Byung Woog Kang

CD274, LAG3, and IDO1 expressions in tumor-infiltrating immune cells as prognostic biomarker for patients with MSI-high colon cancer

PurposeThis study attempted to reveal the prognostic impact of microsatellite instability-high (MSI-H) colon cancer with tumor-infiltrating immune cells (TIICs) and immune checkpoint protein expression, which are good candidates for immunotherapy.Materials and methodsThe study included 89 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Chilgok Hospital. The expression status of specific inhibitory receptors, such as CD274 (programmed death-ligand 1, PD-L1), PDCD1 (programmed cell death 1, PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and indolamine 2′3′-dioxygenase 1 (IDO1), was retrospectively analyzed using immunohistochemistry (IHC).ResultsAmong the 89 patients, CD274, LAG3, and IDO1 expressions in TIICs were observed in 68.6% (61 cases), 13.5% (12), and 28.1% (25) of patients, respectively. Meanwhile, CD274, CTLA4, and IDO1 were expressed in tumor cells of 24.7% (22 cases), 4.5% (4), and 72.0% (64) of patients, respectively. During the median follow-up duration of 39xa0months, 14 (15.7%) patients experienced disease recurrence. Among the five immune checkpoint proteins, CD274, LAG3, and IDO1 expressions in TIICs were significantly associated with a better disease-free survival (DFS) in a univariate analysis (Pu2009=u20090.028, 0.037, and 0.030 respectively). Moreover, co-expression of CD274, LAG3, and IDO1 in TIICs showed an even better survival for DFS (Pu2009=u20090.010). In a multivariate survival analysis, CD274, LAG3, and IDO1 expressions in TIICs remained as independent prognostic factors for a better DFS.ConclusionCD274, LAG3, and IDO1 expressions in TIICs showed a better prognosis for patients with MSI-H colon cancer. Thus, the potential therapeutic implications of these immune checkpoint molecules should be further investigated.

Abstract 1190: Prognostic significance of serine synthesis pathway-related protein expression in patients with resected colon cancer

Background We analyzed the prognostic impact of serine synthesis pathway-related protein expression in a large number of patients with colon cancer. Methods PDK1, PDK2, PKM2, PHGDH, PSAT, and ER betta expression were investigated on the basis of the immunohistochemistry of tissue microarray specimens from 486 colon cancer patients who underwent curative surgery between 2006 and 2010. We scored the staining intensity (0 through 3) and percentage of positive cells (0 through 4), and the staining score was defined as sum of these scores used to categorize the each expression as low (0 through 3) or high (4 or more). Results For the 486 patients, the median age was 66 (30-90) years at the time of surgery. The pathologic stages after the surgical resection were as follows: stage I (n = 98), stage II (n = 213), and stage III (n = 175). A total of 201 (41.4%) was identified as high PDK2 (staining score ≥4). The survival analysis showed that the expression of serine synthesis pathway-related protein had no effect on the overall survival and disease-free survival (DFS) except that the grade of PDK2 expression was significantly associated with the DFS (p = 0.028). On the multivariate analysis that included age, histology, TNM stage, and CEA level, no significant association between the grade of the PDK2 expression and DFS was observed. Conclusion The current study suggests that the tissue expression of serine synthesis pathway-related protein is not an independent prognostic marker for patients with surgically resected colon cancer. Note: This abstract was not presented at the meeting. Citation Format: Byung Woog Kang, Jong Gwang Kim, Yee Soo Chae, Soo Jung Lee, Shinkyo Yoon, Ghil Suk Yoon. Prognostic significance of serine synthesis pathway-related protein expression in patients with resected colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1190. doi:10.1158/1538-7445.AM2015-1190

Abstract CT229: A phase II and biomarker study of an irreversible pan-human EGF receptor (HER) tyrosine kinase inhibitor, dacomitinib, in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN)

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnBackground: Dacomitinib is an oral irreversible tyrosine kinase inhibitor of EGFR, HER2 and HER4 signaling. The goals of this study were to investigate the clinical activity, safety and predictive biomarkers of dacomitinib in R/M-SCCHN.nnMethods: Patients with R/M-SCCHN were eligible if they had progressed on platinum-based chemotherapy or considered platinum-intolerant, and were treated with dacomitinib 45mg/day. The primary endpoint was objective response rate (ORR) by RECIST v1.1; Secondary endpoints included progression-free survival rate (PFS), overall survival (OS) and safety. We charaterized somatic mutations using the Ion AmpliSeq™ platform (2,800 mutations from 50 genes), gene copy number (86 genes) and gene expression (230 genes) using NanoString nCounter® and CDKN2A (p16INK4A) expression by immunohistochemistry, and investigated their relationship with clinical outcomes.nnResults: A total of 48 patients were enrolled and evaluable for efficacy and toxicity. Patient and disease characteristics included median age (61 years; range, 30-82); male (85%); ECOG performance status 0/1/2 (4%/75%/21%); locoregional/distant metastatic/both (31/23/46%); oral cavity/larynx/oropharynx primary (38%/19%/23%); prior chemotherapy regimens 0/1/≥2 (8%/52%/40%). Ten patients (21%) had partial responses and 31 patients (65%) had stable diseases. With a median 8.4 months of follow up, the median PFS and OS were 3.9 months (95% CI, 2.9-5.0) and 8.2 months (95% CI, 5.8-10.3). Adverse events (AEs) were mostly grade 1-2 and manageable. The most common AEs were skin toxicities (paronychia, 65%; acneiform dermatitis, 44%) and diarrhea (52%). Results from the biomarker analyses were available in 28 patients for AmpliSeq™, 31 patients for gene copy number, and 12 patients for gene expression. Mutations in PIK3CA and PTEN was significantly associated with shorter PFS (2.5 vs 5.4 months, P=0.013). There were trends toward higher ORR (23% vs 0) for patients with wild PIK3CA and PTEN, with unusually long durations of response (5.1, 5.4, 5.8, 13.1, and 18.9 months, respectively). Increased gene expression of proinflammatory chemokines and inflammatory response modulators (IL6, IL8, PTGS2, PLA2G2A) was significantly associated with shorter PFS (1.9 vs 6.8 months, P=0.001). Patients with low gene expression of proinflammatory chemokines also tend to have higher ORR (40% vs 0), with unusually long durations of response (18.9 and 5.4 months, respectively).nnConclusions: Dacomitinib demonstrated promising efficacy with manageable toxicity in platinum-failed R/M-SCCHN patients. Screening of PI3K pathway mutation and proinflammatory chemokines may help identify which R/M-SCCHN patients are likely to gain a benefit from dacomitinib.nnCitation Format: Han Sang Kim, Hyung Joo Kwon, Myung-Ju Ahn, Byung Woog Kang, Jong-Mu Sun, Dok-Hyun Yoon, Keon Uk Park, Se-Hoon Lee, Yoon Woo Koh, Se Hun Kim, Eun Chang Choi, Hye Ryun Kim, Hyo Song Kim, Joo Hang Kim, Byoung Chul Cho. A phase II and biomarker study of an irreversible pan-human EGF receptor (HER) tyrosine kinase inhibitor, dacomitinib, in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN). [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 CT229. doi:10.1158/1538-7445.AM2014-CT229

Abstract 1488: Association between microrna binding site polymorphism and susceptibility to colorectal cancer in Korean population

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnBackground : MicroRNAs (miRNAs) play an important role in the colorectal cancer tumorigenesis by regulation of gene expression through binding to 3′ untranslational region (UTR) of target gene. Single nucleotide polymorphism (SNP) within 3′UTR of gene could be affected by miRNA binding. Docking protein 3 (DOK3) is adapter protein that acts as tumor suppressor through modulating tyrosine kinase signaling.nnMethods : One hundred thirty five SNPs were selected in Silico analysis for the current study from 3′UTR SNPs of SNP database, which was based on several miRNA database, calculating miRNA bind efficiency on polymorphism, and HapMap database. Here independent two set of study was designed, 380 healthy controls and 371 colorectal adenocarcinoma patients were enrolled in discovery set, and 524 healthy controls and 521 colorectal adenocarcinoma patients were enrolled in replication set. The SNP genotyping was performed using the Sequenom MassARRAYnnResult: In discovery set, 16 SNPs were significantly associated with colorectal cancer in any genetic model from 135 SNP genotyping. Among 16 SNPs, DOK3 rs2279398G>A was significantly associated in replication set recessive model (adjusted odds ratio (OR) = 0.65, 95% confidence interval (CI) = 0.44-0.97, P = 0.03). In combined analysis, DOK3 rs2279398G>A was associated with significantly decreased risk of colorectal cancer in codominant and recessive model (adjusted OR = 0.84, 95% CI = 0.73-0.96, P = 0.012, adjusted OR = 0.65, CI = 0.49-0.88, P = 0.004, respectively).nnConclusion : DOK3 rs2279398G>A may affect the expression of DOK3 by altering miRNA binding efficiency on miRNA-binding sites of the 3′-UTR of DOK3 and impact on colorectal cancer tumorigenesis. This finding suggests that DOK3 rs2279398G>A may be a useful biomarker for determining the susceptibility to colorectal cancer.nnCitation Format: Byung Woog Kang, Hyosung Jeon, Yee Soo Chae, Soo Jung Lee, Jong Gwang Kim, Hyunchul Lee, Eun-Jin Lee, Myung Hoon Lee, Jae Yong Park, Gyu Seog Choi, Jun Seok Park. Association between microrna binding site polymorphism and susceptibility to colorectal cancer in Korean population. [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 1488. doi:10.1158/1538-7445.AM2014-1488

Abstract 193: Prognostic impact of miR-146 polymorphism in patients with resected colorectal cancer

Background: MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions as tumor suppressors and oncogenes. The rs2910164 is a C to G polymorphism located within the sequence of miR-164a precursor, which leads to a change from a C:U pair to a G:U mismatch in its stem region. Recent evidence suggested that the rs2910164 SNP in miR-146a was associated with development of familial breast and ovarian cancers, and prostatic cancer. The aim of this study was to investigate the association between this genetic variant and prognosis of colorectal cancer (CRC) operated curatively. Methods: A total of 343 CRC patients underwent curative surgery were consecutively enrolled between 2004 and 2006. DNA was extracted from fresh frozen normal tissue and miR-146 polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: With a median follow up of 42.3 months, the combined GG+CG genotype demonstrated a better survival outcome compared with the CC genotype in a Kaplan-Meier survival analysis. Multivariate analysis showed that the G allele of miR-146 was associated with better progression-free and disease-specific survival as a dominant model adjusted to age, sex, histologic grade and stage [HR=0.54 and 0.49; P = 0.018 and 0.025, respectively]. Moreover, the tumors containing the G allele were histologically associated with more prominent lymphovascular invasion. Conclusions: Our results suggest that miR-146 polymorphism is possible prognostic marker in operated CRC patients in Korean. 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 193. doi:1538-7445.AM2012-193