bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of apatinib in treatment of gastric cancer: A real-world study.
Authors: Ma Yijie , Zong Hong , Wang Junsheng , Guo Yanzhen , LIU Huaimin , Li Ning , Cang Shundong , Shang Ke , Chen Xiaobing , Wang Jin , He Dezhi , Deng Wenying , Sun Peichun , Zhang Zhen , Zhang Liguo , Xu Feng , Tian Chuntao , Qiao Chaofeng , Chen Gongbin , Luo Suxia
Published: January 2021

182

Background: Apatinib is a small molecule TKI inhibitor, which had been approved in China for treatment of advanced gastric cancer refractory to two or more lines of prior chemotherapy. Its efficacy and safety have been demonstrated in previous randomized controlled clinical studies. However, the efficacy and safety of apatinib in real world is lacking. This study aimed to evaluate the anti-tumor activity and toxicity of apatinib in real world. Methods: Patients older than 18 years with histologically diagnosed with gastric cancer were enrolled and treated with either apatinib alone or in combination with other drugs. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR) and disease control rate (DCR). The adverse events were also recorded. Results: From March 2018 to March 2019, a total of 1000 patients were enrolled. Among them, 48(0.48%), 13(0.13%), 225 (22.5%), 389 (38.9%), and 325 (32.5%) patients received apatinib as postoperative auxiliary-, neoadjuvant-, first-, second-, and third- or higher line therapy, respectively. Efficacy evaluation was performed in 901 patients. Thirty-five patients achieved complete response (CR), 116 patients achieved partial response (PR), 596 patients achieved stable disease (SD), and 154 patients had progressive disease (PD), illustrating an ORR of 16.76% and a DCR of 82.91%. The mPFS was 5.32 months (95% CI, 4.93-5.75), and mOS was 9.76 months (95% CI, 8.97-10.81). In addition, the mOS of apatinib in first-line, second-line, and third-line treatments were 12.68 months, 9.49 months, and 7.62 months, respectively. Patients received apatinib in combination with other drugs had longer survival than apatinib alone, with mPFS 5.62 months vs 4.47 months and mOS 10.81 months vs 7.95 months. Such phenomenon was also observed in ORR (18.21% vs 13.04%, P< 0.001) and DCR (84.88% vs 77.87%, P< 0.001). The main adverse events (AE) were anemia (67.2%), thrombocytopenia (36.2%), leukopenia (34.5%)and anorexia (37.6%). The most common grade 3-4 adverse events included neutropenia, anemia and thrombocytopenia. Conclusions: In the real world, apatinib showed promising efficacy and manageable toxicities in patients with gastric cancer. Patients benefit more when received apatinib combination therapy. Clinical trial information: NCT03478943.
A multicountry chart review of treatment patterns and outcomes for patients with resected esophageal or gastroesophageal junction cancer.
Authors: Singh Prianka , Gricar Joseph , Mackie deMauri S , Xiao Hong , DeCongelio Marc , Jaffe Dena H.
Published: January 2021

184

Background: Global neoadjuvant and adjuvant treatment patterns among patients with resected Esophageal Cancer (EC) and Gastroesophageal Junction cancer (GEJC) remain unclear. This study describes real-world treatment patterns and outcomes for patients receiving surgery for Stage II or III EC or GEJC. Methods: Physicians in North America (US, Canada), Asia (China, Japan, Taiwan), and Europe (UK, France, Germany, Italy, Spain) provided clinical and treatment data in this retrospective, non-interventional chart review conducted from April-June 2020. Included patients were adults (Japan ≥20 years; elsewhere, ≥18 years), who underwent resection of Stage II or III EC or GEJC between October 2017 and October 2018 and were followed until death, loss to follow up, or end of data collection. Results: Physicians (N = 609) provided data on 1693 patients of mean age of 62.4 years, who received surgery for Stage II or III esophageal squamous cell carcinoma (ESCC) (33.3%), esophageal adenocarcinoma (EAC) (31.5%), or GEJC (35.2%) and were followed a mean (median) of 17.7 (17) months (to death or end of study period). At diagnosis, 85.6% of patients had performance status of 0/1. The majority of patients received an R0 resection (overall, 70.6%; ESCC, 76.6%, EAC, 67.4%, GEJC, 68.0%; p < 0.05); of these, 32.0% had a complete pathological response and 64.1% had a partial pathological response. Neoadjuvant therapy use differed among the treatment groups (ESCC 56.5%; EAC, 65.9%; GEJC, 62.6%, p < 0.05), as did adjuvant therapy (ESCC: 39.8%; EAC, 40.3%; GEJC, 44.5%; p = 0.023). Recurrence rate following surgery did not differ between groups for any recurrence (overall, 21.0%; ESCC 18.5%, EAC 23.6%, GEJC 21.1%); for local or regional recurrence (overall, 11.6%; ESCC, 10.3%; EAC, 12.7%; GEJC, 11.7%); or for metastatic recurrence (overall, 9.5%; ESCC, 8.2%; EAC, 10.9%; GEJC, 9.4%). The median time to local or regional recurrence (for those who progressed during the reporting period) was 8 months from date of initial surgery (overall, 8 mo; ESCC, 8 mo; EAC, 7 mo; GEJC, 8.5 mo; p > 0.05). The frequency of 1L systemic therapy for advanced disease at the time of survey completion was 16.1% overall and differed among patients with ESCC (14.6%); EAC (17.8%); and GEJC (15.9%); p > 0.05. Conclusions: This large multi-country real world data study shows that over half of all patients received neoadjuvant therapy, and over a third received adjuvant treatment. The high unmet need in this population is evident from the post-resection recurrence rate of 21.1% at median 8 months and the high proportion of patients who went on to require advanced disease treatment.
Gastric cancer burden: Evidence from a safety-net hospital.
Authors: Forlemu Arnold , Kosa Dimas , Findakly Dawood , Amar Surabhi
Published: January 2021

187

Background: Gastric cancer is a leading cause of cancer-related deaths worldwide, with more than eleven thousand estimated gastric cancer deaths expected to occur this 2020 in the United States (US). Understanding the burden and trends in gastric cancer across demographics and different locations in the US is crucial to develop effective preventive strategies. This study describes, characterizes, and identifies high risk group gastric cancer patients, who may benefit the most from preventive and management strategies. Methods: A retrospective study was conducted between 2010 to 2019 at our institution to identify patients diagnosed with gastric cancer during that period. Data on demographics, risk factors, mode of presentation, pathology, site, type, and stage of gastric cancer were obtained. Chi-square was used to compare categorical variables. Regression analysis was used to evaluate factors associated with late-stage disease and cancer type. Results: A total of 111 patients were analyzed in this study. The median age of gastric cancer patients was 52 years (range 27 to 87 years). Most of the patients were Hispanic (70.3%), non-citizens (59.5%), were uninsured (69.4%), and 67.6% were living below the federal poverty level (FPL). Also, 31.5% of the patients had a family history of cancer, had diffuse-type adenocarcinoma (61%), late-stage disease (76.6%), 52.4% of the cancers were in the distal portion of the stomach. Uninsured patients were more likely to die compared to insured patients, however, this difference was not statistically significant (64.9% vs 47.1%, p = 0.077). Age below 40, Hispanic ethnicity, being uninsured, and living below FPL were associated with higher rates of late-stage disease and diffuse-type cancer (p < 0.05). Conclusions: Our data suggest a younger age at gastric cancer diagnosis than the national average. Moreover young, and uninsured Hispanics presented with advanced gastric cancer and may represent a high-risk target population for preventive strategies.
Serum pepsinogen as a biomarker for gastric cancer: A nested case-control study using the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial data.
Authors: In Haejin , Friedmann Patricia , Parides Michael , Sarkar Srawani , Castle Philip E. , Epplein Meira
Published: January 2021

188

Background: Gastric cancer (GC) lacks specific symptoms, resulting in diagnosis at later stages and high mortality. Serum pepsinogen is a biomarker for atrophic gastritis, which is an intermittent phase in the development of GC. A serum based biomarker that indicates increased risk of GC would be useful for targeted prevention strategies. Methods: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a large randomized trial conducted over 10 centers in the US between 1993 and 2001. Serum samples were collected at baseline and participants were followed for development of incident GC. ELISA-based pepsinogen tests were conducted on pre-diagnostic serum samples of patients who developed GC and age, sex, and race-matched controls. Pepsinogen negative (PG-) and positive (PG+) status was determined using pepsinogen I (PGI) and pepsinogen I to II ratio (PGR). Those with PGR ≥ 3 and PGI > 70µg/L were considered PG- while those with lower levels on either or both were considered PG+. Cox proportional hazard models were used to determine the hazard ratio (HR) and 95% confidence intervals (95%CI) of PG+ for GC. To examine the association of PG with non-cardia and cardia GC separately, propensity matching was used to create control subsets matched on age, sex, and race. Results: Pepsinogen test results were available on 105 GC cases (70 non-cardia and 35 cardia) and 220 matched controls. Median and range of time from pepsinogen measurement to incident GC diagnosis was 78.6 and 3.0-152.2 months, respectively. GC patients were more likely to be PG+ (31.4% vs 5.5%, p < 0.001) and current smokers (20.0% vs 7.7%, p = 0.004) at baseline than controls. Compared to PG-, PG+ were at an increased risk of any GC (HR = 3.77; 95%CI = 2.50-5.71). After adjusting for family history of GC, smoking, and BMI, PG+ were still at a significantly increased risk of GC compared to PG- (adjusted HR = 4.42; 95%CI = 3.14-6.21). For 138 controls matched to 70 non-cardia cancers, PG+ were at an increased risk of non-cardia GC compared to PG- (HR = 5.65, 95%CI = 3.67-8.70; adjusted HR = 7.26, 95%CI = 4.84-10.90). For 70 controls matched to 35 cardia cancers, PG+ were not at greater risk of cardia GC compared to PG- (HR = 1.79, 95%CI = 0.72-4.44; adjusted HR = 1.95, 95%CI = 0.81-5.37). Conclusions: Pre-diagnostic serum pepsinogen levels from a large prospective cohort study predicted development of non-cardia GC but not cardia GC. PG could be considered as a potential risk biomarker to identify individuals at higher risk of non-cardia GC for targeted screening or interventions.
The association of renal function with safety and efficacy of cisplatin plus S-1 (CS) therapy and docetaxel plus cisplatin plus S-1 (DCS) therapy in patients with advanced gastric cancer (AGC): An exploratory analysis of JCOG1013.
Authors: Hironaka Shuichi , Sadachi Ryo , Hashimoto Tadayoshi , Machida Nozomu , Iwasa Satoru , Yamada Yasuhide , Sasako Mitsuru , Boku Narikazu , Yoshikawa Takaki , Terashima Masanori
Published: January 2021

197

Background: JCOG1013, a phase III study comparing CS therapy with DCS therapy for AGC, failed to demonstrate the superiority of DCS to CS in overall survival (OS) (Yamada Y, Lancet GH 2019). Because cisplatin and gimeracil (an inhibitor of dihydropyrimidine dehydrogenase contained in S-1) are excreted in urine, it is speculated that renal dysfunction may affect the safety and efficacy of CS and DCS in patients (pts) with AGC. Methods: Among 741 all randomized pts, pts with serum creatinine level < 1.2 mg/dL were included in this study. Pts were categorized by creatinine clearance (CrCl) and treatment into A1 (CrCl ≥ 80 mL/min, CS), A2 (60 < CrCl < 80, CS), A3 (CrCl < 60, CS), B1 (CrCl ≥ 80, DCS), B2 (60 < CrCl < 80, DCS), and B3 (CrCl < 60, DCS). Adverse events, OS, progression-free survival (PFS), objective response rate (ORR) were compared by CrCl in group A (A1 vs. A2 vs. A3) and group B (B1 vs B2 vs B3), respectively, and between the treatment groups according to CrCl (A1 vs. B1, A2 vs. B2, A3 vs. B3). Results: Of 723 pts (169/136/57 in A1/A2/A3 and 170/138/53 in B1/B2/B3), the median CrCl was 94.1/71.9/53.4 mL/min in A1/A2/A3 and 98.2/70.0/55.6 mL/min in B1/B2/B3 group. The incidence of Grade (G) 4 hematological toxicity was 7.8/16.3/25.9% in A1/A2/A3 (P < 0.01), and 29.1/29.3/22.0% in B1/B2/B3 (P = 0.44), and that of G3-4 non-hematological toxicity was 46.1/64.4/64.3% in A1/A2/A3 (P < 0.01) and 54.6/64.7/74.5% in B1/B2/B3 (P < 0.01), respectively. The median OS was 15.4/15.5/15.4 months in A1/A2/A3 (P = 0.89) and 15.3/13.7/13.7 months in B1/B2/B3 (P = 0.72). The median PFS was comparable in A1/A2/A3 (7.1/6.8/6.2 months, P = 0.88) and B1/B2/B3 groups (7.5/7.2/7.8 months, P = 0.85). ORR showed no significant difference in A1/A2/A3 (58.9/57.8/46.9%, P = 0.31) and B1/B2/B3 groups (62.0/61.5/51.5%, P = 0.36). Comparisons between treatment arms according to CrCl (A1 vs. B1, A2 vs. B2, A3 vs. B3) did not show any significant difference in OS (P = 0.88, 0.65, 0.83) and PFS (P = 0.91, 0.63, 0.46). Conclusions: In this exploratory analysis of JCOG1013, CrCl might be associated with safety (G4 hematological toxicity for CS, and G3-4 non-hematological toxicity for CS and DCS), but not with efficacy in either group. Clinical trial information: 000007652.
RAINBOW-Asia: A randomized, multicenter, double-blind, phase III study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line chemotherapy with platinum and fluoropyrimidine.
Authors: Xu Rui-hua , Zhang Yan-Qiao , Pan Hongming , Feng Ji Feng , Zhang Tao , Liu Tianshu , Qin Yanru , Han Rubing , Zhang Wanli , Shen Lin
Published: January 2021

199

Background: Ramucirumab (RAM), a fully human IgG1 monoclonal antibody targeting vascular endothelial growth factor receptor 2, has been approved in combination with paclitaxel (PTX) in patients with advanced gastric cancer in the second-line setting outside of China in around 80 countries based on the significant overall survival (OS) benefit in the global phase 3 RAINBOW study. RAINBOW-Asia was a bridging study of RAINBOW to evaluate the efficacy and safety of RAM in a predominantly Chinese population. Methods: Patients with advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma who experienced disease progression on first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomized at a 2:1 ratio to receive RAM (8 mg/kg) on day 1 and 15 plus PTX (80 mg/m²) on day 1, 8, and 15 of a 28-day cycle or placebo (PL) plus PTX. Randomization was stratified by ECOG Performance Status (0 versus 1) and peritoneal metastases (yes versus no). The co-primary endpoints were PFS and OS. Results: From Mar 2017 to Jun 2020, 440 pts were randomized (RAM+PTX: 294; PL+PTX: 146). Median PFS was significantly improved with RAM+PTX compared to PL+PTX (4.14m vs. 3.15m; HR = 0.765 [95% CI: 0.613 to 0.955]; p = 0.0184). Median OS was 8.71m with RAM+PTX and 7.92m with PL+PTX (HR = 0.963 [95% CI: 0.771 to 1.203]; p = 0.7426). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurring in > 5% of patients with RAM+PTX were: neutrophil count decreased (54.3% RAM+PTX; 38.6% PL+PTX), white blood cell count decreased (43.3% vs. 29.0%), anaemia (15.7% vs. 16.6%), hypertension (7.2% vs. 6.2%), and febrile neutropenia (6.1% vs. 0.7%). Conclusions: The combination of RAM+PTX as 2nd-line therapy demonstrated a statistically significant PFS benefit, and OS benefit consistent with RAINBOW study in a predominantly Chinese population with advanced gastric and GEJ cancer. The safety profile of RAM was consistent with previous studies. No new safety signal was observed. Clinical trial information: NCT02898077.
A phase I/II trial of trifluridine/tipiracil in combination with irinotecan in patients with advanced gastric cancer refractory to fluoropyrimidine, platinum, and taxane.
Authors: Hara Hiroki , Mizukami Takuro , Minashi Keiko , Nishina Tomohiro , Takahashi Naoki , Amanuma Yusuke , Nakasha Akio , Takahashi Masaki , Nakajima Takako Eguchi
Published: January 2021

210

Background: Trifluridine/tipiracil (FTD/TPI) or irinotecan is a treatment option in the heavily pretreated patients with advanced gastric cancer (AGC) with the limited efficacy. Thus, we investigated the recommended dose of trifluridine/tipiracil (FTD/TPI) and irinotecan for these patients. Methods: Patients who refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) used a escalated dose of irinotecan [100 (Level 1) or 125 mg/m2 (Level 2) on Days 1 and 15 of a 28-day schedule] with 2 dosage schedules of FTD/TPI:35 mg/m2/dose, twice daily (bid), on days 1-5 and 8-12 of a 28-day cycle (Level A) or on days 1-5 and days 15-19 of a 28-day cycle (Level B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D) for phase I part and the evaluation of disease control rate (DCR) targeting > 55% in all enrolled patients for phase II part. Results: Eleven patients were enrolled from 4 institutions in Japan; 2 at Level 1A, 3 at Level 1B and 6 at Level 2B. DLTs occurred in 2/2 patient at Level 1A (Grade 3 gum infection and Grade 3 febrile neutropenia on Day 29, outside the 28-day DLT assessment period, determined equivalent to DLT), and 2/6 patients at Level 2B (Grade 3 mucositis oral and Grade 3 febrile neutropenia). Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved partial response and the DCR was 72.7% (95% CI 39.0- 94.0%). The median progression-free survival and overall survival was 3.0 months (95% CI 0.92- not reached) and 10.2 months (95% CI 2.2- not reached), respectively. Conclusions: The RP2D was determined to be Level 1B although further investigation to explore optimal regimen is needed. Clinical trial information: UMIN000031346.
The preliminary efficacy and safety of KN046 plus concurrent chemoradiation therapy in recurrent and metastatic esophageal squamous cell carcinoma.
Authors: Qin Bing Song , Zhao Qi , Liu Dong Yan , Xue Jiao , Zhu Xing Jia
Published: January 2021

223

Background: Definitive or palliative chemoradiation therapy has been employed in the management of esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitor has improved outcomes in metastatic stage IV pts. Here we report the addition of KN046, a PD-L1/CTLA-4 bispecific antibody, to concurrent chemoradiation (CRT) therapy to determine the safety and efficacy of this approach (ChiCTR2000031544). Methods: Pts with recurrent or metastatic ESCC, not been treated by CRT or other systemic treatment within 6 months, were recruited and received palliative CRT consisting of cisplatin (75 mg/m2 IV Q3W for 4~6 cycles), paclitaxel (135~175 mg/m2 IV Q3W for 4-6 cycles) and radiation (SBRT or conventional and dose are determined at the investigator’s discretion according to institutional standard). KN046 at ascending doses of 1, 3 and 5 mg/kg Q3W was added within 7-14 days after the completion of radiation therapy (RT) and concurrently with chemotherapy, followed by KN046 Q2W maintenance. Dose limiting toxicities (DLTs) were assessed for the first treatment cycle of KN046. Anti-tumor activity was assessed according to RECIST 1.1 every 6 weeks within the first year, and every 12 weeks thereafter. Results: As of June 30, 2020, 18 subjects were enrolled and received KN046 treatment (1mg/kg, n = 3; 3mg/kg, n = 11; 5mg/kg, n = 4). The median KN046 exposure was 11.5 weeks. No DLT was reported. 3 (16.7%) subjects experienced Grade 3, KN046 related adverse events (1 Grade 3 pneumonitis and 2 Grade 3 colitis recovered after steroid and antibiotic Tx). For 18 evaluable subjects, the disease control rate and objective response rate were 94.4% and 44.4%, respectively. DOR and PFS were not matured yet as of cutoff date. At 3 mg/kg, objective response was observed in 5 out of 9 subjects (55.6%) with measurable disease and disease control rate was 100%; 7/9 (77.8%) subjects experienced further tumor reduction after initiation of KN046 treatment. It is worth to note that, 2 subjects at 3mg/kg achieved complete response after receiving KN046 treatment. Conclusions: The addition of KN046 to CRT was well tolerated and showed promising efficacy signal in recurrent or metastatic ESCC. This pilot study enables further investigation of a new treatment modality of KN046 with CRT in this detrimental disease with poor prognosis. Clinical trial information: 2000031544.
Human oral microbiome dysbiosis as a novel tool for detecting noninvasive biomarkers for colorectal cancer.
Authors: Kong Cheng
Published: January 2021

23

Background: The oral microbiome may play an important role in colorectal carcinogenesis. However, few studies have investigated the association between oral microbiome and the development of colorectal cancer (CRC). We aimed to investigate whether oral health–colorectal tumor association has an underlying microbial basis, in the quest for novel non-invasive biomarkers for CRC. Methods: We collected oral swab samples from 161 patients with CRC, 34 patients with colorectal adenoma (CRA), and 58 healthy volunteers. The oral microbiota was assessed using 16S rRNA sequencing. The oral microbiome was characterized, microbial markers were identified, and colorectal tumor (CRA and CRC) classifiers were constructed and validated. Results: Oral microbial composition and diversity were significantly different among the three groups; the CRA group had the highest diversity. Analysis of the functional potential of oral microbiota demonstrated that the pathway involving cell motility was overrepresented in the CRA and CRC groups relative to that in the healthy controls. Moreover, a random forest model was constructed based on oral microbial markers, which could distinguish the colorectal tumor groups from the healthy controls and achieve a powerful classification potential in the discovery and validation cohorts. Conclusions: This study suggests a potential association between oral microbiome dysbiosis and colorectal cancer. Oral microbiota-based biomarkers may be helpful in predicting the risk of developing CRA and CRC.
Impact of tumor location on effectiveness of first-line 5-FU-based palliative doublet chemotherapy in patients with metastatic gastroesophageal cancer.
Authors: Goksu Suleyman Yasin , Alterio Rodrigo , McGehee Elizabeth , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali , Porembka Matthew R. , Wang Sam C. , Sanford Nina Niu , Wang David H. , Sanjeevaiah Aravind
Published: January 2021

240

Background: While gastroesophageal cancers with different primary tumor locations can have distinct molecular characteristics and clinical outcomes, the efficacy of palliative chemotherapy in tumors with different locations is unknown. Using primary tumor location as a surrogate for molecular subtype, we investigated the differential efficacy of first-line doublet chemotherapy in metastatic gastroesophageal adenocarcinomas. Methods: We performed a retrospective review of patients with metastatic gastroesophageal adenocarcinoma who received first-line palliative chemotherapy at the University of Texas Southwestern Medical Center and the Dallas County Safety Net Parkland Hospital diagnosed between 2011-2019. Cases were identified using cancer registries. We categorized the tumor location as proximal or distal based on endoscopy and imaging studies. Disease response was assessed on the first staging scan and classified as ‘disease shrinkage, stability, or progression.’ Overall and progression-free survival were evaluated using Kaplan-Meier and Cox proportional hazards methods. Results: 99 patients were identified; 58.6% had proximal tumors. Patients with proximal tumors were more likely to be white (38% vs. 13%, p = 0.008) and older with age ≥ 50 years (71% vs. 51%, p = 0.04) and less likely to have peritoneal metastasis (48% vs. 78%, p = 0.003) than distal tumors. Patients with proximal tumors had a higher disease shrinkage than patients with distal tumors (53% vs. 21%, p = 0.004). Patients with proximal tumors also had better overall survival (median 12.5 vs. 8.7 months) and progression-free survival in response to 5-FU based chemotherapy (median 5 vs. 4 months) compared to patients with distal tumors, but this was not statistically significant. On multivariable analysis, tumor location was not independently predictive of progression-free survival after adjusting for age, gender, presence of signet rings, diffuse, intestinal histology, and peritoneal metastasis (HR 1.22 95% CI 0.74-2.00), but pretreatment albumin was (HR 0.63 95% CI 0.43-0.94). Conclusions: Proximal gastroesophageal cancers have a better clinical response to first-line 5FU containing chemotherapy than distal cancers. Currently, there is no platform to determine molecular subgroups that is commercially available. Until testing for this becomes available, differences in response rates to palliative chemotherapy in gastroesophageal cancers with different anatomical locations should be recognized and studied further.
Regulation of p14ARF by Siva1 in H. pylori-infected gastric epithelial cells.
Authors: Palrasu Manikandan , Zaika Elena , Wael El-Rifai , Peek Richard , Zaika Alexander
Published: January 2021

243

Background: Helicobacter pylori ( H. pylori) is the strongest known risk factor for gastric cancer. Bacterial degradation of tumor suppressor proteins affect the host microbe’s interactions and host cellular response, which contribute to tumorigenesis. p14ARF, a crucial tumor suppressor protein that activates p53 protein under oncogenic stress plays a major role in oncogenic stress response (OSR) regulation. However, little is known about the mechanism of ARF and OSR regulation in H. pylori-infected gastric epithelial cells. Methods: The expression of p14ARF and cytotoxin-associated gene A (CagA) were analyzed in gastric cells co-cultured with H. pylori strains isolated from high-gastric risk and low-gastric risk areas by immunoblotting. To investigate the potential role of CagA in regulation of p14ARF, we employed isogenic cagA− and cagE− H. pylori mutants in gastric epithelial cells, and C57BL/6 mice (n = 10). We also analyzed the expression of Siva1 in human individual infected with cagA-positive (n = 13) and cagA-negative (n = 13) bacteria as well as uninfected human subjects (n = 6). siRNA was used to inhibit activity of Siva1 protein. Results: In this study, H. pylori strains expressing high levels of CagA virulence factor and associated with a higher gastric cancer risk more strongly suppress p14ARF compared with low-risk strains in vivo and in vitro. We found that degradation of p14ARF induced by CagA is mediated by E3 ubiquitin ligase Siva1, which works in concert with another E3 ubiquitin ligase TRIP12. Decreased expression of Siva1 protein and consequent up-regulation of p14ARF was also found in gastric mucosa of H. pylori-infected mice and human individuals. Tumorigenic strain 7.13 was more potent in upregulation of Siva1 and downregulation of p14ARF than non-tumorigenic strain B128. Inhibition of p14ARF protein by H. pylori causes inhibition of autophagy in infected cells. Conclusions: Our results provide first evidence that carcinogenic H. pylori strains significantly alter the host tumor suppressor protein p14ARF, leading to suppression of host OSR and autophagy, which may affect host-bacteria interactions and tumorigenic alteration in the stomach.
Development and validation of a targeted sequencing panel for application to treatment-refractory solid tumor.
Authors: Kwon Woo Sun , Che Jingmin , Rha Sun Young , Chung Hyun Cheol , Han Hyo Jun , Kim Jaeyoung , Jadamba Erkhembayar , Lee Yunbeom , Kim Ernie
Published: January 2021

245

Background: Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted sequencing panel for application to treatment-refractory solid tumor types with particular focus on tumours of the stomach cancer, plus test for utility in FFPE, fluid sample and cancer cell lines. Methods: “CancerMaster” is custom RNA probes for target enrichment sequencing. It consists of all unions (7,811 regions, 2.5Mb) of reported exons of 524 tumor and immune related genes. The panel contains special RNA probes, which enables detection of microsatellite instability, Epstein-Barr virus and Human papillomavirus. Also, the CancerMaster panel analyzes 524 genes as well as genomic signatures including microsatellite instability (MSI), tumor mutational burden (TMB) and HLA allele. FFPE samples and 49 gastric cancer (GC) cell lines were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 117), and specificity by Sanger sequencing, pyrosequencing, FoundationOne CDx. Results: We achieved a mean coverage of 1,032x, with sensitivity and specificity of >99% and precision of >97%. In this study, we evaluated 26 Yonsei Cancer Center (YCC) GC cell lines and 23 GC cell lines from other sources (ATCC, KCLB, and JCRB). Application to 49 gastric cancers cell lines resulted in detection of copy number variant (CNV), single number variant (SNV) and small InDel aligned to whole exome sequencing data. In addition to previous novel EBV infected cell line (YCCEL1/YCC-10, J Gen Virol. 2013), we observed amplification and overexpression of receptor tyrosine kinase (RTK) including HER2 (YCC-19, 32, 33, 38), EGFR (YCC-11, 21), Met (YCC-31, 34), and FGFR2 (YCC-28, 30) in YCC GC cell lines; confirming that protein was overexpression by Western blot or Flow cytometry in 19/49 (38.8%). Interestingly, amplification of RTKs was detected mutually exclusive pattern with other RTK amplification. Conclusions: We have developed and validated an analytically-validated panel for application to cancers of treatment-refractory types.
The impact of prior therapies on outcomes with trifluridine/tipiracil (FTD/TPI) in the phase III TAGS trial.
Authors: Shitara Kohei , George Ben , Taieb Julien , Sundar Raghav , Fakih Marwan , Makris Lukas , Benhadji Karim A. , Ghidini Michele
Published: January 2021

247

Background: It is unclear whether prior treatment with ramucirumab (RAM) or RAM plus paclitaxel (PAC), standard second-line treatments for metastatic gastric or gastroesophageal junction cancer (mGC/GEJC), can influence outcomes with third-line chemotherapy in this patient (pt) population (pop). In the phase 3 TAGS trial, FTD/TPI showed a survival benefit vs placebo (PBO) in pts with mGC/GEJC who had received ≥2 prior chemotherapy regimens. Post hoc analyses were performed to assess the impact of prior RAM, PAC or RAM+PAC treatment on the efficacy and safety of FTD/TPI in TAGS. Methods: Pts in the TAGS trial were categorized into 5 subgroups based on prior treatment received as follows: A) RAM (alone or combined with other agents), B) no RAM, C) PAC (but no RAM), D) RAM+PAC (sequentially or in combination) and E) neither PAC nor RAM. While subgroups A and B were prespecified, all other subgroups were identified post hoc. Efficacy (overall survival [OS] and progression-free survival [PFS]) and safety were assessed in these subgroups. Results: In the overall pop (N=507), 33% had received prior RAM (alone/combined); 30% prior RAM+PAC; 27% prior PAC but no RAM; and 40% had received neither PAC nor RAM. As only 3% of all pts received prior RAM but no PAC, that subgroup was not considered in this analysis. FTD/TPI treatment was consistently associated with benefits in OS and PFS vs placebo across all pt subgroups (Table). Among pts randomized to FTD/TPI, OS benefit was similar between pts who received RAM+PAC vs those who received neither (HR, 1.15; 95% CI, 0.84–1.58) and between pts who received PAC (but no RAM) vs those who received neither (HR, 0.91; 95% CI, 0.66–1.25). The FTD/TPI safety profile was consistent across all subgroups, with similar overall incidences of grade ≥3 adverse events (AEs). Minor variations in hematologic toxicities were noted (Table). Conclusions: In the phase 3 TAGS trial, FTD/TPI treatment in the third or later line provided efficacy benefits vs PBO and demonstrated a consistent safety profile in pts with mGC/GEJC regardless of prior treatments. Clinical trial information: NCT02500043. [Table: see text]
Comparison of immune activity profiles of microsatellite instable colon tumors to microsatellite stable tumors having high ColoType CMS1-score.
Authors: Buechler Steven Allen
Published: January 2021

26

Background: Microsatellite instable (MSI) metastatic colorectal cancer (CRC) tumors have been found to be responsive to immune checkpoint inhibitors. Most MSI tumors are in consensus molecular subtype CMS1. Here, in a search for microsatellite stable (MSS) samples that may respond to checkpoint inhibitors, we used the ColoType CMS1-score to identify microsatellite stable (MSS) CRC tumors that have immune activity profiles similar to MSI tumors. Methods: This study was performed in Affymetrix cohort (n = 1,888) of primary CRC tumor samples assayed with hgu133plus2 Affymetrix microarrays. Degrees of infiltration of populations of immune cells were assessed with MCPcounter. Gene Set Enrichment Analysis (GSEA) using the Hallmark gene sets was used to compare biological features between subsets of samples. An 18-gene genomic score (PembroSig) of Ayers, et al, was used to predict response to Pembrolizumab. ColoType 40-gene signature identifies the CMS of a CRC tumor using values of continuous scores, one score for each of CMS1-4. CMS1+ denotes the samples with CMS1-score sufficiently high to predict it is in CMS1. A genomic score was used to predict MSI status for all samples in Affymetrix cohort; MSI predictions using said score had 97% agreement with clinically determined MSI status for 749 Affymetrix cohort samples. Results: The MSI score predicted 240 MSI samples in Affymetrix cohort, and 211 MSS samples in CMS1+ (CMS1+/MSS). The union of MSI and CMS1+/MSS compared to other samples exhibited elevated infiltration of cytotoxic lymphocytes (p < 0.0001) and CD8 T-cells (p < 0.0001), activity of interferon-gamma (p = 0.006) and interferon-alpha signaling (p = 0.012), inflammatory response (p = 0.012), and elevated PembroSig score (p < 0.0001). CMS1+/MSS compared to MSI showed no significance difference in any of these measures. None of the immune regulatory genes PD-1, PD-L1, PD-L2, CTLA4, LAG3, and IDO1 were differentially expressed between CMS1+/MSS and MSI. Of note, the only Hallmark gene sets enriched in MSI compared to CMS1+/MSS were DNA repair (p = 0.002) and MYC targets V1 (p = 0.009) and V2 (p = 0.013). We further analyzed the biological differences between MSI samples in CMS1+ (CMS1+/MSI, n = 190) and MSI samples not in CMS1+ (CMS1-/MSI, n = 50). We found that CMS1+/MSI compared to CMS1-/MSI exhibited elevated cytotoxic lymphocyte infiltration (p < 0.0001), interferon-gamma activity (p = 0.027), and PembroSig score (p < 0.0001), highlighting the relationship between immune activity and CMS1-score. Conclusions: ColoType CMS1-score identified MSS samples in Affymetrix cohort (11%) with similar immune activity as MSI samples (13%) and equivalently high values of a genomic score predictive of Pembrolizumab response.
Second-line tyrosine kinase inhibitors (TKIs) versus immunotherapy (IO) for advanced hepatocellular carcinoma (HCC): Real-world efficacy and safety analysis in patients with varying liver dysfunction.
Authors: Xia Jeffrey , Gelfond Jonathan , Arora Sukeshi Patel
Published: January 2021

271

Background: Within the last 4 years, the FDA approved five drugs as second-line therapies for advanced HCC. At our cancer center, the majority of our patients are Hispanic with varying liver dysfunction, and this real world population is not represented in registration trials of TKIs and IOs. Therefore, we analyzed survival and toxicities among second-line therapies for HCC at our Hispanic-majority NCI-designated cancer center. Methods: Retrospective analysis of patients with advanced HCC diagnosed at Mays Cancer Center from 1/2015-3/2019 who received second-line therapies, including IO (i.e. nivolumab), TKIs (i.e. cabozantinib, regorafenib), or hospice/best supportive care (BSC). Progression-free survival (PFS) was determined using Kaplan-Meier method, and hazard ratios estimated with Cox proportional hazards model. AEs according to Common Terminology Criteria for AEs v5.0 were analyzed with Fisher’s exact test. Results: Of the patients receiving first-line therapy, the median age was 60 years (n=65), and patients were 75% (n=49) Hispanics. 58 (89%) patients went onto receive second-line therapy. Child-Pugh (CP) score: A 17%, B 55%, C 28%. Median PFS was 3.1 months with TKI (n=6), 3.3 months with IO (n=27), and 1.3 months with BSC (n=25) (Table). There was improved survival with IO when compared to BSC (HR=3.26; 95% CI: 1.58-6.72; p=0.00136). There was no significant difference when comparing IO to TKI (HR=0.94; 95% CI: 0.31-2.86; p=0.92), but a trend to improved PFS with TKI when compared to BSC (HR=3.08; 95% CI: 0.96-9.84; p=0.06). TKI group had significantly more rash (p=0.01) and hand-foot syndrome (HFS) (p<0.001) compared to IO and BSC. All other AEs demonstrated no significant difference between groups (Table). Conclusions: In our Hispanic-majority cohort, patients with varying liver dysfunction, including CP B & C cirrhosis, were more likely to receive IO or BSC. Both second-line treatment groups (IO or TKI) had increased mPFS compared to BSC. Both IO and TKI groups were tolerable compared to BSC, with expected toxicity per class of drug. More prospective studies comparing second-line agents should be done in patients with varying liver dysfunction to understand survival, tolerability, and quality of life. [Table: see text]
Real-world effectiveness of lenvatinib monotherapy among unresectable hepatocellular carcinoma patients treated in United States clinical practices.
Authors: Singal Amit G. , Nagar Saurabh P , Hitchens Abigail , Iyer Shrividya
Published: January 2021

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Background: In the United States (U.S.), lenvatinib monotherapy was approved in August 2018 for first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC) based on the pivotal trial, REFLECT. Real-world data are essential to assess if this efficacy translates into effectiveness in clinical practice. The main objective of our real-world data (RWD) study was to assess clinical characteristics and effectiveness of lenvatinib among patients treated in U.S. clinical practices. Methods: A retrospective patient chart review study was conducted among adult patients (≥18 years) in the U.S. initiating lenvatinib monotherapy as first-line (1L) systemic therapy for uHCC between Aug 2018 and Sept 2019 and with ECOG status of 0 or 1. Data were extracted from individual patients’ electronic health records and captured in electronic case report forms. Clinical outcomes assessed include provider-reported best response, progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated using Kaplan-Meier methods. For PFS, patients were censored at end of treatment or end of follow-up in case of ongoing treatment, while censoring occurred at end of follow-up for OS. Results: Among 233 patients treated with 1L lenvatinib monotherapy, majority were male (68%) and most were Caucasian (52%) or African American (25%). Median age was 63 years and median body weight was 76 kg. The most common etiologies of liver disease were hepatitis C (36%), alcohol-related liver disease (28%), hepatitis B (16%) and non-alcoholic steatohepatitis (14%). Most patients had compensated cirrhosis, with 49% Child Pugh A and 43% Child Pugh B. All patients had uHCC, with most having Barcelona Clinic Liver Cancer stage B (29%) or C (44%) disease. Portal vein invasion was reported in 19%, of whom7% had main portal vein involvement. The median starting dose of lenvatinib was 12 mg daily. Over a median follow-up period of 9 months from HCC diagnosis, median PFS and OS were not reached. At 6 and 12 months landmark PFS was 85% and 65%, respectively and landmark OS was 92% and 73%, respectively. In the overall cohort, provider-reported best response was complete response (CR): 21%, partial response (PR):44% and stable disease (SD): 26%. Based on RECIST 1.1 (n = 125) CR:16%, PR:54%, SD:26% and mRECIST (n = 11) CR:73%, PR:0% and SD:18% were reported. Average duration of lenvatinib treatment was 7.4 months (median: 6.7 months) with 61% of patients remaining on lenvatinib at end of follow-up. Second-line (2L) treatment was initiated in 32 patients, with immunotherapy (50%), sorafenib (31%) and regorafenib (9%) being most common. Median time to 2L treatment from initiation of lenvatinib was about 8 months. Conclusions: Results from this retrospective real-world study in an U.S. population affirm the clinical effectiveness of 1L lenvatinib monotherapy among patients with uHCC.
Prospective, multicenter study of apatinib combine with TACE in treating intermediate to advanced stage HCC patients: A real-world study from China.
Authors: Li Hailiang , Hu Hongtao , Cao Guangshao , Wu Gang , Ding Pengxu , Li Zhen , Wei Qiuliang , Niu Huanzhang , Chang Zukuan , Yin Jun
Published: January 2021

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Background: Combination of transcatheter arterial chemoembolization (TACE) with apatinib are emerging as an effective treatment for patients with intermediate to advanced stage HCC. However, the data of HCC treated by apatinib in the real-world setting are not reported. In this real-world study, we aimed to explore the efficacy and safety of HCC pts which underwent TACE combine with apatinib. Methods: This was a prospective, multicenter observational study in a real-world setting and this study was approved by our Ethics Committee. Pts aged ≥18 years with well diagnosed intermediate or advanced stage HCC were included. The pts received apatinib plus TACE treatment as the first-line therapy. TACE treatment was performed on demand, the dose of apatinib was selected by the investigator. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival rate (OS), objective response rate (ORR), disease control rate (DCR) and safety profile. All of the objective response was assessed by independent central review per mRECIST criteria. Results: From Jun 2019 to Feb 2020, a total of 98 well diagnosed HCC pts with age from 31 to 86 were enrolled in this study. As of August 2020, the median follow-up was 9.5 months. The mPFS of 98 pts was 7 months. The ORR, DCR and 6 months OS rate was 35.7%, 76.5% and 82.6%, respectively.The PFS was 7.5 months in intermediate stage and 6.4 months in advanced stage. The ORR was 46.3% in intermediate stage (41 cases) and 28% in advanced stage (57 cases) HCC. And the 6 months OS rate was 90.2% in intermediate stage and 77.1% in advanced stage HCC. Overall, 17 (17.3%) pts had grade≥3 treatment-related AEs. All of the safety adverse effects can be tolerated or reduced after symptomatic treatment and no unexpected adverse events were observed. Conclusions: In this real-world study, apatinib showed a favorable efficacy and safety profile in pts with intermediate and advanced stage cancer. Apatinib combination TACE therapy might lead to better survival benefit in first-line treatment for HCC pts. Clinical trial information: ChiCTR1900024030.
The lines of loco-regional therapies received and the healthcare economic burden of patients newly diagnosed with hepatocellular carcinoma in the United States.
Authors: Seal Brian , Abdulhalim Abdulla M. , Lingohr-Smith Melissa , Lin Jay
Published: January 2021

286

Background: Hepatocelluar carcinoma (HCC) is one of the fastest growing causes of cancer-related deaths in the US. The objectives of this study were to examine the lines of loco-regional therapies received and the healthcare economic burden of patients newly diagnosed with HCC in the US. Methods: Patients (≥18 years of age) diagnosed with HCC who received ≥1 loco-regional therapy (index date) after diagnosis were identified from the MarketScan Commercial and Medicare Supplemental databases (July 1, 2013-May 31, 2018). Patients were required to have ≥6 months of continuous insurance enrollment before the index date and ≥1 month after (follow-up period). The follow-up period was censored when patients received any systemic therapy. During the follow-up periods, the number of patients who received radiation therapy, ablative therapy, and embolization procedures (transarterial embolization/chemoembolization [TAE] and radioembolization [TARE]) were examined. All-cause and HCC-related healthcare costs (total and patient out-of-pocket [OOP] payments per patient per month [PPPM]) were also measured. Results: Among the 2,101 patients newly diagnosed with HCC who received ≥1 loco-regional therapy, median age was 64 years and 75.0% were male; the mean follow-up duration was 11.5 months. During the follow-up periods, 28.1% (n = 590) received radiation therapy, 27.3% (n = 574) ablative therapy, and 77.3% (n = 1,623) embolization therapy (TAE: 68.7% [n = 1,443]; TARE: 20.7% [n = 434]); 30.9% of patients received multiple loco-regional therapies. During the follow-up periods, total all-cause healthcare costs were a mean of $20,316 (OOP: $378) PPPM, of which 70.7% ($14,359; OOP: $227 PPPM) were HCC-related. The breakdown of healthcare costs is shown in the table. Conclusions: According to the findings of this large-scale real-world analysis of patients newly diagnosed with HCC in the US, a vast majority received at least one embolization procedure. The monthly healthcare economic burden of patients with HCC treated with local-regional therapies is relatively high. [Table: see text]
Treatment patterns and survival in patients with late-stage hepatocellular carcinoma in France: A retrospective database analysis.
Authors: Blanc Jean-frederic , Laurendeau Caroline , Kelkouli Nadia , Mathurin Philippe
Published: January 2021

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Background: The prognosis for patients with late-stage hepatocellular carcinoma (HCC) is poor, with only one systemic treatment option available for patients until 2017. Aim: To describe treatment patterns and survival of French patients following diagnosis of late-stage HCC (Barcelona Clinic Liver Cancer classification B, C or D), using a comprehensive nationwide claims database, SNDS. Methods: The SNDS database was searched from 1 January 2015 to 31 December 2017 for patients with a diagnosis of HCC (ICD-10: C220) and late-stage disease, defined by the identification of transcatheter arterial chemoembolization (TACE) or radioembolization (TARE), HCC systemic therapy and/or best supportive care (BSC). Patients were followed up for a maximum of 2 years. Results: 17,298 patients (mean age: 68.7 years (SD: 11.3), 82.6% male) were identified, with 72.4% diagnosed at late stage. During follow-up, 29.6% of patients were treated with TACE or TARE, and 27.1% received systematic therapy (sorafenib in 99.5% of cases). The median duration of systemic treatment was 7.9 (95% CI: 7.4-8.5) months. In 62.5% of cases, this treatment was discontinued at 12 months; this proportion fell to 40.3% when using mortality as a competitive risk. Survival since diagnosis of late stage HCC differed according to the type of first treatment received. Median overall survival was 23.7, 11.9, 7.4 and 1 month in patients initially receiving TACE, TARE, systemic therapy or no treatment, respectively. Conclusions: These results confirm the high clinical burden of late-stage HCC over this period and the need for second-line systemic treatments to improve patient outcomes.