mutation was not associated with clinicopathologic parameters. Patients with KRAS mutations showed a worse response (11.3%) than those with wild-type KRAS (26.2%) and poor survival (mutant KRAS, 5.8 months vs. wild-type KRAS, 8.0 months; P = 0.001). Multivariate analysis revealed good prognostic factors for overall survival as well to moderately differentiated histology (P < 0.001; HR = 0.437, 95% CI: 0.301–0.634), locally advanced disease (P < 0.001; HR = 0.417, 95% CI: 0.255–0.681), response to first-line chemotherapy (P = 0.003; HR = 0.482, 95% CI: 0.297–0.780), and wild-type KRAS (P = 0.001; HR = 0.523, 95% CI: 0.355–0.770). However, the observed survival advantage is derived from the subgroup of patients treated with gemcitabine/erlotinib (9.7 vs. 5.2 months; P = 0.002), whereas no survival difference based on KRAS mutation status is obvious in the other subgroup of patients treated without erlotinib (7.0 vs. 7.0 months; P = 0.121). These results need to be further explored in upcoming prospective studies to provide a rationale for personalized medicine in pancreatic cancer. Mol Cancer Ther; 10(10); 1993–9. ©2011 AACR.

Impact of E2F-1 Expression on Clinical Outcome of Gastric Adenocarcinoma Patients with Adjuvant Chemoradiation Therapy

Purpose: There are no reliable prognostic markers that identify gastric cancer patients who may benefit from adjuvant chemoradiation therapy. E2F-1 was shown to be associated with radiosensitivity and chemosensitivity in certain tumor types. Therefore, we analyzed expression and prognostic significance of E2F-1 along with thymidylate synthase (TS) in R0-resected gastric adenocarcinoma patients, who underwent adjuvant chemoradiation therapy with 5-fluorouracil (5-FU) and leucovorin. Experimental Design: The chemosensitivity to 5-FU and radiosensitivity were tested in three E2F-1–overexpressed gastric cancer cell lines in vitro. The expressions of TS and E2F-1 were analyzed in 467 R0-resected primary gastric cancer patients, who received adjuvant chemoradiation therapy with 5-FU and leucovorin using tissue microarray. Results: The E2F-1 immunopositivity rate was 22.2% (103 of 465 samples) with a cutoff value of 5% immunoreactivity, whereas the TS-positive expression occurred in 19.0% of the 463 tumors tested. Using stepwise Cox proportional hazards regression modeling, multivariate analyses showed that the E2F-1 immunopositivity predicted more favorable survival as compared with the E2F-1 immunonegativity with borderline statistical significance [P = 0.050, hazard ratio (HR) = 0.702, 95% confidence interval, 0.487, 1.013]. However, the E2F-1 immunopositivity did not retain its statistical significance at multivariate analysis for predicting disease-free survival (data not shown, P = 0.270), but stage was the only influential factor for disease-free survival in stages IB to IV (M0) patients (P < 0.001). TS immunopositivity did not influence survival (P = 0.459) or disease-free survival (P = 0.447). Conclusion: E2F-1 is a potentially novel independent prognostic factor that may identify gastric cancer patients who will likely benefit from adjuvant chemoradiation therapy following curative resection.

Gastroenteropancreatic neuroendocrine tumors: Incidence and treatment outcome in a single institution in Korea

Aim:  We studied to identify the clinicopathological features, treatment outcome, and prognostic factors for patients with gastrointestinal and hepatopancreaticobiliary neuroendocrine tumor (NET).

Synergistic Effect of Simvastatin Plus Radiation in Gastric Cancer and Colorectal Cancer: Implications of BIRC5 and Connective Tissue Growth Factor

PURPOSE We investigated the synergistic effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor plus radiation therapy, on the proliferation and survival of gastric cancer (GC) and colorectal cancer (CRC) cells. We also studied several genes involved in the simvastatin/radiation-induced effects. METHODS AND MATERIALS Gastric cancer (AGS, SNU601, MKN1, and MKN28) and CRC (CoLo320, SW48, HT29, and HCT8) cell lines were treated with 0.2 μM simvastatin alone, or in combination with 0 to 4 Gy of radiation, and subjected to clonogenic survival and proliferation assays in vitro. To assess the molecular mechanism of the combination treatment, we performed microarray analysis, immunoblot assays, small interfering RNA knockdown experiments, and plasmid rescue assays. The antitumoral effects of simvastatin and radiation were evaluated in vivo using xenograft models. RESULTS The combination therapy of simvastatin plus radiation inhibited basal clonogenic survival and proliferation of GC and CRC cells in vitro. Simvastatin suppressed the expression of BIRC5 and CTGF genes in these cancer cells. In vivo, the combined treatment with simvastatin and radiation significantly reduced the growth of xenograft tumors compared with treatment with radiation alone. CONCLUSION We suggest that simvastatin has a synergistic effect with radiation on GC and CRC through the induction of apoptosis, which may be mediated by a simultaneous inhibition of BIRC5 and CTGF expression. A clinical trial of simvastatin in combination with radiation in patients with GC or CRC is warranted.

ALK inhibitor crizotinib combined with intrathecal methotrexate treatment for non-small cell lung cancer with leptomeningeal carcinomatosis.

Anaplastic lymphoma kinase (ALK) inhibitor has shown dramatic efficacy in non-small cell lung cancer (NSCLC) patients harboring ALK rearrangements in phase I trial. Herein we report two cases of NSCLC patients with leptomeningeal carcinomatosis (LM), treated with ALK inhibitor under emergent use of investigational new drug combined with intrathecal methotrexate treatment. Progression free survival was 10 months and 6 months, respectively, and little additional toxicities were observed. These results suggest that ALK inhibitor might be safely administered even in patients or those with metastases in central nervous system.

A Retrospective Analysis for Patients with HER2-Positive Gastric Cancer Who Were Treated with Trastuzumab-Based Chemotherapy: In the Perspectives of Ethnicity and Histology.

Purpose While the Trastuzumab for Gastric Cancer (ToGA) trial demonstrated the efficacy and safety of trastuzumab-based chemotherapy in HER2-positive metastatic gastric cancer, the overall survival (OS) benefit was not found in Asian and diffuse-type cancer patients. The aim of the study is to investigate predictive markers for trastuzumab-based chemotherapy. Materials and Methods Data of patients with HER2-positive gastric cancer treated with trastuzumab-based chemotherapy were analyzed retrospectively. Results A total of 168 Asian patients were included. The median age was 60 years (range, 27 to 85 years) and the male:female ratio was 118 (70.2%):50 (29.8%). Fourteen (8.3%), 63 (37.5%), 75 (44.6%), and 11 (6.5%) patients had well, moderately, poorly-differentiated tubular adenocarcinoma and signet ring cell carcinoma, respectively. With 14 complete responses and 73 partial responses, the response rate was 50.6%. The median progression-free survival (PFS) was 10.2 months (95% confidence interval [CI], 8.7 to 11.7), and the median OS was 18.5 months (95% CI, 16.4 to 50.6). Next, we investigated the effect of poorly-differentiated histology (PDH, poorly-differentiated tubular adenocarcinoma+signet ring cell carcinoma) on clinical outcomes. The median PFS (8.9 months vs. 11.5 months, p=0.16) was slightly inferior in PDH patients, and the median OS was significantly shorter in PDH patients (14.6 months vs. 19.0 months, p=0.025). Conclusion While subset analysis of the ToGA trial demonstrated that trastuzumab-based chemotherapy may not be beneficial for Asians and patients with PDH, our data may suggest that even in Asian patients and patients with PDH, trastuzumab-based chemotherapy could be associated with improved clinical outcomes in patients with HER2-positive gastric cancer.

CA 15-3 elevations according to breast cancer subtypes at initial diagnosis of metastatic breast cancer (MBC).

e11109 Background: CA 15-3 is the most commonly used tumor marker for monitoring therapeutic effect in breast cancer and considerable portion of patients show increased CA 15-3 level at initial diagnosis of metastatic breast cancer (MBC). The tumor marker originated from the membrane epithelial mucin 1 gene (MUC1 gene), which is expressed at the luminal epithelial layer where hormone receptor (HR)-related genes are enriched. Because MUC1 is a luminal cell marker, we hypothesized that the elevation of CA 15-3 would be different according to breast cancer subtypes. METHODS A total of 536 patients with newly diagnosed MBC between 2000 and 2009 who had available clinical data including immuhistochemistry (IHC) for ER, PR, and HER2 were included. Patients were classified into three groups according to receptor status; ER and/or PR+ (Hormone Receptor, HR +), ER-/PR-/HER2+ (HER2 enriched), and ER-/PR-/HER2- (triple negative, TN) patients. RESULTS The median levels of CA 15-3 were 15, 22 and 37 for patients with one, two and more than three metastatic sites (p<0.001), respectively. The levels of CA 15-3 increased higher in patients with pleural metastasis than those with the other organ (43 vs 15 U/ml, p=0.006). The incidence of CA 15-3 elevation above upper normal range at the time of metastasis was different according to the subtypes (45.6% for HR+; 24.4% for HER2 enriched, 28.8% for TN, p<0.001). The median levels of CA 15-3 showed significant difference among three groups (24 for HR+; 13 for HER2 enriched; 18 for TN, p<0.001). CONCLUSIONS CA 15-3 level at the time of diagnosis of MBC is significantly different according to the subtypes of BC. Therefore, the use of CA 15-3 as tumor marker, in particular at the time of initial metastasis, may be considered based on breast cancer subtypes according to the receptor status.