3620 Background: The role of adjuvant chemotherapy (CT) in stage II CC is debated. The validated 12-gene Oncotype DX Colon Recurrence Score test provides a Recurrence Score (RS) result (range, 0-100) which estimates recurrence risk (RR) in stage II/III pts. We studied treatment and clinical outcomes in CC pts in whom treatment decisions incorporated the RS result. Methods: This prospectively designed cohort study included all stage II, MMR-P, CC pts who underwent the 12-gene Oncotype DX testing through Clalit between 1/2011 and 12/2016 and had available data with minimum 3-yr follow-up. Kaplan-Meier (KM) estimates and log-rank tests were used to compare RR and CC specific mortality (CCSM) between RS categories. Multivariable analysis (MVA) identified variables associated with RR/CCSM. Results: The analysis included 938 pts. Median age, 68 (IQR, 60-76) yrs; 96% had T3 tumors, and 89% had ≥12 nodes examined. Median RS was 26 (IQR, 19-33). The 3 RS categories (0-29, 30-40, and 41-100) included 65%, 24%, and 11% of pts, respectively. The overall CT use rate was 24%, with a significant difference between the 3 categories (14%, 36%, and 60%, respectively, P< .0001). Pts with very low RS (0-15) comprised 14% of the cohort (CT use rate, 11%). Younger pts, and those with invasion/perforation/obstruction were more likely to receive CT. Clinical outcomes with a median follow up of 6.9 (IQR, 5.5-8.6) yrs are presented (Table). Among untreated pts, KM estimates for RR and CCSM differed significantly between the 3 RS categories ( P< .0001). Outcome of untreated RS 0-15 pts was excellent. In an MVA model, male sex, presence of invasion/perforation/obstruction and higher RS category (RS 41-100 vs 0-29 and vs 30-40, but not RS 30-40 vs 0-29) were associated with increased RR. For CCSM, the results were similar, but this time age ≥70 yrs replaced sex as a significant prognostic variable. Clinical outcomes within each RS group did not differ significantly between treated and untreated pts, but were numerically better with CT in the RS 41-100 group. Conclusions: This real-world analysis showed that the RS results provide independent prognostic information in stage II CC. Further studies are needed to investigate the potential role of the RS result as a predictor of CT benefit, but the data suggest that this benefit may be limited to pts with high RS results. [Table: see text]

Background: Colorectal cancer (CRC) incidence at ages <50 years is increasing worldwide. Screening initiation was lowered to 45 years in the United States. The cost-effectiveness of initiating CRC screening at 45 years in Israel was assessed with the aim of informing national policy and addressing internationally relevant questions.Methods: A validated CRC screening model was calibrated to Israeli data and examined annual fecal immunochemical testing (FIT) or colonoscopy every 10 years from 45 to 74 years (FIT45-74 or Colo45-74) versus from 50 to 74 years (FIT50-74 or Colo50-74). The addition of a fourth colonoscopy at 75 years was explored, subanalyses were performed by sex/ethnicity, and resource demands were estimated.Results: FIT50-74 and Colo50-74 reduced CRC incidence by 57% and 70% and mortality by 70% and 77%, respectively, versus no screening, with greater absolute impact in Jews/Other versus Arabs but comparable relative impact. FIT45-74 further reduced CRC incidence and mortality by an absolute 3% and 2%, respectively. With Colo45-74 versus Colo50-74, CRC cases and deaths increased slightly as three colonoscopies per lifetime shifted to 5 years earlier but mean quality-adjusted life-years gained (QALYGs) per person increased. FIT45-74 and Colo45-74 cost 23,800-53,900 new Israeli shekels (NIS)/QALYG and 110,600-162,700 NIS/QALYG, with the lowest and highest values among Jewish/Other men and Arab women, respectively. A fourth lifetime colonoscopy cost 48,700 NIS/QALYG. Lowering FIT initiation to 45 years with modest participation required 19,300 additional colonoscopies in the first 3 years.Conclusions: Beginning CRC screening at 45 years in Israel is projected to yield modest clinical benefits at acceptable costs per QALYG. Despite different estimates by sex/ethnicity, a uniform national policy is favored. These findings can inform Israeli guidelines and serve as a case study internationally.

In this issue of the Annals of Oncology, Laskar and colleagues report the results of a meta analysis of genome wide association data, with annotating demographic and lifestyle information, to identify genetic profiles in affected cases of early-onset colorectal cancer (EOCRC) , compared to controls[ 1 Laskar. Genome-wide association study and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer. Annals of Oncology. 2024. PMID Google Scholar ]. This important study was performed by a collaboration that includes four well established groups. Using advanced methodology, including Mendelian randomization (MR) analyses, as well as sensitivity analysis stratified by high-penetrance gene mutation status, the authors correlate genetic data with life style factors. They find two novel risk-for EOCRC loci and confirm several other previously identified gene loci, use the data to further identify three new high-risk genes, and describe dysregulated pathways that are enriched in the affected cases. Using MR, they correlate factors in the EOCRC patients such as body fat percentage, waist circumference, waist to hip ratio (a measure of obesity), basal metabolic rate, and fasting insulin which may have causal associations with increased risk for EOCRC. They also correlate level of education as well as lifestyle habits with the genetic findings. This report is the first use of GWAS specifically to study patients with EOCRC. While there are some limitations to the study (eg the participants are primarily of European ancestry), the high quality genetic and annotation data provide important new insights into potential driving factors in the increasing incidence of EOCRC, and potentially identify the genetic profile of the subgroup of young people at risk to develop EOCRC. This is key as although the incidence of EOCRC has sharply increased (see below for time points), the vast majority of people between the ages of 20-49 do not develop colorectal cancer.

This file contains Supplementary Materials and Methods, Supplementary Figure Legends, and 6 Supplementary Figures with their legends

RNA-seq data of PDPN+ cancer-associated fibroblasts (CAFs) from triple-transgenic gastric cancer mice

Distances of patient samples in PCA analysis

The US Surveillance, Epidemiology and End Result (SEER) data indicate an increasing incidence of early-onset cancer across the GI tract. A female predominance has been shown for early-onset pancreatic cancer (EOPC) in the US. Due to environmental factors which may underlie the pathogenesis of early-onset cancer, incidence across the globe may differ. However, data regarding the incidence of gastrointestinal cancers in young patients in Europe is scarce. Therefore, we aimed to investigate patterns of GI cancers in young patients across various European countries. National cancer registries of seven European countries - Germany, Netherlands, Spain, Slovenia, Norway, Czech Republic and Israel - were approached for absolute number of cancer incidences per age group (15-50 years in 5-year intervals) and the size of the population for each age group yearly from 2008-2018. Data was analyzed to calculate year-by-year the Average Annual Incidence Rate Change (AARC) and Average Annual Percent Change (AAPC). We observed heterogeneous patterns in different GI cancers across countries. An increase was noted in oesophageal cancer in females in the Czech Republic and Germany (AAPC 11.65% and 1.11% respectively) and slightly in males in the Netherlands (AAPC 0.88%) and Slovenia (AAPC 0.40%). Gastric cancer increased in females in Norway (AAPC 15.00%) and Slovenia (AAPC 11.90%). An increase in incidence of EOPC in men and women was noted in Germany, Norway and Netherlands and in females in Israel and Slovenia (AAPC 6.0%, 4.30% respectively). Early-Onset Colorectal cancer (EOCRC) is on the rise in men and women in Israel, Netherlands and Norway, while increasing only in males in the Czech Republic (AAPC 1.50%) and only in females in Slovenia (AAPC 5.40%). In Spain, only EOCRC showed an increased incidence. The incidence of early-onset cancer along the GI tract displays differential patterns across countries, which differs from the trends observed in SEER data. In some GI cancers the incidence is stable between 2008-2018 and some are increasing mainly in women. Due to the environmental role in the pathogenesis of early-onset GI cancer, future studies should unravel potential etiologies especially with regard to gender-related factors.

Despite ongoing improvement in long-term survival after esophagectomy, it still entails serious post-operative complications, with anastomotic leak (AL) representing a major one. Various risk factors for AL have been proposed involving both patient and tumoral factors. These include patient's co-morbidities as well as tumor location, surgical technique and perioperative oncological treatment. We aimed to study the microbiome profile of esophageal tumors and their potential correlation with post- esophagectomy AL. Databases of two tertiary centers were reviewed for consecutive patients who underwent esophagectomy and were clinically defined with anastomotic leak and patients who had uneventful post-operative course. Patients who had complete pathological response were excluded from the study due to lack of tumoral tissue for analysis. FFPE and snap frozen surgical specimen comprised of esophageal cancer and adjacent tissue were processed using 16S rRNA amplicon sequencing to characterize bacterial diversity and identity within the two tissues and compared between the two cohorts. Sixty patients were included in the analysis. Patient demographics revealed: 62% male, median age 67y. The most common tumor location in the esophagus was within the criteria of Siewert 2(46.7%) with 68.3% of patients cTNM stage III at the time of diagnosis. Thirty-nine patients underwent Three-field (McKeown) esophagectomy and 21 underwent Ivor Lewis esophagectomy. A total of 28% of patients experienced anastomotic leaks. We Identified bacteria with higher differential abundance in the tumor tissue compared to the adjacent normal tissue; some were previously described as associated with esophageal reflux. Moreover, specific bacterial taxonomic units were significantly associated with the prevalence of AL, mainly Gram negative. These bacteria can be identified by microbial profiling during pre-screening prior to operation. Characterizing the microbial signature of esophageal cancer revealed a differential microbial content in patients with anastomotic leak post esophagectomy, compared with the non-complicated patients. Future studies should explore whether geography and ethnicity may impact this correlation and should be further validated in a prospective study.

Univariate and multivariate analysis of the gastric cancer patient cohort

This cross-sectional study investigates representation of women as principal investigators of clinical trials by study phase, medical specialty, and representation of women trial participants.

Seropositivity persistence six months after vaccination

Gene set enrichment analysis (GSEA) using MSigDB (Hallmark gene sets) on the full stromal patient RNA-seq data

Pathway analysis of PDPN+cancer-associated fibroblasts (CAFs) from triple-transgenic gastric cancer mice

GEA pts with tumor-positive lymph nodes (ypN+) or incomplete surgical resection (R1) following neoadjuvant chemotherapy (chemo) are high risk for relapse. Adjuvant nivolumab is effective in non-pathCR esophageal/GEJ pts following chemoradiotherapy and surgery, and nivolumab and ipilimumab (nivo/ipi) have demonstrated activity in advanced GEA. We hypothesized that high risk (ypN+ and/or R1) post resection GEA pts treated with nivo/ipi would have better disease-free survival (DFS) than pts who continue with standard post-operative chemo. VESTIGE was an European, open label randomized phase II study to evaluate the efficacy of adjuvant nivo/ipi versus standard post-operative chemo in GEA patients with high risk for relapse post resection. Eligible pts were randomized 1:1 to receive post-operative adjuvant chemo (identical regimen as pre-operatively) or nivolumab 3mg/kg IV q2w plus ipilimumab 1mg/kg IV q6w x 1 year. Key inclusion criteria included ypN+ and/or R1 status following neoadjuvant chemo plus surgery and an adequate pre-specified surgical resection. The primary endpoint of the study was DFS, with secondary endpoints of overall survival (OS), safety, toxicity, and quality of life. The study was designed to have 80% power to detect an increase in DFS rate at 1 year from 65% to 74% (HR=0.7) with nivo/ipi vs chemo with a one-sided alpha of 10%. The primary analysis was intent-to-treat. Cox regression was used to estimate treatment effect (hazard ratio, HR). The EORTC IDMC in charge of independently monitoring the study reviewed the data from 191 of a planned 240 pts in June 2022 and recommended to stop further enrolment. At the time of this review, median follow up was 11.1 months (m) for 189 pts (94 chemo: 95 nivo/ipi). Median DFS for the chemo arm was 23.3m (95% CI 11.8- not reached (NR)) vs 11.9m (8.4–16.8m) for nivo/ipi HR 1.80 (95% CI 1.09– 2.98) p=0.02. 12m DFS were 62.2% and 49.3% respectively. Median OS for the chemo arm was not reached vs 25.1m (95% CI 18.6m – NR) HR 1.79 (95% CI 0.89 –3.59) p=0.1. No new toxicity concerns or excess early discontinuations were identified. Nivo/ipi did not improve DFS over chemo in pts with ypN+ and/or R1 GEA following neoadjuvant chemotherapy and surgery. Subgroup and biomarker analysis may be critical to understand whether any subgroup may benefit from adjuvant immunotherapy. The IDMC recommended to perform an analysis after longer follow-up to confirm these preliminary results. Analysis of PD-L1 and MMR status will be presented.

Figure 1: schematic representation of experimental design Figure 2: Histological manifestation of treated uteri at the short-term setting Figure 3: uterine characteristics following "rPEDF prevention" regimen

Clinical characteristics of the gastric cancer patient cohort

Pathway analysis of stroma from gastric cancer patients