bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of Wnt pathway alterations including RNF43, GNAS, CTNNB1, and APC on prognosis and potential therapeutic vulnerability in pancreatic adenocarcinoma (PDAC).
Authors: Takebe Naoko , Blais Edik Matthew , Huynh Jasmine , Thach Dzung , de Arbeloa Patricia Miren , Matrisian Lynn McCormick , Petricoin Emanuel , Pishvaian Michael J. , Chung Vincent , Boland Patrick M , Yaeger Rona , Wadlow Raymond Couric , Hendifar Andrew Eugene , Nevler Avinoam , Cannon Timothy Lewis
Published: January 2024

698

Background: Several Wnt pathway genes (RNF43, GNAS, CTNNB1, APC) are mutated in PDAC but their clinical implications remain unclear. Both RNF43, a membrane E3 ubiquitin ligase that negatively regulates Wnt via FZD, and GNAS, a mediator of GPCR signaling, are enriched in IPMN-associated PDAC whereas CTNNB1 is a hallmark of solid pseudopapillary neoplasms. Here, we retrospectively analyzed progression-free survival (PFS) and overall survival (OS) in a PDAC cohort to understand potential therapeutic and prognostic differences between tumors with (MUT) or without (WT) Wnt pathway mutations. Methods: We analyzed longitudinal outcomes across 774 patients (pts) with NGS results from Perthera’s Real-World Evidence database who received at least 1 line of therapy in the advanced setting for PDAC. PFS was evaluated from initiation of 1st line for advanced disease until discontinuation due to disease progression. Hazard ratios and p-values were computed via Cox regression when comparing PFS within subsets that received either 1st line FOLFIRINOX (FFX) or 1st line gemcitabine/nab-paclitaxel (GA). Differences in frequencies of genomic alterations outside the Wnt pathway were analyzed by Fisher’s exact test. Results: Within the analysis cohort (N = 774), Wnt pathway alterations were present in 72 (9.3%) of PDAC tumors based on mutations in either RNF43 (4%), GNAS (3%), CTNNB1 (<1%), or APC (2%). Median OS (relative to advanced diagnosis) was significantly longer in the MUT subgroup compared to WT (Table). Median PFS on 1st line GA was significantly longer in MUT pts, and a similar insignificant trend was noted for PFS on 1st line FFX (Table). MSI-high and PIK3CA mutations were enriched for co-occurrence with Wnt pathway alterations whereas common PDAC mutations in KRAS and TP53 were less frequent in MUT pts (Table). Gene-specific trends and potential confounders will be discussed in the context of multivariate OS/PFS analyses. Conclusions: The presence of Wnt pathway alterations identifies a subgroup of advanced PDAC with improved PFS and OS.[Table: see text]
Association of longitudinal changes of genomic alteration of circulating tumor DNA with treatment response in pancreatic cancer.
Authors: Choi Jin Ho , Lee Sang Hyub , Paik Woo Hyun , Kim Junyeol , Lee Tae Seung , Lee Myeong Hwan , Cho In Rae , Ryu Ji Kon , Kim Yong-Tae
Published: January 2024

701

Background: Recently, the evaluation of circulating tumor DNA (ctDNA) in pancreatic cancer (PC) patients has gained attention for detection of mutation profile. However, the concordance between tissue next-generation sequencing (NGS) and ctDNA NGS remains unclear. Additionally, the dynamics of genomic alterations during treatment or disease progression are not well understood. Methods: In this prospective cohort study conducted at Seoul National University Hospital from Jan 2022, tissue samples from endoscopic ultrasound-guided fine needle biopsies and blood samples were collected from PC patients. Genomic DNA from the treatment naïve primary tissue and ctDNA from the blood obtained before any treatment and during follow-up with anti-cancer treatment were obtained. Genomic alternation was analyzed based on targeted NGS based panel deep sequencing including 41 genes. Results: The concordance of genomic alteration profiles between tissue NGS and ctDNA NGS was evaluated in 55 patients, and the mutation detection rate of patients who were diagnosed as stage I or II disease were 100% (14 of 14) in tissue NGS and 86% (12 of 14) in ctDNA NGS. That of patients who were diagnosed as stage III or IV disease was 92.7% in tissue NGS (38 of 41) and 90% (37 of 41) in blood ctDNA NGS. Among the study patients, the longitudinal changes of genomic mutation profile were evaluated in the patients at the first treatment response assessment, and patients with progressive disease showed significantly greater amounts of mutations including newly detected Tier1/2 variants than baseline and the previous response assessment. Conclusions: In conclusion, there is comparable mutation detection between tissue genomic DNA and blood ctDNA. The significant increase in ctDNA mutations during disease progression suggests their association with immune evasion and cancer evolution. Further studies utilizing our prospective cohort are needed to explore clinical implications of these results.
Clinical and prognostic characteristics of early onset metastatic pancreatic cancer.
Authors: Pretta Andrea , Giampieri Riccardo , Nichetti Federico , Ziranu Pina , Lupi Alessio , Cimbro Erika , Andena Paola , Felicetti Cristiano , Pircher Chiara Carlotta , Gusmaroli Eleonora , Donisi Clelia , Balconi Francesca , Mariani Stefano , Lai Eleonora , Puzzoni Marco , Pusceddu Valeria , Berardi Rossana , Niger Monica , Scartozzi Mario
Published: January 2024

702

Background: In the last decade several studies have shown an increase in the incidence of early-onset PDAC (EO-PDAC), conventionally defined as cancer that occurs in adults between the ages of 18 and 49. Clinical and prognostic data on this setting are limited and conflicting. The aim of our study was to evaluate the clinical, and prognostic differences in a large group of patients with early onset mPDAC. Methods: We retrospectively collected data from 368 patients affected with metastatic pancreatic ductal adenocarcinoma, from 3 different Italian Institutions. All patients had one or more metastatic sites, and received first-line chemotherapy. The main objective of the study was to evaluate the median overall survival in EO-PDAC patients compared to late onset PDAC (LO-PDAC), while secondary endpoint was evaluations of mPFS. Statistical analysis was performed with the MedCalc package. Results: 30 (8,1%) patients were early onset and 338 (91,9%) were late onset; median age was 46 (±5) and 68 (±8), respectively. M/F ratios were 1:1 in both group. In the overall population mOS was significantly lower in EO-PDAC patients: 10,0 versus 15,0 months ( p = 0,03). Furthermore, mPFS was significantly lower in EO-PDAC patients: 5,0 versus 8,0 months ( p = 0,04). ORR obtained from 244 pts were: 11% in EO-PDAC and 24,7% in LO-PDAC. Conclusions: The results of our work, although limited by the retrospective nature of the study, showed a worse prognosis for patients with early onset PDAC compared to late onsets. Further investigations will be needed to better understand this growing group of patients from a molecular and therapeutic point of view.
Epidemiological characteristics of patients with pancreatic cancer with and without diabetes mellitus: A retrospective cohort study.
Authors: Eichinger Sarah Elizabeth , Nieto Dominguez Alejandro , Guifarro Rivera Daniel , Turk Ekrem , Pan Chun-Wei
Published: January 2024

705

Background: Pancreatic cancer accounts for approximately 3% of new cancers diagnosed in the US and more than 8% of all cancer deaths. Despite the increasing incidence, there are few indicated screenings, mostly in patients with genetic mutations. Pancreatic cancer is associated with several risk factors including tobacco use, family history, heavy alcohol use, and diabetes mellitus (DM). In the US, more than 11% of adults have a diagnosis of diabetes and incidence is projected to rise over the coming years. Given the risk of DM associated with pancreatic cancer, establishing preventative measures, early intervention, and appropriate follow up for diabetic control could be an important step in decreasing the risk of pancreatic cancer. This study examines the demographic characteristics of patients with a diagnosis of pancreatic cancer with and without DM. Methods: We used the 2016-2019 Nationwide Inpatient Sample database, the largest all-payer inpatient care database in the US, to stratify all patients admitted with a diagnosis of pancreatic cancer, with and without DM, to further characterize their epidemiological characteristics. Results: Characteristics of patients with and without DM and pancreatic cancer are shown in the table. There were 150,275 patients diagnosed with pancreatic cancer, of which 44,170 (29%) had a concomitant diagnosis of DM. Of patients with both pancreatic cancer and DM, 53% were women (51% in patients without DM), 64% were white (70% in patients without diabetes), and 63% had Medicare for insurance (60% in patients without DM). Conclusions: Of patients with pancreatic cancer 29% had a concomitant diagnosis of DM(p=0.00). Epidemiological characteristics of patients with pancreatic cancers with and without DM such as age, sex, and insurance status were similar between both groups. However, there was a decreased percentage of Caucasian patients with pancreatic cancer and DM compared to those without DM. Given the association of diabetes with pancreatic cancer, and rising incidence of patients with diabetes in the US, emphasis on diabetes prevention and control may be an important factor in reducing the incidence pancreatic cancer. This study also suggests the need for further research to determine if there is utility in screening for pancreatic cancer in patients with diabetes to decrease the burden of pancreatic cancer in the US population.[Table: see text]
Predicting rapid progression and overall survival in stage II-III pancreatic cancer using a CT-based radiomic signature.
Authors: Xu Qinmei , Santos Toesca Diego Augusto , Schueler Emil , Jamalian Arash , Alkim Emel , Chang Daniel Tandel , Fisher George A. , Vitzthum Lucas , Gevaert Olivier , Itakura Haruka
Published: January 2024

706

Background: We sought to assess the ability of a computed tomography (CT)-derived radiomic signature (RS) feature set to predict rapid tumor progression and overall survival (OS) in patients diagnosed with stage II-III pancreatic cancer undergoing stereotactic body radiation therapy (SBRT) in sequence with chemotherapy. Methods: We conducted a retrospective study on a cohort of 240 stage II-III pancreatic cancer patients who underwent SBRT in sequence with chemotherapy at a single institution (Stanford Hospital and Clinics). Among them, 83 had pre-SBRT contrast-enhanced CT images with segmented tumors, forming the imaging set, from which we extracted 900 radiomic (quantitative pixel-level imaging characteristic) features from delineated tumor regions-of-interest. For RS development, we divided the imaging set into a training set (n = 53) for model development and a test set (n = 30) for evaluation. We built a binary prediction model on the training set to identify patients at risk of rapid tumor progression within three months after SBRT. We utilized logistic regression with the Least Absolute Shrinkage and Selection Operator algorithm for feature selection and classification. To fine-tune parameters, we performed five-fold cross-validation on the training set, repeating each set of parameters five times. Finally, we assessed the model's performance on the test set (n = 30) using the area under the curve (AUC) value. We selected the model with the best AUC, while also generating the predictive radiomic feature set. For OS prognostication, we conducted both univariate and multivariate Cox proportional-hazards analyses using RS and clinical features (age, sex, stage, vessel involvement, tumor location, performance status, body mass index, biological equivalent dose of radiation) as potential predictors. Results: The enrolled cohort consisted of 127 men (mean age, 69 years ± 12 [SD]) and 113 women (mean age, 69 years ± 13 [SD]). Seventeen textural radiomic features were identified as the RS, which demonstrated a high AUC in the test set for the prediction of rapid progression (AUC 0.850; 95% CI: 0.725, 0.975). Age was associated with OS in the multivariate model while high RS (>0.5) was independently associated with OS in both univariate and multivariate models. Conclusions: CT-derived RS, combined with age, represent the most prognostic factors for stage II-III pancreatic cancer. RS, which likely reflects underlying biology or molecular alterations, contributes to the highest HR of poor OS and provide the strongest indicator of outcome following commonly used treatments in this patient population. [Table: see text]
A novel classification of small bowel adenocarcinoma based on a hidden genome classifier: A multi-institutional study.
Authors: Schleimer Lauren E. , Ethun Cecilia Grace , Court Colin , Chou Joanne F. , McIntyre Sarah Margaret Helena , Walch Henry S. , Sigel Carlie S. , Sharib Jeremy , Masoud Sabran , Chen Wei , Aveson Victoria , Wang Huamin , Katz Matthew H. G. , Overman Michael J. , Lidsky Michael , Maithel Shishir K. , Poultsides George A. , Fields Ryan , Gonen Mithat , Jarnagin William R.
Published: January 2024

724

Background: Small bowel adenocarcinoma (SBA) is a rare malignancy with poor prognosis. Data describing the clinical and pathologic characteristics of this disease are sparse, and few studies examine the genetic footprint of SBAs within the continuum of the gastrointestinal tract. Methods: All patients with small bowel adenocarcinoma for whom primary tumor tissue was available from 1993 to 2021 at six institutions were included. A hidden genome classifier (HGC) was developed based on genomic features from 286 gastroesophageal cancers (foregut) and 286 colorectal cancers (hindgut) using targeted tumor sequencing. The SBA samples were run through the HGC to obtain the predicted probability of either foregut or hindgut lineage. For patients submitted to curative intent resection, overall survival (OS) was calculated from 90 days post resection until date of last follow up. Cox regression was used to examine factors associated with OS and to construct the multivariable model. Results: Of a total of 243 patients with SBA, 60% were male. The most common anatomic locations were duodenum (53%), jejunum (28%), and ileum (12%). HGC prediction of foregut lineage was higher for duodenal (55%) and intestinal-type periampullary (64%) tumors, while prediction of hindgut lineage was higher for ileal (68%) and jejunal (54%) tumors. Patients were then divided into three HGC prediction groups based on the lowest-, highest-, and inter-quartile ranges: foregut (n=61), characterized by gene amplification of CDK12, CD3, EGFR, and KRAS and cytoband segmentation of chromosomes 8-p21.1 and 15-q26.3; hindgut (n=61), characterized by APC and KRAS mutations; and mixed-type (n=121) with elements of both. Among those undergoing curative-intent surgery (n=160), median OS was 73 months. On multivariable analysis, HGC prediction group (hindgut vs mixed-type, HR 3.22, 95%CI 1.54-6.73), age (HR 1.03, 95%CI 1.01-1.05) and positive lymph node status (HR 1.96, 95%CI 1.02-3.76) were associated with decreased survival (Table). Neither anatomic site nor the presence of other driver mutations was associated with survival. Conclusions: Small bowel adenocarcinomas display genomic heterogeneity. A novel hidden genome classifier that stratifies SBAs based on homology to foregut or hindgut genomic alterations may be superior to anatomic location for characterizing disease biology. Additional studies are needed to validate and further explore these findings. [Table: see text]
Diversity of patients enrolled in SWOG gastrointestinal cancers therapeutic trials.
Authors: Safyan Rachael A , Colby Sarah , Figueroa-Moseley Colmar , Guthrie Katherine A. , Chiorean E. Gabriela , Philip Philip A.
Published: January 2024

726

Background: Racial/ethnic minorities, elderly, and rural populations are underrepresented in clinical trials. Globally, gastrointestinal (GI) cancers represent more than a quarter of all cancers, and socioeconomic and lifestyle factors impact their incidence. Additionally, racial/ethnic disparities exist across GI tumor types, including early-onset colorectal cancer, and are associated with survival outcomes. Here we examine the proportion of women and minority participants with GI malignancies enrolled on SWOG Cancer Research Network therapeutic trials. Methods: We analyzed data on participants enrolled to SWOG phase I-III GI cancers treatment trials launched and completed between 2011-2021 according to sex, age (< 70 years vs ≥ 70 years), ethnicity (Hispanic vs not Hispanic), Race (Black vs Asian/Pacific Islander (PI) vs Native American vs White), insurance type (Medicaid or no insurance vs other), and residence types (classified as urban, large rural, small rural, and isolated small rural) using Rural-Urban Commuting Area (RUCA) codes based on zip codes. Participants reporting any category of Black, Asian/PI, Native American, or Hispanic were considered minority. Results: In total, n=1486 participants from 10 trials (S1005, S1115, S1201, S1310, S1313, S1406, S1505, S1513, S1613, S1815) conducted in 5 different GI cancers categories were enrolled, of whom 696 (46.8%) were women and 313 (21.1%) were minority. The five cancer types represented were biliary tract (34.0%), colorectal (10.8%), esophageal (4.8%), gastric/gastroesophageal junction (GEJ) (14.5%), and pancreatic (35.9%). Overall, 696 (46.8%) were female, 94 were Black (6.3%), 83 (5.6%) were Asian/PI, 5 (0.3%) were Native American, 132 were Hispanic (8.9%), 349 (23.5%) were ≥ 70 years, 1263 (85.0%) lived in an urban area, and 155 (10.4%) had Medicaid or no insurance. Minority participants were younger on average than non-minority participants (mean 58.7 vs 63.1, p<0.001), more likely to live in urban settings (92.7% vs. 82.9%, p<0.001) and have Medicaid or no insurance (26.5% vs. 6.1%, p<0.001). Over one-third (37.9%) of Hispanic, 22.3% of Black, and 13.3% Asian/PI participants vs 8.0% of White participants had Medicaid or no insurance. Women’s participation varied according to cancer type, ranging from 8.3% for esophageal to 56.2% for biliary tract, as did minority participation, ranging from 5.6% for esophageal to 36.6% for gastric/GEJ. Conclusions: Our findings suggest that racial/ethnic minorities, the elderly, and those residing in non-urban settings were less likely to enroll in SWOG GI cancers treatment trials than were whites, younger patients, and urban residents. Efforts are needed to enhance diverse enrollment, to break down barriers preventing minority participation, and to improve trial access to minimize disparities.
Utility of gene expression–based cancer classification in diagnosis of malignant peritoneal mesothelioma (MPeM): Filling in the gaps in standard pathologic work-up for a rare cancer.
Authors: Allam Joelle , Ma Li , Estrella Jeannelyn , Willett Anneleis , Beaty Karen A. , Matamoros Aurelio , Lano Elizabeth A , Fournier Keith F. , Treuner Kai , Raghav Kanwal Pratap Singh , Huey Ryan W
Published: January 2024

728

Background: Malignant peritoneal mesothelioma (MPeM) is a rare cancer (incidence of 0.12 per 100,000) and an arduous diagnostic challenge, requiring skillful evaluation by expert pathologists. Subjective and experiential immunophenotyping coupled with inattention to this rare entity causes delayed or misdiagnosis and leads to suboptimal treatment and outcomes. Gene-expression-based cancer classification offers an objective molecular assessment of the tissue of origin for cancers with uncertain diagnosis and improves diagnostic accuracy for MPeM compared to standard pathology. Methods: We retrospectively evaluated 23 patients (pts) with cancer of unknown primary (CUP) or uncertain diagnoses, with peritoneal/retroperitoneal carcinomatosis and reported as malignant mesothelioma using a 92-gene assay (CancerTYPE ID), a validated classifier for predicting tumor types, between January 2013 to December 2016. Pathology was verified by central review. Clinicopathologic data including immunohistochemistry (IHC) was collected using archived pathology specimens and reports. Results: Pts had a median age of 64 years (range: 39 – 93) at diagnosis, 57% were females and 74% had biopsy from omentum/peritoneum. Original histopathology was reported as poorly differentiated in 81% and as adenocarcinoma, carcinoma and malignant neoplasm in 10 (43%), 7 (30%) and 6 (27%) of cases, respectively. The number of IHC stains performed ranged between 0 and 28 (median: 10). Key IHC stains are shown in the table. Conclusions: In this cohort of CUP or uncertain diagnoses with a molecular cancer classification of malignant mesothelioma, we found huge variability and critical gaps in pathological work-up. Integration of molecular cancer classification using the 92-gene assay helped resolve this diagnostic uncertainty, further supporting its clinical utility to complement standard pathology. The impact of these findings goes beyond just MPeM and may benefit numerous pts with orphan cancers, who account for nearly 20% of all cancers diagnosed globally. [Table: see text]
Comprehensive analysis of differentially methylated regions in colorectal cancer (CRC).
Authors: Solari Omid , Constantin Tudor , Jiang Yuqian , Chan Wengching , Tunc Ilker , Srinivasan Preethi , Kordi Misagh , Santaguida Marianne , Mitchell Breeana L. , Aleshin Alexey , Swenerton Ryan , Babiarz Joshua , Kawli Trupti , Reiter Johannes G.
Published: January 2024

73

Background: Epigenetic alterations have been shown to govern many disease states, including cancer. A key epigenetic mark is the DNA methylation of CpGs. Large studies, like The Cancer Genome Atlas, have shown that DNA methylation can differentiate between cancer status and type. Here, differentially methylated genomic patterns were defined between patients with CRC and healthy individuals by utilizing patterns of co-methylation of adjacent CpG loci. Methods: Deep, whole genome bisulfite sequencing (WGBS) was conducted on DNA samples from 100 healthy individuals (median effective coverage of 352x±38x) and from 75 patients with CRC (median effective coverage of 48x±18x). The two cohorts were chosen to be balanced in terms of age (CRC: 58±11 years; healthy: 57±8 years) and to represent major ethnicities in the USA, and the CRC cohort was chosen to represent all stages, histologies and morphologies, and microsatellite instability (MSI, 23%). A novel machine learning model was developed to discover differentially methylated regions between the healthy and CRC cohorts as well as between subpopulations within the CRC cohort, including age, sex, stage, histology, and MSI vs microsatellite stability (MSS). Results: In total, we discovered 132,911 differentially methylated regions between healthy and CRC cohorts, spanning more than 1.14 million CpGs. 76% of all discovered regions were hypermethylated (70% CpG islands, 1.3% CpG shelves, 21% CpG shores) and the rest were hypomethylated (7.3% CpG islands, 8.6% CpG shelves, 25% CpG shores). We also discovered 220 hypermethylated regions that were differentially methylated between CRC MSI samples and CRC MSS samples and healthy cfDNA samples. Furthermore, we discovered subtype-specific differentially methylated regions, such as 62 hyper-methylated regions that were differentially methylated between mucinous adenocarcinoma samples and the rest of the cohort. Conclusions: Based on deep WGBS data from heterogeneous cohorts, representative of the US population eligible for CRC screening, we identified many differentially methylated regions as strong biomarker candidates for the early detection of cancer. Compared to recurrently mutated driver genes in CRC, we find that differential methylation profiles of CRC samples are generally much more homogenous and are therefore ideal biomarkers for targeted sequencing panels with the purpose of early cancer detection. Further, analysis of these patterns based on clinicopathologic factors enabled discovery of subtype specific markers, which can be incorporated to ensure equivalent performance for underrepresented subtypes or subpopulations.
A retrospective analysis of the efficacy and safety of imatinib in elderly patients with advanced gastrointestinal stromal tumor.
Authors: Awatsu Takahito , Hirano Hidekazu , Matsuguma Kunihito , Hirose Toshiharu , Okita Natsuko Tsuda , Shoji Hirokazu , Takashima Atsuo , Kato Ken
Published: January 2024

730

Background: Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor arising from the gastrointestinal tract, characterized by a high predominance of the elderly population. Imatinib is the standard first-line therapy for advanced GIST with a median survival of around 4 years in pivotal clinical trials. However, clinical data for the elderly population is not known well. The aim of this study is to evaluate the efficacy and safety of imatinib for advanced GIST in the elderly population in comparison with the non-elderly population. Methods: We extracted clinical data of patients with advanced GIST treated with imatinib as first-line therapy at our institution between January 2010 and July 2023. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events (AEs) were assessed and compared between the elderly group (age: ≥ 70 years, E group) and the non-elderly group (age: < 70 years, NE group). Multivariable analyses were performed using Cox proportional hazard models to evaluate the prognostic significance of age groups. Results: A total of 91 patients were included in this analysis with 32 patients in the E group and 59 patients in the NE group with a median follow-up duration of 39.8 months. Patient characteristics were as follows (the E group vs. the NE group): median age 76 (70–90) vs. 54 (29–69) years, male: 50% vs. 56%, performance status 0: 19% vs. 63%, disease status (: 47% vs. 44%), stomach primary 44% vs. 34%, KIT mutation (exon 11: 50% vs. 61%), and maximum tumor diameter (≥8cm: 66% vs. 51%). The proportion of patients with a reduced starting dose of imatinib was significantly higher in the E group (34% vs. 2%, p <0.0001). Median PFS in the E group and the NE group were 29.4 months and 60.0 months (HR=2.04, log-rank p=0.035). Median OS in the E group and the NE group were 91.5 months and not reached (HR=2.74, log-rank p=0.02). ORR was 53% in the elderly group and 66% in the non-elderly group (p=0.32). In for OS, age was not an independent prognostic factor (HR=2.09, p=0.14) with a significant independent prognostic factor of disease status (unresectable/initially metastatic vs. recurrent (reference): HR=3.58, p=0.03). The occurrence of ≥ grade 2 non-hematologic AEs was more common in the elderly group compared to the non-elderly group (78% vs. 32%, p<0.001). Conclusions: The elderly population with advanced GIST may achieve a survival period comparable to that observed in pivotal trials with imatinib. Even with reduced doses of imatinib, careful monitoring is necessary because of the high frequency of non-hematologic ≥ grade 2 AEs in the elderly population.
Patient-reported outcomes in patients with gastrointestinal cancer on oral chemotherapy.
Authors: Zhang Kevin Juan , Tehranchi Kian , Academia Emmeline C , Celmen Melis , Doolin Jim W , Hotait Mohamad , Lasoff Arielle , Tong Patricia , Berkowitz Seth J , Bullock Andrea J. , Zerillo Jessica Ann
Published: January 2024

732

Background: Over the last several years, patient reported outcomes (PROs) have been demonstrated to address patient symptoms, improve outcomes, and reduce health care utilization. We aim to provide an electronic PRO (ePRO) tool for gastrointestinal (GI) oncology patients with the goals of improving adherence, reducing toxicity, and enhancing patient access to the clinical team. Methods: Patients are provided an ePRO tool consisting of a cellphone app integrated into the electronic health record with questions on adherence and 10 questions on symptoms adapted from the NCI PRO-CTCAE for local use. Emails are sent to the clinical team for nonadherence, new or worsening symptoms, or patient requested callback. Outcomes including time to first symptom assessment, emergency department (ED) visit and/or hospitalization at 30 and 90 days from enrollment will be compared with historical controls. Other outcomes including adherence and patient-reported access to the clinic will be assessed. Results: Six patients have been enrolled between May 1, 2023 and September 4, 2023. Five patients were newly starting oral chemotherapy agents and one patient had already been on therapy. Types of cancers included colon cancers (2), rectal cancer (1), pancreatic cancer (1), GIST (1), and cholangiocarcinoma (1). Types of oral chemotherapy included capecitabine (4), olaparib (1), and imatinib (1). Five patients have submitted a total of ten responses. Of the five who completed the ePROs, patients responded a median of one time (range 1-5). Reported symptoms were fatigue (4), pain (2), nausea (1), diarrhea (1), other symptoms (2) and a request callback (1). Seven (70%) responses have prompted emails alerts for clinical symptoms and one (10%) for adherence concerns. All alerts were resolved; average time to alert response 1.6 calendar days (range 1-3). Among historical controls, time to first symptom assessment after a new oral chemotherapy prescription was seven days, 30-day rate for ED and/or hospitalizations was 12%, and 90-day rate of ED visits and/or hospitalizations was 28%. Conclusions: Early data suggests a new process to manage ePROs can provide timely responses to email alerts. Of the responses thus far, 70% prompted email alerts due to clinical symptoms and 10% reported nonadherence, suggesting a high need for ongoing ePRO tools. Results are forthcoming on outcomes including time to symptom assessment/clinical action, ED visit/hospitalization and access.
Real-world data of anlotinib for gastrointestinal tumors with liver metastases in China.
Authors: Zhu Yujia , Zhuo Minglei , Xu Xiaoxian , Qin Yanru , Wang Zhehai
Published: January 2024

738

Background: Patients with advanced gastrointestinal tumors, such as gastric cancer (GC), colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC), biliary tract cancer (BTC) and pancreatic cancer (PC), often develop liver metastases with poor prognosis. Recent clinical studies have implicated that anlotinib (a novel anti-angiogenesis agent) could improve survival outcomes in gastrointestinal tumors with liver metastases, albeit with limited real-world evidence. This study aimed to report the efficacy and safety of anlotinib for gastrointestinal tumors with liver metastases in real-world practice. Methods: Demographic and clinical data of patients treated with anlotinib in any line of treatment for solid tumors with liver metastases (excluding primary liver cancer) was collected retrospectively through 5 large hospitals in China, between Jan, 2016 and Feb, 2023. The primary endpoints were progression-free survival (PFS) and objective overall response (ORR). Secondary endpoints included overall survival (OS), hepatic PFS (hPFS), hepatic ORR (hORR) and safety. In this abstract, we present data from patients with gastrointestinal tumors. PFS, hPFS and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: A total of 475 patients were enrolled in the study and 238 patients with gastrointestinal tumors were analyzed, including 73 (30.7%) GC, 71 (29.8%) CRC, 46 (19.3%) ESCC, 24 (10.1%) PC, and 24 (10.1%) BTC. 75.2% were <75 years old, 82.4% were male, 63.9% had a normal body mass index (BMI) (18.5-24 kg/m2), 87.8% received third-line anlotinib, and 90.3% received anlotinib monotherapy. At data cut-off (Feb 28, 2023), the median PFS was 5.90 months (95% CI: 5.23-6.77), the median hPFS was 6.20 months (95% CI: 5.27-6.77), and the median OS was 9.37 months (95% CI: 8.40-NR). There was no statistically significant difference according to the tumor types in terms of PFS (p=0.66), hPFS (p=0.8) and OS (p=0.72). We also found patients with a BMI < 18.5 kg/m2 had significantly shorter PFS (p=0.005) and hPFS (p=0.01). Adverse events (AEs) were manageable and tolerable, 30 (12.6%) patients had treatment-emergent adverse events (TEAEs) and 3 patients (1.3%) had ≥3 TEAEs. The most common treatment-related adverse events (TRAEs) were leukopenia (5.9%). Conclusions: To our knowledge, this is the first real-world report about anlotinib for gastrointestinal tumors with liver metastases in China, showed the clinical benefit of anlotinib in any line of treatment for gastrointestinal tumors with liver metastases and indicated that anlotinib could be a feasible treatment option in this specific population.
Clinicopathologic characteristics of patients with early-onset colorectal cancer.
Authors: Takagi Maki , Takao Misato , Funatsu Nozomi , Natsume Soichiro , Nakano Daisuke , Kawai Kazushige , Yamaguchi Tatsuro
Published: January 2024

74

Background: Although the incidence of colorectal cancer has been declining in the United States in recent years, the incidence of young patients under 50 years of age has been reported to be increasing by several percent per year. Various studies have been conducted to characterize early-onset colorectal cancer (EO-CRC); however, it has been unclear whether it is a different entity from late-onset colorectal cancer (LO-CRC). In this study, we evaluated the clinicopathologic characteristics of EO-CRC in Japan. Methods: This study included 1,336 patients who underwent surgical resection for colorectal cancer at Tokyo Metropolitan Komagome Hospital from January 2015 to December 2019. We performed genetic testing for patients with suspected Lynch syndrome after providing genetic counseling and obtaining informed consent. The study protocol was approved by the Institutional Review Board. Results: Of the 1,336 colorectal cancer patients, 117 (8.9%) had EO-CRC with a median age at the diagnosis of 44 (17–49) years. Tumors were located at right-sided colon in 23 patients and left-sided colorectum in 92 patients with EO-CRC, respectively. The clinical stage of the tumor was I in 19, II in 23, III in 50, and IV in 23 patients with EO-CRC, respectively. Histologically, differentiated type, undifferentiated type, and mucinous carcinoma were 106, 5, and 3 patients, respectively. KRAS mutation was detected in 25.0% and BRAF V600E was detected in 4.3% of patients with EO-CRC. In the microsatellite status, MSI-High was detected in 6 (5.1%) patients with EO-CRC, of whom 3 (2.6%) were diagnosed with Lynch syndrome by genetic testing. Causative genes were MLH1 in 2 patients and MSH2 in one patient. In hereditary tumors, 2 patients with familial adenomatous polyposis were included in addition to Lynch syndrome. On the other hand, 1,219 (91.2%) had LO-CRC with 34.5% of KRAS mutation and 6.4% of BRAFV600E. MSI-High was detected in 69(5.7%) patients with LO-CRC，of whom 5 (0.4%) were diagnosed with Lynch syndrome. Lynch syndrome was significantly more common in EO-CRC (p=0.026). Conclusions: The alterations of KRAS and BRAF tended to be more frequent in EO-CRC. The frequency of hereditary CRC was more frequent in EO-CRC than in LO-CRC.
Genetic testing of Japanese patients with serrated polyposis syndrome: A multicentric study.
Authors: Takao Akinari , Yamaguchi Tatsuro , Eguchi Hidetaka , Okazaki Yasushi , Ishikawa Hideki , Akagi Kiwamu , Ishida Hideyuki
Published: January 2024

75

Background: Serrated polyposis syndrome (SPS) is a rare condition associated with an increased risk of colorectal cancer. Previous studies have identified germline truncating variants of the RNF43; however, patients harboring these variants comprise a small part of those with SPS, in most of whom the causative gene remains unknown. To date, no study has described the genetic features of Japanese patients with SPS. The present study aimed to identify candidate causative genes of SPS in Japanese patients. Methods: Captures for equal to or more than 55 gene regions were performed using Agilent HaloPlex or Ion AmpliSeq technologies in SPS patients enrolled in The Study Group for Establishment of Diagnosis of Hereditary Gastrointestinal Tract Cancer Syndromes Based on a Next-Generation Sequencing Technology (SGHGCS). Whole exome sequencing of tumor tissue was performed whenever a candidate gene was identified. Results: Eleven patients (four males, seven females) were enrolled. Of these, nine had a history of colorectal cancer; four had a family history of colorectal cancer; and two had a family history of polyposis. Genetic testing identified two variants of VUS, POLD1 c.670C>T (p.R224C) and BRCA2 c.4169T>G (p.L1390W). Additionally, a nonsense variant, BUB1:c.1543G>T p.Gly515Ter was deemed likely to be pathogenic. The patient with the BUB1 variant was 47-year-old female with transverse colon cancer with more than 50 serrated polyps. She was a non-smoker. The variants detected in the transverse colon cancer did not include the canonical variants in common colorectal cancer, such as APC, KRAS or TP53 and were mostly transition substitutions (C>T). Conclusions: BUB1 was identified as a novel candidate causative gene of SPS in a patient with SPS with no smoking habit. These findings will hopefully contribute to our understanding of the genetic basis of SPS.
One of these is not like the others: A descriptive study of the attenuated phenotype of PMS2.
Authors: Esplin Edward D. , Heald Brandie , Nielsen Sarah M. , Ellsworth Rachel , Russell Emily M. , Pineda Alvarez Daniel Esteban
Published: January 2024

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Background: Data from Lynch syndrome (LS) registries reveal that patients (pts) with PMS2 pathogenic germline variants (PGVs) have the lowest cancer risk. This retrospective study of pts undergoing germline genetic testing (GGT) for any indication compared the phenotypes of PMS2 carriers to other LS pts. We hypothesized that PMS2 pts were more likely to have no cancer or non–LS associated cancers than other LS pts. Methods: All Pts with a single PGV in any LS gene were identified from a commercial laboratory database. Demographics and personal and family cancer history data were clinician-reported on the test requisition form. Data from PMS2 pts were compared to MSH6 and MLH1/MSH2/EPCAM pts using descriptive statistics, unpaired two-samples t tests, Chi-square tests, and multivariate logistic regression analyses that also included patients with no PGVs, with p<0.05 defining significance. Results: 17,711 pts met inclusion criteria (5,189 PMS2, 5,182 MSH6, and 7,340 MLH1/MSH2/EPCAM). PMS2 pts were significantly older at testing (mean 55.1±16.0y) than MLH1/MSH2/EPCAM (48.7±15.7y) and had significantly less family cancer history (84.9%) than both MSH6 (86.8%) and MLH1/MSH2/EPCAM (86.6%) pts. PMS2 pts had lower odds of any colorectal and uterine cancers than the MSH6 and MLH1/MSH2/EPCAM cohorts (Table). All LS-related PGVs were significantly associated with lower odds of breast, pancreatic, and prostate cancer. Conclusions: Pts with PMS2 PGVs were older at the time of testing and had lower odds of any and LS-related cancers than other LS pts. These data are consistent with prior registry studies and can aid in counseling and management of PMS2 pts. [Table: see text]
Insulin resistance and impaired insulin secretion and gastrointestinal cancer risk in Korean adults: Preliminary results from Korean Genome and Epidemiology study.
Authors: Jo Hyemin , Shin Cheol Min , Ahn Soyeon , Ohn Jung Hun , Ji Eunjeong , Choi Yonghoon , Jun Yu Kyung , Yoon Hyuk , Park Young Soo , Kim Nayoung , Lee Dong Ho
Published: January 2024

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Background: To date, few studies conducted on the effect of insulin resistance or insulin secretory function on cancer risk in non-diabetic population. This study evaluated whether insulin resistance and/or insulin secretory function affect gastrointestinal cancer risk in the Korean population. Methods: We analyzed data from Korean Genome and Epidemiology Study, Korea Association Resource dataset. It consists of 10,030 participants aged 40-69y observed from 2001 to 2018. The risk of all cancers, and gastrointestinal cancers were assessed. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Homeostasis Model Assessment of Beta-cell function (HOMA-β) were used as indicators of insulin resistance and insulin secretory function. Results: In the final dataset, 8,649 individuals without previous history of any cancers were included. During an average follow-up of 15 years, 415 subjects (4.8%) developed cancers. Compared to the low HOMA-IR/high HOMA-β group (reference), diabetic patients had the highest risk of overall cancers, followed by high HOMA-IR/low HOMA-β group (Adjusted hazard ratio[95% confidence interval]: 1.74 [1.11 - 2.75] and 1.40 [0.96 – 2.06], respectively) Among gastrointestinal cancers, the risk of gastric cancer was higher in the low HOMA-IR/low HOMA-β and high HOMA-IR/high HOMA-β groups (1.92 [1.06 - 3.47] and 2.27 [1.26 - 4.06], respectively) When further analyzed by HOMA-β stratified by quartiles, the lowest quartile (Q1) showed an increased risk of gastric cancer compared to the highest-quartile (Q4; 1.84 [0.98 – 3.46], p = 0.06) In contrast, no significant results were observed regarding the colorectal cancer risk, when analyzed based on HOMA-IR and HOMA-β. However, when further analyzed by HOMA-IR stratified by quartiles, the highest quartile (Q4) exhibited a significantly elevated colorectal cancer risk compared to the lowest quartile (Q1; 2.14 [1.11 - 4.11], P for trend = 0.04). Conclusions: Insulin resistance and impaired insulin secretion function may increase the risk of cancer, but the underlying mechanisms may differ by cancer type.
Characterizing the rare abdominal neoplasms of peritoneum, retroperitoneum, and overlapping sites of peritoneum and retroperitoneum: A review of NCDB database.
Authors: Jafry Baqir , Kazmi Syed Mohammad Ali
Published: January 2024

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Background: The tumor characteristics of the rare abdominal tumors including peritoneum (PT), retroperitoneum (RT) and overlapping sites of peritoneum and retroperitoneum (OT) remain unexplored. Methods: From the National Cancer Database, we identified all patients who were diagnosed with tumors in PT, RT or OT from 2004 to 2016. We evaluated the incidence of each tumor across time and compared population characteristics of each of these tumors. Results: We identified a total of 47300 patients - 22090 had PT, 11837 had RT and 13373 had OT. The mean age of PT was 66.9 while that of RT and OT was 61.2 and 68.1 respectively. All three cancers had a higher percentage of females compared to males (93.8% for peritoneum; 50.4% for retroperitoneum; 50.6% for overlapping sites), whites (88.8% for PT; 83.6% for RT; 81.5% for OT), insured patients (97.8% for PT; 96.2% for RT; 96% for OT) and patients without any existing comorbidities (75.9% for PT; 77.5% for RT; 67.7% for OT). The most common histology was adenocarcinoma in OT, leiomyosarcoma in RT, serous epithelial carcinoma among the PT population. These neoplasms had higher proportions of grade 3 tumors (58% for PT; 32.2% for RT; 50.9% for OT), patients with income > $63,333 (38.6% for PT; 38.1% for RT; 36.6% for OT), and patients residing in an area where 6.3%-10.8% did not graduate from high school (29.8% for PT; 29.7% for RT; 23.8% for OT). From 2004 to 2016, there was a significant increase in the number of tumors of overlapping sites (566 in 2004 to 1848 in 2016) while the number of PT (1580 in 2004 to 1586 in 2016) and RT (726 in 2004 to 980 in 2016) did not change significantly. Conclusions: Among the rare abdominal neoplasms, the number of OT have increased from 2004-2016 while that of PT and RT tumors have remained stable. The histology patterns are consistent with known cancers that involve these regions.
Impact of revising colorectal cancer screening guidelines on health care resources in Canada.
Authors: Chia Brendan , Ruan Yibing , Brown Carl J. , Brenner Darren R , Loree Jonathan M.
Published: January 2024

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Background: The rising incidence of early-onset colorectal cancer (CRC) has prompted U.S. organizations to lower the recommended CRC screening age for average risk adults from 50 to 45 years old, while Canadian programs remain unchanged. Canadian guidelines also differ from the U.S. in preferentially screening with a fecal immunochemical test (FIT) and recommending against colonoscopies as a screening test. Differences in national healthcare administration warrants investigation into the resource impact of updating screening guidance in Canada. Methods: Microsimulation modeling was performed using OncoSim (version 3.6) to project health and economic outcomes of different CRC screening strategies based on Canadian population data. Four simulated birth cohorts of the Canadian population born between 1973–1992 were tracked for a 40-year span from the year the oldest in each cohort turned 40 until the youngest in the same cohort turned 75. Colorectal adenoma rates were adjusted according to cohort risk ratios estimated from historical incidence data to reflect real-world CRC rates. Outcomes were reported for the cumulative cohort. Results: Compared to FIT screening at age 50, FIT screening at 45 reduced deaths by 5,220, incidence by 11,980, and added 96,100 health-adjusted life years (HALY). Colonoscopy screening at age 45 led to 17,870 fewer deaths, 74,250 fewer cases and added 314,960 HALYs. FIT and colonoscopy screening at age 45 had incremental costs of CAD$3,259 and $7,881 per HALY gained vs. a FIT at age 50, respectively. Across screening strategies, the greatest benefits were observed in the youngest cohort. Colonoscopy screening at age 45 resulted in 10,679,540 more total colonoscopies than the current capacity of 8,966,979 with FIT screening at age 50. Lowering the screening age to 45 with a FIT increased colonoscopy demand by 329,555. The total cost of CRC care (screening, diagnosis and treatment) increased with lower screening ages and colonoscopy first modalities, while the cost of CRC management (diagnosis and treatment) decreased with lower screening ages and colonoscopy first approaches. Conclusions: Adjusting current CRC screening guidelines demonstrates significant resource implications with proportional health benefits. Lower screening ages and colonoscopy first approaches have the largest resource demand and greatest health outcomes, while the incremental cost per HALY gained for all screening strategies is modest compared to standard benchmarks. [Table: see text]