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Dong-Hoe Koo,1,* Keun Seok Lee,2,* Sung Hoon Sim,2 Heejung Chae,2 Eun-Gyeong Lee,2 Jai Hong Han,2 So-Youn Jung,2 Seeyoun Lee,2 Han-Sung Kang,2 Eun Sook Lee,2 Cheol-Young Park,1,* Sang Woo Oh3,* 1Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 2Center for Breast Cancer, Research Institute and Hospital, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea; 3Department of Family Medicine, Center for Obesity, Metabolism, and Nutrition, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi-do, Republic of Korea*These authors contributed equally to this workCorrespondence: Cheol-Young Park, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul, 03181, Republic of Korea, Tel +82-2-2001-1869, Fax +82-2-2001-1588, Email cydoctor@chol.com Sang Woo Oh, Center for Obesity, Nutrition, and Metabolism, Department of Family Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, 27 Donggung-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10326, Republic of Korea, Tel +82-31-961-7000, Email osw6021@gmail.comBackground: We have reported that serum progranulin (PGRN) levels are clinically significant in predicting recurrence in patients with HR-positive breast cancer. The aim of the present study was to examine whether PGRN levels might be associated with breast cancer mortality.Methods: This was a cohort study of 695 newly diagnosed breast cancer patients who underwent curative surgery between 2001 and 2004. The relationship between breast cancer mortality and pre-operative serum PGRN levels in these patients with a median follow-up of 12.7 years was evaluated until May 2020.Results: A total of 118 (17%) deaths were identified in the cohort. According to the HR status, (10, 15, and 20)-year overall survival (OS) rates were (91.4, 81.1, and 75.9) % for HR-positive patients, and (76.5, 74.2, and 69.8) % for HR-negative patients, respectively (p = 0.003). Higher levels of PGRN were significantly associated with poor OS in the HR-positive group (p for trend = 0.001). In particular, hazard ratios for PGRN quartiles suggested a dose–response relationship, with the highest quartile having the worst OS in the HR-positive group (highest vs lowest: 15-year OS, (68.3 vs 90.0) %; 20-year OS, (62.3 vs 84.8) %, even after adjusting for age, tumor stage, and metabolic confounders.Conclusion: Pre-operative serum PGRN levels had clinical significance for predicting cancer mortality in breast cancer patients independent of tumor stage and metabolic parameters, especially in HR-positive tumors.Keywords: breast cancer, progranulin, mortality, long-term follow-up

Purpose: The goals of this study were to investigate the clinical activity, safety, and biomarkers of dacomitinib, an irreversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, in recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN).Experimental Design: Patients were eligible if the diseases were not amenable to curative treatment and had progressed on platinum-based chemotherapy, and were treated with dacomitinib 45 mg/day. The primary endpoint was objective response rate by RECISTv1.1. Exploratory analysis included the characterization of somatic mutation, gene copy number, gene expression, p16INK4A expression by IHC, and investigation of their relationship with clinical outcomes.Results: Forty-eight patients were evaluable for efficacy and toxicity. Ten patients (20.8%) had partial responses and 31 patients (65%) had stable diseases. The median progression-free survival (PFS) and overall survival (OS) were 3.9 months [95% confidence interval (CI), 2.9–5.0] and 6.6 months (95% CI, 5.4–10.3). Adverse events were mostly grade 1–2. Mutations in the PI3K pathway (PIK3CA, PTEN) and high expression of inflammatory cytokines (IL6, IL8, IL1A, IL1B, IL4, and TNF) were significantly associated with shorter PFS (2.9 vs. 4.9 months without mutations, P = 0.013; 2.8 vs. 9.9 months with low expression, P = 0.004). Those harboring PI3K pathway mutations or high inflammatory cytokine expression had shorter median OS (6.1 vs. 12.5 months lacking PI3K pathway mutations and with low inflammatory cytokine expression, P = 0.005).Conclusions: Dacomitinib demonstrated clinical efficacy with manageable toxicity in platinum-failed R/M-SCCHN patients. Screening of PI3K pathway mutation and inflammatory cytokine expression may help identify which R/M-SCCHN patients are likely to gain benefit from dacomitinib. Clin Cancer Res; 21(3); 544–52. ©2014 AACR.

Supplementary Methods and Materials, Figures S1-S3, Tables S1-S5. 1. Supplementary Methods. page 2-4 -Gene set analysis for gene expression data -Immunohistochemistry and fluorescent in situ hybridization (FISH) -Enzyme-linked immunosorbent assay (ELISA) 2. Supplemental Figures. Figure S1: CONSORT diagram. page 5 Figure S2: Kaplan-Meier estimates of progression-free survival and overall survival according to p16 status. page 6 Figure S3: Analysis of fibroblast growth factor receptor 1 (FGFR1) gene amplification by fluorescent in situ hybridization. page 7 3. Supplemental Tables Table S1: Gene list and platforms for biomarker analysis. page 8-12 Table S2: Loci information of somatic mutations. page 13 Table S3: Gene expression profile in 230 cancer genes. page 14-20 Table S4: Gene set enrichment analysis. page 21-22 Table S5: Copy number aberrations in 86 cancer genes. page 23

BACKGROUND New prognostic factors have been reported in patients with metastatic or recurrent gastric cancer (MRGC), necessitating modifications to the previous prognostic model. AIM To develop a new model, MRGC patients who received fluoropyrimidines/ platinum doublet chemotherapy between 2008 and 2015 were analyzed. METHODS A total of 1883 patients was divided into a training set (n = 937) and an independent validation set (n = 946). RESULTS Multivariate analysis showed that the following six factors were associated with poor overall survival (OS) in the training set: Eastern Cooperative Oncology Group performance score ≥ 2 and bone metastasis (2 points each), peritoneal metastasis, high alkaline phosphatase level, low albumin level, and high neutrophil-lymphocyte ratio (1 point each). A prognostic model was developed by stratifying patients into good (0-1 point), moderate (2-3 points), and poor (≥ 4 points) risk groups. In the validation set, the median OS of the three risk groups was 15.8, 10.1, and 5.7 mo, respectively, and those differences were significant (P < 0.001). CONCLUSION We identified six factors readily measured in clinical practice that are predictive of poor prognosis in patients with MRGC. The new model is simpler than the old and more easily predicts OS.

This study assessed the use of pretreatment albumin–-bilirubin (ALBI) grade as a prognostic factor in patients with hepatocellular carcinoma (HCC) receiving combined transarterial chemoembolization (TACE) and radiotherapy (RT). Patients who underwent RT following TACE between January 2011 and December 2020 were analyzed retrospectively. The survival outcomes of patients in regard to the ALBI grade and Child–Pugh (C–P) classification were evaluated. A total of 73 patients with a median follow-up of 16.3 months were included. Thirty-three (45.2%) and forty patients (54.8%) were categorized into ALBI grades 1 and 2–3, respectively, while sixty-four (87.7%) and nine (12.3%) were C–P classes A and B, respectively (p = 0.003). The median progression-free survival (PFS) and overall survival (OS) for ALBI grade 1 vs. 2–3 were 8.6 months vs. 5.0 months (p = 0.016) and 27.0 months vs. 15.9 months (p = 0.006), respectively. The median PFS and OS for C–P class A vs. B were 6.3 months vs. 6.1 months (p = 0.265) and 24.8 months vs. 19.0 months (p = 0.630), respectively. A multivariate analysis showed that ALBI grades 2–3 were significantly associated with worse PFS (p = 0.035) and OS (p = 0.021). In conclusion, the ALBI grade could be a good prognosticator in HCC patients who were treated with combined TACE-RT.

In this multi-center phase II trial, we evaluated the efficacy and safety of a quadruplet regimen (pembrolizumab, trastuzumab, and doublet chemotherapy) as first-line therapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) (NCT02901301). The primary endpoints were recommended phase 2 dose (RP2D) for phase Ib and objective response rate (ORR) for phase II. The secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to response and safety. Without dose-limiting or unexpected toxicities, the starting dose in the phase Ib trial was selected as RP2D. In 43 patients, the primary endpoint was achieved: the objective response rate was 76.7% (95% confidence interval [CI]: 61.4–88.2), with complete and partial responses in 14% and 62.8% of patients, respectively. The median progression-free survival, overall survival, and duration of response were 8.6 months, 19.3 months, and 10.8 months, respectively. No patients discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 status was not related to survival. Post hoc analyses of pretreatment tumor specimens via targeted sequencing indicated that ERBB2 amplification, RTK/RAS pathway alterations, and high neoantigen load corrected by HLA-B were positively related to survival. The current quadruplet regimen shows durable efficacy and safety for patients with HER2-positive AGC.

Purpose This study aimed to evaluate the survivals of patients with metastatic or recurrent gastric cancer (MRGC) over a period of 16 years and to investigate the recent changes in chemotherapy patterns. Materials and Methods A total of 5,384 patients who received chemotherapy for MRGC between 2000 and 2015 were analyzed. The analysis focused on a comparison of the first-line chemotherapy between four periods: 2000–2003 (period 1), 2004–2007 (period 2), 2008–2011 (period 3), and 2012–2015 (period 4). Results There were 880 patients (16%) in period 1, 1,573 (29%) in period 2, 1,435 (27%) in period 3, and 1,496 (28%) in period 4. Cytotoxic doublet-based therapy was the most commonly used (78%) first-line chemotherapy, and the combination of trastuzumab and doublet chemotherapy was provided to 288 patients. The overall survival (OS) rates at 12 and 24 months were steadily improved as follows: 39.2% and 14.6% in period 1, 43.5% and 17.6% in period 2, 50.3% and 20.6% in period 3, and 51.7% and 24.1% in period 4, respectively (p < 0.001). Among the patients who received the doublet-based chemotherapy, the median OS of those who received trastuzumab was 18.0 months (95% confidence interval [CI], 15.5 to 20.6), while that of those who received other doublet therapies was 11.2 months (95% CI, 10.8 to 11.6). Conclusion The OS was improved over time with advancements in chemotherapy, particularly the introduction of the anti-HER2–targeted agent, which contributed to the increase in the number of long-term survivors and established the superiority of OS for the treatment of MRGC.

We aimed to investigate how much cumulative hyperglycemia exposure increases pancreatic cancer risk.This study used the National Health Insurance Service Database of Claims and included 3,138,099 individuals who underwent four consecutive annual health screenings between 2009 and 2013. We defined hyperglycemic burden in two ways. First, the hyperglycemic burden was given a score from 0 to 4, with one point assigned for each time blood glucose was ≥100 mg/dL or the use of an antidiabetic drug. Furthermore, we performed semiquantitative scoring of a pre-diabetic (100-125; 1 point) and diabetic level (≥126; 2 points) and categorized into one of nine groups (hyperglycemic score 0-8).During the median 6.2 years of follow-up, groups with a hyperglycemic burden of 1, 2, 3, and 4 had a 15%, 30%, 26%, and 67% increased pancreatic cancer risk compared with normal subjects. In semiquantitative analyses, individuals with a pre-diabetic glucose level on at least one occasion had a 14% increased the risk. Furthermore, individuals with a burden score of 8 had an 89% higher risk than subjects with a normal range.The pancreatic cancer incidence increased significantly according to the hyperglycemic burden, defined as sustained hyperglycemic exposure, including pre-diabetic levels.

Radiofrequency ablation (RFA) has been increasingly used for the treatment of pulmonary metastases in various malignancies.A retrospective analysis was performed to establish the safety and efficacy of cone-beam computed tomography (CBCT)-guided RFA in patients with metastatic colorectal cancer between 2016 and 2019, and the prognostic factors of local tumor control were assessed.A total of 31 patients with colorectal cancer underwent 48 sessions of lung RFA. The mean diameter of metastases targeted for RFA was 11 mm (range: 4-32), and the RFA was technically successful in 43 sessions (90%). There were 14 complications (29%), the majority of which required no intervention, with no cases of mortality. The median follow-up duration from RFA in the surviving 29 patients was 18.0 months. Only two patients (6%) died of disease progression, and the 3-year overall survival rate was 91% (95% CI: 83-99). Local tumor progression (LTP) of the RFA site was observed in 27%, and the LTP-free survival rates at 1 and 2 years were 81% (95% CI: 70-82) and 64% (95% CI: 50-77), respectively. Multivariate analysis showed that the progression of extra-RFA sites and the presence of extrapulmonary metastasis were independent prognostic factors significantly associated with LTP at RFA site.Lung RFA using CBCT guidance is a comparatively safe and effective option for the treatment of lung metastases from colorectal cancer. However, the control of extrapulmonary metastases should be accompanied by combined or sequential systemic treatment and local treatment.

Background: BOLD-100 is a first-in-class ruthenium-based anticancer agent in Phase 1b/2a clinical development for the treatment of advanced gastrointestinal (GI) cancers in combination with FOLFOX. BOLD-100 demonstrated synergy in established preclinical models in combination with various anticancer therapies, particularly in resistant cell lines. In the first interim analysis of the phase 1b dose-escalation component of the clinical trial, BOLD-100 plus FOLFOX was well-tolerated in patients (pts) with advanced GI solid cancers. Methods: This is a prospective, Phase 1b dose-escalation (Part A) and Phase 2a dose-expansion (Part B) study of BOLD-100 in combination with FOLFOX for colorectal (CRC), pancreatic (PDAC), gastric (GC) and biliary tract (BTC) cancers. Pts receive BOLD-100 with FOLFOX on day 1 of each 14-day cycle. In Part A, pts were enrolled in a 3+3 design to determine the combination recommended Phase 2 dose (RP2D), with BOLD-100 dose-escalation (420, 500 and 625 mg/m2). Part B comprises 4 cohorts treated at the RP2D of 625 mg/m2 until progressive disease or unacceptable toxicity. The primary objective of Part B is to evaluate the efficacy of BOLD-100 in three clinical endpoints (PFS, OS, and ORR). Bayesian modelling is used to continually reassess these endpoints; the posterior probability of superiority to a historical landmark for each endpoint. Results: As of 31 Dec 2022, 17 pts with advanced metastatic colorectal cancer median age 62 years were treated. Pts received a median of 4 prior systemic therapies, 14 had received prior FOLFOX and 16 (94%) were enrolled with stage IV disease. Median number of cycles completed was 7 (range 1-12). Median PFS was 4.7 [2.9,8.6] months, median OS 9.8 [5.2,22] months, and ORR 13% [3,36] compared to the historical benchmark of 2.0 months, 7.1 months, and 1.6% respectively for similar patients treated with approved standard of care. Two pts achieved a partial response and 11 pts had stable disease for an overall disease control rate of 87% (13/15 [64%,97%]). This compares favorably to the historical control 44%. 16 pts reported 1 or more treatment-emergent adverse events (AEs), most commonly neutrophil count decreased (n=9, 52.9%), fatigue (n=6, 35.3%), pyrexia (n=4, 23.5%), platelet count decreased (n=4, 23.5%) and decreased appetite (n=4, 23.5%). Most of the AEs were grade (G) 1-2. 12 G3 AEs were observed (mostly neutrophil count decreased [8]). Conclusion: BOLD-100 plus FOLFOX is an active and well-tolerated treatment regimen in the heavily pre-treated metastatic CRC trial population. There were no new safety signals. PK and PD data are forthcoming. The preliminary mPFS, mOS, ORR and DCR data in this interim analysis demonstrate significant improvement over the currently available approved therapies. Citation Format: Jennifer Spratlin, Grainne O'Kane, Do-Youn Oh, Sun Young Rha, Elaine McWhirter, Elena Elimova, Petr Kavan, Moon Ki Choi, Dae Won Kim, Rachel Goodwin, J Randolph Hecht, Seung Tae Kim, Dong-Hoe Koo, Khalif Halani, E Russell McAllister, Michelle Jones, Malcolm Snow, Yasmin Lemmerick, Gonzalo Spera, Jim Pankovich. BOLD-100-001 (TRIO039): a phase 1b/2a dose-escalation study of BOLD-100 in combination with FOLFOX chemotherapy in patients with pre-treated advanced colorectal cancer: interim efficacy, safety and tolerability analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT149.

IntroductionPatients who underwent curative gastrectomy for gastric cancer are regularly followed-up for the early detection of recurrence and postoperative symptom management. However, there is a lack of evidence with regard to proper surveillance intervals and diagnostic tools. This study aims to evaluate whether frequent surveillance tests have a survival benefit or improve the quality of life in patients who underwent curative resection for advanced gastric cancer.Methods and analysisThe STOFOLUP trial is an investigator-initiated, parallel-assigned, multicentre randomised controlled trial involving 16 hospitals in the Republic of Korea. Patients (n=886) diagnosed with pathological stage II or III gastric adenocarcinoma will be randomised to either the 3-month or the 6-month group at a 1:1 ratio, stratified by trial site and tumour stage. Patients allocated to the 3-month group will undergo an abdominal CT scan every 3 months postoperatively and those allocated to the 6-month group will undergo CT every 6 months. The primary endpoint is 3-year overall survival and the secondary endpoints are quality of life, as assessed using KOrean QUality of life in Stomach cancer patients Study group-40, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the stomach cancer-specific module (STO22), and nutritional outcomes. Other survival data including data concerning 3-year disease-free survival, recurrence-free survival, gastric cancer-specific survival and postrecurrence survival will also be estimated. The first patient was enrolled on July 2021 and active patient enrolment is currently underway.Ethics and disseminationThis study has been approved by the Institutional Review Board of eight of the participating hospitals (NCC 2021-0085, KBSMC2021-01-059, SMC 2021-01-140, KC21OEDE0082, 4-2021-0281, AJIRB-MED-INT-20-608, 2021-0515 and H-2102-093-1198). This study will be disseminated through peer-reviewed publications, national or international conferences.Trial registration numberNCT04740346.

Background & aims Fentanyl buccal tablets (FBTs) are a rapid-onset opioid indicated for breakthrough cancer pain (BTcP) and FBT titration is needed to optimize BTcP management. We aimed to predict which patients could tolerate a high dose of FBT (400 μg or more at a time). Methods A retrospective analysis was performed to assess the final FBT dose. The final FBT doses were compared according to the clinical features. The prediction accuracy of patients tolerant of 400 μg or higher FBT was compared using the area under the receiver operating characteristic (ROC) curves. A risk scoring model based on the odds ratio (OR) was developed from the final multivariable model, and patients were assigned into two groups: low tolerance (0–1 point) and high tolerance (2–3 points). Results Among 131 patients, the most frequently effective dose of FBT was 200 μg (54%), followed by 100 μg (30%). The median value of morphine equivalent daily doses (MEDD) was 60 mg/day, and the most common daily use was 3–4 times/day. In multivariable analysis, male sex, younger age, and use of FBTs three or more times per day were independently associated with high-dose FBT. According to the risk scoring model, the patients with a final FBT of 400 μg or higher were significantly more in the high tolerance group (17%) compared to the low tolerance group (3%; p = 0.023) Conclusions According to the dose relationship between the final FBT dose and the clinical features, three factors (sex, age, daily use of FBT) were independently associated with the final dose of FBT. Our risk score model could help predict tolerance to high-dose FBT and guide the titration plan for BTcP.

Objective To evaluate complications after consecutive 100 sessions of cone-beam computed tomography (CBCT)-guided radiofrequency ablation (RFA) of lung tumors Materials and methods A retrospective study was conducted from January 2016 and October 2018. All procedures were performed using a CBCT virtual navigation guidance system, combining three-dimentional CBCT, needle planning software, and real-time fluoroscopy. Complications were evaluated for each RFA session in 63 consecutive patients (31 male, 32 female; mean age 58.0 years) with 121 lung tumors who underwent 100 sessions of CBCT-guided lung ablation with an internally cooled RFA system. Complications were recorded using the Common Terminology Criteria of Adverse Events (CTCAE) 5.0. A major complication was defined as a grade 3 or 4 adverse event. Results There was no postprocedural mortality. The major and minor complication rates were 5% and 28%, respectively. The major complications were significant pulmonary hemorrhage (1%), large hemothorax requiring drainage (1%), pneumonia treated with antibiotics (2%), and delayed bronchopleural fistula (1%). The minor complications were pneumothorax (15%), hemoptysis (11%), and subcutaneous emphysema (2%). Of the 15 pneumothoraces, percutaneous catheter drainage was required in six sessions. Pneumothorax was more likely to occur if RFA was performed on two or more tumors at one session. Immediate, periprocedural and delayed complications were 23%, 9%, and 1%, respectively. Conclusion CBCT-guided RFA of lung tumors is a relatively safe procedure with acceptable morbidity.

Before developing a national screening program for pancreatic cancer, more detailed and reliable estimation of pancreatic cancer incidence rate is needed according to sex, age, and diabetes mellitus status. Among populations who underwent a biennial or annual evaluation provided by the National Health Insurance Service Database of Claims between 2006 and 2015, data were evaluated from the medical records of 34.2 million individuals aged 30 years and over. The annual incidence rate (IR; per 100,000) of pancreatic cancer in 2006 was 5.96, and the IR in 2015 increased to 8.92. The IRs increased consistently and significantly with age (p for trend

Context It has been unclear whether the risk of pancreatic cancer is different according to glucose levels. Objective To determine the association between fasting glucose levels and pancreatic cancer risk using prospectively collected nationwide population-based cohort data in Korea. Design The National Health Insurance Service database of claims and preventive health check-up data recorded was used between 2009 and 2015. Setting and Participants A total of 25.4 million patients who had participated in a preventive health check-up between 2009 and 2013 were evaluated for pancreatic cancer incidence rates according to fasting glucose level. Main Outcomes Measures The cumulative incidence rate for pancreatic cancer was calculated after grouping according to fasting glucose levels as follows: (i) low normal ( Results The 5-year cumulative incidence rates (per 100,000) were as follows: (i) low normal = 32; (ii) high normal = 41; (iii) prediabetes level 1 = 50; (iv) prediabetes level 2 = 64; (v) diabetes = 75; and (vi) on anti-diabetic medications = 121. The risk of pancreatic cancer increased continuously with elevating fasting glucose levels (P < 0.0001). The incidence of pancreatic cancer increased significantly with increasing fasting blood glucose levels even after adjusting for age, sex, smoking, drinking, exercise, body mass index, and diabetes duration (P < 0.0001). Conclusions The cumulative incidence rate of pancreatic cancer significantly increased as the fasting glucose level elevated, even in populations with a normal glucose level range.

KEYNOTE-063 (NCT03019588) investigated pembrolizumab versus paclitaxel as second-line therapy in Asian patients with advanced programmed death ligand 1 (PD-L1)-positive (combined positive score ≥1) gastric/gastroesophageal junction (GEJ) cancer.This randomized, open-label, phase 3 study was conducted at 36 medical centers in China (mainland), Malaysia, South Korea, and Taiwan. Patients were randomly assigned 1:1 to 200 mg of pembrolizumab intravenously every 3 weeks for ≤2 years or 80 mg/mBetween February 16, 2017, and March 12, 2018, 94 patients were randomly assigned (47 pembrolizumab/47 paclitaxel) after screening; enrollment was stopped on March 12, 2018, based on the results of the global KEYNOTE-061 study, and patients were followed until the last patient's last visit. Median OS was 8 months (95% confidence interval [CI], 4-10 months) with pembrolizumab versus 8 months (95% CI, 5-11 months) with paclitaxel (hazard ratio [HR], 0.99; 95% CI, 0.63-1.54). Median PFS was 2 months (95% CI, 1-3 months) with pembrolizumab versus 4 months (95% CI, 3-6 months) with paclitaxel (HR, 1.62; 95% CI, 1.04-2.52). ORR was 13% for pembrolizumab versus 19% for paclitaxel. Any-grade treatment-related adverse events occurred in 28 pembrolizumab-treated patients (60%) and 42 paclitaxel-treated patients (96%); grades 3 to 5 events occurred in 5 patients (11%) and 28 patients (64%), respectively.Definitive conclusions about the efficacy of second-line pembrolizumab in Asian patients with advanced PD-L1-positive gastric/GEJ cancer are limited because of insufficient power, but pembrolizumab was well tolerated in this patient population. Efficacy followed a trend similar to that observed in the phase 3 KEYNOTE-061 trial.

BACKGROUND/AIM Lymph node metastasis is an important prognostic factor in gastric cancer patients. In node-negative (N0) gastric cancer patients, additional prognostic factors are needed to reinforce TNM staging. PATIENTS AND METHODS We semi-quantitatively recorded the presence of lymphatic, venous, and perineural invasion and evaluated the possibility that they could be used as upstaging factors in N0 gastric cancer by comparing N0 gastric cancer cases with N1 cases. RESULTS Venous (p

4001 Background: To explore proper agents for AGC patients as 2nd-line treatment based on optimal biomarker, we conducted K-Umbrella GC study with standard of care (SOC) controlled umbrella trial design. Methods: HER2-negative AGC patients from 6 Korean cancer centers were centrally screened for druggable targets by IHC and in situ hybridization. Patients were randomized to the biomarker vs. control group with SOC as 4:1 ratio. In the biomarker group, patients were treated with specific targeted agents in combination with weekly paclitaxel; 1) EGFR 2+/3+ patients for pan-ERBB inhibitor (afatinib; EGFR cohort), 2) PTEN loss/null (H-score

Combining programmed cell death 1 (PD-1) and human epidermal receptor 2 (HER2) targeting agents has shown synergy in HER2-positive preclinical cancer models. Here, we describe a single-arm multi-institutional phase Ib/II trial combining pembrolizumab, trastuzumab, and chemotherapy (capecitabine plus cisplatin) as first-line therapy for HER2-positive advanced gastric cancer (AGC). With a median follow-up of 18.2 months, 3 out of 43 enrolled patients remained in the treatment and 7 finished 2-year treatment without progression. Objective response rate was 76.7% (complete response 16.3%, partial response 60.5%, conversion surgery 4.6%), with 26 patients (56.6%) showing tumor reduction of more than 50%. Median progression-free survival was 8.6 months (95% confidence interval [CI] 7.2–16.4) and median overall survival was 19.3 months (95% CI 16.5–not reached). There was no patient with microsatellite instability-high or Epstein–Barr virus-positive tumor. No patient discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 (PD-L1) status, metastatic organ, or baseline tumor burden were not related to survival. Molecular analyses of pre-treatment tumor samples using next-generation panel sequencing (NGS) showed that HER2 amplification, RTK/RAS pathway alteration, and neoantigen load corrected by HLA-B were related to survival. Comparison analyses of sequentially biopsied samples identified sensitive and resistant sub-clones with spatial and longitudinal tumor heterogeneity. This study provided insight into potentially relevant NGS-based genomic changes to identify patients who may benefit from quadruplet regimen (pembrolizumab, trastuzumab, capecitabine, and cisplatin), which was active and safe for HER2-positive AGC.

This study sought to adapt the existing value framework (VF) to produce a reliable and valid Korean oncology VF. Two VFs developed by The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) were selected for examination in the present study. Forward and backward translations were conducted for six high-priced drugs indicated for non-small-cell lung cancer and multiple myeloma. Inter-rater reliability was measured based on the intraclass correlation coefficient (ICC) and variation was described using the coefficient of variation. The relative weights of factors critically considered by Korean oncologists were derived following the analytic hierarchy process (AHP), and focus group interviews (FGIs) were used to obtain qualitative data regarding the applications of these two VFs in the Korean setting. The ICCs of the Korean VFs were 0.895 (0.654–0.983) for ASCO and 0.726 (0–0.982) for ESMO translations, suggesting excellent reliability for ASCO and good reliability for ESMO. AHP demonstrated that clinical benefit has the highest priority, which is consistent with the ASCO VF. The FGIs suggested that the result for AHP is acceptable and that both ESMO and ASCO VFs should be used complementarily. Although further evaluation with a larger sample size is needed, the Korean versions of ESMO/ASCO VFs are valid and reliable tools and are acceptable to Korean stakeholders, yet they should be applied with caution.

Background & aims Progranulin (PGRN) is known to promote tumorigenesis and proliferation of several types of cancer cells. However, little is known about the clinicopathological features of patients with gastrointestinal stromal tumors (GISTs) with regard to PGRN expression. Methods A retrospective analysis was performed on patients with GISTs who underwent curative surgical resection between 2007 and 2017. PGRN expression was evaluated by immunohistochemical (IHC) analysis and semi-quantitatively categorized (no expression, 0; weak, 1+; moderate, 2+; strong, 3+). Tumors with a staining intensity of 2+ or 3+ were considered high PGRN expression. Results Fifty-four patients were analyzed; 31 patients (57%) were male. The median age at surgery was 60 years (range, 33–79), and the most common primary site was the stomach (67%). Thirty-five patients (65%) had spindle histology; 42 patients (78%) were separated as a high-risk group according to the modified National Institutes of Health (NIH) classification. High PGRN-expressing tumors were observed in 27 patients (50%), had more epithelioid/mixed histology (68% vs. 32%; p = 0.046), and KIT exon 11 mutations (76% vs. 24%; p = 0.037). Patients with high PGRN-expressing tumors had a worse recurrence-free survival (RFS) (36% of 5-year RFS) compared to those with low PGRN-expressing tumors (96%; p60 years) were independent prognostic factors for poor RFS. Conclusions High PGRN-expressing GISTs showed more epithelioid/mixed histology and KIT exon 11 mutations. PGRN overexpression was significantly associated with poor RFS in patients with GISTs who underwent curative resection.

Old age alone does not reflect an intolerability to chemotherapy. However, upfront dose reduction (UDR) of the first cycle of first-line palliative chemotherapy has sometimes been chosen by physicians for older adults with metastatic cancer due to concerns regarding adverse events. The development of predictive factors for UDR of palliative chemotherapy would be helpful for treatment planning among older adults. This was a secondary analysis of a study on predicting adverse events of first-line palliative chemotherapy in 296 patients (&ge, 70 years) with solid cancer. We assessed the prevalence of UDR of the first cycle of first-line chemotherapy and the association of UDR with the variables of geriatric assessment (GA) and chemotherapy compliance. Among the 296 patients, 177 (59.8%) patients were treated with UDR. The mean percentage of UDR for the total patient group was 19.2% (range: 4&ndash, 47%) of the standard dose. In a multivariate analysis, poor performance status (PS) and living without a spouse were independent predictive factors of UDR of first-line palliative chemotherapy in older adults. Patients with UDR showed fewer grade 3&ndash, 5 adverse events versus the standard dose group. Study completion as planned was significantly higher in the UDR group versus the standard dose group. Older adults with UDR better tolerated chemotherapy than patients with a standard dose.

Purpose The purpose of this study was to evaluate chemotherapy patterns and changes in quality of life (QOL) during first-line palliative chemotherapy for Korean patients with unresectable or metastatic/recurrent gastric cancer (GC). Materials and Methods Thiswas a non-interventional, multi-center, prospective, observational study of 527 patients in Korea. QOL assessments were conducted using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ)-C30 and QLQ-STO22 every 3 months over a 12-month period during first-line palliative chemotherapy. The specific chemotherapy regimens were selected by individual clinicians. Results Most patients (93.2%) received combination chemotherapy (mainly fluoropyrimidine plus platinum) as their first-line palliative chemotherapy. The median progression-free survival and overall survival were 8.2 and 14.8 months, respectively. Overall, “a little” changes (differences of 5-10 points from baseline)were observed in some of the functioning or symptom scales; none of the QOL scales showed either “moderate” or “very much” change (i.e., ≥ 11 point difference from baseline). When examining the best change in each QOL domain from baseline, scales related to some aspects of functioning, global health status/QOL, and most symptoms revealed significant improvements (p < 0.05). Throughout the course of first-line palliative chemotherapy, most patients’ QOL was maintained to a similar degree, regardless of their actual response to chemotherapy. Conclusion This observational study provides important information on the chemotherapy patterns and QOL changes in Korean patientswith advanced GC. Overall, first-line palliative chemotherapy was found to maintain QOL, and most parameters showed an improvement compared with the baseline at some point during the course.

Progranulin (PGRN) has been characterized as an autocrine growth and survival factor and is known to stimulate tumorigenesis and proliferation of several types of cancer cell. However, little is known about the prognostic role of PGRN in colorectal cancer (CRC). A retrospective analysis was performed for patients with colorectal cancer who underwent curative resection between May 2013 and June 2015. PGRN expression in tumor cells was semi-quantitatively categorized (no expression, 0; weak/focal, 1+; moderate/focal or diffuse, 2+; strong/diffuse, 3+), and high expression was considered for tumors graded ≥2+ staining intensity. A total of 109 patients (28 stage I, 32 stage II, and 49 stage III) were analyzed. Thirty-eight patients (35%) had tumors with high PGRN expression, and there was a trend of elevated pre-operative CEA and CA19–9 levels in patients with high PGRN-expressing tumors compared to those with low PGRN-expressing tumors (CEA, 49% vs. 21%; CA19–9, 21% vs. 7%). The 3–year recurrence-free survival (3Y–RFS) and overall survival rates were 83.7% (95% CI, 76.8–90.6) and 96.0% (95% CI, 92.3–99.7), respectively. Patients with high PGRN-expressing tumors had a worse rate of 3Y–RFS (66.8%) compared to those with low PGRN-expressing tumors (92.4%; p = 0.010). Multivariate analysis showed that high PGRN expression, age (>66 years), stage (III), and perineural invasion (+) were independent prognostic factors associated with poor RFS after adjusting for confounding factors including sex, MSI, tumor location, KRAS, and lympho-vascular invasion. PGRN overexpression was significantly associated with poor RFS in patients with CRC who have undergone curative resection.

Manifestations of malignant pleural effusions (MPEs) are alleviated by local therapies as well as by systemic treatment. After 2009, when commercial use of talc was discontinued in Korea, we have used Helixor-M, which is derived from the European mistletoe (Viscum album), as an alternative sclerosing agent for pleurodesis. We aimed to evaluate the efficacy and safety of Helixor-M for controlling MPE. Between 2009 and 2015, we consecutively enrolled 52 patients with lung cancer, who underwent pleurodesis to treat MPE and were analyzed retrospectively. On day 1, 100 mg of Helixor-M was instilled via pleural catheter. If the procedure was not effective, it was repeated every other day up to five times, and the dose increased each time by 100 mg. The primary study outcome was reappearance of pleural effusion at 1 month after the last pleurodesis procedure. The median age of patient was 63 years, and 77% of the 52 patients were male. About 85% of pleural effusions were found to be malignant by cytogenetic analysis. Forty-two (81%) patients were evaluable for recurrence of MPE. The 1-month recurrence rate was 48% (20/42). Among the 20 patients who developed recurrent MPE, 6 required therapeutic thoracentesis. Thirteen (25%) patients experienced procedure-related pain requiring medication. Eight (15%) had fever > 38 °C. Our results suggest that a pleurodesis with Helixor-M was an effective and tolerable procedure for controlling MPE in lung cancer patients.

Background/aims Managing breakthrough pain (BTP) is important for many cancer patients because of the rapid onset and unpredictable nature of the pain episodes. Fentanyl buccal tablets (FBTs) are a rapid-onset opioid indicated for BTP management. However, FBT titration is needed to optimize BTP management. In this study, we aimed to evaluate the safety and efficacy of initiating 200 μg FBTs in Korean cancer patients. Methods A retrospective analysis of medical records was performed on all advanced cancer patients treated with FBTs for BTP between October 2014 and July 2015. Patients who received initial doses of 200 μg FBTs for at least 3 days and cases in which FBT was available at doses of 200, 400, and 800 μg were included. Results A total of 56 patients with a median age of 62 years (range, 32 to 80) were analyzed, 61% of whom were male. The median and mean values of morphine equivalent daily doses were 60 mg/day (range, 15 to 540) and 114.8 ± 124.8 mg/day, respectively. The most frequent effective doses of FBT were 200 μg (41 patients, 74%) and 400 μg (12 patients, 21%). Three patients (5%) could not tolerate 200 μg of FBT and discontinued treatment. Nausea, vomiting, somnolence, and dizziness were the most frequent treatment-related adverse events (AEs), and all AEs were grade 1 (mild) or 2 (moderate). Conclusions FBT at the initial 200 μg dosage was well-tolerated and effective as a BTP management strategy in Korean cancer patients. Further prospective studies are needed to determine appropriate initiating doses of FBT in Korean patients with opioid tolerance.

Background Older patients have increased risk of toxicity from chemotherapy. Current prediction tools do not provide information on cumulative risk. Methods Patients aged ≥ 70 years with solid cancer were prospectively enrolled. A prediction model was developed for adverse events (AEs) ≥ Grade 3 (G3), based on geriatric assessment (GA), laboratory, and clinical variables. Results 301 patients were enrolled (median age, 75 years). Median number of chemotherapy cycles was 4. During first-line chemotherapy, 53.8% of patients experienced AEs ≥ G3. Serum protein < 6.7 g/dL, initial full-dose chemotherapy, psychological stress or acute disease in the past 3 months, water consumption < 3 cups/day, unable to obey a simple command, and self-perception of poor health were significantly related with AEs ≥ G3. A predicting model with these six variables ranging 0–8 points was selected with the highest discriminatory ability (c-statistic= 0.646), which could classify patients into four risk groups. Predicted cumulative incidence of AEs ≥ G3 was discriminated according to risk groups. Conclusions This prediction tool could identify the risk of AEs ≥ G3 after chemotherapy and provide information on the cumulative incidence of AEs in each cycle. Clinical Trial Id WHO ICTRP number, KCT0001071

330 Background: HER-RAM study is the phase Ib/II multicenter study to evaluate the safety and efficacy of adding trastuzumab to ramucirumab and paclitaxel as a second-line treatment in HER2-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer progressed from trastuzumab containing chemotherapy. We report survival follow up and exploratory biomarker results. Methods: Patients with HER2-positive advanced G/GEJ cancer who progressed after first-line trastuzumab containing chemotherapy were enrolled. Trastuzumab 4mg/kg on day 1 followed by 2mg/kg on days 8, 15, and 22, ramucirumab 8mg/kg on days 1 and 15, and paclitaxel (dose level 1: 80mg/m2, dose level -1: 70 mg/m2) on days 1, 8, and 15 of a 28-day cycle was tested. After safety analysis of lead-in safety cohort (phase 1b), phase 2 part was conducted to evaluate the primary endpoint of progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: No dose limiting toxicity at the dose level 1 was observed at the phase Ib part, the dose level 1 with full dose combination was determined as recommended phase 2 dose. At the time of data lock on September 7th, 2021, 50 patients including 3 patients from the phase 1b part were evaluable for response and safety. Median age was 60 years old (range 29-82) and most patients were male (40/50). At baseline, 39 patients had tumors with HER-2 3+ by immunohistochemistry (IHC) and 11 had those with HER-2 2+ by IHC with ERBB2 amplification by in situ hybridization. With median follow-up duration of 18.8 months, median PFS and OS were 7.0 months (95% confidence interval [CI]: 4.9-9.2 months) and 13.6 months (95% CI: 9.5-17.6 months), respectively. ORR was 54% (27/50, complete response = 1, partial response = 26) and DCR was 96% (48/50), respectively. On the exploratory analysis, HER-2 positivity of tumor tissue was lost after fist-line chemotherapy in 8 of 23 patients (34.7%) without any definite association between loss of HER-2 and outcomes. Most common hematologic adverse event (AE) was neutropenia (all grade: 64%, grade 3/4: 52%) with 1 case of febrile neutropenia (2%). Most common non-hematologic AE was peripheral sensory neuropathy and anorexia (all grade: 32%, grade 3: 2%, respectively). Gastrointestinal (GI) bleeding occurred in 6 cases (grade 3 upper GI bleeding: 3 patients, grade 1/2 lower GI bleeding: 3 patients), whereas GI perforation was not observed. Hypertension occurred in 3 patients (grade 1/2: 1 patient, grade 3: 2 patients). No new or unexpected AEs were observed. Conclusions: The continuous use of trastuzumab in combination with ramucirumab and paclitaxel showed promising activity and manageable safety profile in HER2-positive G/GEJ cancer patients who progressed after trastuzumab containing chemotherapy. Clinical trial information: NCT04888663.

The role of sodium caprate (C10) in enhancing drug absorption is well established; however, little information is available on its role as an anticancer drug. This study aimed to evaluate the anticancer effect of C10 in gastric cancer cells. The mechanism of cytotoxicity of C10 was evaluated by western blotting following treatment of the gastric cancer cells with various concentrations of C10. C10 cytotoxicity was measured via MTS (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium), lactate dehydrogenase (LDH), cAMP, and ATP assays. Gastric cancer cells were observed by electron microscopy following treatment with C10. Then, xenograft mice that were inoculated with gastric cancer cells were treated with C10 for 4 weeks, after which the changes in tumor size were measured. C10 triggered apoptosis in the gastric cancer cells through the mitochondrial pathway at concentrations of more than 0.2 mM. However, 15 mM of C10 induced necrosis in gastric cancer cells by causing cellular swelling and the formation of holes in the cell membrane. Levels of cAMP and ATP decreased significantly following exposure to 15 mM C10 for 1 h. Additionally, the size of the xenograft tumors was significantly reduced by 24% after 4 weeks of C10 treatment ( p < 0.05). This study indicates that C10 induces apoptosis and necrosis in a concentration-dependent manner and has clear anticancer effects on gastric cancer cells.

BACKGROUND To assess whether the rotation of dexamethasone to methylprednisolone decreases the intensity of dexamethasone-induced hiccup (DIH) in cancer patients treated with chemotherapy. MATERIALS AND METHODS Adult patients who experienced DIH within 3 days after the administration of dexamethasone as an antiemetic were screened. Eligible patients were randomly assigned to receive dexamethasone (n = 33) or methylprednisolone (n = 32) as an antiemetic (randomization phase). In the next cycle of chemotherapy, the dexamethasone group received methylprednisolone and vice versa in the methylprednisolone group (crossover phase). The primary endpoint was the difference in hiccup intensity as measured using the numeric rating scale (NRS) between two groups. RESULTS No female patients were enrolled, although the study did not exclude them. At the randomization phase, hiccup frequency was 28/33 (84.8%) in the dexamethasone group versus 20/32 (62.5%) in the methylprednisolone group (p = .04). Intensity of hiccup was significantly higher in the dexamethasone group than that in the methylprednisolone group (mean NRS, 3.5 vs. 1.4, p

Ubiquitin-specific proteases (USPs) play an important role in fundamental cellular processes. Among these, USP10 is known for its association with tumor development and progression of multiple cancers. We aimed to investigate the clinical significance of USP10 expression in colorectal cancer and examined the potential link between USP10 and p14ARF in patients with colorectal cancer. USP10 and p14ARF protein expression was assessed via immunohistochemistry (IHC) on a tissue microarray from 280 colorectal cancer cases. IHC scores were evaluated by digital image analysis and compared with patients' outcomes. In addition, we examined DNA hypermethylation in colorectal cancer cell lines and tissues, which were matched with adjacent normal colon samples. USP10 expression was lost (USP10loss) in 18.6% of samples (52/280 cases), which was linked to lymphovascular invasion (p = 0.019) and distant metastases (p < 0.001). Similarly, loss of p14ARF expression (p14ARFloss) was associated with more advanced tumors. USP10 expression correlated positively with p14ARF expression (r = 0.617, p < 0.001). USP10loss, p14ARFloss, and dual loss of USP10 and p14ARF were significantly associated with shorter disease-free survival and overall survival in comparison to USP10intact, p14ARFintact, and dual loss of USP10 and p14ARF, respectively. Multivariate analysis revealed that USP10loss (p = 0.030) and dual loss of USP10 and p14ARF (p = 0.014) are independent prognostic factors for poor disease-free survival in colorectal cancer patients. Furthermore, aberrant hypermethylation of the USP10 promoter region was found in colorectal cancer cell lines and tissues. The present results suggest that USP10loss is a potential prognostic marker for colorectal cancer.

PurposeThe purpose of this study was to compare ramosetron (RAM), aprepitant (APR), and dexamethasone (DEX) [RAD] with palonosetron (PAL), APR, and DEX [PAD] in controlling highly-emetogenic chemotherapy (HEC)–induced nausea and vomiting. Materials and MethodsPatients were randomly assigned (1:1) to receive RAD or PAD:RAM (0.3 mg intravenously) or PAL (0.25 mg intravenously) D1, combined with APR (125 mg orally, D1 and 80 mg orally, D2-3) and DEX (12 mg orally or intravenously, D1 and 8 mg orally, D2-4). Patients were stratified by gender, cisplatin-based chemotherapy, and administration schedule. The primary endpoint was overall complete response (CR), defined as no emesis and no rescue regimen during 5 days of HEC. Secondary endpoints were overall complete protection (CP; CR+nausea score < 25 mm) and total control (TC; CR+nausea score < 5 mm). Quality of life was assessed by Functional Living Index Emesis (FLIE) questionnaire on D0 and D6.ResultsA total of 279 patients receiving RAD (n=137) or PAD (n=142) were evaluated. Overall CR rates in RAD and PAD recipients were 81.8% and 79.6% (risk difference [RD], 2.2%; 95% confidence interval [CI], −7.1 to 11.4), respectively. Overall CP and TC rates for RAD and PAD were 56.2% and 58.5% (RD, −2.3%; 95% CI, −13.9 to 9.4) and 47.5% vs. 43.7% (RD, 3.8%; 95% CI, −7.9 to 15.5), respectively. FLIE total score ≥ 108 (no impact on daily life) was comparable between RAD and PAD (73.9% vs. 73.4%, respectively). Adverse events were similar between the two groups.ConclusionIn all aspects of efficacy, safety and QOL, RAD is non-inferior to PAD for the control of CINV in cancer patients receiving HEC.

Neutrophil-to-lymphocyte ratio (NLR) is associated with poor prognosis in patients with lung cancer, but the predictive role of NLR on the risk of developing lung cancer is unknown. We investigated the association between NLR and lung cancer mortality in lung cancer-free adults. A cohort study was performed with 527,124 Korean adults who were free of lung cancer and were followed for up to 16 years. Vital status and lung cancer-related deaths were ascertained through national death records. Hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer mortality were estimated using a Cox proportional hazards model. During 4,567,495.8 person-years of follow-up, 574 lung cancer deaths were identified. A higher NLR was positively associated with lung cancer mortality. The multivariable-adjusted HR (95% CI) for lung cancer mortality comparing quintiles 2, 3, 4 and 5 of NLR to the lowest quintile were 1.26 (0.96-1.67), 1.23 (0.93-1.63), 1.33 (1.01-1.75) and 1.47 (1.13-1.92), respectively. The highest risk of lung cancer mortality was also observed in the highest NLR quintile among never-smokers and low-risk individuals after adjusting for lung function and other possible confounders. Platelet-to-lymphocyte ratio showed an inverse J-shaped association with lung cancer mortality in men but the trends in women, low-risk individuals or never-smokers were neither linear nor U-shaped. In this large cohort of young and middle-aged individuals, NLR was independently associated with increased risk of lung cancer mortality in low-risk individuals, indicating a role of systemic inflammation in lung cancer mortality in our study population.

Background: Pembrolizumab monotherapy did not improve overall survival compared with paclitaxel in second-line treatment for AGC in Keynote-061. Here, we report the results of patients (pts) with evaluable lesions treated with combination of nivolumab (Nivo) and paclitaxel (PTX) in AGC who progressed on first-line chemotherapy with a platinum and fluoropyrimidine. Methods: This open label, single arm, phase 1b/2 study is part of biomarker-integrated umbrella study conducted at multi-centers in South Korea. Phase 1b included 6 all-comer pts irrespective of biomarkers in a 3+3 design. In phase 2, 47 pts with either EBV-related, deficient mismatch repair (dMMR)/MSI-H or PD-L1 positive were enrolled. PD-L1 was defined as combined positive score (CPS) of >1. The primary endpoints were determining maximum tolerated dose (MTD) and recommended phase II dose (RP2D) for phase 1b, and progression-free survival (PFS) for phase 2. Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), PFS rate at 6 months and toxicity. Results: In phase 1b, dose limiting toxicities were not observed, and the RP2D was Nivo (3 mg/kg on days 1 and 15) combined with PTX (80 mg/m2 on days 1, 8 and 15) every 28 days. Phase 2 pts included CPS >1 (n=41), EBV positive (n=2), and 4 patients showed more than one biomarkers: CPS >1, EBV positive (n=2), CPS >1, dMMR/MSI-H (n=1), and CPS >1, EBV positive, dMMR/MSI-H (n=1). With a median follow-up period of 12.1 months, 7 pts remain on treatment (treatment duration: 1.1 to 23.1 months) as of August, 2020. In patients with measurable lesions (n=33), ORR was 24% (CR 9%, PR 15%) and DCR was 39%. Median duration of response was 18.4 months (95% CI, 3.2-19.8). Median PFS was 3.9 months (95% CI, 2.9-4.9) and PFS rate at 6 months was 32%. Median OS was 18.9 months (95% CI, 8.8-28.9). There was no statistical difference in PFS or OS by all biomarkers, including CPS cutoff for 1, 5, and 10. Of the 40 pts who had disease progression, 23 pts (49%) were treated with subsequent therapy. Treatment-related AEs (≥G3) occurred in 22 pts (47%), and immune-related AE (>G3) was observed in 3 pts (6%), including pneumonitis (G3) (n=1, 2%). Exploratory analysis of 13 cytokines from plasma at baseline showed an increase of interleukin-1 receptor antagonist (IL-1ra) (p=0.05), and increasing tendency of IL-8 and IL-12 in non-responders (PFS 8 mo.). Conclusion: Combination of Nivo and PTX demonstrated antitumor activity with manageable toxicity profiles as second-line treatment for AGC. Genomic analysis of tumor tissues by targeted next-generation sequencing are awaiting. Clinical trial information: NCT02951091 Citation Format: Rha Sun Young, Jii Bum Lee, Hyo Song Kim, Minkyu Jung, Choong-kun Lee, Sook Ryun Park, Dong-Hoe Koo, Hyun Woo Lee, Woo Kyun Bae, Hei Cheul Jeung, Hyun Cheol Chung. Open label, single-arm, multi-center phase Ib/II study to evaluate the safety and efficacy of nivolumab in combination with paclitaxel in Epstein-Barr virus (EBV)-related, or microsatellite instability-high (MSI-H), or programmed cell death ligand 1 (PD-L1) positive advanced gastric cancer (AGC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT159.

4063 Background: We evaluated the safety and efficacy of adding trastuzumab to ramucirumab and paclitaxel (TRP) as a second line treatment in human epidermal growth factor receptor 2 (HER-2)-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer progressed from trastuzumab containing chemotherapy. Methods: Patients with HER-2-positive advanced G/GEJ cancer who progressed after first-line chemotherapy with trastuzumab in combination with fluoropyrimidine and platinum were eligible. Trastuzumab (Herzuma[CT-P6], Celltrion Inc.) 4mg/kg on day 1 followed by 2mg/kg on days 8, 15, and 22, ramucirumab 8mg/kg on days 1 and 15, and paclitaxel (dose level 1: 80mg/m2, dose level -1: 70 mg/m2) on days 1, 8, and 15 of a 28-day cycle was tested. After safety analysis of lead-in safety cohort (phase 1b), phase 2 part was conducted to evaluate the primary endpoint of progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: At the phase 1b part, as there was no dose limiting toxicity in 3 patients at the dose level 1, dose level 1 with full dose combination was determined as recommended phase 2 dose. At the time of data lock on Jan. 31, 2021, 45 patients among enrolled 50 patients were evaluable for response and safety including 3 patients from phase 1b part. Median age was 59 years old (range 30-82) and most patients were male (37/45). At baseline, 33 patients had tumors with HER-2 3+ by immunohistochemistry (IHC) and 12 had those with HER-2 2+ by IHC with ERBB2 amplification by in situ hybridization. With median follow-up duration of 11.6 months, median PFS and OS were 7.2 months (95% confidence interval [CI]: 6.0-8.5 months) and 13.6 months (95% CI: 10.3-16.9 months), respectively. ORR was 55.6% (25/45, complete response = 1, partial response = 24) and DCR was 95.6% (43/45), respectively. Most common hematologic adverse event (AE) was neutropenia (all grade: 64.4%, grade 3/4: 51.1%) with 1 case of febrile neutropenia (2.2%). Most common non-hematologic AE was peripheral sensory neuropathy (all grade: 33.3%, grade 3: 2.2%). Gastrointestinal (GI) bleeding occurred in 4 patients (grade 3 upper GI bleeding: 6.7%, grade 1 lower GI bleeding: 2.2%), whereas GI perforation was not observed. Hypertension occurred in 3 patients (all grade: 6.7%, grade 3: 4.4%). No new or unexpected AEs resulting in treatment cessation were observed with this combination regimen. Conclusions: The continuous use of trastuzumab beyond progression in combination with ramucirumab and paclitaxel showed promising activity and manageable safety profile in HER2 positive G/GEJ cancer patients who progressed after trastuzumab containing chemotherapy. Updated outcomes for ongoing patients will be presented.

PURPOSE This study was conducted to explore the process and operation of a cancer multidisciplinary team (MDT) after the reimbursement decision in Korea, and to identify ways to overcome the major barriers to effective and sustainable MDTs. MATERIALS AND METHODS Approximately 1,000 cancer specialists, including medical oncologists, surgical oncologists, radiation oncologists, pathologists, and radiologists in general hospitals in Koreawere invited to complete the survey. The questionnaire covered the following topics: organizational structure of MDTs, candidates for consulting, the clinical decision-making initiative, and responsibility for dealing with legal disputes. RESULTS We collected a total of 179 responses (18%) from physicians at institutions where an MDT approach was active. A surgical oncologist (91%), internist (90%),radiologist (89%),radiation oncologist (86%), pathologist (71%), and trainees (20%) regularly participated in MDT operations. Approximately 55% of respondents stated that MDTs met regularly. In cases of a split opinion, the physician in charge (69%) or chairperson (17%) made the final decision, and most (86%) stated they followed the final decision. About 15% and 32% of respondents were "very satisfied" and "satisfied," respectively, with the current MDT's operations. Among 38 institutional representatives, 34% responded that the MDT operation became more active and 18% stated an MDT was newly implemented after the reimbursement decision. CONCLUSION The reimbursement decision invigorated MDT operations in almost half of eligible hospitals. Dissatisfaction regarding current MDTs was over 50%, and the high discordance rates regarding risk sharing suggest that it is necessary to revise the current system of MDTs.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors originating in the gastrointestinal tract. With the introduction of molecular-targeted therapy for GISTs which has yielded remarkable outcomes, these tumors have become a model of multidisciplinary oncological treatment. Although Western clinical guidelines are available for GISTs, such as those published by the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology (ESMO), the clinical situations in Asian countries are different from those in Western countries in terms of diagnostic methods, surgical approach, and availability of new targeted agents. Accordingly, we have reviewed current versions of several GIST guidelines published by Asian countries (Japan, Korea, China, and Taiwan) and the NCCN and ESMO and discussed the areas of dissensus. We here present the first version of the Asian GIST consensus guidelines that were prepared through a series of meetings involving multidisciplinary experts in the four countries. These guidelines provide an optimal approach to the diagnosis and management of GIST patients in Asian countries.

BACKGROUND/AIMS Aberrant DNA methylation has a specific role in field cancerization. Certain molecular markers, including secreted frizzled-related protein 2 (SFRP2), tissue factor pathway inhibitor 2 (TFPI2 ), N-Myc downstream-regulated gene 4 (NDRG4) and bone morphogenic protein 3 (BMP3), have previously been shown to be hypermethylated in colorectal cancer (CRC). We aim to examine field cancerization in CRC based on the presence of aberrant DNA methylation in normal-appearing tissue from CRC patients. METHODS We investigated promoter methylation in 34 CRC patients and five individuals with normal colonoscopy results. CRC patients were divided into three tissue groups: tumor tissue, adjacent and nonadjacent normal-appearing tissue. The methylation status (positive: methylation level >20%) of SFRP2 , TFPI2 , NDRG4 , and BMP3 promoters was investigated using methylation-specific PCR. RESULTS The methylation frequencies of the SFRP2 , TFPI2 , NDRG4 and BMP3 promoters in tumor/adjacent/nonadjacent normal-appearing tissue were 79.4%/63.0%/70.4%, 82.4%/53.6%/60.7%, 76.5%/61.5%/69.2%, 41.2%/35.7%/50.0%, respectively. The methylation levels of the SFRP, TFPI2, NDRG4 and BMP3 promoters in tumor tissues were significantly higher than those in normal-appearing tissue (SFRP2, p=0.013; TFPI2, p

218 Background: We report the updated clinical data and molecular profiling results of a multi-institutional phase Ib/II trial of triple combination (pembrolizumab, trastuzumab, and chempotherapy) as first line therapy for HER2 positive advanced gastric and gastroesophageal junction (AGC/GEJ) cancer. (PANTHERA trial; NCT02901301). Methods: Pembrolizumab 200mg IV D1, Trastuzumab 6mg/kg (after 8mg/kg load) D1, Capecitabine 1000mg/m2 bid D1-14, and Cisplatin 80mg/m2 D1 every 3 weeks was selected as recommended phase II dose. The primary endpoint for phase II was ORR per RECIST v1.1. Secondary endpoints included PFS, OS, DOR, safety, and predictive biomarker analysis by targeted NGS. Results: At the time of data lock on Aug 31, 2020, total of 43 patients were treated with median follow up of 18.2 months, and 3 patients remained on the treatment, and 6 patients finished 2-year treatment without progression. ORR was 76.7% (CR 16.3%, PR 60.5%, conversion surgery 4.6%) with 26 pts (56.6%) showing more than 50% of tumor burden reduction. Median PFS was 8.6 months (95% CI 7.2-16.5) and median OS was 19.3 months (95% CI 16.5-NR). There were no MSI-H/dMMR or EBV-positive pts. No patient discontinued pembrolizumab because of immune-related adverse events. Clinical features including PD-L1 status (55.3% of pts ≥ CPS 1 and 13.2% of pts ≥ CPS 10 among available 38 pts), metastatic organ or baseline tumor burden was not related to the survival. Ninety-eight tumor tissues from 39 pts (paired tumor tissues from 22 pts) were analyzed with targeted NGS. Although every pts were HER2 IHC-positive, baseline HER2 amplification by NGS was related to the survival ( HER2 amp (n=8) vs HER2 non-amp (n=23); mPFS, not reached vs 7.7 months, P=0.0178; mOS, not reached vs 17.9 months, P=0.044) but no other signaling pathways predicted pts’ survival. HER2 mutations including L869R or D769H were related to the acquired resistance. High TMB showed a tendency toward better survival (mPFS; High (n=7) vs Low (n=24) TMB, 22.0 vs 8.2, P=0.2835) due to small number of patients. Updated immune markers and serial NGS analyses will be presented. Conclusions: First-line triplet regimen (Pembrolizumab, Trastuzumab, and Chemotherapy) showed promising efficacy based on HER2 amplification by NGS regardless of PD-L1 status in AGC/GEJ cancer. Correlative biomarkers found from NGS study need to be validated through on-going phase III Keynote-811 study. Clinical trial information: NCT02901301. [Table: see text]