bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular landscape and clinical implication of CCNE1-amplified esophagogastric cancer.
Authors: Moy Ryan H. , Wu Sharon , Xiu Joanne , Walker Phillip , Korn Wolfgang Michael , Lou Emil , Shields Anthony Frank , Goel Sanjay , Saeed Anwaar , Bass Adam Joel
Published: January 2023

440

Background: Cyclin E1 ( CCNE1) amplification ( CCNE1Amp) drives chromosomal instability (CIN) and is associated with immune cell exclusion, liver metastasis, therapeutic resistance, and poor survival in gastric adenocarcinoma (GA). However, the clinical relevance of CCNE1Amp in a larger real-world population is unknown. Therefore, we profiled the molecular landscape of CCNE1-amplified (amp) esophagogastric cancer (EGC) and explored treatment response outcomes. Methods: Tumors were analyzed by next-generation sequencing (NGS) of DNA (592 genes, NextSeq; WES, NovaSeq) and RNA (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Deficiency in mismatch repair or microsatellite instability (dMMR/MSI-H) was tested by fragment analysis, IHC, and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (high>10 mt/MB). PD-L1 was tested by IHC (22C3, 1+). Real world overall survival (OS) was extracted from insurance claims and calculated from first of treatment to last contact using Kaplan-Meier survival curves for molecularly defined cohorts. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q<0.05). Results: CCNE1Amp (copy number, CN ≥6) was identified in 142/2276 (6.2%) esophageal adenocarcinoma (EA), 101/1449 (7.0%) esophagogastric junction carcinoma (EJC), 109/2607 (4.2%) GA, and 6/751 (0.8%) esophageal squamous cell carcinoma (ESCC) samples. Metastatic sites such as lymph node and liver showed higher frequency of CCNE1Amp compared to primary sites. TMB, dMMR/MSI-H, and PD-L1 expression were similar in CCNE1-amp vs non-amp tumors. CCNE1Amp was enriched in CIN type tumors (defined by increased TP53 and ERBB2 amp) and was associated with decreased mutation of CDKN2A and CDH1. In addition, CCNE1-amp tumors showed increased HER2 positivity/ ERBB2 amplification by IHC (14.3% vs 10.1%) or CN analysis (19.1% vs 10.3%). Differential gene expression analysis demonstrated increased liver X receptor/retinoid X receptor (LXR/RXR) pathway activation in tumors harboring CCNE1Amp. While there were no differences in OS between CCNE1-amp vs non-amp GA, CCNE1Amp was associated with worse OS after trastuzumab in the IHC HER2+ cohort (N=9 vs 28; HR (95% CI): 2.95 (1.18 – 7.34), p = 0.015). By contrast, there was a trend toward improved OS after immunotherapy in CCNE1-amp GA (N=9 vs 194; HR (95% CI): 0.34 (0.11 –1.07), p = 0.054). Conclusions: CCNE1Amp is associated with a distinct molecular profile in EGC and resistance to HER2-targeted therapy. While CCNE1-amp tumors are thought to be generally “immune-cold,” CCNE1-amp GA demonstrated potentially improved outcomes with immunotherapy. Further investigation of CCNE1Amp as a predictive biomarker is warranted, particularly as novel therapeutics selectively targeting CCNE1Amp are under clinical investigation.
Examination of antagonistic metabolic reactions and nicotinamide/methylnicotinamide as a biomarker in gastric cancer.
Authors: Shi Min , Jiang Yu , Wang Yawen , Huang Qiong , Wu Qijing , Chen Guofeng , Liang Bishan , Wang Jiao , Li Shaowei , Wu Jianhua , Sun Li , Guo Jian , Liao Wangjun
Published: January 2023

442

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the therapy pattern of advanced gastric cancer (GC), but the efficacy is still unsatisfactory. The role of metabolism in the immune landscape of tumor microenvironment (TME) has been emphasized for the past few years. As the mediators of cellular interactions in TME, more metabolic biomarkers and their predictive value remain to be revealed. Methods: Metabolite activity scoring gene sets were constructed based on metabolite-protein interaction network. Integrated metabolite profile was collected from metabolic reactions in KEGG database. Transcriptome of ACRG (n=299) and anti-PD-1 cohort (PRJEB25780, n=45) were utilized to generate metabolite activity scores via GSVA algorithm. Cox regression was performed to calculate the hazard ratio (HR) to overall survival of metabolites in each metabolic reaction. Plasma samples (n=55) were obtained to measure nicotinamide metabolites from GC patients in Nanfang Hospital before and after ICIs treatment. Results: 78 metabolic reactions (78/6429) with opposite prognostic value among metabolic substrates and products were identified via the antagonistic metabolism screening workflow. Notably, nicotinamide (NAM)-methylnicotinamide (MNAM) (KEGG REACTION: R01269) showed significant antagonistic relationship (NAM, HR=0.76, 95% CI: 0.64-0.89, P<0.001; MNAM, HR=1.28, 95% CI: 1.09-1.49, P=0.002). NNMT, the rate-limiting enzyme catalyzing the formation of MNAM from NAM, was also correlated with poor prognosis (log-rank P=0.013). In terms of therapeutic prediction, NAM/MNAM ratio in plasma of GC patients was significantly correlated with anti-PD-1 response (PR vs SD/PD, median NAM/MNAM ratio (ng·mL-1/ng·mL-1) = 26.76 vs 10.40, P<0.0001). Compared with baseline, decreased plasma NAM/MNAM ratio was found in all (7/7) PR patients ( P=0.0011), while 73.33% (11/15) of non-responders showed a higher NAM/MNAM ratio after ICIs treatment ( P=0.0283). Correlation analysis of key metabolites with TME cells revealed that MNAM activity score was positively correlated with fibroblasts, MDSCs and M2 macrophages infiltration (Pearson correlation: R=0.60, P<0.001; R=0.42, P<0.001; R=0.34, P<0.001), suggesting that MNAM has a potential impact on immune-suppressive cells recruitment and functions. Conclusions: Nicotinamide metabolism was an indicator of prognosis in GC patients. Circulating NAM/MNAM ratio can be a novel metabolic biomarker in dynamic monitoring for ICIs therapy.
Serum IL-6 level to predict survival and treatment response in gastric and gastroesophageal junction cancer.
Authors: Karalis John D , Ju Michelle R , Yoon Lynn Y , Castro-Dubon Esther C , Hammer Suntrea , Porembka Matthew R. , Wang Sam C.
Published: January 2023

444

Background: There are few biomarkers to guide treatment for gastric and gastroesophageal junction adenocarcinoma (G+GEJ). The systemic inflammatory response, which is reflected by circulating serum cytokine levels, of G+GEJ patients is associated with survival. In this study, we evaluated the relationship of circulating serum cytokine levels with overall survival (OS) and pathologic tumor regression grade (TRG) in G+GEJ patients. Methods: A retrospective review of a prospectively maintained biobank was performed to identify patients diagnosed with G+GEJ from 2016-2022. Pre-treatment serum was collected at the time of diagnosis. For patients who received neoadjuvant therapy, an additional serum sample was collected immediately prior to surgical resection. A multivariable Cox proportional hazards model was used to assess the association of cytokine concentration with OS. In patients who received neoadjuvant therapy, we assessed whether the change in IL-6 (ΔIL-6) after therapy was associated with TRG. Results: We first measured the pre-treatment levels of 17 different cytokines in a 67-patient cohort to determine if certain circulating cytokines were prognostic for OS. In a multivariable analysis adjusted for clinical stage and the expression level of the other cytokines, the only circulating cytokine level that was independently associated with OS was IL-6 (HR: 1.06 per 1 pg/ml increase, 95% CI: 1.04-1.08). We then analyzed the serum IL-6 level in an additional 134 patients, resulting in a final cohort of 201 patients. Serum IL-6 level ranged from 0.3-196.7 pg/ml. In a multivariable analysis adjusted for age, sex, clinical stage, pathologic differentiation, Lauren classification, H. pylori status and neutrophil-to-lymphocyte ratio, IL-6 level was independently associated with OS (HR: 1.012 per 1 pg/ml increase, 95% CI: 1.006-1.019). Patients in the top tercile of pre-treatment IL-6 level had worse median OS (10.6 months) compared to patients in the intermediate (17.4 months) and bottom tercile (35.8 months, p < 0.0001). Among patients who received neoadjuvant therapy (n = 50), ΔIL-6 ≤ 0 had a sensitivity of 80% and specificity of 80% for predicting complete or near-complete pathologic tumor regression (TRG 1). Conclusions: Pre-treatment serum level of IL-6 is a promising prognostic biomarker for patients with G+GEJ. ΔIL-6 may predict response to neoadjuvant therapy.
Proposal of a coagulation score to predict postoperative survival of patients undergoing neoadjuvant therapy followed by subtotal esophagectomy for squamous cell carcinoma of the esophagus.
Authors: Sugiyama Fumitake , Shimizu Dai , Kanda Mitsuro , Tanaka Chie , Takami Hideki , Inokawa Yoshikuni , Hattori Norifumi , Hayashi Masamichi , Nakayama Goro , Fujiwara Michitaka , Kodera Yasuhiro
Published: January 2023

448

Background: Despite advances in multimodality treatment of esophageal squamous cell carcinoma (ESCC), the recurrence rate after curative resection remains high. Assessment of the risk of disease recurrences after curative resection of ESCC will be helpful for optimization of individual patient management. The close association between coagulation status and progression of malignant tumors has been previously reported. We herein sought to identify sensitive prognostic factors in ESCC by combining multiple coagulation markers. Methods: A total of 200 patients who underwent curative subtotal esophagectomy after neoadjuvant treatment for ESCC between January 2012 and December 2020 were included in the analysis. We retrospectively evaluated the correlation of preoperative plasma D-dimer (upper limit of normal, 1.0 μg/mL), fibrinogen (upper limit of normal, 350 mg/dL) levels and the coagulation score, which is calculated by combining levels of D-dimer and fibrinogen, with postoperative prognosis. The coagulation score was determined as follows. 0, neither D-dimer nor fibrinogen were elevated; 1, either D-dimer or fibrinogen was above the upper limit of normal; 2, both were elevated. Results: There was no significant difference in postoperative recurrence-free survival between the high and low groups for either preoperative D-dimer alone or preoperative fibrinogen alone. 59 patients (29.5%), 99 patients (49.5%) and 42 patients (21%) were categorized into coagulation score 0, 1 and 2, respectively. Patients in the coagulation score 1-2 group had a significantly shorter recurrence-free survival time than those in the coagulation score 0 group (hazard ratio 1.99, P = 0.0223). Conclusions: The coagulation score combining with plasma D-dimer and fibrinogen levels was suggested to be a simple predictor of postoperative recurrences in patients undergoing curative subtotal esophagectomy after neoadjuvant treatment for ESCC.
Clinical significance of D-amino acid profile for cancer detection in early stage and prediction of efficacy of nivolumab in gastric cancer.
Authors: Tsugaru Kai , Sujino Tomohisa , Mita Masashi , Sasabe Jumpei , Chida Akihiko , Harada Yosuke , Hirata Kenro , Sukawa Yasutaka , Kato Motohiko , Kawakubo Hirofumi , Hamamoto Yasuo , Kanai Takanori
Published: January 2023

453

Background: Some metabolites from gut microbiota are reported to associate with immunotherapy response. D-amino acids (D-AAs), enantiomer of L-amino acids (L-AAs), mainly produced by gut microbe and brain, are rare but important metabolite in mammals. Little is known about their biological and immunological significance in cancer patients (pts) as its difficulty of stable measurement. Methods: We first analyzed L/D-AAs in plasma of pts with each disease stage of gastric cancer (GC) before treatment, then compared with healthy control (HC). Second, we analyzed L/D-AAs in plasma of advanced GC pts planned nivolumab (NIVO) monotherapy, and compared among two groups divided based on treatment efficacy of progressive disease (PD) or non-PD. All pts with GC and HC were recruited in Keio University Hospital from October 2017 till March 2022. Concentration of L/D-AAs was measured with Two-Dimensional HPLC-MS/MS System. Results: In the first part, 108 pts with GC before treatment and 87 HC were recruited. D-Ser, D-Asn, D-Ala, D-Pro were detected in plasma of both pts with GC and HC, and their concentration was significantly higher in GC pts rather than in HC, even in pStage 1 ( p<0.0001 of each D-AA, values in table). D-Ser showed an increasing trend as the disease stage progressed. The AUC value of ROC curve to discriminate Stage 1 GC pts from HC were 0.976 with D-AAs. In the second part, 28 pts with advanced GC before NIVO monotherapy were recruited. The best response was PD in 10 pts, and non-PD in 18 pts. D-Ser and D-Asn in plasma were significantly higher in PD group rather than non-PD group ( p=0.0025 and p=0.0158, respectively). The AUC value of the ROC curve discriminating NIVO PD was highest for the equation mainly with D-Ser at 0.933. Pts with poor progression free survival (PFS) and overall survival (OS) could be distinguished by the determined cutoff value of the equation [median PFS: 1.1m vs 3.8m, HR 5.1 ( p=0.0003), median OS: 3.4m vs 18.9m, HR 7.1( p=0.0010)]. Conclusions: D-AAs in plasma significantly increased in pts with GC rather than HC even in early stage. Moreover, higher D-Ser in plasma associated with poor efficacy and prognosis of NIVO in GC pts. We firstly reported D-AA is a novel biomarker of both cancer detection and efficacy of NIVO.[Table: see text]
Unique microbial profile identified in patients with gastric cancer with pathologic response to neoadjuvant chemotherapy.
Authors: Drebin Harrison M. , Abate Miseker , Fei Teng , Tang Laura H. , Laszkowska Monika , Maron Steven Brad , Shimada Shoji , Vardhana Santosha , Vanderbilt Chad , Strong Vivian E.
Published: January 2023

458

Background: Microbial dysbiosis has been shown to be associated with the pathogenesis of gastric cancer (GC). However, the relationship between the GC microbiome and response to systemic therapy, such as neoadjuvant chemotherapy (NAC), is largely unknown. This study aims to explore changes in the microbiome after neoadjuvant chemotherapy, by analyzing the microbial profile of patients who received NAC and comparing differences among those with varied pathologic response to therapy. Methods: A microbiome bioinformatics pipeline using multiple next generation sequencing platforms was developed and used for analysis. GC tissue from patients who received NAC (n=101) and those who did not (n=85) were acquired at the time of surgical resection. Shannon alpha diversity plot and enrichment analyses by odds ratio were used to compare the microbial differences of the treatment cohorts. The microbial profiles of patients with pathologic response to NAC (>20% response) were characterized. Results: Of patients who received NAC, 66 (65.3%) experienced a greater than 20% response to NAC, and 35 (34.6%) demonstrated a 20% or lower response. Patients with a pathologic response to NAC were enriched for Rhizobium, Streptomyces, Comamonas, Sphingomonas, Micrococcus, Mycobacterium, Thauera, Hyphomicrobium, and Sinorhizobium (OR>4). There were no statistically significant differences in alpha diversity (p>0.05). Conclusions: Our results demonstrate that patients with a greater than 20% pathologic response to NAC have a distinct microbial enrichment compared to those with a poor pathologic response. Given the variable NAC treatment responses in GC, understanding unique microbial signatures in tumors will provide the landscape to explore key microbial contributors to GC NAC treatment response that may improve our understanding of treatment response variability among patients. [Table: see text]
Body composition assessment in patients with gastric cancer.
Authors: Nakamura Shun , Kanetaka Kengo , Matsumoto Ryo , Hashimoto Yasumasa , Kobayashi Shinichiro , Arai Junichi , Kobayashi Kazuma , Ito Shinichiro , Hidaka Masaaki , Nagayasu Takeshi , Eguchi Susumu
Published: January 2023

460

Background: The number of overweight patients with gastric cancer who underwent gastrectomy has increased in Japan. In addition to obesity, sarcopenia is a risk factor of severe surgical complication. The study aimed to elucidate the relationship between body composition and surgical outcome of gastrectomy for gastric cancer. Methods: This study was a retrospective, cohort study that include 701 patients who underwent gastrectomy in our institution between May 2008 and July 2017. Using preoperative computed tomography (CT), body composition such as psoas muscle index (PMI) and visceral fat area (VFA) were measured in the third lumber section. The patients were divided into two groups according to PMI (cut-off value 5.2 cm2/m2 in male and 3.5 in female) or VFA (cut-off value 155 cm2 in male and 116 in female), respectively. Surgical outcomes and postoperative complications were compared between the low and high groups for each PMI and VFA value. Results: There were 53 severe complications (14 anastomotic leakage, 14 pancreatic fistula, 8 respiratory failure, and 7b intraabdominal abscess) in this cohort. Some 701 patients were included in the study, 528 of whom were classified as normal PMI and 173 were as low PMI. In addition, 528 of whom were classified as normal VFA and 173 were as low PMI. In multivariate analysis, age and gender were independent risk factor for severe postoperative complication, however, low PMI was not. Conclusions: Our analysis showed no relationship between preoperative low PMI and postoperative complications. [Table: see text]
Immunohistochemistry-based molecular classification of gastric cancer in India: How are we different?
Authors: Dubashi Biswajit , L Charles , Nisha Yadav , Ganesh Rajesh Nachiappa , Kate Vikram , Penumadu Prasanth , Selvarajan Sandhiya , Raja Kalayarasan , Kayal Smita , Ganesan Prasanth
Published: January 2023

462

Background: TCGA and ACRG have classified gastric cancer (GC) into molecular subgroups using genomics. We attempted to classify GC from our region using IHC (Immunohistochemistry) to understand its prognostic significance and compare with similar data from other parts of the world. Methods: This was a retrospective cohort of GC patients from years 2017-18. EBV (LMP), MSI (MLH1, MSH2, PMS2, MSH6),p53, E-cadherin and PIK3CA were assessed by IHC. Clinicopathological characteristics and survival were evaluated for association with molecular subtypes as defined by TCGA and ACRG classification system. Results: A total of 191patients were included with EBV positivity 35 (18.3 %), MSI 33(17.3 %), p-53 aberration 25(13.1%), E-cadherin negative (29.3%). On univariate analysis, p53 aberration was associated with higher age (>60 yrs), E- cadherin negative with diffuse histology & antro-pyloric region as predominant site. MSI with intestinal histology & antro-pyloric region as predominant site with MSI. The TCGA classification revealed EBV 35 (18%), MSI 28 (15 % ), GS 48 (25 %) and CIN 80 (42% ) subtypes respectively. CIN subtype was seen predominantly above 40 yrs of age (P=0.04), GS subtype was frequently associated with diffuse histology P<0.0001. The ACRG classification revealed MSI 33(17%), MSS/EMT 51 (26.7%), MSS/ p53 normal 91 (47.6%) and MSS/p53 aberrant 16 (8.4) subtypes. MSS/E-cad- subtype was associated with diffuse histology. PIK3CA positivity was higher in CIN (TCGA )& MSI (dmr) (ACRG) respectively. The median OS in MSI was 35 and 32 months higher compared to other subtypes (P<0.0001) in TCGA and ACRG classification respectively. Conclusions: The TCGA and ACRG classification identified molecular subtypes based on IHC from our region and significantly correlated with clinical factors and survival. PIK3CA as an additional marker may be further explored to be included in the classification system. Abbreviation: EBV - Epstein–Barr-virus, MSI – Microsatellite-Instability, GS- Genomic-instability, CIN- Chromosomal-instability, MSS- Microsatellite-stable, EMT-Epithelial-mesenchymal-transition.[Table: see text]
Effect of PD-1 inhibition on macrophage population in human tissue cultures.
Authors: Hoang Ngoc , Welling Charlotte , Husstegge Marlon , Koerfer Justus , Monecke Astrid , Weimann Arved , Gockel Ines , Lordick Florian , Kallendrusch Sonja
Published: January 2023

463

Background: Moderate response rates of PD-1 inhibition in gastric and esophagogastric junction cancers (GC/EGJC) urge for reliable biomarkers. To further improve treatment outcomes, patients need targeted therapy based on clinically relevant biomarkers and predictive test systems for assessing individual drug susceptibility. We have previously established patient derived tissue cultures (PDTC) as a comprehensive ex-vivo drug testing system for GC/EGJC patients. Methods: The standardized PDTC) model was developed using tissue from surgical resection specimens to investigate response to the PD-1 inhibitor Nivolumab and the macrophage depriving bisphosphonates clodronate and zoledronic acid. Resident macrophage population (CD68, CD163), tumor proliferation (Ki67) and apoptosis (cPARP), as well as bulk gene expression data (nanoString technology) were analysed after 72 hours of PD-1 inhibition. Additionally, supernatants were collected, and cytokine concentrations are measured based on Luminex technology. Results: Macrophage depletion could lead to enhanced anti-tumoral effects in PDTCs after PD-1 inhibition. Gene signatures for Interferon γ-mediated inflammation and myeloid cell activity were identified and found to be relevant indicators for tissue response upon immune checkpoint inhibition. We observed alterations in cytokine and soluble surface marker concentrations, such as IL-8, IL-17A and IL-23 or PD-L2, LAG3 and CTLA4. Conclusions: Yielding an organotypic cell composition, we were able to demonstrate individual response patterns and immunological characteristics to identify responsiveness to PD-1 inhibition in GC and EGJC tissue. PDTCs are potent to define biological marker sets ex vivo and to differentiate and predict clinical patient response as well as their inherent immune cell capacity and plasticity.
Effect of temperature on gastro-esophageal cancer outcomes: A SEER study.
Authors: Gupta Kush , Gupta Ashish , George Anthony , Attwood Kristopher , Gandhi Shipra , Siromoni Beas , Mukherjee Sarbajit
Published: January 2023

467

Background: Cold stress suppresses antitumor response in animal models, leading to tumor growth . Recent studies have also shown a negative correlation between the average annual temperature (AAT) and cancer incidence. We hypothesized that esophageal cancer (EC) and gastric cancer (GC) patients living in warmer climates have improved overall (OS) and disease-specific survival (DSS) than those living in colder climates. Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER) database from 1996 to 2015. AAT at the county level was calculated based on the National Centers for Environmental Information. Cox multivariate regression models were performed to measure the association between temperature (measured continuously at diagnosis and in 5-degree increments) and OS/DSS, adjusting for variables. All associations were compared at a significance level of 0.05. The OS and DSS were summarized using Kaplan-Meier methods. All statistics were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results: A total of 17,408 EC patients were analyzed. The average age of the cohort was 65 years, 79% of which were male and 21% were female. Of them, 61.6% had adenocarcinoma, and 37.6% were squamous. After adjusting for covariates, patients in regions with AAT >53.5°F had an 11% improvement in OS [HR 0.89 (95% CI 0.86-0.92), p<0.0001] and 12% in DSS [HR 0.88 (95% CI 0.85-0.91), p<0.0001]. When the temperature was analyzed in 5°F increments, with each increment, there was a 3% improvement in OS [HR 0.97 (95% CI 0.96-0.98), p<0.0001] and 4% in DSS [HR 0.96 (95% CI 0.95-0.97), p<0.0001]. Subgroup analysis of squamous and adenocarcinoma showed similar results. These findings were validated in 20,553 GC patients. After adjusting for covariates, patients in regions with AAT >53.5 had a 12% improvement in OS [HR 0.88 (95% CI 0.85-0.90), p<0.0001] and 14% in DSS [HR 0.86 (95% CI 0.83-0.89), p<0.0001]. When analyzed in 5°F increments, with each increment, there was a 4% improvement in OS [HR 0.96 (95% CI 0.95-0.97), p<0.0001] and 4% in DSS [HR 0.96 (95% CI 0.95 - 0.97), p<.0001]. Conclusions: We showed for the first time that higher environmental temperatures are associated with significant improvements in OS and DSS in patients with gastro-esophageal cancer. Further confirmatory and mechanistic studies are required to implement specific interventional strategies.[Table: see text]
The role of primary tumor resection in synchronous stage IV colorectal cancer: Subgroup analysis.
Authors: An Hojung , Shin Ji Eun , Shim Byoung Yong , Kim Hyunho , Park Hyung Soon , Cho Hyeon-Min , Kye Bong-Hyeon , Yoo Ri Na , Kim Sung Hwan , Lee Jong Hoon , Lee Kang-Moon , Lee Ji Min , Jung Ji-Han
Published: January 2023

47

Background: The standard treatment for synchronous stage IV colorectal cancer (CRC) is systemic chemotherapy. There have been attempts to conduct elective primary tumor resection (PTR) as an upfront treatment to prevent complications in primary tumor sites, or improve prognosis. However, there are controversies about the role of PTR in stage IV CRC. We investigated the prognostic role of PTR and tried to find subgroups who might get benefit from upfront PTR in this population. Methods: Between 2010 and 2020, 330 patients diagnosed with synchronous stage IV CRC at St. Vincent Hospital in Korea were retrospectively reviewed. We excluded patients underwent PTR and metastasectomy at the same time, PTR for emergencies (perforation, acute bleeding with hemodynamic instability, fistula, and/or obstruction), or received chemoradiotherapy as an initial treatment. Overall survival (OS) was measured from the date of diagnosis until death resulting from any cause or the last censored date during follow-up. OS were calculated using the Kaplan-Meier method, and differences in survival between groups were compared by the log-rank test. Variables with p value <0.05 were included in the Cox regression multivariable model. Results: Total 223 patients were analyzed. Patients were divided into two groups; 45 patients receiving upfront elective PTR (PTR group), and the 178 patients receiving upfront systemic treatment (non-PTR group). Two groups were not different in terms of age ( p = 0.979), ECOG performance status ( p = 0.488), and serum CEA levels ( p = 0.252). However, the PTR group showed lesser number of metastatic organ compared to the non-PTR groups ( p = 0007). The PTR group survived longer than the non-PTR group ( p = 0.015). Multivariate analysis revealed that age≥60 (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.15-2.09; p = 0.004,), CEA≥30 ng/mL (HR, 1.32; 95% CI, 0.99-1.75, p = 0.061), PTR (HR, 0.66; 95% CI, 0.45-0.95; p =0.027), adding targeted agent (HR, 0.71; 95% CI, 0.53-0.96; p = 0.026), and ECOG≥3 (HR, 1.649; 95% CI, 1.15-2.37, p = 0.007) were associated with OS. Subgroup analysis showed that PTR might be beneficial in patients with low CEA (<30 ng/mL, p = 0.032), old age (≥60, p = 0.028), ECOG (≤2, p = 0.006), M1a stage ( p = 0.008), and receiving bevacizumab ( p = 0.016). Conclusions: Upfront PTR was conducted in selected patients with lower number of metastasis, but associated with OS after adjusting other prognostic factors. We suggested that PTR could be an option for patients with low CEA (<30 ng/mL), old age (≥60), ECOG (≤2), M1a stage, or receiving bevacizumab in this population.
The role of education in adjusting to changes in clinical practice for gastric or gastroesophageal junction adenocarcinomas.
Authors: Ackbarali Tariqa , Janjigian Yelena Y. , Van Cutsem Eric
Published: January 2023

470

Background: Gastric or gastroesophageal junction (GEJ) adenocarcinomas are difficult to treat and associated with poor prognosis, specifically in advanced disease. Recently approved and investigational immune checkpoint inhibitors (ICIs) and HER2-directed antibody-drug conjugates (ADCs) are changing the treatment landscapes for gastric cancer and GEJ cancer, allowing clinicians to manage difficult-to-treat patients. However, these advances also create knowledge and practice gaps that pose many challenges warranting education to close these gaps and to assess current practices. Methods: PlatformQ Health’s proprietary workflow digital technology was utilized to launch a 4-part CME series online in December 2021 which remains on-demand through December 2022 at OMedLive.com. Each module focused on the following topics: 1) HER2 testing, 2) Current care for HER2+ gastric or GEJ cancer, 3) Treatment for unresectable disease and trastuzumab-resistant disease, and 4) adverse event management. This series was conducted in partnership with the American Gastroenterological Association and accredited by the Postgraduate Institute for Medicine. Clinicians engaging in this educational series were assessed at pre- and immediate post-activity. Practice pattern insights and education impact were assessed post-activity. Results: To date, 2,568 US-based clinicians have participated in the educational series. All 6 questions across the 4 modules in the series showed significant improvements in knowledge and competence related to HER2 testing, defining the standard of care, treatment beyond trastuzumab resistance, treatment for unresectable disease, and managing adverse events. Provider insights evaluated post-series revealed 41% of clinicians will consult with a pulmonologist upon development of interstitial lung disease; 51% identified trastuzumab deruxtecan as a novel HER2-targeted therapy having the greatest potential to improve patient outcomes; and 26% reported not repeating HER2 expression testing following progression on a trastuzumab-containing regimen. Evaluating the impact of the educational series, 88% of clinicians reported a positive impact on patient experience and 94% on clinical practice change following participation. The qualitative data depicting the reported impact will be shared. Conclusions: This serialized education was effective in improving knowledge and competence across four major themes of practice within gastric and GEJ cancer management. Provider insights revealed practice shifts following participation and practice impact assessments demonstrated the rapid application of real-time digital education.
Time to first treatment and optimal adjuvant treatment strategy in patients with resectable gastric cancer pathologically upstaged to lymph node–positive disease.
Authors: Ajay Pranay Shah , Sok Caitlin , Goyal Subir , Switchenko Jeffrey M. , Maegawa Felipe , Gillespie Theresa Wicklin , Paulos Chrystal M , Kooby David A. , Kennedy Timothy , Shah Mihir Maheshkumar
Published: January 2023

473

Background: Treatment strategies in resectable gastric cancer (GC) patients include perioperative chemotherapy (PEC), postoperative chemoradiation therapy (POCR), and postoperative chemotherapy (POC). Treatment delay can lead to metastases with unfavorable outcomes. We aim to identify the distribution of patients upstaged to pathologically node positive disease (pLN+) stratified by time and the optimal treatment in this cohort. Methods: We analyzed resected GC patients in the National Cancer Database (2004-2016) with clinically node negative disease (cLN-). Time from diagnosis to first definitive therapy was stratified as ≤2, >2 to ≤4, and >4 weeks. The distribution of patients upstaged from cLN- to pLN+ disease, the concordance between cLN- and pathologically lymph node negative (pLN-) disease based on treatment strategy, and time to first definitive therapy was analyzed. POC and POCR were compared to evaluate their effect on overall survival (OS) in patients with cLN- upstaged to pLN+ disease. Kaplan-Meier test, log-rank test, multivariable Cox proportional hazards analysis (MVA) were performed. Results: Of the 4,828 gastric cancer patients with cLN- disease, 514 (10.65%) patients received PEC and 4,314 (89.35%) patients received upfront surgery followed by POCR/POC. Distribution of patients stratified by time between diagnosis to first definitive treatment - chemotherapy (PEC) or surgery (POC/POCR), for ≤2 weeks was 9.5% vs. 33%, >2 - ≤4 weeks was 28.4% vs. 24.2% and >4weeks was 62% vs 42.7%, respectively. Patients upstaged from cLN- to pLN+ disease in the PEC group was 43.37%(n=206), and 70%(n=2574) in the upfront surgery group (POC/POCR). Of the 206 (43.37%) patients upstaged from cLN- to pLN+ in the PEC cohort, the upstage rate was 7.77% when chemotherapy was started within 2 weeks of diagnosis, compared to 27.67% with >2 to ≤4 weeks, and 64.56% with >4 weeks. Of the 2,574 (70%) patients upstaged in the upfront surgery cohort (POCR/POC), 30.61% were upstaged in ≤2 weeks, 24.95% in >2 to ≤4 weeks, and 44.44% in ≥4 weeks. On MVA, patients with cLN- disease that were pLN- (POCR=766, POC=341) had no significant difference in OS when treated with POCR (HR 1.11, p=0.39) compared to POC. Patients with pLN+ (POCR=2300, POC=907) disease had an association with improved OS when treated with POCR (HR 0.78, p<0.001) compared to POC. Conclusions: When resectable gastric cancer patients undergoing upfront surgery are upstaged from clinically node negative to pathologically node positive disease, postoperative chemoradiation therapy may be the optimal treatment strategy compared to postoperative chemotherapy. Clinical nodal status may not be an optimal predictor of nodal disease.
Racial and ethnic disparities in multinational phase III clinical trials in liver and biliary tract cancer.
Authors: Monge B. M. Cecilia , McGlynn Katherine , Greten Tim F.
Published: January 2023

497

Background: Racial and ethnic diversity ensures validity of clinical research and opens novel oncologic treatments to all population groups. Hispanics and non-Hispanic Blacks (NHB) are the largest racial/ethnic groups in the United States after non-Hispanic Whites (NHW). Hispanics accounted for 19%, while NHB accounted for 14% of the population in 2021. From 2012 to 2019 the proportion of hepatocellular carcinomas (HCC) and biliary tract cancers (BTC) occurring in Hispanics was 23.2% and 22.6% respectively; the proportion of HCC and BTC occurring in NHB was 11.1% and 8.3% respectively. We examined the participation of NHB and Hispanics in multinational phase III clinical trials of HCC and BTC in the last ten years. A participant to population ratio (PPR) of 0.8-1.2 reflects adequate ethnic/racial representation; a lower PPR indicates underrepresentation. Methods: A database search was performed in PubMed, Embase and Web of Science: Core Collection (Cl for multinational phase III clinical trials of HCC or BTC, studying first and second line treatments published from August 2012 to August 2022.Trials meeting these criteria were identified and the percentage of NHB and Hispanics included was calculated and compared to the proportion of NHB and Hispanics affected by HCC and BTC as per the National Cancer Institute Surveillance, Epidemiology, and End Results Program. Results: Eighteen multinational phase III clinical trials studying first- and second-line treatments for HCC and BTC were identified. The trials enrolled a total of 12464 patients; 27% (n=5 trials) did not report racial/ethnic characteristics. Of the 9991 patients included in trials for which race/ ethnicity was provided, 11 (0.08%) were Hispanics and 88 (0.7%) were NHB. The participant to population ratio (PPR) in Hispanics for HCC was 0.003 and 0 for BTC, meanwhile the PPR in NHB was 0.6 for HCC and 0 for BTC. Conclusions: NHB and Hispanics are underrepresented in HCC and BTC in multinational phase III trials relative to the U.S population. Most patients included in trials were Asian, consistent with the global incidence of HCC. It may be important for phase III clinical trials seeking FDA approval to require mandatory racial/ethnic diversity that is reflective of the US population.
Incidence and costs associated with clinically significant events in real-world patients with unresectable hepatocellular carcinoma on systemic therapy.
Authors: Healey Marcus , Simmons Daniel , Valerio Stephen J , Sah Janvi , Pierce Debra , Jiang Zhuoxin , Thomas Darren , Levingston Mac Leod Jesica , Lin Yian
Published: January 2023

514

Background: First-line (1L) treatments for unresectable HCC (uHCC) include atezolizumab plus bevacizumab (ATEZO+BEV), and the tyrosine kinase inhibitors (TKIs) sorafenib (SOR) and lenvatinib (LEN). In clinical trials, these therapies were associated with clinically significant events (CSEs): bleeding, clotting, encephalopathy, and portal hypertension. The objective of this study was to evaluate the real-world incidence of these CSEs and their impact on healthcare resource utilization (HCRU) and costs in patients with uHCC receiving ATEZO+BEV or a TKI. Methods: We conducted a retrospective, observational, cohort study using Clinformatics Data Mart to characterize 1379 US patients diagnosed with uHCC between January 2007 and June 2021 who received treatment with ATEZO+BEV (n=271) or a TKI (SOR, n=891; LEN, n=217). Incidence of the selected CSEs was evaluated as incident cases per 100-person-years (PY) of treatment. Descriptive statistics assessed patient characteristics, HCRU, and medical costs. Results: Mean age at diagnosis was 67.7 years; most patients were male (76.1%), white (52.4%), and had Medicare (74.2%); these characteristics were consistent across treatment groups. While on ATEZO+BEV, SOR or LEN, 147 (54.2%), 481 (54.0%), and 121 (55.8%) patients experienced ≥1 CSEs, respectively. For the ATEZO+BEV group, the most common CSEs were clotting (61.2 cases/100-PY [95% confidence interval {CI}: 45.1, 81.1]) and bleeding (55.4 [40.3, 74.4]). For the SOR group the most common CSEs were encephalopathy (54.5 [46.9, 63.1]) and clotting events (51.3 [44.1, 59.4]), for the LEN group the most common CSEs were clotting events (63.5 [47.4, 83.3]) and encephalopathy (56.7 [42.2, 74.5]). Overall, mean HCRU was high in the outpatient visits, while increases in the cohorts and among events (e.g., for surgery and inpatient visits) were seen in patients with ≥1 CSEs versus those without CSEs. Mean monthly medical costs were also substantially higher with ≥1 CSEs (Table). Conclusions: There were high levels of CSEs in patients receiving ATEZO+BEV or TKIs for 1L uHCC, and the occurrence of these events is associated with an economic burden to the healthcare system. Safety should continue to be monitored for patients treated for uHCC and new therapy options with reduced risks for developing CSEs are needed. [Table: see text]
Trends in incidence, treatments, and clinical outcomes of cholangiocarcinoma diagnosed in British Columbia, Canada, from 2005 through 2019.
Authors: Boutin Mélina , Yang Jenny , Safro Maria , Jafari Helia , Davies Janine Marie , Gill Sharlene
Published: January 2023

522

Background: While only accounting for 3% of gastrointestinal malignancies, cholangiocarcinoma (CC) has poor prognosis. New targeted therapies are on the horizon and understanding the potential size of the population eligible for such therapies is of importance. Contemporary incidence and outcomes in Canada have not been studied. Methods: Patients diagnosed with CC between 2005-2019 in British Columbia were identified using the BC Cancer Registry. Patient characteristics, treatments received and outcomes were collected and analyzed. Results: A total of 1520 patients were identified. Median age at diagnosis was 69 (interquartile 61-76) and 52% were female, 594 patients presented with localized disease (39%) of whom 416 had disease recurrence. The proportion of intrahepatic CC (ICC) rose from 17% in 2005-2009 to 44% in 2015-2019 while the incidence of extrahepatic (ECC) and gallbladder (GB) cancers followed populational trends. More patients with ICC had stage IV cancer at the time of diagnosis (64% vs 43% for ECC and 45% for GB, p<0.01). Treatments received are shown in the table. Among 1086 patients with recurrent or metastatic disease, 54% and 14% respectively received first- and second-line chemotherapy. Overall survival (OS) was 13.7 months [HR 0.43 (95% CI 0.37-0.49)] with 1 line of treatment and 21.3 months with 2 lines [HR 0.30 (95% CI 0.24-0.37)], compared to 4.8 months with best supportive care. On multivariate analysis, ECOG, first and second-line treatment and liver-directed therapy remained associated with improved outcomes while tumor site or time period did not. Conclusions: The incidence of CC is rising and most patients present with advanced disease. Treatment attrition is high and few patients receive second line therapies. The outcomes of patients receiving first line, second line and liver-directed therapies are significantly better than those receiving supportive care only. Understanding contemporary trends in presentation and treatment patterns is essential as we consider strategies to improve implementation and access of emerging novel therapies in this setting. [Table: see text]
Attitudes toward prevention options in Lynch syndrome (LS): Comparing frameshift peptide vaccination (FSPVAX), colonoscopy (COLO), and aspirin (ASA) chemoprevention.
Authors: Hall Michael J. , Riggs Emma D , Chertock Yana , Daly Mary Beryl
Published: January 2023

526

Background: LS is among the most common cancer (CA) syndromes affecting 1:280 individuals and portends high lifetime CA risk. Clinical trials are currently evaluating whether FSPVAX could reduce LS CA risk. FSPVAX enhance immune response to diverse FSP neoantigens in MSI-H tumors and have shown promising results in an MSH2-mutant mouse model and metastatic MSI-H CRC. However, negative public attitudes towards vaccination could undermine this novel therapy. Here, we benchmark attitudes towards FSPVAX for CA prevention against intensive colonoscopy, for which uptake is high in LS, and aspirin chemoprevention, where uptake is generally lower. Methods: The PREVENTLynch survey was distributed electronically to participants in the Fox Chase Cancer Center (FCCC) Risk Registry. LS patients were invited to complete the one-time survey after providing informed consent, and received a gift card incentive upon completion. The study was approved by the FCCC IRB (20-8014). Demographic/personal/familial CA history were collected. Attitudes were measured on 9-point scales indicating low vs high agreement with belief statements: e.g.“Colonoscopy is a convenient way to lower my risk of LS-related CA.” Results: Overall 116 out of 220 invited LS patients completed the survey (response rate 53%). 76% were female, and mean age was 52.7 yrs. 72% had personal history of CA. COLO uptake was high (96%), while ASA uptake for prevention was modest (22%). Side effect concerns were higher for FSPVAX compared to both COLO and ASA (both p<0.001). FSPVAX offered patients significantly less reassurance than COLO (p<0.001) and was significantly less likely to be endorsed/pursued as a treatment (p<0.001). Convenience of FSPVAX was similar to COLO but less than ASA (p<0.001). LS patients with (vs w/o) a personal history of CA(p<0.05) and those >50 yrs old (vs<50)(p<0.05) were more likely to participate in a FSPVAX trial. Conclusions: LS patients’ attitudes towards FSPVAX are mixed. Concerns about side effects and efficacy may limit future uptake similar to ASA. [Table: see text]
Promoting multidisciplinary care for patients with unresectable hepatocellular carcinoma (HCC): Findings from a quality improvement initiative across two community cancer centers.
Authors: Baron Ari David , Delcuze Bethany , Guzzone Francesca , Carter Jeffrey D. , Heggen Cherilyn
Published: January 2023

528

Background: Evolving treatment paradigms in HCC are increasing the need for multidisciplinary coordination and a focus on patient-centered care. Identifying real-world challenges HCC care teams face in implementing these critical practices is necessary to inform educational interventions and optimize patient outcomes. Methods: In March–April 2021, 22 health care professionals (HCPs) who treat HCC at 2 US community oncology clinics completed surveys assessing practice patterns, challenges, and confidence related to multidisciplinary and patient-centered care in HCC and participated in interdisciplinary audit and feedback sessions. Patient charts evaluated pre- and post-intervention assessed changes in clinical practice. Inclusion criteria included confirmed HCC diagnosis, age ≥ 18 years, and ≥ 2 visits in the one-year chart abstraction period. Results: Participants represented the interprofessional HCC care team: medical oncologists (38%), gastroenterologists (8%), hepatologists (4%), internal medicine (17%), advanced practice professionals (4%), and nurses (29%). Baseline and follow-up patient charts included 50% and 47% Stage II-III HCC patients and 50% and 53% Stage IV HCC patients, respectively. Top reported barriers to multidisciplinary tumor board use were ineffective interdepartmental coordination/collaboration (43%) and low volume of referrals (38%). HCPs aimed to resolve these gaps through improved collaboration between multidisciplinary teams (33%) and earlier referrals to a medical oncologist (29%). Providing patient-centered supportive care was identified by 33% of HCPs as the top challenge in HCC patient care. Of HCPs surveyed, 77% estimated that ≤ 25% of patients are evaluated for/referred to distress/behavioral health services. Chart audits after educational intervention and action plan implementation showed improvements in supportive care utilization (see table). A critical component of patient-centered care, shared decision-making (SDM) was reported by 24% of HCPs. HCPs reported patient resistance to SDM (33%) and low patient health literacy (29%) as top barriers to SDM. Chart documentation of HCP participation in SDM increased post intervention (see table). Conclusions: In current real-world practice, HCC care teams report challenges in interdisciplinary collaboration and referrals, providing supportive care, and involving patients in SDM. These identified gaps represent key opportunities for future interventions to improve HCC care. [Table: see text]