bluuebunny/crossref_metadata_2025 huggingface dataset:
Emergence of RAS mutations in RAS wild type metastatic colorectal cancer patients receiving cetuximab as first-line treatment: A prospective study.
Authors: Tsai Hsiang-Lin , Wang Jaw-Yuan
Published: January 2023

38

Background: Metastatic colorectal cancers (mCRC) with wild-type KRAS are often sensitive to anti-EGFR, but occasionally develop resistance within treatment. A major limitation of treatment that selectively target kinase signaling pathways is the emergence of secondary resistance. However, interlink between emergence of KRAS mutations and secondary resistance to anti-EGFR remains to be further elucidated. In this study, we investigate evolutional changes of KRAS mutations through liquid biopsy in mCRC patients under cetuximab-treatment. Methods: Patients enrolled to receive cetuximab plus FOLFIRI or mFOLFOX6 as first-line treatment. The treatment was anticipated to be continued until disease-progression, intolerable toxic effects, or withdrawal of consent. Blood samples from patients were collected before and every three months during the cetuximab-treatment, and were required at disease-progression. These samples were evaluated for KRAS mutation using the MassARRAY platform. The primary endpoint was the percentage of patients with KRAS mutation detected during treatment. The clinical outcomes of these patients with emergence of mutant KRAS were further analyzed. Results: 108 mCRC cetuximab-treated patients, 95 patients combined with FOLFIRI and 13 patients with mFOLFOX6, were enrolled between January 2018 and June 2020. The median follow-up time was 26.5 months [interquartile range (IQR), 17.0-37.0 months]. The median duration of cetuximab-treatment was 9.0 months (IQR, 5.0-12.0 months). The percentage of detected KRAS mutations during cetuximab-treatment was 9.26%. Median emergent time of KRAS mutation from initial treatment was 5.0 months (IQR, 2.0-7.5 months). The median duration from KRAS mutation to disease-progression was 3.0 months (IQR, 2.0-6.5 months). The median progression-free survival (PFS) and overall survival (OS) of emergent RAS mutations and RAS wild-type were 8.0 versus 19.0 months ( P = 0.002) and 20.0 versus not-reach months ( P = 0.027), respectively. Conclusions: The identified KRAS mutations as a predictor of early resistance during cetuximab therapy, indicating that emergence of KRAS-mutant clones can be detected 3 months prior to radiographic progression. Emergent RAS mutations were associated with less favorable patient outcomes. Clinical trial information: NCT03401957 .
Five-year follow-up results of a randomized phase III trial comparing 4 and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer: JCOG1104 (OPAS-1).
Authors: Nunobe Souya , Yoshikawa Takaki , Nishida Yasunori , Yamada Takanobu , Kaji Masahide , Takagane Akinori , Teshima Shin , Matsushita Hisayuki , Tanaka Ryo , Hihara Jun , Katayama Hiroshi , Mizusawa Junki , Fukuda Haruhiko , Boku Narikazu , Terashima Masanori
Published: January 2023

381

Background: Postoperative S-1 (80 mg/m2/day for 4 weeks and 2 weeks rest in one course) for 1 year corresponding to 8 courses is a standard adjuvant chemotherapy for pathological stage (pStage) II gastric cancer. To shorten the duration of S-1 chemotherapy, we conducted a phase III trial to confirm non-inferiority in relapse-free survival (RFS) of 4 courses of S-1 to 8 courses of S-1 for pStage II gastric cancer. When 590 patients were enrolled, the study was closed at the first interim analysis because of futility. The RFS at 3 years was 89.8% for 4-courses and 93.1% for 8-courses (HR 1.84, 95% confidence interval (CI) 0.93-3.63). This is a final 5-year follow-up results of this study. Methods: Key eligibility criteria were pStage II except for T1 and T3N0 (7th edition of TNM), ECOG performance status 0-1, R0 resection with D2 lymph node dissection for >clinical stage (cStage) II or D1+ lymph node dissection for cStage I, within 7 weeks after surgery, and age between 20 and 80 years. The total sample size was determined to be 1,000 with a 3-year RFS of 85% in both arms and non-inferiority margin of hazard ratio (HR) of 1.37, with one-sided alpha of 5% and 80% power. Results: Between Feb 2012 and Mar 2017, 590 patients, 295 for each arm, were enrolled. When closing the study, the patients who were allocated to the 4-courses arm were informed of the primary results and the recommendation to continue S-1 until 8 courses as an off-protocol when they were receiving S-1. The cut-off date for the final follow-up data was March 22, 2022 with a median follow-up period for surviving patients of 6.0 years (IQR; 5.0-7.2). In 4-courses arm, 27 patients were receiving S-1 when the study was closed at the interim analysis. Among them, 22 patients expressed their will to continue until 8 courses. The RFS at 3/5 years was 90.1%/85.6% for 4-courses and 92.2%/87.7% for 8-courses (HR 1.27, 95% CI 0.85-1.89). The overall survival at 3/5 years was 93.2%/88.6 for 4-courses and 94.9%/89.7 for the 8-courses (HR 1.12, 95% CI 0.72-1.75). The HR of the cumulative incidence of the recurrence was 1.38 (95% CI 0.85-2.24) for the 4-courses against 8-courses. Recurrence was frequently observed in patients who received up to 4 courses of S-1 (38 for 4-courses vs. 28 for 8 courses). The HR of the cumulative incidence of the peritoneal recurrence was 1.54 (95% CI 0.82-2.89) for the 4-courses against 8-courses. Conclusions: This final follow-up data confirmed the primary results presented at the interim analysis. S-1 adjuvant chemotherapy for 1 year for pStage II gastric cancer is highly recommended. Clinical trial information: 000007306 .
The effect of potassium-competitive acid blocker tegoprazan on gastric cancer cells.
Authors: Lee Sang Kil
Published: January 2023

385

Background: Proton pump inhibitors (PPI) and potassium-competitive acid blocker (P-CAB) are both effective gastric acid secretion blockers. PPI was reported to inhibit proliferation and induce apoptosis of gastric cancer. However, no study on the effect of Tegoprazan, a novel P-CAB, on gastric cancer have been attempted. Methods: In this study, the anti-cancer effect of tegoprazan in gastric cancer cell line AGS and MKN74 were analyzed with esomeprazole (PPI) as a control. After treatment with tegoprazan and esomeprazole, AGS cells were analyzed with with RNA sequencing and Ingenuity Pathway Analysis (IPA). MTT assays, AnnexinV-FITC/PI staining, flow cytometry and western blot were used for subsequent analysis. The wound-healing assay, matrigel chamber assays, colony forming assay, and western blot of epithelial-mesenchymal transition (EMT) markers were used for analysis of oncogenic and migratory ability. Results: In RNA sequencing and subsequent IPA analysis, tegoprazan significantly increased the pathways involved in cell death of gastric cancer cell compared to esomeprazole. MTT assays proved that tegoprazan inhibits proliferation of AGS and MKN74 cells in dose-dependent manner. AnnexinV-FITC/PI staining and western blot demonstrated that tegoprazan stimulates apoptosis of gastric cancer cells. PI staining and flow cytometry confirmed that tegoprazan blocks G1/S phase entry, finally leading to cell cycle arrest. Moreover, wound-healing assay, matrigel chamber assays, colony forming assay, and western blot of epithelial-mesenchymal transition (EMT) markers indicated that tegoprazan inhibits cell migration, invasion, colony formation, and EMT. To determine key molecule of anti-cancer effect of tegoprazan, upstream regulator analysis in IPA was done and cMYC has strong effect on G1/S phase entry, through PI3K/AKT/GSK3β signaling pathway in this experiment. In this study, the experimental results for tegoprazan showed significant changes compared to esomeprazole. Conclusions: Our findings showed that tegoprazan has more evident anti-cancer effect than esomeprazole. cMYC could be a key molecule for anti-cancer effect through PI3K/AKT/GSK3β signaling pathway by tegoprazan in gastric cancer.
Local recurrence after curative resection of early gastric cancer by endoscopic submucosal dissection.
Authors: Joo Moon Kyung , Park Jong-Jae , Lee Beom Jae , Kim Sunsuk , Chun Hoon Jai
Published: January 2023

388

Background: We investigate the local recurrence rate and its risk factors among patients who underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) and are judged as curative resection. Methods: We enrolled patients who were diagnosed as EGC and underwent ESD during 2006 and 2020. Local recurrence after ESD was confirmed by histopathologic evaluation by endoscopic biopsy at ESD site during endoscopic surveillance. Results: A total of 936 patients underwent ESD for EGC, achieved curative resection and were followed up more than 12 months. Among them, 14 cases of local recurrence were found (14/936, 1.5%) during 53.2 months of follow-up. Compared with patients without local recurrence, those with local recurrence showed male-predominance (677/922 vs. 14/14, P=0.025), frequent presence of synchronous tumor (123/922 vs. 6/14, P=0.001) and larger tumor size (16.3 vs. 26.3 mm, P=0.001). Kaplan-Meier graph also showed that local recurrence significantly occurred in subgroup with male, presence of synchronous tumor and tumor size ≥ 20 mm ( P=0.028, 0.009 and <0.001 by log rank test, respectively). After propensity score matching for gender, age and comorbidities with 1:5 ratio, tumor size ≥ 20 mm was the only significant factor for local recurrence (odds ratio: 3.886, 95% confidence interval: 1.012-14.922, P=0.048) Conclusions: Endoscopists need to be cautious for local recurrence at ESD site even after curative resection of EGC, especially for large tumor size.
Tislelizumab combined with anlotinib and chemotherapy (XELOX) in the treatment of advanced gastric carcinoma: Preliminary results of a single-arm, open-label phase I/IIa trial (TALENT study).
Authors: Chen Xiaofeng , Wang Deqiang , Yuan Yuan , Tang Jie , Guo Fen , Chen Yizhang , Ding Junli , Hong Tingting , Lu Binbin , Li Wei , Wang Rong , Tian Yitong , Pan Lanlan , Zhang Jiaguang , Zhang Xinyi , Xu Tongpeng , Xu Hao , Shu Yongqian
Published: January 2023

396

Background: PD-1 inhibitor combined with chemotherapy is one of the standard regimens for first line gastric. The addition of anti-vascularization agents has been reported to help improve the overall survival (OS) in GC/GEJC patients (pts) through vascular-normalization in the microenvironment. In this phase I/IIa study, we aim to explore the safety and efficacy of tislelizumab combined with anlotinib and XELOX (TAXE regimen) as first line treatment for advanced GC/GEJC. Methods: This prospective, multicenter, phase I/IIa study planned to enroll 9 patients in phase I and 57 patients in Phase IIa. The aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and safety of 8 mg, 10 mg or 12 mg anlotinib in combination with XELOX and tislelizumab. The maximum tolerable dosage (MTD) would be administered to all pts in phase II. The primary and objective response rate(ORR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), OS, and safety. The exploring endpoint was to evaluate the association between the efficacy and the expression of biomarkers including PD-L1, microsatellite instability profile, and genome stability (GS). Results: From march 2021 to August 2022, 38 pts were enrolled (9 pts in phase 1). Phase 1 was completed without dosage limiting toxicities (DLTs). 12mg anlotinib was recommended for phase 2. Thirty two (84.21%) pts had at least one treatment-related adverse events (TRAEs), and 7 patients (18.42%) had at least one grade 3/4 TRAEs. Anemia (15 pts, 39.47%), leukopenia (12 pts, 31.58%) and fatigue (10 pts, 26.32%) were the most common TRAEs. Two pts achieved complete response (CR), 20 pts achieved partial response (PR), and 7 pts achieved stable disease (SD). The ORR was 75.86% (95% CI: 57.89%-87.78%), and the DCR was 100%. Conclusions: The preliminary results of this Phase I/IIa trial by using tislelizumab combined with anlotinib and XELOX had shown great potential in improving the response rate in advanced GC/GEJC patients with manageable toxicity. Clinical trial information: NCT04963088 .
A phase II biomarker-oriented study to evaluate paclitaxel, olaparib, and durvalumab combination in patients with advanced gastric cancer.
Authors: Kim Tae-Yong , Yoon Jeesun , Lee Dae-Won , Im Seock-Ah , Nam Ah-Rong , Bang Ju-Hee , Oh Kyoung-Seok , Kim Jae-Min , Jeong Yoojin , Choo Sea Young , Kim Hyo Jung , Lee Su In , Oh Do-Youn
Published: January 2023

404

Background: DNA damage response (DDR) gene alterations are observed in 27% of gastric cancer (GC), therefore, targeting DDR might be an interesting strategy in GC. Olaparib plus paclitaxel showed numerically improved overall survival (OS) compared to paclitaxel in 2L GC patients (pts), even though it did not meet the endpoint. (Lancet Oncol 2017). Besides DNA damage repair, olaparib induces immune modulation. The role of immune checkpoint inhibitor (ICI) is established in 1L and 3L+ GC. The combination of cytotoxic chemotherapy, DDR acting agent and ICI might have synergistic effects in GC, which has not been tested in clinical studies. Here, we report biomarker-oriented phase II study of paclitaxel/olaparib/durvalumab combination in 2L GC. (NCT03579784). Methods: Advanced GC pts who have failed to 1L chemotherapy were enrolled. During 1st cycle, paclitaxel (80 mg/m2, D1, 8, 15 Q 4wk) and olaparib (150mg bid, D1-28) was administered. From 2nd cycle, durvalumab (1500 mg, D1 Q 4wk) was added on them. Tumor biopsy (pretreatment, after 1st cycle, at disease progression) and blood collection (every cycle) was mandatory. Primary endpoint was the disease control rate (DCR). Secondary endpoints included ORR, DoR, PFS, OS and safety. For biomarker study, multiplex IHC, NGS, ctDNA, and cytokines and angiogenic factors analysis were performed. Efficacy analysis set (ES) and safety analysis set (SS) were defined as pts who underwent at least one tumor assessment and all pts who received cycle1 day1 or more, respectively. Results: Fifty pts were enrolled (6 screening fail or withdrawal of consent, 44 in SS, 38 in ES) HER2+ GC were 13.2%. Among 38 in ES, DCR and ORR were 84.1% (95% CI, 72.5-95.7) and 39.5% (95% CI, 24.0-55.0) (1 CR, 14 PR and 17 SD). PFS, DoR and OS were 6.7 (95% CI, 4.5-10.3), 6.5 (95% CI, 5.1-10.7) and 11.4 (95% CI, 9.2-13.2) months. Homologous recombination repair (HRR) genetic alterations (9.6 vs. 5.9 in PFS, p=0.037), high CD8/CD3 ratio (8.8 vs. 3.7 in PFS, p=0.008), high PD-L1 (CPS≥10) (9.6 vs 5.1 in PFS, p=0.031), low ATM IHC (13.3 vs. 9.8 in OS, p=0.066), and low serum IL-6 (12.9 vs. 8.3 in OS, p=0.001) were associated with prolonged PFS or OS. In SS, most adverse events (AEs) were mild, and Gr 3/4 leukopenia and anemia were observed in 52.2% and 31.8%. There were no treatment related AEs resulted in study discontinuation. Conclusions: Paclitaxel/olaparib/durvalumab is a promising combination in 2L GC, and is worth to be further explored, especially in biomarker-enriched patients with HRR, specific T-cells subsets, high PD-L1, low ATM and IL-6. Clinical trial information: NCT03579784 .
Endoscopic prediction of depth of tumor invasion in early gastric cancer in the upper third of the stomach.
Authors: Moon Hee Seok , Cnuhgi Cnuhgi
Published: January 2023

406

Background: The endoscopic features of early gastric cancer (EGC) arising from the upper third of the stomach (upper body, fundus, and cardia) has not been well studied. If EGC in the upper third of the stomach can be predicted to have invaded the mucosal (M) or submucosal (SM) layer, endoscopic or surgical treatment can be determined. This study evaluated the endoscopic features of EGC in the upper third of the stomach as well as risk factors for SM invasion. Methods: We retrospectively reviewed patients' medical records from a single tertiary hospital (Daejeon) and investigated endoscopic findings and clinical data. Patients with EGC in the upper third of the stomach who underwent surgery or endoscopic resection between January 2016 and April 2022 were included. Logistic regression was used to determine the risk factors of the SM cancer group. Results: In total, 173 patients were enrolled in this study: 94 with SM cancer and 79 with M cancer. Risk factors for SM invasion determined by univariate logistic regression were clubbing of converging folds (OR 6.279, p=0.000), fusion of converging folds (OR 9.179, P=0.000), irregular nodule in the central lesion (OR 2.336, p=0.016), margin with elevation (OR 2.520, P=0.031), and ulceration (OR 9.686, p=0.000). However, in the multivariate logistic regression analysis, only ulceration was identified as a risk factor (OR 6.598, p=0.007). Conclusions: In EGC occurring in the upper third of the stomach, ulceration is a risk factor for SM invasion. Surgical treatment should be considered if this characteristic is present.
Anlotinib combined with paclitaxel and cisplatin as neoadjuvant treatment for esophageal squamous cell carcinoma (ESCC).
Authors: Jiang Gongqian , Wang Guolei
Published: January 2023

409

Background: Preoperative chemoradiotherapy before esophagectomy in esophageal squamous cell carcinoma (ESCC) can obtain significant survival benefits for patients compared with surgery alone. The antiangiogenic drugs have shown efficacy in many cancers including esophageal cancer. The benefits of antiangiogenic drugs in neoadjuvant therapy for ESCC still worth exploring. Anlotinib was an effective second-line monotherapy for ESCC in China and the combination of anlotinib and chemotherapy might be a promising strategy as neoadjuvant treatment. Methods: This was a single-arm, non-interventional study. Patients diagnosed stage II-III ESCC confirmed by histopathology would be enrolled(N=30). Patients received neoadjuvant therapy with anlotinib (12 mg, po, d1-14, 21 days per cycle) combined with paclitaxel (135 mg/m2 iv d1, 21 days per cycle) and cisplatin (60-75mg/m2 iv d1, 21 days per cycle). The primary endpoints were pathologic complete response (pCR) rate, rate of R0 resection and disease-free survival (DFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and safety profile. Results: From July 2020 to September 2022, 20 pts (15 males and 5 females) were enrolled with a median age of 66 years (range: 48-75). 12 pts (60%) had ECOG PS 1, 8 pts had ECOG PS 2. 17/1/2 pts received 2/3/4 cycles of neoadjuvant treatment respectively. In best overall response assessment, ORR was 95% and DCR was 100%. Among them 18 pts underwent esophagectomy and all of them obtained R0 resection, as the rate of R0 resection was 90%. 6 pts (30%) were confirmed to be pCR. The median DFS was not yet available. The safety profile suggested that 3 (15%) pts occurred grade 1-2 treatment-related adverse events (TRAEs), including decreased leukocyte count (5%), diarrhea (5%), nausea and vomiting (5%). No grade ≥3 TRAEs were observed. Conclusions: The preliminary results of this study show promising efficacy and safety of anlotinib combined with paclitaxel and cisplatin as neoadjuvant therapy for patients with esophageal squamous cell carcinoma. More ESCC patients would be recruited in the future. Clinical trial information: ChiCTR2100054374 .
MicroRNAs (miRs) as biomarkers of resistance to trastuzumab in HER2-positive oesophago-gastric cancer: Sub-study within the Planning Treatment for Oesophago-Gastric Cancer—A Randomised Maintenance Therapy Trial (PLATFORM).
Authors: Lote Hazel , Mousoullou Florentia , Vlachogiannis George , Fong Caroline , Satchwell Laura , Peckitt Clare , Begum Ruwaida , Kidd Shannon , Cromarty Susan , Gordon Anderley , Fribbens Charlotte Victoria , Watkins David J. , Rao Sheela , Chau Ian , Starling Naureen , Cunningham David , Valeri Nicola
Published: January 2023

419

Background: A predictive biomarker for resistance to trastuzumab in HER2 positive oesophago-gastric cancer would refine patient selection. Our preclinical studies suggest that patients with HIGH baseline plasma miR-148a-3p levels will experience shorter Overall Survival (OS), Progression Free Survival (PFS), and worse Progression Free Rates (PFR) than those with LOW plasma miR-148a-3p levels. Methods: This sub-study is a prospective biomarker analysis of baseline plasma samples for HER2 positive advanced oesophago-gastric cancer patients registered within Arm B1 of the Phase 2 open label, multicentre, randomised PLATFORM trial (NCT02678182). All HER2 positive patients assessable for clinical response and miR signatures were included. Copies of miR-148a-3p and miR-16 per ml of plasma were quantified using Digital Droplet Polymerase Chain Reaction (ddPCR). OS as primary endpoint for miR-148a-3p LOW (≤median) versus HIGH (>median) was analysed using Kaplan-Meier curves and Cox model regression. Secondary endpoints were PFS and PFR. OS and PFS are from start of 1st line therapy; PFR are from start of maintenance trastuzumab. Sensitivity analysis normalised miR-148a-3p to miR-16. Results: Of 63 patients with analysable lab samples and available survival data, normalisation was possible for 41 patients. Median follow-up was 38 months. There was no statistically significant relationship between OS and miR-148-3p copies/μl of ddPCR reaction LOW versus HIGH (n= 62, Hazard Ratio (HR) 0.98, p=0.933), PFS (n=62, HR 1.08, p=0.759) or PFR (n=31, Odds Radio (OR) 0.67, p=0.577). Normalised miR-148a-3p (NmiR-148a-3p) LOW versus HIGH demonstrated a statistically significant difference in PFR at 3 months (n=23, OR=0.11, p=0.027) but no difference in OS or PFS. A model adjusting for primary tumour site, metastatic disease and number of sites demonstrated a statistically significant difference in PFR at 3 months (aOR=0.03, p=0.029). Conclusions: Patients with HIGH NmiR-148-3p have 0.03 times the odds of being progression-free at 3 months than patients with LOW NmiR-148a-3p in this population, when adjusted for key factors. Limitations include small sample size and normalisation. Clinical trial information: NCT02678182 . [Table: see text]
Sex differences in the clinicopathological and molecular biological features of gastric cancer.
Authors: Terashima Masanori , Yagi Taisuke , Hatakeyama Keiichi , Furukawa Kenichiro , Fujiya Keiichi , Tanizawa Yutaka , Bando Etsuro , Yamaguchi Ken
Published: January 2023

421

Background: The prevalence of gastric cancer is higher in males than in females. Reports have revealed that female gastric cancer patients exhibit some distinctive features, such as a high proportion of undifferentiated cancer and poor survival outcomes. The therapeutic effects of anti-PD-1 antibody have also been reported to be different between males and females. However, precise differences in molecular profiling features between males and females are yet to be reported. To elucidate sex differences in the clinicopathological and molecular biological characteristics of gastric cancer, we performed whole-exon sequencing and comprehensive gene expression analysis. Methods: We compared the clinicopathological factors and disease-specific survival (DSS) in 499 patients who underwent gastrectomy for gastric cancer between January 2014 and April 2019, excluding those with special types of gastric cancer and R2 resection. We also performed whole-exome sequencing using peripheral blood and tumor tissue, gene panel testing, and transcriptome analysis of tumor and nontumor tissues. Results: Among the 499 patients, 358 were male and 141 were female. Women had significantly more undifferentiated and M-region cancers (P < 0.05 for both). In terms of gene mutations, TP53 mutations were significantly more common in males (P = 0.002), whereas CDH1 (P = 0.005), PIK3CA (P = 0.046), and ERBB3 (P = 0.021) mutations were significantly more common in females. Expression profiles reflecting the tumor microenvironment were classified into two groups: T cell high group (290 patients) and T cell low group (209 patients), via cluster analysis. Men in the T-cell high group had significantly better DSS than those in the T-cell low group (P = 0.005), whereas no significant difference was observed among women in the T-cell high and low groups (P = 0.402). Among the 136 genes significantly upregulated in the T-cell high group, CCL18 (P = 0.048) gene was significantly upregulated in males and CD8A (P = 0.026) gene was upregulated in females. Conclusions: TP53 mutations were more common in male patients with gastric cancer, whereas CDH1, PIK3CA, and ERBB3 mutations were more common in female patients with gastric cancer. Additionally, women did not demonstrate good survival outcomes even in the T-cell high group considered to have enhanced tumor immunity.
Multidimensional characterization of early-stage gastric cancer: Preliminary results of MIMETIC trial.
Authors: Catanese Silvia , Catozzi Carlotta , Macandog Angeli Dominique , Fazio Nicola , Fumagalli Uberto , De Roberto Giuseppe , De Pascale Stefano , Funicelli Luigi , Sabbatini Annarita , Gnagnarella Patrizia , Nezi Luigi , Gervaso Lorenzo , Cella Chiara Alessandra
Published: January 2023

422

Background: Gastric adenocarcinoma (GA) represents a leading cause of cancer death worldwide. For localized and locally advanced (LA) GA, accounting for 30% of new diagnoses, surgery, with or without peri-operative chemotherapy (CTX), remains the cornerstone of treatment. Nevertheless, the cure rate remains unsatisfactory. Genomic biomarkers have been tested to tailor anticancer treatments, but no one is able to guide the treatment choice in GA. Gut microbiota represents an emerging area of investigation in cancer, as a key modulator of host immune response. However, its role in GA on treatment tolerability and outcome is not unraveled. Additionally, radiomics, which can perform massive data mining to increase diagnostic power, and extensive dietary assessment are fast-growing tools. Our aim is to set an innovative approach to mapping the interaction among nutrition, microbiome, genomics, and radiomics and correlate them with clinical outcomes. Methods: We are conducting a prospective observational trial in GA patients (pts), candidates to receive peri-operative CTX or upfront surgery. For each patient, we longitudinally collect blood, fecal and salivary samples, alongside clinical and nutritional information. Additionally, past dietary consumption is measured using the food frequency questionnaire. At baseline, CT scan for staging, radiomic analysis, upper digestive endoscopy with biopsy, and molecular biomarkers are performed. Additional samples are taken from tumor and surrounding normal mucosa (1 to 3 cm) for microbiome analysis. Genomic DNA from stool, buccal and gastric tissue samples will be extracted and subjected to 16S metagenomic sequencing. Taxonomic and functional features within and between anatomical compartments will be correlated with clinical and radiomic data. Results: Here, we are presenting preliminary data of fecal samples from 35 GA pts in comparison with a cohort of healthy subjects (HCs) collected at our Institution. Pts’ characteristics are outlined here. We observed that the structure of the gut microbiota of GA pts is distinct from HCs in terms of beta diversity, and this difference is maintained after CTX. In particular, GA’s microbiota was enriched in S. anginosus, among other taxa. Conclusions: Our preliminary data support the feasibility of the study. The differences in structure and composition of the gut microbiota of GA pts compared to HCs confirm previous reports while providing the rationale for developing gut microbiota profiling into a non-invasive biomarker, to implement early diagnosis and prevention. The study is ongoing and actively recruiting.[Table: see text]
Development of a novel chimeric oncolytic viral platform, CF33 and its derivatives, for peritoneal-directed CF33-OV treatment of gastric cancer peritoneal carcinomatosis.
Authors: Yang Annie , Zhang Zhifang , Chaurasiya Shyambabu , Park Anthony K , Jung Audrey , Lu Jianming , Kim Sang-In , Priceman Saul , Fong Yuman , Woo Yanghee
Published: January 2023

428

Background: Peritoneal carcinomatosis (PC) is a deadly end-stage manifestation of gastric cancer (GC). CF33, a chimeric oncolytic virus, and its genetically modified derivatives have shown exclusive cancer selectivity and oncolytic potency against various solid tumors. Intravenous and intratumoral CF33-hNIS and CF33-hNIS-antiPDL1 have entered phase I trials to treat triple-negative breast cancer and unresectable solid tumors. Here, we investigated the antitumor activities of CF33-OVs against GCPC. Methods: We infected six GC cell lines, including both intestinal-type (AGS and MKN-74) and diffuse-type (KATO III, MKN-45, SNU-1, and SNU-16) with CF33, CF33-GFP, or CF33-hNIS-antiPDL1 at various multiplicities (MOI 0.01, 0.1, 1.0 and 10.0) to examine viral proliferation and cytotoxicity by using standard plaque assay and cell proliferation assay. We performed immunofluorescence imaging and flow cytometric analysis to verify virus-encoded gene expression and blockade of PD-L1 binding by virus-encoded anti-PD-L1 scFv. A mouse model of peritoneal dissemination xenograft of SNU-16-ffluc cells was set up to evaluate the antitumor activity of intraperitoneal (IP) CF33-hNIS-antiPDL1 treatment (3x105 pfu x 3 doses). Results: CF33-OVs showed dose-dependent infection, replication, and killing of human GC cell lines. Immunofluorescence imaging showed virus-encoded GFP, hNIS, and anti-PD-L1 scFv expression in CF33-OV-infected GC cells. GC cell surface PD-L1 binding was blocked by virus-encoded anti-PD-L1 scFv. In the xenograft model, IP CF33-hNIS-antiPDL1 treatment significantly reduced peritoneal tumors (p<0.0001), decreased amount of ascites (62.5% PBS vs. 25% CF33-hNIS-antiPLD1), and prolonged animal survival (p<0.01). Conclusions: CF33-OVs demonstrate effective antitumor activity and can deliver functional proteins in vitro and in vivo. CF33-hNIS-antiPDL1 treatment induced sustained regression of GCPC and prolonged survival. These promising preclinical results support peritoneal-directed strategies with CF33-hNIS-antiPDL1 in GCPC patients.
Intertumor heterogeneity of locally advanced gastric cancer.
Authors: Belyak Natalia P. , Kutukova Svetlana , Orlova Rashida , Kaledina Ekaterina , Androsova Alexandra , Zhukova Natalia V.
Published: January 2023

435

Background: The aim of the present study was to determine to the effect of HER2, dMMR, PD-L1 status in the primary tumor and in metastasis to the regional lymph node of GC patients. Methods: A total of 44 patients with primary loco-regional (N+) gastric adenocarcinoma were recruited, and two formalin-fixed paraffin-embedded (FFPE) tumor-containing blocks of each patient (one block with primary tumor and one block with metastasis to the regional lymph node)were selected for HER2, dMMR, PD-L1 (CPS) immunohistochemical (IHC) assay. Clinicopathological characteristics were recorded, and intertumoral heterogeneity of HER2, dMMR, PD-L1 IHC expression was determined. Results: The study included 19 women and 25 men, 30 patients had Laurén’s intestinal type of cancer, 14 had a Laurén’s diffuse type. In 5 patients (11.4%) overexpression of Her-2 neu was detected, and heterogeneity was detected in all five cases: in three patients with HER2 overexpression in the primary tumor, no overexpression was detected in the metastasis to the regional lymph node, in two cases overexpression was detected in the metastasis, while no overexpression was observed in the primary tumor. 2 patients showed signs of dMMR (4.5%), in one case, heterogeneity in dMMR status was also revealed: signs of dMMR in the primary tumor and its absence in regional metastasis (pMMR). Assessment of PD-L1 status was carried out using the CPS formula. Ten patients (22.7%) had a negative PD-L1 status (CPS=0) both in the primary tumor and in regional metastasis. Positive PD-L1 status in the primary tumor: in 24 patients CPS= 0-5 (54.5%), in 5 patients CPS= 5-10 (11.4%) and 5 patients CPS= 10 or more (11.4% ). Positive PD-L1 status in regional lymph node metastasis: in 24 patients CPS= 0-5 (54.5%), in 5 patients CPS= 5-10 (11.4%) and in 5 patients CPS= 10 or more ( 11.4%). In 5 cases (11.4%) marked heterogeneity in PD-L1 status between the primary tumor and its regional metastasis (1 case with dMMR heterogeneity). Conclusions: The research findings in this paper indicate that the intertumoral heterogeneity of HER2 overexpression is common in GC patients, We highly recommend multi-block HER2 assessment for accurate diagnosis of GC. Given the rarity of status detection dMMR, a study in a larger number of patients is required, however, our data also confirm the presence of heterogeneity in dMMR status, and probably the possibility of metastasis of a more aggressive pMMR clone. Heterogeneity in PD-L1 status is quite rare and amounted to only 11.4%, which also has important practical significance.
Clinicopathological features of HER2-low expressed advanced gastric cancers.
Authors: Nakayama Izuma , Takahari Daisuke , Chin Keisho , Wakatsuki Takeru , Ooki Akira , Ogura Mariko , Fukuda Koshiro , Osumi Hiroki , Fukuoka Shota , Shinozaki Eiji , Yamaguchi Kensei
Published: January 2023

459

Background: The DESTINY-Breast04 data demonstrated the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) was also effective for metastatic breast patients (pts) with HER2-low expression. Now that the HER2-low expressed cancer is categorized as an independent subset in breast cancer patients. It is unknown whether patients with the HER2-low expression are distinguishable from the HER2 negative or positive and are potential candidates for the anti-HER2 therapy in advanced gastric cancer (AGC) patients. Methods: We retrospectively reviewed the medical records of AGC pts who received standard chemotherapy with platinum containing regimens as the first-line treatment between Jan, 2011 and Dec, 2018 at the Cancer Institute Hospital of the JFCR. AGC pts were classified according to the HER2 status using immunohistochemistry (IHC) and in situ hybridization (ISH) as follows; HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-) and HER2 positive (IHC2+/ISH+ or 3+). This study was conducted to investigate the clinicopathological features and prognosis of HER2-low AGC pts compared with HER2 negative and positive. Results: A total of 734 AGC pts were received HER2 testing and classified into three groups according to HER2 status (HER2 negative; n=410, HER2-low; n=154, HER2 positive; n=170). The proportion of male (negative; 61.5%, low; 63.6% and positive; 69.4%), intestinal histology (negative; 21.0%, low; 44.2% and positive; 59.8%), liver metastases (negative; 18.3%, low; 24.8% and positive; 46.5%), higher serum CEA level (>ULN) (negative; 32.2%, low; 41.6% and positive; 56.5%) and higher serum CA19-9 level (>ULN) (negative; 34.1%, low; 36.7% and positive; 56.5%) were gradually increased along with HER2 expression level. The proportion of peritoneum metastasis (negative; 56.3%, low; 44.8% and positive; 21.8%) was decreased along with the HER2 expression level. One hundred and fifty-two pts (89.4%) received combination chemotherapy with trastuzumab in the first-line treatment. Sixteen pts received trastuzumab in the HER2-low (n=3) and HER2 negative (n=13) in the clinical trial. The median survival time (MST) of pts with HER-low was the same with that of HER2 negative (15.7ms). The statistically significant difference was observed in OS between the HER2-low and HER2 positive (HR 1.43 95% CI: 1.12-1.83, P=0.003). Conclusions: AGC Pts with HER2-low have intermediate clinicopathological features between HER2 negative and positive. A Novel effective anti-HER2 therapy for the HER2-low expressed tumor would be warranted in AGC treatment.
Prognostic value of mismatch repair deficiency in patients receiving first-line fluoropyrimidine plus platinum chemotherapy for metastatic, recurrent, or locally advanced unresectable gastric cancer.
Authors: Oh Chung Ryul , Kim Eo Jin , Chae Heejung , Park Young Soo , Ryu Min-Hee , Kim Hyung-Don , Kang Yoon-Koo
Published: January 2023

461

Background: In localized gastric cancer (GC), deficient mismatch repair (dMMR) tumors reportedly have a favorable prognosis. However, a potentially detrimental effect of the dMMR status was suggested in patients treated with adjuvant chemotherapy. It remains unclear whether the mismatch repair (MMR) status can impact clinical outcomes in patients with metastatic GC (mGC) receiving palliative chemotherapy. We examined the impact of the MMR status on survival outcomes of patients with HER2-negative mGC receiving first-line fluoropyrimidine plus platinum (FP) chemotherapy. Methods: We reviewed patients with histologically confirmed metastatic, recurrent, or locally advanced unresectable adenocarcinoma of the stomach or gastroesophageal junction receiving first-line FP chemotherapy between January 2015 and August 2018 at Asan Medical Center, Korea. MMR status was correlated with clinical characteristics and survival outcomes for patients with available MMR immunohistochemistry results. Results: Of 895 patients, we analyzed 543 with available MMR protein expression results, and dMMR was detected in 4.4% (n=24). Patients with dMMR exhibited a significantly higher median age than those with proficient MMR (pMMR) (64 vs. 58 years, p=0.044). No signet ring cell carcinoma (SRCC) was detected among dMMR tumors, whereas SRCC was found in 17.5% of pMMR tumors. Based on our prognostic model (Koo DH et al, 2011), only 4.2% of patients with dMMR were classified as the poor-risk group (vs. 16.8% of patients with pMMR, p=0.097). No significant difference in progression-free survival (PFS) was noted between patients with dMMR and pMMR tumors (median, 5.6 vs. 5.8 months, p=0.266). Patients with dMMR tumors tended to have better overall survival than those with pMMR tumors; this difference was not statistically significant (median, 17.9 vs. 12.2 months, p=0.183). In the good-risk subgroup, patients with dMMR tumors had a significantly worse PFS than those with pMMR tumors (median, 5.6 vs. 9.2 months, p=0.009); multivariate analysis revealed that MMR status was an independent factor for poor PFS in this subgroup. Conclusions: Survival outcomes of dMMR mGC did not differ from pMMR in patients who received first-line FP chemotherapy. However, in the good-risk subgroup, patients with dMMR tumors had a significantly shorter PFS than those with pMMR, suggesting a potentially reduced efficacy of cytotoxic chemotherapy in these patients.
Dosimetric comparison of target volume coverage and sparing of organs at risk (OARs) between helical intensity modulated radiotherapy (H-IMRT) versus volumetric arc therapy (VMAT) for mid and lower thoracic oesophageal carcinoma.
Authors: Yagnik Vatsala , Batham Samir , Jani Kinjal , Gandhi Maitri , Jain Vega , Rajgor Ruchi , Kothari Jagdish , Parikh Devendra , Lavingia Viraj Kiran , Prajapati Bharat
Published: January 2023

469

Background: To evaluate the effectiveness of H-IMRT and VMAT in covering target volume while adequately sparing the OARs for patients with mid and distal oesophageal carcinoma, on the basis of dosimetric analysis. Methods: The target areas and organs at risk in 30 patients with locally advanced carcinoma oesophagus undergoing neo-adjuvant chemo-radiotherapy were specified and transmitted to Eclipse, Version 13.6, Varian Medical Systems) & Accuray Treatment Planning System (Accuray Precision, Version 2.1.4, Accuray Medical System). Two plans (H-IMRT and VMAT) were generated for each patient for a total dose of 41.4 Gy delivered to the PTV in 23 fractions, and the Homogeneity Index (HI), Conformity Index (CI) and the dose distribution to the OARs (spinal cord, heart, lungs, kidneys and liver) were compared using dose volume histograms. Results: H-IMRT resulted in a more homogeneous dose distribution to the target (HI- 0.059) as compared to VMAT (HI- 0.07) [p-0.004]. The Conformity Indices showed no significant difference between the two techniques (H-IMRT – 0.989, VMAT – 0.987) [p-0.66]. VMAT resulted in a significantly less dose to the spinal cord (23.598 Gy vs .25.657 Gy) [p-0.021]. With VMAT plans, the heart mean dose (18.101 Gy vs. 20.031) [p- 0.00007], heart V40 (4.902% vs. 6.143) [p-0.002,] the averaged lung V20 [p-0.00005] and the mean dose to the left kidney (3.84 Gy vs. 4.721 Gy) [p- 0.010] were significantly less as compared to H-IMRT No statistically significant difference in both techniques with respect to heart V30, Mean Lung Dose (MLD), and mean dose to the righ and left kidney was observed Conclusions: VMAT proved to be better at sparing of OARs whilst providing almost the same Conformity as compared to a H-IMRT. H-IMRT has statistically better dose homogeneity but, it tends to deposit a slightly higher dose to the OARs. Whether the aforementioned differences in the dosimetric parameters translate into clinical benefits has to be evaluated by clinical outcome studies.
Adjuvant transarterial chemoembolization with sorafenib for patients with hepatocellular carcinoma with portal vein tumor thrombus after surgery: A phase III, multicenter, randomized, controlled trial.
Authors: Kuang Ming , Peng Zhenwei , Fan Wenzhe , Liu Zelong , Xiao Han , Tu Jianfei , Tang Rong , Huang Zhen , Cheng Yu , Li Fuliang , Lu Mingjian , Li Jiaping
Published: January 2023

493

Background: To compare the efficacy and safety of sorafenib plus transarterial chemoembolization (SOR-TACE) versus sorafenib alone as postoperative adjuvant therapy for hepatocellular carcinoma (HCC) patients with portal vein thrombus (PVTT). Methods: This was a phase III, multicenter, randomized, control clinical trial. Eligible HCC patients with PVTT were included and randomly assigned (1:1) to receive SOR-TACE or sorafenib alone as postoperative adjuvant therapy. Sorafenib treatment was started within 3 days after randomization, with an initial dose of 400mg twice a day. In the SOR-TACE group, TACE was performed one day after the administration of sorafenib. The primary endpoint was recurrence-free survival (RFS). Results: From October 2019 to March 2022, a total of 158 HCC patients with PVTT from China were enrolled and randomized. After a median follow-up duration of 28.4 months, the median RFS was significantly longer in the SOR-TACE group (16.8 vs. 12.6 months; hazard ratio, 0.57; P = 0.002). The median overall survival (OS) was also significantly longer with SOR-TACE than with sorafenib (30.4 vs. 22.5 months; hazard ratio, 0.57; P = 0.017). Multivariable analysis indicated SOR-TACE treatment was an independent risk factor for both RFS and OS. The SOR-TACE group did not show additional toxicity compared with the sorafenib alone group. Conclusions: The combination of sorafenib and TACE as postoperative adjuvant therapy in HCC patients with PVTT resulted in longer RFS and OS compared to sorafenib alone and was well tolerated. Clinical trial information: NCT04143191 .
Cost-effectiveness of gemcitabine plus cisplatin with and without durvalumab in patients with advanced cholangiocarcinoma.
Authors: Maldonado J. Alberto , Greten Tim F. , Monge B. M. Cecilia
Published: January 2023

498

Background: Based on the results from the TOPAZ-1 study, current standard of care treatment for patients with advanced biliary tract cancer is gemcitabine and cisplatin (Gem/Cis) plus durvalumab (Durva). The addition of Durva improved progression-free survival (PFS) and overall survival (OS) compared to Gem/Cis alone. Considering that the epidemiology of cholangiocarcinoma may indicate some racial and ethnic groups may have a higher incidence and poorer prognosis; we present a cost analysis of this new treatment option. Methods: We calculated the unit prices of Durva and Gem/Cis with the information provided by the LexiComp (accessed September 2022). The drug cost per cycle was calculated for each drug; assuming an average patient surface area of 1.9m2 for men and 1.6m2 for women. In both cases, the chosen vial was the same and, thus, pricing was the same. Costs of administration, adverse effect and follow up were excluded. As per the TOPAZ-1 study design, the first 8 cycles included either Durva (day 1) + Gem/Cis (days 1 and 8) or placebo (day 1) + Gem/Cis (days 1 and 8) every 3 weeks, followed by Durva or placebo alone every 4 weeks until disease progression. The total treatment cost was composed of the sum of all treatment cycles received on study. Cost per life year gained was calculated using the total cost per year in each group and treatment duration as the denominator. Results: Cost per cycle for Durva, Gem, and Cis was $13,797, $282, and $87, respectively. The patients in the TOPAZ-1 trial who were randomized to the Durva arm had a median treatment duration of 7.3 months while patients in the Gem/Cis arm had a median treatment duration of 5.8 months. PFS was similar with a median time of 7.2 months and 5.7 months, respectively. This difference in both treatment duration and PFS (both 1.5 months) was associated with an increased cost of $124,170 over the course of treatment for Durva + Gem/ Cis compared to Gem/Cis alone ($127,119 vs $2,949). Durva + Gem/Cis has a medication only cost of $1,655,604 per life year gained as compared to Gem/Cis alone. Total yearly cost by treatment arm was higher for the Durva + Gem/Cis group ($209,899 vs $2,949). Conclusions: Durvalumab combined with gemcitabine and cisplatin is associated with an increase of 1.5 months in both treatment duration and PFS without additional toxicity observed when compared to Gem/Cis alone; however, Durva + Gem/Cis was associated with a drug cost over 40 times higher when compared Gem/ Cis alone for first-line treatment of advanced biliary tract cancer. Further research should focus on cost-effective solutions to treat advanced cholangiocarcinoma.