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// 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.

We investigated which subgroups might benefit from adjuvant radiotherapy (RT) and suggested optimal RT targets by analyzing the results of the Adjuvant Chemoradiation Therapy in Stomach Cancer (ARTIST) trial.We conducted randomized controlled trial in 458 gastric cancer patients. Patients were randomly assigned to XP (6 cycles of capecitabine and) or XPRT (2 cycles of XP+RT 45Gy/25 fraction with capecitabine+2 cycles of XP) groups after D2 resection. Minimum follow-up was 5years.During follow-up, 77 patients (33.8%) in the XP arm and 60 (26.1%) in the XPRT arm experienced recurrence. Among these patients, locoregional recurrence (LRR) developed in 44 (9.6%; 29 in XP, 15 in XPRT; P=0.03). The local recurrence rate (4.8%) did not vary between arms. Regional recurrence was the most important difference between the two groups (23 in the XP arm, 5 in the XPRT arm, P0.001). LRR-free survival (LRRFS) was significantly different between study arms (P=0.03), especially in patients with LN metastasis (P=0.009).Adjuvant RT after D2 resection in gastric cancer reduced LRR, especially in group 3 LNs, and improved LRRFS. Patients with LN metastasis benefited more from the adjuvant RT treatment than the other subgroups.

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.

Fifteen patients with treatment-refractory colorectal cancer were enrolled on a phase 1b study of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia designed to selectively replicate in cancer cells. Pexa-Vec was administered intravenously every 14 days, at dose levels of 1 × 10(6), 1 × 10(7), or 3 × 10(7) plaque-forming units (pfu)/kg. The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacokinetics and pharmacodynamics as well as antitumor activity. Patients were heavily pretreated (mean 4.5 lines of therapy). All patients received at least two Pexa-Vec doses (median = 4; range = 2-4). No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. The most common adverse events were grade 1/2 flu-like symptoms, generally lasting24 hours. During the first and last cycles, genome pharmacokinetics were unchanged. Infectious pfu could be detected in plasma up to 2 hours after cycle 1 and up to 30 minutes after cycle 4 (when antivaccinia antibody titers are known to have peaked). Ten patients (67%) had radiographically stable disease. Given the acceptable safety profile of multiple intravenous Pexa-Vec infusions in patients with treatment-refractory colorectal cancer, further trials evaluating efficacy of intravenous Pexa-Vec, as monotherapy or in combination with chemotherapeutic agents, is warranted in this patient population.

// 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.

// 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.

Purpose To evaluate the appropriateness of prophylactic inguinal nodal irradiation (PINI), we analyzed patterns of failure in anal cancer patients who were inguinal node-negative at presentation and did not receive PINI. Materials and methods We retrospectively reviewed the records of 33 anal cancer patients treated by definitive concurrent chemoradiation therapy (CCRT) between 1994 and 2013. Radiotherapy consisted of a total dose of 44-45 Gy (22-25 fractions in 5 weeks) on the whole pelvis, anus, and perineum. Except inguinal lymphadenopathy was present at initial diagnosis, the entire inguinal chain was not included in the radiation field. In other words, there was no PINI. Results The median follow-up duration was 50 months (range, 4 to 218 months). Median survival and progression-free survival (PFS) were 57 months (range, 10 to 218 months) and 50 months (range, 4 to 218 months), respectively. Among the survival, the median follow-up duration was 51 months (range, 12 to 218 months). The 5-year overall survival and PFS rates were 93.4% and 88.8%, respectively. Although none of the patients received inguinal node irradiation for prophylactic purposes, there was no inguinal recurrence. Conclusion Treatment of anal cancer by omitting PINI might be considered in selected patients with clinically uninvolved inguinal nodes.

Evidence suggests that combined gemcitabine-cisplatin chemotherapy extends survival in patients with advanced biliary tract cancer (BTC). We conducted a systematic review in order to collate this evidence and assess whether gemcitabine-cisplatin efficacy is influenced by primary tumor site, disease stage, or geographic region, and whether associated toxicities are related to regimen. MEDLINE (1946-search date), EMBASE (1966-search date), ClinicalTrials. gov (2008-search date), and abstracts from major oncology conferences (2009- search date) were searched (5 Dec 2013) using terms for BTC, gemcitabine, and cisplatin. All study types reporting efficacy (survival, response rates) or safety (toxicities) outcomes of gemcitabine-cisplatin in BTC were eligible for inclusion; efficacy data were extracted from prospective studies only. Evidence retrieved from one meta-analysis (abstract), four randomized controlled trials, 12 nonrandomized prospective studies, and three retrospective studies supported the efficacy and safety of gemcitabine-cisplatin for BTC. Median overall survival ranged from 4.6 to 11.7 months, and response rate ranged from 17.1% to 36.6%. Toxicities were generally acceptable and manageable. Heterogeneity in study designs and data collected prevented formal meta-analysis, however exploratory assessments suggested that efficacy did not vary with primary tumor site (gallbladder vs. others), disease stage (metastatic vs. locally advanced), or geographic origin (Asia vs. other). Incidence of grade 3/4 toxicities was not related to gemcitabine dose or cisplatin frequency. Despite individual variation in study designs, the evidence presented suggests that gemcitabine-cisplatin is effective in patients from a diverse range of countries and with heterogeneous disease characteristics. No substantial differences in toxicity were observed among the different dosing schedules of gemcitabine and cisplatin.

// Jun Ho Yi 1, 5, * , Jiryeon Jang 1, * , Jeonghee Cho 2, * , In-Gu Do 3 , Mineui Hong 4 , Seung Tae Kim 1 , Kyoung-Mee Kim 4 , Sujin Lee 1 , Se Hoon Park 1 , Joon Oh Park 1, 4 , Young Suk Park 1 , Won Ki Kang 1 , Ho Yeong Lim 1 and Jeeyun Lee 1 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Samsung Genome Institute, Seoul, Korea 3 Department of Pathology, Kangbuk Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 5 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 Keywords: gastric cancer, MerTK, patient-derived cells Received: February 28, 2014 Accepted: April 08, 2015 Published: April 20, 2015 ABSTRACT Introduction: The role of MerTK has not been assessed in gastric cancer (GC). The aim of this study was to identify a subgroup of GC patients with MerTK tumor overexpression, and to evaluate MerTK as a potential therapeutic target in this disease. Methods: Protein and mRNA expression of MerTK were evaluated, and other various in vitro analyses including shRNA transfection, cell cycle anslysis, MTS assay and colony forming assay were carried out with GC cell lines and GC patient-derived cells (PDCs). Results: shRNA-mediated knockdown of MerTK resulted in inhibition of cell growth, as well as increased cellular apoptosis in MerTK positive GC cells. Out of 192 GC patients, 16 (8.3%) patients showed strong protein expression and they had a significantly shorter overall survival compared to those with no MerTK expression. In 54 cases of GC PDCs, 4 cases (7.4%) showed mRNA overexpression, which was comparable to the protein expression rate. When we administered UNC1062, a novel MerTK-selective small molecular tyrosine kinase inhibitor, proliferation of MerTK overexpressing GC cells and PDCs were considerably inhibited. Conclusion: MerTK may be involved in GC carcinogenesis, and it could be a potential novel therapeutic target in GC patients.

// Guhyun Kang 1,8,* Hongseok Yun 1,2,* , Choong-Hyun Sun 2 , Inho Park 2 , Seungmook Lee 2 , Jekeun Kwon 2 , Ingu Do 1,3,4 , Min Eui Hong 1,4,9 , Michael Van Vrancken 1 , Jeeyun Lee 5 , Joon Oh Park 5 , Jeonghee Cho 6 , Kyoung-Mee Kim 1,4 and Tae Sung Sohn 7 1 Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Bioinformatics Laboratory, Samsung SDS Co., Ltd., Seoul, Korea 3 Samsung Cancer Research Institute, Samsung Medical Center, Seoul, Korea 4 Center for Cancer Companion Diagnostics, Samsung Medical Center, Seoul, Korea 5 Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 6 Samsung Genome Institute, Samsung Medical Center, Seoul, Korea 7 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 8 Department of Pathology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea 9 Current address: Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Kyoung-Mee Kim, email: // Tae Sung Sohn, email: // Keywords : high-throughput nucleotide sequencing; gastrointestinal stromal tumor; exome; transcriptome Received : January 30, 2015 Accepted : March 10, 2015 Published : March 30, 2015 Abstract Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. We sequenced nine exomes and transcriptomes, and two genomes of GISTs for integrated analyses. We detected 306 somatic variants in nine GISTs and recurrent protein-altering mutations in 29 genes. Transcriptome sequencing revealed 328 gene fusions, and the most frequently involved fusion events were associated with IGF2 fused to several partner genes including CCND1 , FUS , and LASP1 . We additionally identified three recurrent read-through fusion transcripts: POLA2 - CDC42EP2 , C8orf42 - FBXO25 , and STX16 - NPEPL1 . Notably, we found intragenic deletions in one of three exons of the VHL gene and increased mRNAs of VEGF , PDGF-β , and IGF-1/2 in 56% of GISTs, suggesting a mechanistic link between VHL inactivation and overexpression of hypoxia-inducible factor target genes in the absence of hypoxia. We also identified copy number gain and increased mRNA expression of AMACR , CRIM1 , SKP2 , and CACNA1E . Mapping of copy number and gene expression results to the KEGG pathways revealed activation of the JAK-STAT pathway in small intestinal GISTs and the MAPK pathway in wild-type GISTs. These observations will allow us to determine the genetic basis of GISTs and will facilitate further investigation to develop new therapeutic options.

The regulator of G-protein signaling protein type 4 (RGS4) accelerates the guanosine triphosphatase activity of G(αi) and G(αo), resulting in the inactivation of G-protein-coupled receptor signaling. An opioid receptor (OR), a G(αi)-coupled receptor, plays an important role in pain modulation in the central nervous system. In this study, we examined whether (1) spinal RGS4 affected nociceptive responses in the formalin pain test, (2) this RGS4-mediated effect was involved in OR activation, and (3) the µ-OR agonist-induced antinociceptive effect was modified by RGS4 modulation.Formalin (1%, 20 µL) was injected subcutaneously into the right hindpaws of male 129S4/SvJae×C57BL/6J (RGS4(+/+) or RGS4(-/-)) mice, and the licking responses were counted for 40 minutes. The time periods (seconds) spent licking the injected paw during 0 to 10 minutes (early phase) and 10 to 40 minutes (late phase) were measured as indicators of acute nociception and inflammatory pain response, respectively. An RGS4 inhibitor, CCG50014, and/or a µ-OR agonist, [D-Ala², N-MePhe⁴, Gly-ol]-enkephalin (DAMGO), were intrathecally injected 5 minutes before the formalin injection. A nonselective OR antagonist, naloxone, was intraperitoneally injected 30 minutes before the CCG50014 injection.Mice that received the formalin injection exhibited typical biphasic nociceptive behaviors. The nociceptive responses in RGS4-knockout mice were significantly decreased during the late phase but not during the early phase. Similarly, intrathecally administered CCG50014 (10, 30, or 100 nmol) attenuated the nociceptive responses during the late phase in a dose-dependent manner. The antinociceptive effect of the RGS4 inhibitor was totally blocked by naloxone (5 mg/kg). In contrast, intrathecal injection of DAMGO achieved a dose-dependent reduction of the nociceptive responses at the early and late phases. This analgesic effect of DAMGO was significantly enhanced by the genetic depletion of RGS4 or by coadministration of CCG50014 (10 nmol).These findings demonstrated that spinal RGS4 inhibited the endogenous or exogenous OR-mediated antinociceptive effect in the formalin pain test. Thus, the inhibition of RGS4 activity can enhance OR agonist-induced analgesia. The enhancement of OR agonist-induced analgesia by coadministration of the RGS4 inhibitor suggests a new therapeutic strategy for the management of inflammatory pain.

We conducted a phase II trial of 5-fluorouracil and oxaliplatin combination chemotherapy as a second-line treatment in unresectable/metastatic biliary tract cancer patients who had failed gemcitabine-based chemotherapy. Patients treated with gemcitabine-based palliative treatment were enrolled in this study. Patients were received modified FOLFOX3 (mFOLFOX3) consists of oxaliplatin 85 mg/m2 (day 1) and leucovorin 30 mg (days 1, 2) followed by 5-fluorouracil 1,500 mg/m2 (days 1, 2) every 2 weeks. Between March 2010 and June 2012, a total of 30 patients were enrolled in this study. Twenty-eight patients were measurable for treatment response. One achieved complete response, and one a partial response was observed. Overall response rate was 7.1 % (95 % confidence interval 0.9–23.5 %). The median progression-free survival was 1.6 months, and the median overall survival was 4.4 months. Grade 3–4 hematologic toxicities included neutropenia (6.7 %) and thrombocytopenia (3.4 %). The most common non-hematologic toxicity was neuropathy (22.2 %). However, the most common grade 3–4 non-hematologic toxicity was hyperbilirubinemia (5.0 %). There was one treatment-related death due to neutropenic infection. mFOLFOX3 as a second-line regimen has modest effect and tolerable toxicity in unresectable/metastatic biliary tract cancer patients who have been treated previously via gemcitabine-based chemotherapy.

Background: Anti-EGFR antibodies are effective therapies for many late-stage colorectal cancer (CRC) patients; however, many tumors are unresponsive or develop resistance. Methods: We performed whole exome sequencing and RNA sequencing of 25 CRC patients who received cetuximab treatment. We obtained tissue specimens at acquired resistance and performed genomic analysis. Findings: Of 25 patients, 13 were categorized as intrinsic resistant and 12 were intrinsic sensitive tumor to cetuximab regardless of lines of therapy. Of 12 cetuximab sensitive tumors, we obtained 6 samples at acquired resistance to cetuximab. In the resistance group, we identified iNCOA4-RET and LMNA-NTRK1 fusions and NRG1 and GNAS amplifications without any aberrations in RAS/RAF pathway genes. For cetuximab-sensitive tumors, there were no major aberrations in the RAS pathway in all 12 tumors. Two PR patients showed KRAS K117N and A146T mutations, which are in KRAS exon 4 rather than in the more dominant exon 2. Other genomic aberrations found in the 12 PR patient cohort were BRAF V600E, AKT1 E17K, PIK3CA E542K, FGFR1, and ERBB2 CN amplifications. The comparison between baseline and at progression samples revealed an extreme loss and simultaneous gain of somatic variants in acquired resistance tumors suggesting that cetuximab exposure dramatically selected for rare resistant subclones of the baseline tumor that were initially undetectable. There was an increase in epithelial to mesenchymal transition (EMT) at acquired resistance with a reduction in the immune infiltrate. Interpretation: Each patient demonstrated varying genomic alterations which may facilitate in understanding the underlying culprit mechanism for cetuximab resistance at baseline. Funding Statement: This work was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2750 to YSP, HI14C3418 to JL), the SMC Biobank (to HCK and JL). Declaration of Interests: Lilly employees: SB, PJE, JNC, IHW, TG, SSW, HQ, JCT, JL, MW, RDN, AA, CR No conflicts of interest declared (JL, STK, SYK, JYH, YSP, JOP, HL, WKK, HCK) Ethics Approval Statement: All study participants provided written informed consent and the study was approved by the institutional review board.

Background: Capecitabine plus oxaliplatin (XELOX) has shown modest activity and tolerable toxicity in a phase two trial for biliary tract cancers (BTCs). Meanwhile, gemcitabine plus oxaliplatin (GEMOX) has been the reference arm in recent phase two and three trials for BTCs. We aimed to investigate the efficacy of XELOX versus GEMOX as first-line therapy for advanced BCTs. Methods: In this open-label, randomized, phase three, non-inferiority trial, we randomly selected patients with metastatic BCTs to receive GEMOX (gemcitabine 1000 mg/m2 on days 1 and 8, and oxaliplatin 100 mg/m2 on day 1) or XELOX (capecitabine 1000 mg/m2, twice daily, on days 1-14 and oxaliplatin 130 mg/m2 on day 1) as first-line treatment, given every 3 weeks, totaling 8 cycles. The primary endpoint was to prove the non-inferiority of XELOX to GEMOX in terms of 6-month progression-free survival (PFS) rate. Findings: In total, 114 patients randomly received GEMOX and 108 randomly received XELOX. The median PFS was 5·3 months for the GEMOX group and 5·8 months for the XELOX group. The 6-month PFS rate was 44·5% for the GEMOX group and 46·7% for the XELOX group. The 95% confidence interval of the 6-month PFS rate difference between both groups was -12% to 16%, meeting the criteria for non-inferiority of XELOX to GEMOX. There was no difference in objective response (p=0·171) and median overall survival (p=0·131) between both groups. The most common grade three to four adverse events were neutropenia and thrombocytopenia. No patient died of treatment-related causes. The XELOX group had significantly lower frequencies of hospital visits than the GEMOX group (p

Background Samsung Advance Institute of Technology-301 (SAIT301) is a human immunoglobulin G2 antibody that can specifically target mesenchymal epithelial transition factor (c-MET). This novel antibody has higher priority over hepatocyte growth factors when binding to the Sema domain of c-MET and accelerates the internalization and degradation of c-MET, proving its powerful antitumor activities in intra- as well as extracellular areas. Materials and Methods SAIT301 was administered intravenously once every 3 weeks in c-MET overexpressed solid tumor patients, focusing on metastatic colorectal cancer (CRC) according to common clinical phase I criteria. Dose escalation was performed according to a modified Fibonacci design, following the conventional 3+3 design. The purpose of this phase I study was to assess the safety profile, to establish the recommended dose for clinical phase II studies and to assess potential anticancer activity of the compound. Results Sixteen patients with a median age of 56 (range, 39-69) years were enrolled in the study. The most common adverse events were decreased appetite (50.0%), hypophosphatemia, fatigue and dizziness (25.0%, respectively), and diarrhea, blood alkaline phosphatase increased and dyspnea (18.8%, respectively). For tumor response, no patients achieved complete response. One (9.1%) CRC patient had a partial response in the 1.23 mg/kg group, 4 (36.4%) patients achieved stable disease (2 in the 0.41 mg/kg group, 2 in the 1.23 mg/kg group, 0 in the 3.69 mg/kg group, and 1 in the 8.61 mg/kg group). Because of the increase in dose-limiting toxicities (DLTs) at 8.61 mg/kg, the 3.69 mg/kg dose was considered the maximum tolerated dose and selected for further assessment in phase II. Conclusion We successfully completed a phase I trial with MET antibody in a MET-overexpressed patient population focusing on CRC, and found that the DLTs were alkaline phosphatase elevation or hypophosphatemia. The recommended dose of SAIT301 for phase II is the dose of 3.69 mg/kg.

// Jung Eun Kim 1, * , Youjin Kim 1, * , Gary Li 2, * , Seung Tae Kim 1 , Kyung Kim 1 , Se Hoon Park 1 , Joon Oh Park 1 , Young Suk Park 1 , Ho Yeong Lim 1 , Hyuk Lee 2 , Tae Sung Sohn 2 , Kyoung-Mee Kim 3 , Won Ki Kang 1 and 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, CA, USA 3 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Jeeyun Lee, email: jyunlee@skku.edu Keywords: MerTK; gastric cancer; patient-derived tumor cells Received: June 20, 2017 Accepted: October 05, 2017 Published: November 11, 2017 ABSTRACT RXDX-106 is a potent and selective type II pseudo-irreversible (slow off-rate) inhibitor of TYRO3, AXL, MER and c-MET. MER tyrosine kinase (MerTK) is expressed in a variety of malignancies, including gastric cancer (GC). The oncogenic potential of MerTK is supported by various lines of evidence. First, we surveyed 10 GC cell lines for MerTK protein overexpression and MerTk phosphorylation. We next evaluated the change of downstream signaling molecules including (p)-ERK and (p)-AKT, following RXDX-106 treatment. We also investigated the effect of RXDX-106 in patient-derived cell lines to mimic the in vivo condition. The prevalence of MerTK protein overexpression was evaluated in 229 cancer tissue specimens. We have found that MerTK inhibitor treatment resulted in considerable inhibition of cell growth and downstream signaling. In addition, MerTK phosphorylation, not total MerTK expression, is likely more predictive of therapeutic success. p-MerTK protein overexpression by IHC was found in 18% (17/87) of GC patients. Lastly, RXDX-106 inhibited cell proliferation in MerTK activated gastric cancer cell line. These findings provide further evidence of oncogenic roles for MerTK in GC, and demonstrate the importance of kinase activity for MerTK tumorigeneicity and validate RXDX-106, a novel MerTK inhibitor, as a potential therapeutic agent for treatment of GC.

Purpose The purpose of this study was to investigate the clinical outcomes and prognostic factors of concurrent chemoradiotherapy (CCRT) for locally recurrent biliary tract cancer (BTC) after curative surgical resection. Methods We performed a retrospective cohort study of patients with locally recurrent BTC treated with CCRT between October 2004 and December 2013. The study included and analyzed 42 patients with a history of curative-intent surgical resection of confirmed adenocarcinoma originating from the biliary tract. Results The median time to recurrence after surgery was 16.1 months (range, 4.5-77.8 months). Median follow-up after CCRT was 26.9 months (range, 5.2-81.9) with no grade 3 or higher gastrointestinal toxicities. Analysis of the first site of failure showed local progression (LP) developed in 20 patients (47.6%); among these, 16 (38.1%) had isolated LP. The median values were 15.8 months (range, 1.7-81.7) for LP-free survival (LPFS), 10.6 months (range, 1.7 - 81.7) for progression-free survival (PFS) and 41.2 months (range, 5.2-81.9) for overall survival (OS). Multivariate analysis showed that the level of pre-CCRT carbohydrate antigen (CA) 19-9 and the chemotherapy regimen were significant prognostic factors for LPFS and PFS; pT stage was the only significant prognostic factor for OS. Conclusions CCRT for locally recurrent BTC showed promising outcomes as a salvage modality, but LP was still frequent. The pre-CCRT CA 19-9 level and the chemotherapy regimen were prognostic factors for LPFS and PFS.

Purpose Retrospective studies have demonstrated that cell-free circulating tumor DNA (ctDNA) hotspot testing predicts matched therapy response to first- and second-line therapies in patients with advanced non–small-cell lung cancer (NSCLC). However, no prospective outcomes studies have evaluated ctDNA-guided matched therapy decision making on the basis of comprehensive plasma genomic testing including all four major classes of alterations. Here, we report the clinical utility of this approach in advanced solid tumor cancers. Patients and Methods We conducted a multiple parallel cohort, open-label, clinical trial using ctDNA-guided matched therapy when tissue was insufficient or unobtainable for next-generation sequencing. Plasma-based digital sequencing identified point mutations in 70 genes and indels, fusions, and copy number amplifications in selected genes. Patients with prespecified targetable alterations in metastatic NSCLC, gastric cancer (GC), and other cancers were matched to several independent targeted agent trials at a tertiary academic center. Results Somatic alterations were detected in 59 patients with GC (78%), and 25 patients (33%) had targetable alterations ( ERBB2, n = 11; MET, n = 5; FGFR2, n = 3; PIK3CA, n = 6). In NSCLC, 62 patients (85%) had somatic alterations, and 34 (47%) had targetable alterations ( EGFR, n = 29; ALK, n = 2; RET, n = 1; ERBB2, n = 2). After confirmation of ctDNA findings on tissue (to meet trial eligibility criteria), 10 patients with GC and 17 patients with NSCLC received molecularly matched therapy. Response rate and disease control rate were 67% and 100%, respectively, in GC and 87% and 100%, respectively, in NSCLC. Response was independent of targeted alteration variant allele fraction in NSCLC ( P = .63). Conclusion To our knowledge, this is the first prospective feasibility study of comprehensive ctDNA-guided treatment in advanced GC and lung cancers. Response rates in this interim analysis are similar to those in tissue-based targeted therapy studies.

This study investigated the prognostic impact of serum carcinoembryonic antigen (CEA) level in recurrent rectal cancer. We reviewed 745 patients who developed recurrence after curative treatment for rectal cancer between January 2000 and December 2012. Multivariate analyses for survival revealed that age > 60 years (p = 0.005), r-CEA ≥ 5 ng/ml (p < 0.001), disease free interval (DFI) < 12 months (p < 0.001), and palliative or conservative treatment (p < 0.001) were unfavorable factors.

Purpose To report patient-focused outcomes as measured by quality of life (QoL) and performance status (PS) in REACH, a phase III placebo-controlled randomised study, assessing ramucirumab in advanced hepatocellular carcinoma (HCC) patients who received prior sorafenib. Methods Eligible patients had advanced HCC, Child-Pugh A, PS 0 or 1 and prior sorafenib. Patients received ramucirumab (8 mg/kg) or placebo (1:1) on day 1 of a 2-week cycle. QoL was assessed by FACT Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL (EQ-5D) at baseline; cycles 4, 10, and 16; and end of treatment. PS was assessed at baseline, each cycle, and end of treatment. Deterioration in FHSI-8 was defined as a ≥3-point decrease from baseline and PS deterioration was defined as a change of ≥2. Both intention-to-treat and pre-specified subgroup of patients with baseline serum alpha-fetoprotein (AFP) ≥400 ng/mL were assessed. Results There were 565 patients randomised to ramucirumab and placebo. Compliance with FHSI and EQ-5D was high and similar between groups. In the ITT population, deterioration in FHSI-8, EQ-5D, and PS was similar between ramucirumab and placebo. In patients with baseline AFP ≥400 ng/mL, ramucirumab significantly reduced deterioration in FHSI-8 at the end of treatment compared with placebo (P = 0.0381), and there was a trend towards a delay in the deterioration of symptoms in FHSI-8 (HR 0.690; P = 0.054) and PS (HR 0.642; P = 0.057) in favour of ramucirumab. Conclusions We report one of the most comprehensive data sets of QoL and symptom burden in patients undergoing systemic therapy for advanced HCC. Ramucirumab was associated with no worsening of QoL. In patients with baseline AFP ≥400 ng/mL, the significant survival benefit observed in patients treated with ramucirumab was coupled with a trend in patient-focused outcome benefits. Clinical trial registration NCT01140347 .

SummaryBackground Tanibirumab is a fully human monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a first-in-human phase I study of tanibirumab in patients with solid tumors refractory to standard chemotherapy. Primary endpoints were evaluating safety, pharmacokinetics (PKs), estimating maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Methods We designed our study to escalate tanibirumab at 9 different dose levels with a 3 + 3 method and tanibirumab (1–28 mg/kg) was administered intravenously on D1, 8, 15 in 28-day courses. Dose limiting toxicities (DLTs) were only assessed during the first cycle of treatment and response evaluation was performed every 2 cycles. The effects of tanibirumab on several angiogenic factors were analyzed. Results From October 2011 to September 2013, a total of 26 patients with refractory solid tumors were enrolled. The median age was 58 years (range, 27–75) and 20 patients were male. The most common tumor type was colorectal cancer (N = 19) and seven patients had a history of previous bevacizumab treatment. As hemangioma continued to occur, the final dose level, 28 mg/kg, was not performed. DLTs were not found, and the MTD was confirmed to be 24 mg/kg. Hemangioma was observed in 16 patients (61.5%), but all were grade 1–2 and disappeared after discontinuation of the study drug. Among the 18 patients in the efficacy set, no objective response was observed, but 11 patients showed stable disease. PKs were characterized by dose-dependent linear exposure and the mean trough concentrations exceeded biologically relevant target levels at 12 mg/kg and above. Serum VEGF, soluble VEGFR-2, and PlGF increased at the 4 mg/kg dose level and above. Conclusions Treatment with tanibirumab showed a tolerable toxicity profile and modest clinical efficacy in patients with refractory solid tumors. A phase II trial of tanibirumab is ongoing now.

Background The benefit of adjuvant chemotherapy for patients with locally advanced rectal cancer who have received neoadjuvant concurrent chemoradiation therapy (CCRT) and undergone curative resection remains unclear. Methods This study was a retrospective review of prospectively collected data. Patients with locally advanced rectal cancer who underwent curative surgery after neoadjuvant CCRT between January 2006 and March 2011 were identified. Four hundred forty-one patients who completed adjuvant chemotherapy (chemo group) were compared with 35 patients who did not receive any adjuvant treatment (nonchemo group). Results The 5-year disease-free survival (DFS) was significantly higher in the chemo group (78.5% vs. 63.1%, P = 0.016). After stratification of the patients according to nodal status, these differences were no longer significant, but there were trends toward inferior DFS in the nonchemo group in all survival curves. In multivariate Cox regression analysis, no adjuvant chemotherapy (HR, 2.306; 95% CI, 1.101–4.829; P = 0.027) emerged as an independent prognostic factor associated with decreased DFS. Conclusions Adjuvant chemotherapy was significantly associated with increased DFS among patients who had undergone neoadjuvant CCRT and radical resection for locally advanced rectal cancer. Adjuvant chemotherapy should be considered in every patient after neoadjuvant CCRT irrespective of the final pathology stage. J. Surg. Oncol. 2015 111:439–444. © 2014 Wiley Periodicals, Inc.

Purpose We aimed to the addition of synthetic 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin to capecitabine–cisplatin (XP) in patients with previously untreated advanced gastric cancer (AGC). Methods In this double-blind, placebo-controlled, phase III study, we enrolled patients aged 18 years or older with histological or cytological confirmed metastatic adenocarcinoma of the stomach or gastroesophageal junction (GEJ) at nine centres in Korea. Patients, stratified by disease measurability and participating site, were randomly assigned (1:1) to receive capecitabine 1000 mg/m2 twice daily for 14 days and cisplatin 80 mg/m2 on day 1 every 3 weeks plus either simvastatin 40 mg or placebo, once daily. Cisplatin was given for 8 cycles; capecitabine and simvastatin were administered until disease progression or unacceptable toxicities. This study is registered with ClinicalTrials.gov, number NCT01099085 . Results Between February 2009 and November 2012, 244 patients were enrolled and assigned to treatment groups (120 simvastatin, 124 placebo). Median progression free survival (PFS) for 120 patients allocated XP plus simvastatin was 5.2 months (95% confidence interval (CI) 4.3–6.1) compared with 4.63 months (95% CI 3.5–5.7) for 124 patients who were allocated to XP plus placebo (hazard ratio 0.930, 95% CI 0.684–1.264; p = 0.642). 63 (52.5%) of 120 patients in simvastatin group and 70 (56.4%) of 124 had grade 3 or higher adverse events. Conclusions Addition of 40 mg simvastatin to XP does not increase PFS in our trial, although it does not increase toxicity. Low dose of simvastatin (40 mg) to chemotherapy is not recommended in untargeted population with AGC.

Pazopanib is an orally bioavailable, ATP-competitive, multitargeted tyrosine kinase inhibitor mainly targeting VEGFR2 and PDGFR tyrosine kinases, but the biologic sequences of pazopanib activities beyond antiangiogenesis are poorly defined. We used a panel of 38 gastric cancer cell lines to test the efficacy of pazopanib. In a growth inhibition assay, genomic changes indicated that pazopanib had differential effects on cell growth. Treatment of the KATO-III, OCUM-2M, SNU-16, and HSC-39 gastric cancer cell lines harboring FGFR2 amplification with pazopanib resulted in marked decreases of cell survival with IC50 in ranges of 0.1 to 2.0 μmol/L, whereas the same treatment of those cell lines without FGFR2 amplification had no growth-inhibitory effects. In the ectopic FGFR2-expressing model, treatment with the indicated concentrations of pazopanib significantly inhibited cell growth and colony formation by FGFR2-expressing NIH 3T3 cells with wild-type (WT) FGFR2 and mutant FGFR2 (S252W). Pazopanib also selectively suppressed constitutive FGFR2 signaling and phosphorylation of downstream effectors. In cell-cycle analysis, FGFR2-amplified cells underwent cell-cycle arrest at the G1–S phase after pazopanib treatment, whereas there were no significant effects on cell-cycle progression in cells without FGFR2 amplification treated with pazopanib. In addition, pazopanib increased a substantial fraction of sub-G1 only in FGFR2-amplified cells. These findings show that the activation of FGFR2 signaling by amplification may be a critical mediator of cell proliferation in a small subset of gastric cancer patients and that pazopanib may provide genotype-correlated clinical benefits beyond the setting of highly vascular tumors. Mol Cancer Ther; 13(11); 2527–36. ©2014 AACR.

This study investigated the outcomes of salvage radiation therapy (RT) for isolated local recurrence of extrahepatic cholangiocarcinoma (EHCC) after radical surgery. Between May 2003 and July 2011, 25 patients with isolated recurrence of EHCC received RT with the aim of salvage. The most common primary cancer was common bile duct cancer (n = 15) followed by hilar cholangiocarcinoma (n = 7) and pancreaticobiliary type of ampulla of Vater cancer (n = 3). The median disease-free interval from initial operation to recurrence was 12 months. The criteria for diagnosis of recurrence were based on radiographic findings with either computed tomography or positron emission tomography. The radiation dose ranged from 40 to 54 Gy (median 54 Gy), and concurrent chemotherapy was administered to 19 patients. The median follow-up period was 16 months. Local progression occurred in nine patients (36 %). The 2-year local failure-free survival rate was 44 % during a median follow-up period of 14 months. The 2-year overall survival rate was 55 % during a median follow-up period of 24 months. A normal level of CA 19-9 at recurrence and concurrent chemotherapy were favorable prognostic factors for both local control and overall survival. Distant metastasis developed in 11 patients, and the liver was the most common site (n = 7) of distant metastasis. No severe radiation-induced gastrointestinal toxicities developed. Salvage RT with or without concurrent chemotherapy resulted in a median survival of 24 months for patients with isolated local recurrence of EHCC. The treatment was feasible and safe with minimal toxicities.

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

Although gastric cancer is quite common in Korea, the treatment outcome is relatively favorable compared to those in western countries. However, there are currently no Korean multidisciplinary guidelines for gastric cancer. Experts from related societies developed guidelines de novo to meet Korean circumstances and requirements, including 23 recommendation statements for diagnosis (n=9) and treatment (n=14) based on relevant key questions. The quality of the evidence was rated according to the GRADE evidence evaluation framework: the evidence levels were based on a systematic review of the literature, and the recommendation grades were classified as either strong or weak. The applicability of the guidelines was considered to meet patients' view and preferences in the context of Korea. The topics of the guidelines cover diagnostic modalities (endoscopy, endoscopic ultrasound, and radiologic diagnosis), treatment modalities (surgery, therapeutic endoscopy, chemotherapy, and radiotherapy), and pathologic evaluation. An external review of the guidelines was conducted during the finalization phase.

Vitamin C (L-Ascorbic acid, VC), an anti-oxidant has been studied as the possible potent chemotherapeutic drug in various cancers including colorectal cancer, breast cancer, ovarian cancer, prostate cancer and lung cancer. In particular, it is recently reported that VC kills efficiently colorectal cancer cells with KRAS or BRAF mutations. Give fact that pancreatic cancer has high frequency of KRAS mutation rate and is one of the most aggressive and lethal cancers with lack of effective therapy targeting the KRAS mutations, we would like to investigate whether VC effectively kills pancreatic cancer cells with various types of KRAS mutation. We first tested cytotoxicity and cell growth inhibition effect of VC on pancreatic cancer cell lines. In growth inhibition and colony formation assay, VC showed differential effect on cell growth and colony formation according to the KRAS genotypes. Treatment of the pancreatic cancer cell lines harboring KRAS G12D mutation with VC resulted in marked decrease of cell survival and colony formation, while same treatment of the cell lines with other KRAS mutations or wild type had no growth inhibitory effect. Interestingly, although there was no dramatic difference in well-known VC transporters, Glut1 expression according to the KRAS genotypes, sodium-dependent vitamin c transporter 2 (SVCT2) expression was relatively lower in KRAS G12D-mutant pancreatic cancer cells than other cells. To study possible mechanisms of VC-induced growth inhibition and cell death, we also tested whether glycolysis was inhibited or not though extracellular acidification rate (ECAR) measurement. After 1mM VC injection, ECAR decreased dramatically in KRAS G12D-mutant pancreatic cancer cells compared to the other genotypes. In cell cycle phospho-antibody array analysis, the results indicated that VC significantly increased the expression of DNA damage-associated proteins. Finally, we also found that cell death measured by apoptosis increased in KRAS G12D-mutant pancreatic cancer cells with VC through annexin V-PI staining FACS analysis. In conclusion, we showed VC selectively induces the apoptosis and cell growth inhibition in KRAS G12D-mutant pancreatic cancer cells than other KRAS mutations by inhibition of glycolysis and induction of DNA damage-associated proteins. Our findings suggest that VC is needed to further investigate as the potential novel agent with cytotoxic chemotherapies for the treatment of pancreatic cancer. Citation Format: Hye-Lim Jang, Jung Yong Hong, Seung Tae Kim, Jeeyun Lee, Se Hoon Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Joon Oh Park. Vitamin C preferentially induces growth inhibition and cell death in KRAS G12D-mutant pancreatic cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C058. doi:10.1158/1535-7163.TARG-19-C058

Background: ctDNA has the potential to identify patients (pts) with early stage cancer; however, current assays are challenged by limited sensitivity (~50%), reliance on a single analyte (e.g. somatic mutation detection), and/or the need for tumor tissue or genomic DNA sequencing to interpret ctDNA results. Recent studies have demonstrated that ctDNA can be detected using other biomarkers including DNA methylation. We developed a technology in which both somatic mutations and epigenomic alterations can be analyzed in a single assay. Methods: Using a large database of cell-free DNA (cfDNA) profiles generated from advanced cancer patients, we designed a targeted sequencing assay that detects somatic variants, methylation alterations, and other epigenomic variations at transcription factor binding sites associated with CRC. Total cfDNA was extracted, partitioned based on methylation level, and analyzed. Data were then filtered using a variant classifier to differentiate tumor- from non-tumor-derived alterations without a priori knowledge of tissue or germline sequencing results. A machine learning model was trained on 111 cfDNA samples from 38 late stage and 10 early stage CRC pts and 63 age-matched cancer-free controls. For the independent test set, plasma samples (4-5mL) were collected from 72 pts with stage I-IV CRC prior to and 4 weeks after (N = 50, total of 122 samples) surgical resection. 35 age-matched cancer-free controls were similarly analyzed in the test set. Results: Of the 72 pts, 62.5% were male, and median age at CRC diagnosis was 61.5 years (range 36-85). Stage distribution was 52.8% stage I/II, 40.3% stage III, and 6.9% stage IV. In the 50 pts with post-surgical samples, clinical follow-up was available for 49 (median post-surgery follow-up: 314 days; range 15-472). Utilizing this assay, pre-surgery ctDNA detection rate was 94% (68/72); 97% in stage I/II, 90% in stage III, and 100% in stage IV. Epigenomic analysis significantly enhanced ctDNA detection relative to somatic mutational analysis alone (94% vs. 56%; p Discussion: Utilizing a plasma-only sequencing assay incorporating somatic genomic variant detection, epigenomic analysis, and a bioinformatic classifier to filter non-tumor derived variants, ctDNA detection rate in early stage CRC (I-III) is 94% (63/67; 95% confidence interval 86%;98%) with 94% specificity, far outperforming the detection rate of somatic sequence variant detection alone. Clinical follow-up is ongoing to evaluate post-surgery ctDNA detection rate and disease recurrence. These results have significant implications for the clinical utility of ctDNA in early stage cancer management. Citation Format: Seung-Tae Kim, Victoria M. Raymond, Joon Oh Park, Elena Zotenko, Young Suk Park, Matthew Schultz, Won Ki Kang, Oscar Westesson, Hee-Cheol Kim, Yupeng He, Justin I. Odegaard, Stefanie A. Mortimer, William J. Greenleaf, Ariel Jaimovich, Jeeyun Lee, AmirAli Talasaz. Combined genomic and epigenomic assessment of cell-free circulating tumor DNA (ctDNA) improves assay sensitivity in early-stage colorectal cancer (CRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 916.

We performed prospective immunohistochemical analysis of LAG3 for 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016. Most patients (428/430, 99.5%) were evaluable for LAG3 expression by immunohistochemistry. In total, 18.5% (79/428) of the evaluated cancers expressed LAG3, including pancreatic (33.3%, 2 of 6), gastric (24.7%, 21 of 85), colorectal (23.6%, 48 of 203), melanoma (12.5%, 1 of 8), genitourinary (9.5%, 4 of 46), biliary tract (6.3%, 1 of 16), and sarcoma (5.4%, 2 of 37), but not miscellaneous (0.0%, 0 of 14) or hepatocellular (0.0%, 0 of 15) cancer. Among 149 metastatic CRC patients, there was no statistically significant difference in gender, age, primary tumor site, pathologic differentiation, KRAS and NRAS status, BRAF status, and microsatellite instability according to LAG3 status (expressed vs. non-expressed). Among 53 metastatic GC patients, LAG3 was only significantly associated with EBV status (P = .042). Our results add to the emerging literature on LAG3 expression in various cancer types and support the need for extended clinical exploration of this target for immunotherapy. Citation Format: Su Jin Lee, Sun-ju Byeon, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim, Kyoung-Mee Kim, Seung Tae Kim. LAG3 in Solid Tumors as a Potential Novel Immunotherapy Target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1107.

4124 Background: Pancreatic cancer (PC) is characterized by a highly immunosuppressive microenvironment, and immune checkpoint inhibitors as monotherapy have been ineffective to date. TGFβ is commonly viewed as a powerful immunosuppressive cytokine, and inhibition of its signaling reverses this suppression and activates adaptive immune responses. A combination of TGFβ and PD-L1 inhibition may act synergistically to induce immune restoration and to improve antitumor responses. This Phase 1b study (NCT02734160) evaluated the combination of galunisertib plus durvalumab in recurrent or refractory metastatic PC. Methods: Eligible patients (pts) were ≥18 years old, had ECOG status ≤1, and had not received treatment with anti-PD-1, anti-PD-L1, or TGFβ R1 kinase inhibitors. The primary objective was to assess the safety and the recommended dose of galunisertib given 14 days on/14 days off in combination with durvalumab 1500 mg every 4 weeks. Four dose levels of galunisertib were tested in the dose escalation portion of the study: 50 mg QD, 50 mg BID, 80 mg BID and 150 mg BID, followed by the cohort expansion portion of the study at the recommended Phase 2 dose (RP2D). Secondary objectives included preliminary assessment of activity by response rate, (RECIST v1.1), median PFS (mPFS), and OS (mOS). Results: 42 pts (25F/17M) were treated in the study (median age 56.5 y; 71.4% had received ≥2 prior systemic regimens). There was no dose limiting toxicity and galunisertib 150 mg BID was chosen as the RP2D. In the 32 pts treated at this dose, Grade ≥3 related AEs included AST and GGT elevations (2 pts each), and ALT and alkaline phosphatase elevations, and neutropenia (1 pt each). One partial response and 7/32 stable diseases were observed (disease control rate 25%); mPFS was 1.9 months (95% CI: 1.5, 2.2) and mOS was NR (95% CI: 3.6, NR). Biomarker data will be presented at the meeting. Conclusions: The combination of galunisertib plus durvalumab had an acceptable tolerability and safety profile. The activity of this combination in second and third line PC patients warrants further consideration. Clinical trial information: NCT02734160.

3104 Background: It has been demonstrated in vivo that HGF-MET signaling axis is a key molecular determinant in tumor invasion and there is a significant association in HGF expression and mesenchymal phenotype in addition to immune cell recruitment. We have developed a HGF neutralizing humanized monoclonal antibody antibody, YYB-101. The aim of this study was to determine the maximum tolerate dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of YYB101, in patients with refractory solid tumors. Methods: YYB101 was administered intravenously at once every 2 weeks doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Enrolled patients were planned to receive YYB101 until disease progression or intolerable toxicity. The escalation and expansion cohorts (20mg/kg) were completed. Pre-planned biomarker analysis was performed in parallel. Results: 39 heavily pre-treated refractory cancer patients were enrolled and received YYB101. No DLT was observed. YYB101 demonstrated dose proportional PK up to the dose of 30 mg/kg. No patients discontinued treatment because of adverse events. Based on PK analysis and toxicity data, the recommended dose was determined as 20 mg/kg. Of 39 evaluation patients, there was 1 confirmed partial response for > +14months (2.5%, N = 1; 1 (of 2) sebaceous carcinoma) and 17 stable disease as best response (43.5%, N = 17; 7 (of 13) CRC, 3 (of 4) melanoma, 1 (of 2) sebaceous carcinoma, 1 (of 3) gastric, 1 (of 1) basal cell carcinoma, 2 (of 10) ovarian cancer, 1 (of 1) HCC, 1 (of 1) lung cancer). Of note, 1 sebaceous carcinoma patient who have failed to ≥2+ lines of chemotherapy, have been responding to YYB for 14 months. The MET and HGF expressions by immunohistochemistry (IHC) were evaluated in 19 and 17 tumor specimens, respectively. Neither protein expressions were significant predictors for treatment response to anti-HGF antibody. However, we have observed significant reduction in HGF in responders to YYB. Two long-term responders had mesenchymal signature in RNA sequencing. Conclusions: YYB101 has a favorable safety profile in patients with refractory solid tumors and a dose-proportional PK. Efficacy data are encouraging and phase II combination therapy with YYB101 is planned to be open in metastatic CRC patients as salvage treatment. The predictive power of mesenchymal signature in YYB responders will be defined prospectively. Clinical trial information: 02499224.

4064 Background: The absence of tumor cells enables an enriched stromal environment to generate RNA signatures and through assembling genes involved in tumor stroma, four distinct stromal signatures that reflected biological processes such as signature vascular mature (VM), vascular mature/inflammatory (VMI), vascular immature/noninflammatory (VINI) and inflammatory alone (I) depending on mature of vasculature. We hypothesized that these stromal specific signatures may provide additional information to the pre-existing TCGA/ACRG subtypes when predicting response to anti-angiogenesis agent such as ramucirumab. Methods: We conducted a single-center phase II trial in which we treated 61 unselected patients with metastatic GC with ramucirumab plus paclitaxel as second line therapy and performed pre-planned integrated genomic profiling. Results: Sixty-two patients were enrolled in this study between May 2014 and June 2017. The cut-off date for treatment outcome analysis was January 2, 2019, at which time response evaluations were available for 57 patients with a median follow-up of 30.2months. In an intent-to-treat analysis cohort, there was no CR and 22 patients achieved confirmed PRs resulting in an ORR of 35.5% (95% CI: 23.6 – 47.4). The response rate to ramucirumab was considerably enriched in VM/VMI group (29.2%) (P = 0.0003) when compared to I ( < 10%) or VINI group ( < 10%). The strongest response defined by maximal response to ramucirumab was shown in GC patients with VM/VMI signatures. Of note, VM/VMI patients had prolonged duration of response to ramucirumab/paclitaxel demonstrating that these patients not only respond to ramucirumab but also had durable response. Conclusions: This is the first study to demonstrate a clinically robust correlation between stromal-based signature and response to anti-angiogenesis inhibitor in GC. Clinical trial information: 02628951.

4117 Background: Patients (pts) with advanced CCA who progressed on or after first line chemotherapy have no approved treatment options. Fibroblast growth factor receptor (FGFR) gene alterations are observed in many tumor types including 14-17% in CCA. Erdafitinib, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown clinical activity against solid tumors with FGFR alterations. Methods: LUC2001 is an open-label, multicenter, Ph2a study in advanced CCA pts with FGFR alterations (FoundationOne), who progressed after ≥ 1 prior treatment. The primary endpoint is objective response rate (ORR; RECIST 1.1). The secondary endpoints are disease control rate (DCR), progression free survival (PFS), duration of response (DOR), safety and pharmacokinetics (PK). Disease is evaluated every 8 weeks until disease progression (PD). Results: As of 3 Dec 2018, 222 CCA pts were molecularly screened; 34 had FGFR alterations, of whom 14 (8 FGFR2 fusion, 3 FGFR2 mutation, 1 FGFR3 fusion, 2 FGFR3 mutation) were dosed 8 mg once daily with up titration option. Median age was 51.5 years. 13/14 and 12/14 pts had prior platinum or gemcitabine based therapy respectively, 7/14 pts got re-treated with platinum or gemcitabine based therapy, and 9/14 pts had ≥2 prior lines of therapy. Median number of treatment cycles was 5.0 (range: 1; 22) and treatment duration was 4.83 (range: 0.5; 20.3) months. In 12 evaluable pts, there were 6 confirmed partial response (PR), 4 stable disease (SD) and 2 PD; ORR (CR+PR) was 6/12 (50.0%), DCR (CR+PR+uCR+uPR+SD) was 10/12 (83.3%); median DOR was 6.83 months (95% CI: 3.65; 12.16); median PFS was 5.59 months (95% CI: 1.87, 13.67). In 10 evaluable FGFR2+ pts, ORR was 6/10 (60.0%); DCR was 10/10(100%); median PFS was 12.35 months (95% CI: 3.15, 19.38). The most common TEAEs ( > 30%) were hyperphosphatemia, dry mouth, stomatitis, and dry skin. 9 pts had ≥ Grade 3 AEs (8 Grade 3,1 Grade 5), of which 7 drug related. TEAE led to treatment 1 discontinuation, 6 dose reductions and 1 death (not drug related). The results of PK and PK/PD relationship were consistent with other erdafitinib studies in different ethnic background pts. Conclusions: Asian advanced CCA pts with FGFR alterations treated with erdafitinib had encouraging efficacy and acceptable safety profile similar to experience in other tumor types and populations. Clinical trial information: NCT02699606.

3023 Background: Antiangiogenic therapy has been a successful clinical strategy for the treatment of various cancer types. To date, all approved antiangiogenic drugs primarily inhibit the VEGF/VEGFR pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis. A dual blockade of both VEGF and DLL4 could be a promising strategy to overcome anti-VEGF therapy resistance. ABL001 (NOV1501) has been developed as a bispecific antibody to bind and inhibit both DLL4 and VEGF thereby significantly suppressing tumor angiogenesis. Methods: In a classical 3+3 dose-escalation design, ABL001 was administered IV at doses ranging from 0.3, 1, 2.5, 5, and 7.5 mg/kg biweekly (NCT03292783: the next doses of ABL001 are 10 and 12.5 mg/kg). After the first administration of ABL001 in each cohort, DLT (dose limiting toxicity) was observed for 3 weeks. Tumor assessments were performed every 6 weeks and cardiac assessments were performed every cycle. Results: From 2017 November to February 2019, 18 patients were enrolled on this trial. All patients were heavily pre-treated with at least 3 prior lines of chemotherapy. All patients in cohort 4 and 5 were either metastatic colorectal cancer or gastric cancer. Of the 5 cohorts, there was no DLT observed during dose escalation. In addition, there was no maximum tolerated dose identified up to 7.5 mg/kg dose. The most common treatment-related adverse events (AEs) (including all dose levels and all grades) occurred were hypertension, anorexia, general weakness, headache and anemia. Preliminary results of pharmacokinetic (PK) analysis demonstrated slightly shorter mean half-life than conventional monoclonal tantibodies due to the bispecific nature of the ABL-001. In addition, preliminary pharmacodynamic (PD) biomarker analysis using PBMC and plasma samples showed engagement of both VEGF/VEGFR and DLL4/Notch1 pathway modulation after ABL001 administration. One gastric cancer patient at 7.5 mg/kg achieved unconfirmed partial response at the time of this writing. Conclusions: ABL001 therapy has been well tolerated up to 7.5 mg/kg with no significant treatment related adverse events and showed preliminary anti-tumor activity in heavily pre-treated cancer patients. After completion of this ongoing phase 1a study, phase 1b/2a study is planned in combination of ABL001 with chemotherapy or anti-PD-1 antibody. Clinical trial information: 03292783.

344 Background: Nal-IRI plus 5-FU/LV has demonstrated efficacy in mPDAC pts who previously received gemcitabine-based therapy in the pivotal NAPOLI-1 trial. Real-world data are helpful to measure the clinical outcomes and safety profile of this regimen in daily practice setting. Methods: Between January 2017 and April 2018, a Named Patient Program (NPP) was activated to provide controlled, pre-approval access of nal-IRI in Korea. This analysis is multicenter retrospective study for patients who received nal-IRI plus 5-FU/LV under the NPP. Results: A total of 86 patients entered into this NPP among 10 Korean institutions. Median age was 61 years (range, 37-79) and 52 pts (60%) were male. Liver (n=49, 57%), peritoneum (30, 35%), and lung (27, n=31%) were the most common metastatic sites. All patients had ECOG performance status 0-1 and previously received gemcitabine-based therapy. Prior to nal-IRI plus 5-FU/LV, 35 (41%) and 51 (59%) patients received

213 Background: Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a heterogeneous disease in terms of embryonic origin, aggressiveness, prognosis, and genomic profiling. Data regarding the efficacy of etoposide and cisplatin (EP) as a standard treatment of the primary tumor site in GEP-NEC are limited. Methods: We analyzed 64 patients with histopathologically confirmed metastatic GEP-NEC who received EP at Samsung Medical Center, Seoul, Korea, between January 2010 and January 2018. Based on primary tumor site, outcome of treatment with EP was evaluated. Results: Primary sites included 22 foregut-derived GEP-NECs (stomach, n = 6; duodenum, n = 4; pancreas, n = 12), 4 midgut-derived GEP-NECs, 5 hindgut-derived GEP-NECs of the rectum, 25 GEP-NECs originating from the hepatobiliary (HB) tract, and 12 GEP-NECs involving only intra-abdominal lymph nodes. No patient had a complete response (CR) and 17 had a partial response (PR), resulting in a 27.9% response rate (RR). When evaluating the efficacy of EP based on primary tumor site, the RR was most favorable in GEP-NECs involving only intra-abdominal lymph nodes, followed by GEP-NECs originating from foregut, midgut, HB, and hindgut. However, no statistically significant difference was observed for RR based on primary tumor site (p = 0.821). Similarly, no significant differences were found for progression-free survival (PFS) among patients with GEP-NECs arising from various primary tumor sites. Conclusions: Results from this study showed thatRR and PFS associated with EP treatment were not different based on the primary tumor site in patients with advanced or metastatic GEP-NEC.

Molecular profiling of actionable mutations in refractory cancer patients has the potential to enable "precision medicine," wherein individualized therapies are guided based on genomic profiling. The molecular-screening program was intended to route participants to different candidate drugs in trials based on clinical-sequencing reports. In this screening program, we used a custom target-enrichment panel consisting of cancer-related genes to interrogate single-nucleotide variants, insertions and deletions, copy number variants, and a subset of gene fusions. From August 2014 through April 2015, 654 patients consented to participate in the program at Samsung Medical Center. Of these patients, 588 passed the quality control process for the 381-gene cancer-panel test, and 418 patients were included in the final analysis as being eligible for any anticancer treatment (127 gastric cancer, 122 colorectal cancer, 62 pancreatic/biliary tract cancer, 67 sarcoma/other cancer, and 40 genitourinary cancer patients). Of the 418 patients, 55 (12%) harbored a biomarker that guided them to a biomarker-selected clinical trial, and 184 (44%) patients harbored at least one genomic alteration that was potentially targetable. This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase. Implications for practice This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase.

Importance REACH is the first phase 3 trial to provide information on hepatocellular cancer (HCC) in the second-line (postsorafenib) setting categorized by Child-Pugh score, a scoring system used to measure the severity of chronic liver disease. This exploratory analysis demonstrates the relationship between a potential ramucirumab survival benefit, severity of liver disease, and baseline α-fetoprotein (αFP). Objective To assess treatment effects and tolerability of ramucirumab by Child-Pugh score in patients with HCC enrolled in the REACH trial. Design, Settings, and Participants Randomized, double-blind, phase 3 trial of ramucirumab and best supportive care vs placebo and best supportive care as second-line treatment in patients with HCC enrolled between November 4, 2010 and April 18, 2013, from 154 global sites. Overall, 643 patients were randomized and included in this analysis; 565 patients considered Child-Pugh class A (Child-Pugh scores 5 and 6) and 78 patients considered class B (Child-Pugh scores 7 and 8). Interventions Ramucirumab (8 mg/kg) or placebo intravenously plus best supportive care every 2 weeks. Main Outcomes and Measures Overall survival (OS), defined as time from randomization to death from any cause. Results In the randomized population of 643 patients (mean [SD] age, 62.8 [11.1] years) in this analysis, a potential ramucirumab OS benefit was observed for patients with a Child-Pugh score of 5 (hazard ratio [HR], 0.80; 95% CI, 0.63-1.02; P = .06) but no apparent benefit for patients with Child-Pugh scores of 6 or 7 and 8. In patients with baseline αFP levels of 400 ng/mL (to convert ng/mL to μg/L, multiply by 1.0) or more, a ramucirumab OS benefit was significant for a score of Child-Pugh 5 (HR, 0.61; 95% CI, 0.43-0.87; P = .01) and Child-Pugh 6 (HR, 0.64; 95% CI, 0.42-0.98; P = .04), but was not significant for Child-Pugh 7 and 8. The overall safety profile of ramucirumab, regardless of Child-Pugh score, was considered manageable. Regardless of treatment arm, patients with Child-Pugh scores of 7 and 8 experienced a higher incidence of grade 3 or higher treatment–emergent adverse events, including ascites and asthenia, and special-interest events, including liver injury and/or failure and bleeding, compared with patients with Child-Pugh scores of 5 or 6. Conclusions and Relevance In unselected patients, a trend for ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. In patients with baseline αFP levels of 400 ng/mL or more, a ramucirumab survival benefit was observed for Child-Pugh scores of 5 and 6. Ramucirumab had a manageable toxic effect profile. These results support the ongoing REACH-2 study of ramucirumab in patients with advanced HCC with underlying Child-Pugh A cirrhosis and baseline αFP levels of 400 ng/mL or more. Trial Registration clinicaltrials.gov Identifier:NCT01140347

Background: c-MET is a proto-oncogene that encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). Activation of HGF-c-MET signaling involves cell invasiveness and evokes metastasis through direct involvement of tumor angiogenesis. However, the value of c-MET overexpression is still unknown in metastatic biliary tract cancer (BTC). Methods: We analyzed the incidence and clinicopathologic characteristics of c-MET overexpression in advanced BTC. Moreover, we investigated the value of c-MET overexpression in predicting response to gemicitabine plus cisplatin (GC), a first line standard regimen, and as a prognostic marker in metastatic BTC. Results: The BTC subtype distribution (N=44) was as follows: intrahepatic cholangiocarcinoma (IHCC, n=7), extrahepatic cholangiocarcinoma (EHCC, n=25) and gallbladder cancer (GBC, n=12). Liver (52.3%) was the predominant metastatic site, followed by lymph nodes (36.4%) and bone (15.9%). Among the 44 patients analyzed for c-MET expression, 15 (34.1%) exhibited c-MET overexpression in tumor tissues. There was no significant difference in the prevalence of c-MET overexpression among primary sites in EHCC (7/25, 28.0%), IHCC (3/7, 42.9%), and GBC (5/12, 41.7%). There was also no significant correlation between specific clinicopathologic variables and c-MET expression. Comparing the tumor-response to GC according to c-MET expression (overexpression vs. non-overexpression), there was no significant difference in either RR or DCR (p=0.394 and p >0.999, respectively). The median PFS for all 44 patients was 9.00 months (95% CI, 7.5-10.5 months) and there was no significant difference for PFS between patients with c-MET overexpression and those without (p=0.917). The median OS was 14.4 months (95% CI, 11.9-16.9 months). There was no significant difference in OS between patients with c-MET overexpression compared to those without (13.7 vs. 14.4 months, respectively; p=0.708). Conclusions: c-MET overexpression was detected in 34.1% of advanced BTC patients irrespective of tumor location. c-MET overexpression did not predict response to GC or survival. Further studies are needed to fully elucidate the value of c-MET overexpression as a novel biomarker in these patients.

Objectives More than half of cases of gastric cancer (GC) are diagnosed in elderly patients (≥70years). While doublet combination with fluoropyrimidines and platinum is currently considered standard first-line chemotherapy in advanced GC, the main goal of chemotherapy remains palliation. Materials and Methods In a multi-center phase III trial, patients with chemotherapy-naive, metastatic GC, aged 70years or older were randomized 1:1 to receive X monotherapy (capecitabine 1000mg/m 2 bid po on days one to fourteen) or XELOX (X plus oxaliplatin 110mg/m 2 iv on D1). Treatment was repeated every 21days until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint was overall survival (OS). Results In total, 50 patients with a median age of 77 (range, 70 to 84) were enrolled (X, n=26; XELOX, n=24). No treatment-related serious adverse events or unexpected toxicities were observed. The most frequently observed toxicities were nausea and hand-foot syndrome, with fatigue and peripheral neuropathy more common in XELOX than in X patients. Median OS was 11.1months for XELOX arm and 6.3months for X arm (HR 0.58, 95% CI 0.30–1.12, P=0.108). Although the difference was not significant, on the basis of evidence of superiority of XELOX seen in the first interim analysis, an independent data monitoring committee recommended early stopping of the trial. PFS was significantly longer (HR 0.32, 95% CI 0.17–0.61, P Conclusion Platinum-based combination chemotherapy was associated with survival benefit, as compared with X monotherapy in elderly patients with GC.

In patients with refractory cancer, the effect of additional chemotherapy is very limited. Targeted agents for molecular pathways associated with cancer cell progression and survival have emerged as attractive options in several cancer types. The current pilot study assessed the efficacy and safety of sirolimus in patients with refractory cancer with PIK3CA mutation/amplification. Refractory cancer patients with PIK3CA mutation/amplification were enrolled, irrespective of tumor-types. Enrolled patients received a daily dose of 1 mg sirolimus and one cycle defined as 28 days. An assessment of the efficacy and safety of sirolimus was performed. Overall, 4 patients were enrolled between October 2014 and April 2015. The median of 2.5 cycles of sirolimus was administered. Three patients had advanced gastric cancer and one had advanced cholangiocarcinoma. The overall response rate was 0%, three patients (75%) had stable disease following one cycle and one patient (25%) received sirolimus for 4 cycles without disease progression. The median progression free survival was 1.9 months [95% confidence interval (CI), 0.3-3.5 months], and the median overall survival was 3.6 months (95% CI, 0.4-6.8 months). Grade 3 or greater hematologic/non-hematologic toxicity was not observed. Grade 1 nausea was reported in one patient each. There were no treatment-associated mortalities. Sirolimus had modest efficacy and a tolerable toxicity-profile in patients with refractory cancer with PIK3CA mutation/amplification.

// Jae-Han Kim 1 , Sung Hyeon Lee 2 , Sookyung Choi 2 , Unyong Kim 3 , In Seok Yeo 4 , Su Hee Kim 2 , Myung Jin Oh 3 , Hantae Moon 3 , Jua Lee 3 , Seunghyup Jeong 3 , Min Gew Choi 5 , Jun Ho Lee 5 , Tae Sung Sohn 5 , Jae Moon Bae 5 , Sung Kim 5 , Yang Won Min 5 , Hyuk Lee 5 , Jun Haeng Lee 5 , Poong-Lyul Rhee 5 , Jae J. Kim 5 , Su Jin Lee 5 , Seung Tae Kim 5 , Jeeyun Lee 5 , Se Hoon Park 5 , Joon Oh Park 5 , Young Suk Park 5 , Ho Yeong Lim 5 , Won Ki Kang 5 , Hyun Joo An 3 , Jung Hoe Kim 4 1 Department of Food and Nutrition, Chungnam National University, Yuseong-Gu, Deajeon, Korea 2 GLYCAN Co., Ltd., Healthcare Innovation Park, Bundang-Gu, Seongnam, Korea 3 Graduate School of Analytical Science and Technology, Chungnam National University, Yuseong-Gu, Deajeon, Korea 4 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Yuseong-Gu, Daejeon, Korea 5 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Correspondence to: Se Hoon Park, email: hematoma@skku.edu Keywords: stomach neoplasm, haptoglobin, N-glycan, glycoprotein, biomarker Received: October 05, 2016 Accepted: December 21, 2016 Published: December 29, 2016 ABSTRACT Based on our previous studies, differential analysis of N-glycan expression bound on serum haptoglobin reveals the quantitative variation on gastric cancer patients. In this prospective case-control study, we explore the clinically relevant glycan markers for gastric cancer diagnosis. Serum samples were collected from patients with gastric cancer ( n = 44) and healthy control ( n = 44). N-glycans alteration was monitored by intact analysis of Hp using liquid chromatography–mass spectrometry followed by immunoaffinity purification with the serum samples. Intensity and frequency markers were defined depending on the mass spectrometry data analysis. Multiple markers were found with high diagnostic efficacy. As intensity markers ( I -marker), six markers were discovered with the AUC > 0.8. The high efficiency markers exhibited AUC of 0.93 with a specificity of 86% when the sensitivity was set to 95%. We additionally established frequency marker ( f -marker) panels based on the tendency of high N-glycan expression. The AUC to conclude patients and control group were 0.82 and 0.79, respectively. This study suggested that N-glycan variation of serum haptoglobin were associated with patients with gastric cancer and might be a promising marker for the cancer screening.

// Sung Hee Lim 1, * , Sun-Young Kim 1, * , Kyung Kim 2 , Hyojin Jang 1 , Soomin Ahn 2 , Kyoung-Mee Kim 2 , Nayoung K.D. Kim 3 , Woongyang Park 3 , Su Jin Lee 1 , Seung Tae Kim 1 , Se Hoon Park 1 , Joon Oh Park 1 , Young Suk Park 1 , Se-Hoon Lee 1 , Ho Yeong Lim 1 , Keunchil Park 1 , Won Ki Kang 1 , Jeeyun Lee 1 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Department of Pathology and Translational Genomics, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Samsung Genome Institute, Samsung Medical Center, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Jeeyun Lee, email: jyunlee@skku.edu Keywords: solid tumors, FLT3 amplification, regorafenib Received: August 02, 2016 Accepted: November 15, 2016 Published: November 29, 2016 ABSTRACT We investigated the patients with solid cancers harboring Fms-like tyrosine kinase 3 (FLT3) amplification using targeted sequencing of tumor tissue specimen and FISH assay. Simultaneously, FLT3-amplified patient-derived cells (PDCs) were generated to evaluate the sensitivity to FLT3 inhibition. A patient with metastatic colon cancer who was previously treated with more than 3 rd line cytotoxic chemotherapy was found to have FLT3 amplification and then received regorafenib showing partial response. In two PDC cell lines with FLT3 amplification, FLT3 mRNA expression was increased, however, the growth of tumor cells was not significantly inhibited by either regorafenib or sorafenib which is known to block the activity FLT3. Additional drug combinations with mTOR inhibitor did not affect the cell proliferation of PDC. FLT3 amplification in solid cancers is infrequently observed using targeted genomic profile, as yet, FLT3 amplification does not seem to be an actionable target or a proper biomarker for FLT3 inhibitor sensitivity.

To evaluate the clinical course of disappearing colorectal liver metastases (DLM) or residual tiny (≤5 mm) colorectal liver metastases (RTCLM) on gadoxetic acid-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) in patients who had colorectal liver metastases (CLM) and received chemotherapy. Among 137 patients who received chemotherapy for CLM and underwent gadoxetic acid-enhanced MRI and DWI between 2010 and 2012, 43 patients with 168 DLMs and 48 RTCLMs were included. The cumulative in situ recurrence rate of DLM and progression rate of RTCLM and their predictive factors were evaluated. A total of 150 DLMs and 26 RTCLMs were followed up without additional treatment. At 1 and 2 years, respectively, the cumulative in situ recurrence rates for DLM were 10.9 % and 15.7 % and the cumulative progression rates for RTCLM were 27.2 % and 33.2 %. The in situ recurrence rate at 2 years was 4.9 % for the DLM group that did not show reticular hypointensity of liver parenchyma on hepatobiliary phase. DLM on gadoxetic acid-enhanced liver MRI and DWI indicates a high possibility of clinical complete response, especially in patients without chemotherapy-induced sinusoidal obstruction syndrome. Thirty-three percent of RTCLMs showed progression at 2 years. • DLMs on gadoxetic acid-enhanced MRI and DWI showed low recurrence rates. • If there is sinusoidal obstruction syndrome, evaluation of DLM needs special care. • The progression rate for residual tiny CLMs was 33.2 % at 2 years.

Purpose: Although anemia is considered to be a contributor to intra-tumoral hypoxia and tumor resistance to ionizing radiation in cancer patients, the impact of pretreatment anemia on local control after neoadjuvant concurrent chemoradiotherapy (NACRT) and surgery for rectal cancer remains unclear. Materials and Methods: We reviewed the records of 247 patients with locally advanced rectal cancer who were treated with NACRT followed by curative-intent surgery. Results: The patients with anemia before NACRT (36.0%, 89/247) achieved less pathologic complete response (pCR) than those without anemia (p = 0.012). The patients with pretreatment anemia had worse 3-year local control than those without pretreatment anemia (86.0% vs. 95.7%, p = 0.005). Multivariate analysis showed that pretreatment anemia (p = 0.035), pathologic tumor and nodal stage (p = 0.020 and 0.032, respectively) were independently significant factors for local control. Conclusion: Pretreatment anemia had negative impacts on pCR and local control among patients who underwent NACRT and surgery for rectal cancer. Strategies maintaining hemoglobin level within normal range could potentially be used to improve local control in rectal cancer patients.

Background To investigate the efficacy and safety of bevacizumab beyond first progression combined with doublet chemotherapy in patients with metastatic colorectal cancer. Methods This multicenter phase II study included 76 patients with metastatic colorectal cancer progressed after first-line bevacizumab plus doublet chemotherapy. Study treatment consisted of second-line continuation of bevacizumab plus crossover standard doublet chemotherapy, consisting of FOLFOX, CapeOX, or FOLFIRI. Bevacizumab was administered in doses of 5 mg/kg/2-week or 7.5 mg/kg/3-week according to the schedules of the combined regimen. Results Median progression-free survival (PFS) and overall survival (OS) was 6.5 months (95 % CI, 5.2–7.8) and 12.8 months (95 % CI, 8.8–16.9), respectively, with no significant differences according to combined doublet chemotherapy. The response rate (RR) was 17.1 % (95 % CI, 8.6–5.6) with no statistical significance between regimens (p = 0.053). The first-line RR and PFS did not affect the second-line efficacy outcomes; RR (14.0 % vs 21.2 %, p = 0.405), median PFS (5.6 vs 6.7 months, p = 0.335), and OS (15.4 vs 11.0 months, p = 0.383) were not different between previous responders and non-responders, and the median PFS (p = 0.186) and OS (p = 0.495) were not different either according to the length of first-line PFS; however, OS from the first-line chemotherapy was longer in patients with longer first-line PFS (26.4 vs 14.8 months, p = 0.010). Bevacizumab-related significant adverse events included proteinuria (1.3 %) and thromboembolism (1.3 %). Conclusions Bevacizumab beyond first progression could be considered a treatment strategy even in patients progressed after first-line bevacizumab plus doublet chemotherapy. Second-line efficacy outcomes did not differ according to the first-line responses.