Showing papers by "Won Ki Kang published in 2015"
TL;DR: This work uses gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis in gastric cancer, and describes key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays.
Abstract: Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research.
1,377 citations
TL;DR: In D2-resected GC, both adjuvant chemotherapy and chemoradiotherapy are tolerated and equally beneficial in preventing relapse.
Abstract: Purpose The Adjuvant Chemoradiotherapy in Stomach Tumors (ARTIST) trial tested whether the addition of radiotherapy to adjuvant chemotherapy improved disease-free survival (DFS) in patients with D2-resected gastric cancer (GC).
342 citations
Genome Institute of Singapore1, University of California, Berkeley2, University of Leeds3, VU University Amsterdam4, Yonsei University5, Yokohama City University6, University of Melbourne7, Peter MacCallum Cancer Centre8, University Health System9, National University of Singapore10, Sungkyunkwan University11, Maastricht University12
TL;DR: It is suggested that Asian and non-Asian GCs exhibit distinct tumour immunity signatures related to T-cell function, and these differences may influence geographical differences in clinical outcome, and the design of future trials particularly in immuno-oncology.
Abstract: Objective Differences in gastric cancer (GC) clinical outcomes between patients in Asian and non-Asian countries has been historically attributed to variability in clinical management. However, recent international Phase III trials suggest that even with standardised treatments, GC outcomes differ by geography. Here, we investigated gene expression differences between Asian and non-Asian GCs, and if these molecular differences might influence clinical outcome. Design We compared gene expression profiles of 1016 GCs from six Asian and three non-Asian GC cohorts, using a two-stage meta-analysis design and a novel biostatistical method ( RUV-4 ) to adjust for technical variation between cohorts. We further validated our findings by computerised immunohistochemical analysis on two independent tissue microarray (TMA) cohorts from Asian and non-Asian localities (n=665). Results Gene signatures differentially expressed between Asians and non-Asian GCs were related to immune function and inflammation. Non-Asian GCs were significantly enriched in signatures related to T-cell biology, including CTLA-4 signalling. Similarly, in the TMA cohorts, non-Asian GCs showed significantly higher expression of T-cell markers (CD3, CD45R0, CD8) and lower expression of the immunosuppressive T-regulatory cell marker FOXP3 compared to Asian GCs (p Conclusions Analyses of >1600 GCs suggest that Asian and non-Asian GCs exhibit distinct tumour immunity signatures related to T-cell function. These differences may influence geographical differences in clinical outcome, and the design of future trials particularly in immuno-oncology.
187 citations
TL;DR: Given the acceptable safety profile of multiple intravenous Pexa-Vec infusions in patients with treatment-refractory colorectal cancer, further trials evaluating efficacy of intravenously PX-594, as monotherapy or in combination with chemotherapeutic agents, is warranted in this patient population.
139 citations
TL;DR: High concordance to tDNA is shown suggesting that the DST approach may be used as a non-invasive biopsy-free alternative to conventional sequencing using tumor biopsy.
Abstract: Sequencing of the mutant allele fraction of circulating cell-free DNA (cfDNA) derived from tumors is increasingly utilized to detect actionable genomic alterations in cancer. We conducted a prospective blinded study of a comprehensive cfDNA sequencing panel with 54 cancer genes. To evaluate the concordance between cfDNA and tumor DNA (tDNA), sequencing results were compared between cfDNA from plasma and genomic tumor DNA (tDNA). Utilizing next generation digital sequencing technology (DST), we profiled approximately 78,000 bases encoding 512 complete exons in the targeted genes in cfDNA from plasma. Seventy-five patients were prospectively enrolled between February 2013 and March 2014, including 61 metastatic cancer patients and 14 clinical stage II CRC patients with matched plasma and tissue samples. Using the 54-gene panel, we detected at least one somatic mutation in 44 of 61 tDNA (72.1%) and 29 of 44 (65.9%) cfDNA. The overall concordance rate of cfDNA to tDNA was 85.9%, when all detected mutations were considered. We collected serial cfDNAs during cetuximab-based treatment in 2 metastatic KRAS wild-type CRC patients, one with acquired resistance and one with primary resistance. We demonstrate newly emerged KRAS mutation in cfDNA 1.5 months before radiologic progression. Another patient had a newly emerged PIK3CA H1047R mutation on cfDNA analysis at progression during cetuximab/irinotecan chemotherapy with gradual increase in allele frequency from 0.8 to 2.1%. This blinded, prospective study of a cfDNA sequencing showed high concordance to tDNA suggesting that the DST approach may be used as a non-invasive biopsy-free alternative to conventional sequencing using tumor biopsy.
85 citations
TL;DR: TkrA IHC is an effective, initial screening method for NTRK1 rearrangement detection in the clinic and inhibition of the TrkA kinase is a promising targeted therapy for cancer patients whose tumors harbor a NTRKR rearrangements.
Abstract: // Su Jin Lee 1, * , Gang Gary Li 2, * , Seung Tae Kim 1, * , Min Eui Hong 3 , Jiryeon Jang 1 , Nara Yoon 3 , Soo Min Ahn 3 , Danielle Murphy 2 , Jason Christiansen 2 , Ge Wei 2 , Zachary Hornby 2 , Dong Woo Lee 4 , Joon Oh Park 1, 7 , Young Suk Park 1 , Ho Yeong Lim 1 , Sung No Hong 5 , Seok-Hyeong Kim 3 , Won Ki Kang 1 , Keunchil Park 1 , Woong Yang Park 6 , Kyoung-Mee Kim 3, 7 , Jeeyun Lee 1 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Ignyta Inc, San Diego, California, USA 3 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Samsung Electrics, Seoul, Korea 5 Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 6 Samsung Genome Institute, Seoul, Korea 7 The Innovative Cancer Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Jeeyun Lee, e-mail: jyunlee@skku.edu Kyoung-Mee Kim, e-mail: kkmkys@skku.edu Keywords: colorectal cancer, NTRK1 rearrangement, TRKA immunohistochemistry Received: June 22, 2015 Accepted: September 30, 2015 Published: October 12, 2015 ABSTRACT Background: We have investigated the incidence of NTRK1 rearrangements in metastatic gastrointestinal cancer patients and demonstrated the potential for clinical response of these patients to targeted therapy. Methods: We prospectively collected tumor tissue specimens for one year and simultaneously generated patient-derived tumor cells (PDCs). Specimens were initially screened for TrkA protein expression using TrkA immunohistochemistry (IHC). In the case of TrkA IHC positive results, samples were further examined by fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) to confirm the presence of NTRK1 rearrangements. Results: From January 2014 to December 2014, a total of 74 metastatic colorectal cancer (CRC) patients and 66 gastric cancer (GC) patients were initially screened by TrkA IHC. Two of the 74 CRC patients (2.7%) and one of the 66 GC patients (1.5%) were positive for TrkA expression by IHC. All three IHC positive cases had evidence of NTRK1 rearrangements by FISH. NGS was performed on the 3 IHC positive cases and confirmed TPM3- NTRK1 rearrangements in the two CRC cases. One GC patient with TrkA expression by IHC did not harbor an NTRK1 rearrangement. PDCs established from the NTRK1 positive CRC patients were positive for the NTRK1 rearrangement. Entrectinib, a pan-TRK inhibitor, profoundly inhibited cell proliferation of NTRK1 -rearranged PDCs with such inhibition associated with inactivation of TrkA, and down-regulation of downstream signaling pathways. Conclusion: TrkA IHC is an effective, initial screening method for NTRK1 rearrangement detection in the clinic. Inhibition of the TrkA kinase is a promising targeted therapy for cancer patients whose tumors harbor a NTRK1 rearrangement.
56 citations
TL;DR: METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification.
Abstract: Recently, MET exon 14 deletion (METex14del) has been postulated to be one potential mechanism for MET protein overexpression. We screened for the presence of METex14del transcript by multiplexed fusion transcript analysis using nCounter assay followed by confirmation with quantitative reverse transcription PCR with correlation to MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH). We extracted RNAs from 230 patients enrolled onto the prospective molecular profiling clinical trial (NEXT-1) (NCT02141152) between November 2013 and August 2014. Thirteen METex14del cases were identified including 3 gastric cancer, 4 colon cancer, 5 non-small cell lung cancer, and one adenocarcinoma of unknown primary. Of these 13 METex14del cases, 11 were MET IHC 3+ and 2 were 2+. Only one out of the 13 METex14del cases was MET amplified (MET/CEP ratio > 2.0). Growths of two (gastric, colon) METex14del+ patient tumor derived cell lines were profoundly inhibited by both MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. In conclusion, METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification. Substantial growth inhibition of METex14del+ patient tumor derived cell lines by several MET targeting drugs strongly suggests METex14del is a potential actionable driver mutation in GI malignancies.
54 citations
TL;DR: Evidence is provided that the patient-derived tumor cell (PDC) model was a promising model for preclinical experiments and closely resembled the patient tumor genome and clinical response.
Abstract: // Ji Yun Lee 1, * , Sun Young Kim 1, * , Charny Park 1, * , Nayoung K.D. Kim 2, * , Jiryeon Jang 1 , Kyunghee Park 2 , Jun Ho Yi 7 , Mineui Hong 3, 4 , Taejin Ahn 2 , Oliver Rath 5 , Julia Schueler 5 , Seung Tae Kim 1 , In-Gu Do 4 , Sujin Lee 1 , Se Hoon Park 1 , Yong Ick Ji 6 , Dukwhan Kim 6 , Joon Oh Park 1, 3 , Young Suk Park 1 , Won Ki Kang 1 , Kyoung-Mee Kim 3, 4 , Woong-Yang Park 2, 6 , Ho Yeong Lim 1 , Jeeyun Lee 1, 3 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Samsung Genome Institute, Samsung Medical Center, Seoul, Korea 3 Innovative Cancer Medicine Institute, Samsung Cancer Center, Samsung Medical Center, Seoul, Korea 4 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Oncotest, Freiburg, Germany 6 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea 7 Division of Hematology-Oncology, Department of Medicine, Hanyang University Hospital, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Ho Yeong Lim, e-mail: hoylim@skku.edu Jeeyun Lee, e-mail: jyunlee@skku.edu Woong-Yang Park, e-mail: woongyang@skku.edu Keywords: gastric cancer, patient-derived cells, genomic analysis, targeted therapy Received: February 15, 2015 Accepted: July 03, 2015 Published: July 16, 2015 ABSTRACT Background: In this study, we established patient-derived tumor cell (PDC) models using tissues collected from patients with metastatic cancer and assessed whether these models could be used as a tool for genome-based cancer treatment. Methods: PDCs were isolated and cultured from malignant effusions including ascites and pleural fluid. Pathological examination, immunohistochemical analysis, and genomic profiling were performed to compare the histological and genomic features of primary tumors, PDCs. An exploratory gene expression profiling assay was performed to further characterize PDCs. Results: From January 2012 to May 2013, 176 samples from patients with metastatic cancer were collected. PDC models were successfully established in 130 (73.6%) samples. The median time from specimen collection to passage 1 (P1) was 3 weeks (range, 0.5–4 weeks), while that from P1 to P2 was 2.5 weeks (range, 0.5–5 weeks). Sixteen paired samples of genomic alterations were highly concordant between each primary tumor and progeny PDCs, with an average variant allele frequency (VAF) correlation of 0.878. We compared genomic profiles of the primary tumor (P0), P1 cells, P2 cells, and patient-derived xenografts (PDXs) derived from P2 cells and found that three samples (P0, P1, and P2 cells) were highly correlated (0.99–1.00). Moreover, PDXs showed more than 100 variants, with correlations of only 0.6–0.8 for the other samples. Drug responses of PDCs were reflective of the clinical response to targeted agents in selected patient PDC lines. Conclusion(s): Our results provided evidence that our PDC model was a promising model for preclinical experiments and closely resembled the patient tumor genome and clinical response.
45 citations
TL;DR: The findings indicate that additional alterations implemented for prediction of clinical benefit from HER2-targeting agents in GC remained unclear and further studies will be needed to elucidate the role of each specific biomarker and to optimize therapeutic approaches.
Abstract: Clinical benefit from trastuzumab and other anti-human epidermal growth factor receptor-2 (HER2) therapies in patients with HER2-positive gastric cancer (GC) remains limited by primary or acquired resistance. We aimed to investigate the impact of concomitant molecular alterations to HER2 amplification on the clinical outcome of trastuzumab-treated patients. Using immunohistochemistry (IHC), copy number variations (CNVs), and Ion Ampliseq Cancer Panel, we analyzed the status of concomitant alterations in 50 HER2-positive advanced GC patients treated with trastuzumab in combination with other chemotherapeutic agents. The percentage of tumor samples with at least one concomitant alteration was 40% as assessed by IHC, 16% by CNVs, and 64% by Ampliseq sequencing. Median progression-free survival (PFS) was 8.0 months (95% confidence interval, 4.8-11.3). Patients were divided into two subgroups according to PFS values with a cutoff point of 8 months; results show that concomitant genomic alterations do not correlate with trastuzumab response. However, CNVs of CCNE1 significantly correlated (p < 0.05) with a shorter survival time. Our findings indicate that additional alterations implemented for prediction of clinical benefit from HER2-targeting agents in GC remained unclear. Further studies will be needed to elucidate the role of each specific biomarker and to optimize therapeutic approaches.
43 citations
TL;DR: Since the improvement in PFS was only slight and there was no difference in OS, both SP3 and SP5 can be recommended as first-line treatments for patients with advanced GC.
39 citations
TL;DR: It is demonstrated that the combination of HER2‐inhibitor (lapatinib) and MET‐ inhibitor offered a more profound inhibition in the ERK/AKT pathway and cell proliferation than lapatinib alone.
Abstract: Growth factor receptors, often carrying tyrosine kinase activities in their cytoplasmic domains, are overexpressed in many cancers. Coactivation of receptor tyrosine kinases (RTKs) plays a critical role in tumor response to targeted therapeutics. We examined concomitant overexpression of EGFR and MET in patients with HER2(+) and HER2(-) gastric cancers (GCs). Tissue microarray samples obtained from 1,589 GC patients who received R0 gastrectomy with extensive node dissection and adjuvant chemoradiationtherapy were analyzed by immunohistochemistry and fluorescence in situ hybridization. HER2(+) was observed in 169 patients (11%). Out of 169 HER2(+) patients, 15 (9%) were EGFR(+) and MET(+) , 29 (17%) were EGFR(+) , 37 (22%) were MET(+) and the remaining 88 patients (52%) were HER2(+) only, without concomitant EGFR or MET overexpression. Greater number of overexpressed RTKs correlated with younger age (p < 0.001), larger tumor size (p = 0.027), intestinal histology (p < 0.001) and shorter overall survival (p = 0.002). The mean overall survival was 113 months for HER2(-) /EGFR(-) /MET(-) and 63 months for HER2(+) /EGFR(+) /MET(+) subgroups. Patients with HER2(+) /EGFR(+) /MET(+) GCs had a substantial risk of death with a hazard ratio of 3.01 (95% CI: 1.54-5.90), compared with HER2(-) /EGFR(-) /MET(-) GC patients. Using patient-derived tumor cell models isolated from pericardial effusion of HER2(+) and MET(+) GC cases, we demonstrated that the combination of HER2-inhibitor (lapatinib) and MET-inhibitor offered a more profound inhibition in the ERK/AKT pathway and cell proliferation than lapatinib alone. Co-overexpression of RTKs was demonstrated in small subsets of GC associated with aggressive behavior and in these cases, combination therapy may be considered as potential treatment options.
TL;DR: ALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC and is a potential actionable driver mutation in CRC based on survival inhibition of patient tumor-derived cell line by potent ALK inhibitors.
Abstract: // Jeeyun Lee 1, * , Hee Cheol Kim 2, * , Jung Yong Hong 3, * , Kai Wang 4 , Sun Young Kim 1 , Jiryeon Jang 1 , Seung Tae Kim 1 , Joon Oh Park 1 , Ho Yeong Lim 1 , Won Ki Kang 1 , Young Suk Park 1 , Jiyun Lee 1 , Woo Yong Lee 2 , Yoon Ah Park 2 , Jung Wook Huh 2 , Seong Hyeon Yun 2 , In-Gu Do 5 , Seok Hyung Kim 5 , Sohail Balasubramanian 4 , Philip J. Stephens 4 , Jeffrey S. Ross 4, 6 , Gang Gary Li 7 , Zachary Hornby 7 , Siraj M. Ali 4 , Vincent A. Miller 4 , Kyoung-Mee Kim 5, 8 , Sai-Hong Ignatius Ou 9 1 Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 2 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 3 Department of Internal Medicine, Chung-Ang University College of Medicine, Dongjak-Gu, Seoul, Republic of Korea 4 Foundation Medicine Inc, Cambridge, Massachusetts, USA 5 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 6 Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA 7 Ignyta Inc, San Diego, California, USA 8 Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Korea 9 Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA * These authors have contributed equally to this work Correspondence to: Sai-Hong Ignatius Ou, e-mail: Ignatius.ou@uci.edu Kyoung-Mee Kim, e-mail: kkmkys@skku.edu Keywords: colorectal carcinoma, anaplastic lymphoma kinase (ALK) rearrangement, immunohistochemistry, next generation sequencing Received: April 02, 2015 Accepted: June 19, 2015 Published: July 01, 2015 ABSTRACT Purpose: Anaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies. Experimental designs: Tissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgical resection at Samsung Medical Center, Seoul, Korea were screened by IHC using ALK monoclonal antibody 5A4. IHC positive cases were confirmed by FISH, nCounter assays, and NGS-based comprehensive genomic profiling (CGP). ALK IHC was further applied to CRC patients enrolled in a pathway-directed therapeutic trial. Results: Four hundred thirty-two GC and 172 CRC cases were screened by IHC. No GC sample was ALK IHC positive. One CRC (0.6%) was ALK IHC positive (3+) that was confirmed by ALK FISH and a novel CAD-ALK (C35; A20) fusion variant that resulted from a paracentric inversion event inv(2)(p22–21p23) was identified by CGP. One out of 50 CRC patients enrolled in a pathway-directed therapeutic trial was ALK IHC positive (3+) confirmed by ALK FISH and found to harbor the EML4-ALK (E21, A20) fusion variant by CGP. Growth of a tumor cell line derived from this EML4-ALK CRC patient was inhibited by ALK inhibitors crizotinib and entrectinib. Conclusions: ALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC. ALK rearrangement is a potential actionable driver mutation in CRC based on survival inhibition of patient tumor-derived cell line by potent ALK inhibitors.
TL;DR: In this trial, it is demonstrated that genome-matched treatment based on molecular profiling result in better treatment outcome in terms of response rate.
Abstract: // Seung Tae Kim 1, * , Jeeyun Lee 1, * , Mineui Hong 2, 3, * , Kyunghee Park 4, 5, * , Joon Oh Park 1 , Tae Jin Ahn 3, 4 , Se Hoon Park 1 , Young Suk Park 1 , Ho Yeong Lim 1 , Jong-Mu Sun 1 , Jin Seok Ahn 1 , Myung-Ju Ahn 1 , Hee Cheol Kim 6 , Tae Sung Sohn 6 , Dong Il Choi 7 , Jong Ho Cho 8 , Jin Seok Heo 6 , Wooil Kwon 6 , Sang Won Uhm 9 , Hyuk Lee 10 , Byung-Hoon Min 10 , Sung No Hong 10 , Duk Hwan Kim 5, 11 , Sin Ho Jung 12 , Woongyang Park 4, 5 , Kyoung-Mee Kim 2, 3 , Won Ki Kang 1 , Keunchil Park 1, 2 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Innovative Cancer Medicine Institute, Samsung Cancer Center, Samsung Medical Center, Seoul, Korea 3 Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Samsung Genome Institute, Seoul, Korea 5 Samsung Biological Research Institute, Seoul, Korea 6 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 7 Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 8 Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 9 Division of Pulmonology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 10 Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 11 Medical Translational Research Center, Samsung Biological Research Institute, Seoul, Korea 12 Biostatistics and Clinical Epidemiology, Samsung Medical Center, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Won Ki Kang, e-mail: wkkang@skku.edu Kyoung-Mee Kim, e-mail: kkmkys@skku.edu Keunchil Park, e-mail: kpark@skku.edu Keywords: molecular profiling, genome, ampliseq Received: July 01, 2015 Accepted: August 27, 2015 Published: September 09, 2015 ABSTRACT We conducted a prospective genomic screening trial with high throughput sequencing and copy number variation (CNV) assay, and immunohistochemistry array in metastatic solid cancer patients. We used Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay (21 genes) to identify molecular targets for potential matched therapy. Metastatic solid tumor patients were prospectively consented for molecular profiling tests. The primary outcome for this trial was the feasibility of molecular tests and response rate (matched vs non-matched treatment). Between November 2013 and August 2014, a total of 428 metastatic solid tumor patients were enrolled on to this study. The mutational profiles were obtained for 407 (95.1%) patients. CNV 21-gene assays were successfully performed in 281 (65.7%) of 428 patients. Of the 407 patients with molecular profiling results, 342 (84.0%) patients had one or more aberrations detected. Of the 342 patients, 103 patients were matched to molecularly targeted agents in the context of clinical trials or clinical practice. The response rate was significantly higher in the genome-matched treated group for gastrointestinal/hepatobiliary/rare tumors (matched vs non-matched treatment, 42.6% vs 24.3%, P = .009) and lung cancer cohort (matched vs non-matched treatment, 61.2% vs 28.6% < P = .001) when compared with the non-matched group. In this trial, we demonstrate that genome-matched treatment based on molecular profiling result in better treatment outcome in terms of response rate.
TL;DR: Adjuvant RT after D2 resection in gastric cancer reduced LRR, especially in group 3 LNs, and improved LRRFS, and patients with LN metastasis benefited more from the adjuvant RT treatment than the other subgroups.
TL;DR: This study suggests CTCs are associated with poor response to chemotherapy in metastatic GC patients and a multivariate Cox proportional hazards regression model showed that CTC positivity was an independent adverse factor for progression-free survival and overall survival.
Abstract: BackgroundThe aim of this study was to investigate the impact of number of circulating tumor cells (CTCs) on the treatment outcome for metastatic gastric cancer (GC) following palliative chemothera...
TL;DR: It is suggested 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.
Abstract: 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.
TL;DR: Except tumour size and necrosis, conventional MR imaging findings did not correlate with the risk grade of gastrointestinal stromal tumours, however, the ADC value can be used as an imaging biomarker to assess the riskgrade of GISTs, regardless of tumours size.
TL;DR: Investigating the prognostic role of the estrogen receptor (ER) in gastric cancer patients and suppressing ER by fulvestrant, paclitaxel and ER siRNA showed increased expression of E-cadherin, which is a crucial factor in diffuse-type carcinogenesis.
Abstract: To investigate the prognostic role of the estrogen receptor (ER) in gastric cancer (GC) patients, tumor tissues from 932 patients with advanced GC were assessed for ER expression using immunohistochemistry, and their clinicopathologic features were evaluated. Forty patients (4.3%) had ER expression and they were more frequently associated with diffuse type gastric cancer and shorter disease free survival. Furthermore, we carried out in vitro analysis to evaluate the effect of ER modulation on the proliferation of GC cell lines. Estradiol enhanced proliferation of ER positive GC cells while it did not show any effect on ER negative GC cells. When ER was inhibited by fulvestrant and ER siRNA, estradiol-induced proliferation of ER positive GC cell was suppressed. Paclitaxel showed synergistic anti-proliferative impacts with fulvestrant. Suppressing ER by fulvestrant, paclitaxel and ER siRNA showed increased expression of E-cadherin, which is a crucial factor in diffuse-type carcinogenesis.
TL;DR: In patients with wild-type KRAS who were treated with GEMOX plus erlotinib, ETS was a significant prognostic factor for PFS (p < 0.01), and may be an indication for adding erlot inib to chemotherapy for BTC patients wild- type KRAS.
Abstract: The aim of this study was to determine whether early tumor shrinkage (ETS) at 6 weeks after treatment correlates with progression-free survival (PFS) and overall survival (OS) in advanced biliary tract cancer (BTC) patients receiving gemcitabine plus oxaliplatin (GEMOX), with or without erlotinib. This was a multicenter, open label, randomized, phase III trial of 103 BTC patients (ClinicalTrials.gov Identifier; NCT01149122, and Rigistration date; January, 7, 2010), comparing GEMOX with GEMOX plus erlotinib. Tumor shrinkage was expressed as a relative decrease compared to baseline and was dichotomized according to a previously reported cutoff value of 10 %. Fifty-four patients (52.4 %) received GEMOX and 49 patients (47.6 %) received GEMOX plus erlotinib. The latter achieved a better overall response rate (RR) (40.8 % vs. 18.6 %, p = 0.02) and showed ETS more frequently (63.2 % vs. 40.7 %, p = 0.03). ETS was significantly correlated with the overall RR (correlation coefficient, 0.53; p < 0.01). The median PFS and OS did not differ according to erlotinib administration. However, the median PFS (7.3 vs. 2.1 months, p < 0.01) and OS (10.7 vs. 5.8 months, p < 0.01) were significantly longer amongst patients with ETS at 6 weeks after treatment, irrespective of erlotinib administration. In patients with wild-type KRAS who were treated with GEMOX plus erlotinib, ETS was a significant prognostic factor for PFS (p < 0.01). ETS might predict PFS and OS in BTC patients treated with GEMOX with or without erlotinib. Additionally, ETS may be an indication for adding erlotinib to chemotherapy for BTC patients wild-type KRAS. These findings need to be prospectively validated.
TL;DR: This study demonstrates that KRAS mutational status might be considered a predictive biomarker for the response to erlotinib in BTCs and the mutation status of PIK3CA may be a determinant for adding erlot inib to chemotherapy in KRAS wild-type BTCs.
TL;DR: Low-level PIK3CA mutations were detectable in the serum indicating the utility of cell free DNA from serum as a DNA source to detect cancer-derived mutations in metastatic biliary cancers.
Abstract: // Seung Tae Kim 1, * , Maruja Lira 2, * , Shibing Deng 2 , Sujin Lee 1 , Young Suk Park 1 , Ho Yeong Lim 1 , Won Ki Kang 1 , Mao Mao 3 , Jin Seok Heo 4 , Wooil Kwon 4 , Kee‑Taek Jang 5 , Jeeyun Lee 1, 6 , Joon Oh Park 1, 6 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Precision Medicine, Oncology Research Unit, Pfizer, Inc, San Diego, CA, USA 3 WuXi AppTec, Shanghai, China 4 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 6 Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Joon Oh Park, e-mail: oncopark@skku.edu Jeeyun Lee, e-mail: jyunlee@skku.edu Keywords: cell free DNA (cfDNA), PIK3CA mutation, droplet digital PCR (ddPCR) Received: July 13, 2015 Accepted: October 05, 2015 Published: October 16, 2015 ABSTRACT PIK3CA mutation is considered a good candidate for targeted therapies in cancers, especially biliary tract cancer (BTC). We evaluated the utility of cell free DNA (cfDNA) from serum by using droplet digital PCR (ddPCR) as an alternative source for PIK3CA mutation analysis. To identify matching archival tumour specimens from serum samples of advanced BTC patients, mutation detection using ddPCR with Bio-Rad’s PrimePCR mutation and wild type assays were performed for PIK3CA p.E542K, p.E545K, and p.H1047R. Thirty-eight patients with metastatic BTC were enrolled. Only one (BTC 29T) sample ( n = 38) was positive for PIK3CA p.E542K and another (BTC 27T) for p.H1047R mutation; none was positive for PIK3CA p.E545K. Matched serum sample (BTC 29P) was positive for PIK3CA p.E542K with 28 mutant copies detected, corresponding to 48 copies/ml of serum and an allelic prevalence of 0.3%. Another matched serum sample (BTC 27P) was positive for PIK3CA p.H1047R with 10 mutant copies detected, i.e. 18 copies/ml and an allelic frequency of 0.2%. High correlation was noted in the PIK3CA mutation status between tumour gDNA and serum cfDNA. Low-level PIK3CA mutations were detectable in the serum indicating the utility of cfDNA as a DNA source to detect cancer-derived mutations in metastatic biliary cancers.
TL;DR: This study revealed that changes of the plasma CgA levels were associated with tumour response, and biochemical response based on serial C gA may be a predictive marker for PFS in GEP-NETs.
Abstract: Purpose Chromogranin A (CgA) has been considered to be valuable not only in the diagnosis but also in monitoring the disease response to treatment. However, only a few studies have been published on this issue. We purposed to evaluate whether biochemical response using plasma CgA level is reliable in concordance with the clinical response of grade 1-3 nonfunctiong gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Materials and methods Between March 2011 and September 2013, a total of 27 cases in 18 patients were analysed, clinically and radiologically while serial CgA tests were also conducted during treatment. Tumor responses were defined by both Response Evaluation Criteria in Solid Tumors (RECIST) criteria ver. 1.1 and biochemical criteria based on the CgA level. Results Among the 27 cases analysed, no difference in the basal CgA level was observed with regard to gender, primary tumor site, tumor grade (World Health Organization classification), liver metastasis, number of metastatic site, and line of chemotherapy. The overall response rate (RR) by RECIST criteria ver. 1.1 was six out of the 27 cases (22.2%) and eight out of the 27 cases (29.6%) for biochemical RR. The overall concordance rates of the response based on RECIST and biochemical criteria were 74%. In grades 1 and 2 GEP-NETs (n=17), the concordance rate of the disease control was 94.1%. There was a significant difference for progression-free survival (PFS) between responders and non-responder in accordance to biochemical criteria (35.73 months vs. 5.93 months, p=0.05). Conclusion This study revealed that changes of the plasma CgA levels were associated with tumour response. Additionally, biochemical response based on serial CgA may be a predictive marker for PFS in GEP-NETs.
TL;DR: Compared disease-free survival (DFS) in Korean patients with D2-resected GC is reported and patients with node-positive disease and intestinal type GC may have benefit with the addition of radiotherapy to adjuvant chemotherapy.
Abstract: TPS228 Background: Treatment of gastric cancer (GC) has some notable differences between Asia and Western countries including the extent of surgery and the type of adjuvant therapy. In ARTIST trial comparing adjuvant chemotherapy involving capecitabine plus cisplatin with chemoradiotherapy, we reported comparable disease-free survival (DFS) in Korean patients with D2-resected GC. In subset analyses, patients with node-positive disease and intestinal type GC may have benefit with the addition of radiotherapy to adjuvant chemotherapy. Methods: ARTIST 2 (ClinicalTrials.gov, NCT0176146) is a 3-arm, multi-center, open-label phase III trial comparing adjuvant chemotherapy involving S-1 (40 mg/m2 bid 4-weeks-on/2-weeks-off) for one year (arm A) with S-1 plus oxaliplatin (SOX, S-1 40 mg/m2 bid 2-weeks-on/1-week-off plus oxaliplatin 130 mg/m2 iv on day 1) for 8 cycles (arm B) and chemoradiotherapy (arm C). Arm C patients receive SOX for 2 cycles, then concurrent chemoradiotherapy 45 Gy with S-1 40 mg bid daily, fo...
TL;DR: It is demonstrated that expression nature of kinase genes such as PSKH1, TLK2 and PHKG2 may be informative to predict the efficacy of CI in wild type KRAS CRC.
Abstract: More than half of the patients selected based on KRAS mutation status fail to respond to the treatment with cetuximab in metastatic colorectal cancer (mCRC). We designed a study to identify additional biomarkers that could act as indicators for cetuximab treatment in mCRC. We investigated 58 tumor samples from wild type KRAS CRC patients treated with cetuximab plus irinotecan (CI). We conducted the genotyping for mutations in either BRAF or PIK3CA and profiled comprehensively the expression of 522 kinase genes. BRAF mutation was detected in 5.1 % (3/58) of patients. All 50 patients showed wild type PIK3CA. Gene expression patterns that categorized patients with or without the disease control to CI were compared by supervised classification analysis. PSKH1, TLK2 and PHKG2 were overexpressed significantly in patients with the disease control to IC. The higher expression value of PSKH1 (r = 0.462, p < 0.001) and TLK2 (r = 0.361, p = 0.005) had the significant correlation to prolonged PFS. The result of this work demonstrated that expression nature of kinase genes such as PSKH1, TLK2 and PHKG2 may be informative to predict the efficacy of CI in wild type KRAS CRC. Mutations in either BRAF or PIK3CA were rare subsets in wild type KRAS CRC.
TL;DR: The status of IGFBP-3 methylation as measured by methylation-specific polymerase chain reaction proposed the modest role for predicting survival in specific subgroups of patients with early-stage gastric cancer who undergo curative surgery.
TL;DR: The doublet combination with fluoropyrimidines and platinum is currently considered standard first-line chemotherapy in AGC, but there has been a price to pay in terms of toxicity.
Abstract: 4051 Background: While doublet combination with fluoropyrimidines and platinum is currently considered standard first-line chemotherapy in AGC, there has been a price to pay in terms of toxicity. S...
TL;DR: A single-arm, open label phase II study is designed to determine the efficacy and toxicity of the combination of pazopanib with CapeOx (capecitabine and oxaliplatin) in metastatic breast cancer.
Abstract: 4049 Background: We designed a single-arm, open label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx (capecitabine and oxaliplatin) in metastatic ...
TL;DR: A first-in-human phase I study of Tanibirumab in patients with solid tumors which were refractory to standard chemotherapy, evaluating safety, pharmacokinetics (PKs), estimating maximum-tolerated dose (MTD) and recommended phase II dose (RP2D).
Abstract: 2522 Background: Tanibirumab is a fully human monoclonal antibody to the vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a first-in-human phase I study of Tanibirumab in patie...
TL;DR: This trial shows that the matched therapy group has longer PFS than the non-matched group, and uses Digital Sequencing technology (DST) to enable single-molecule sensitivity using current next-generation sequencers with nearly-perfect specificity.
Abstract: e12540 Background: The NEXT-2 trial is cfDNA genomics master protocol to enroll refractory cancer patients and to guide matched trial according to cfDNA genomics of 56 genes. Methods: Using Digital...
TL;DR: The combination of pazopanib and CapeOx showed moderate activity and an acceptable toxicity profile as a first-line treatment in metastatic / recurrent advanced gastric cancer patients.