bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of plasma circulating tumor DNA in borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant modified FOLFIRINOX: Clinical relevance of DNA damage repair gene alterations.
Authors: Lim Dong-Hoon , Hyung Jaewon , Lee Sang Soo , Jeong Jae Ho , Ryoo Baek-Yeol , Kim Kyu-Pyo , Yoo Changhoon
Published: January 2023

737

Background: There is no reliable biomarker to guide treatment for patient with borderline resectable pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant modified (m)FOLFIRINOX. We investigated the role of plasma circulating tumor DNA (ctDNA) sequencing to discover potential biomarkers for patients treated with neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (ClinicalTrials.gov identifier: NCT02749136). Methods: Among 44 patients enrolled in the trial, patients with plasma ctDNA analysis performed at baseline or post-operative period were included in the analysis. Plasma cell-free DNA isolation and sequencing of ctDNA were performed using the Guardant 360 assay. Association of clinical outcomes with germline or somatic mutations of DNA damage repair (DDR) genes was analyzed. Somatic alterations other than DDR genes were also analyzed to find potential biomarkers of neoadjuvant mFOLFIRINOX. Progression free-survival (PFS) was defined as time from the initiation of mFOLFIRINOX to disease progression or any cause of death. Overall survival (OS) was defined as the time from the initiation of mFOLFIRINOX to any cause of death. Results: Among 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study (15 patients with baseline data only, 3 patients with post-operative data only, and 10 patients with both baseline and post-operative data). Median age was 59 (range, 41-73) years and 15 patients (53.6%) were male. Among 25 patients with baseline plasma ctDNA data, 11 patients (44%) had somatic or germline alteration of DDR genes detected at baseline including ATM, BRCA1, BRCA2 and MLH1, and showed significantly better PFS than those without such DDR gene alterations (median 26.6 vs. 13.5 months, log-rank p = 0.004). Although there was a trend for better OS in patients with DDR gene alterations, this was not statistically significant (log-rank p = 0.29). The most observed baseline somatic alteration was TP53 (n = 7, 28%), followed by KRAS (n = 6, 24%). Patients with somatic KRAS mutation at baseline had significantly worse OS (median 8.5 months vs. not applicable, log-rank p = 0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, 8 patients (61.5%) had detectable somatic alterations. Conclusions: Detection of germline or somatic mutations of DDR genes from plasma ctDNA at baseline was associated with better survival outcomes of patients with borderline resectable PDAC treated with neoadjuvant mFOLFIRINOX. Detection of DDR gene alterations from plasma ctDNA may have a potential role as biomarker for prognosis in patients with borderline resectable PDAC treated with mFOLFIRINOX.
Relationship between inflammatory indexes and Khorana score (KS) with prognosis and survival in pancreatic ductal adenocarcinoma (PDAC).
Authors: Martín Lozano Rocío , Jiménez Rodríguez Roberto , Gonzalez Caraballo Irene , Lobato Delgado Bárbara , Gómez María Palma , Muñoz Marc Ariant Cañete , de Lucas Mónica Benavente , López Jiménez Carlos , Tirado Anula Victoria , Morón García Blanca , de Toro Carmena María , Bringas Beranek Marianela , Soto Alsar Javier , Torres Pérez-Solero Gabriela , Calvo Aitana , Ortega Laura , Soria Jose Manuel , Garcia-Alfonso Pilar , Martin Miguel , Muñoz Martín Andrés J.
Published: January 2023

740

Background: Several inflammatory scores such as the Systemic Inflammation Response Index (SIRI), the Inflammation Index Score (IIS), and the Neutrophil Lymphocyte Ratio (NLR) have been reported to have prognostic value in PDAC with different results. We hypothesize that the KS, designed to predict the risk of cancer-associated thrombosis, may also be a surrogate marker for inflammation to be included as a relevant prognostic index for PDAC. Methods: Baseline characteristics and individual SIRI, IIS, NLR and KS indexes from 197 PDAC patients diagnosed in our center between 2019 and 2021 have been retrospectively recorded. PFS and OS (Log-rank test) have been used to compare the different scores of each index in the whole population as well as in the metastatic setting. Kruskal-Wallis test and Mann-Whitney test were also done to determine if the SIRI varies significantly between KRS values. Results: Of the 197 patients analyzed, 41 were resectable (20.8%), 54 locally advanced (27.4%) and 102 metastatic (51.8%). Patients with intermediate risk according to KS (2 points, n = 131, 66.5%) had a significantly higher median PFS (8.4 vs. 4.8 months, p = 0.03) and significantly higher OS (12.9 vs. 7.7 months, p = 0.002) than those with high-risk (> 3 points, n = 66, 33.5%). The median OS for patients with low (< 3,000) and high (> 3,000) SIRI was 13.1 and 9.3 months respectively (p = 0.05). No significant differences were observed in PFS. In the metastatic setting, a low SIRI was significantly associated with higher OS (10.6 vs. 5.8, p = 0.016). No significant differences were observed in patients with low vs. high IIS and NLR. The Kruskal-Wallis test indicates that SIRI values vary between at least two KS values (p < 0.001). The Mann-Whitney test found significant differences between the SIRI values from S 2 and 3 (p = 0.002) as well as 2 and 4 (p = 0.04). SIRI values were higher in patients with KRS > 3 vs. 2. Conclusions: This retrospective analysis showed that patients with lower KS live longer and progress later than those with higher KS. Lower SIRI is associated with better survival in metastatic patients, being on the verge of statistical significance in the whole cohort. There is a strong correlation between SIRI and KS. In this cohort of unselected PDAC patients, KS is a prognostic factor for OS and PFS that correlates with subclinical inflammation and demonstrates to be a better predictor than other inflammatory indexes that deserves further analysis.
Development of artificial intelligence–derived histological biomarkers for first-line treatment selection in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Krishna Viswesh , Tiu Ekin , Krishna Vrishab , Vrabac Damir , Shah Kunal , Abuzeid Waleed , Smith Katelyn , Davelaar John , Nuesca Christopher , Larson Brent K , Fountzilas Christos , Rajpurkar Pranav , Hendifar Andrew Eugene , Collisson Eric Andrew , Joshi Anirudh , Singhi Aatur D.
Published: January 2023

743

Background: The prognosis of metastatic pancreatic ductal adenocarcinoma (mPDAC) remains poor with a median survival time of 10-12 months. First-line treatment is largely influenced by performance status with fit patients more often receiving FOLFIRINOX (FFX) than Gemcitabine+Nab-Paclitaxel (GNP). Although the two regimens have improved outcomes over gemcitabine monotherapy, no biomarkers routinely used in clinical practice can predict which regimen is optimal to facilitate a precision medicine approach. We developed two signatures (V-FFX and V-GNP) associated with treatment outcomes for the respective first-line regimens using a retrospective cohort of mPDAC cases. Methods: We conducted a retrospective study of mPDAC patients treated at two institutions (UPMC and Cedars Sinai) from 2014 to 2021. Digitized histological H&E sections corresponding to 145 metastatic PDAC patients treated with either first-line FFX or GNP were included. Independent randomized training and test datasets were constructed for FFX-treated (train: 41, test: 25) and GNP-treated (train: 49, test: 30) patients. To construct the histological assay, a deep-learning algorithm then segmented nuclei to extract quantitative histological features. Features associated with disease-specific survival (DSS) for FFX and GNP were identified utilizing univariate Cox proportional hazards (CPH) models for the respective training sets and V-FFX and V-GNP signatures were constructed. DSS stratification of the V-FFX and V-GNP signatures were examined using Kaplan-Meier analysis and the log-rank test and DSS percentages at 12 months were calculated on the respective test sets. Results: The V-FFX and V-GNP signatures were found to be significantly associated with treatment outcomes stratified in the respective test sets (log-rank test, V-FFX: p=0.046, V-GNP: p=0.004). 29 of 55 patients tested positive for only one of either V-FFX and V-GNP signatures. Kaplan-Meier analysis demonstrated robust separation with hazard ratios for the V-FFX and V-GNP signatures of 3.01 (95% CI: 0.96, 9.45) and 4.81 (95% CI: 1.74, 13.3). DSS at 12 months for patients in V-FFX +ve vs -ve groups were 88% (8/9) vs 50% (7/14). DSS at 12 months for patients in V-GNP +ve vs -ve groups were 66% (8/12) vs 15% (2/13). Conclusions: AI derived V-FFX and V-GNP morphological signatures were strongly associated with treatment outcomes for first-line FFX and GNP and can potentially aid in the selection of first-line treatment for mPDAC patients.
Impact of KRAS mutation variants on clinicopathological features and outcomes in patients with metastatic pancreatic adenocarcinoma.
Authors: Patel Chirag , Sha Wei , Salem Mohamed E. , Musselwhite Laura W. , Hwang Jimmy J. , Kadakia Kunal C.
Published: January 2023

749

Background: Most pancreatic ductal adenocarcinoma (PDAC) exhibit KRAS mutations. A subset of PDACs harbor KRAS wild-type (WT) and appear to carry better prognosis. Given the recent development of KRAS G12C inhibitors, it is imperative to better understand KRAS variants in contemporary cohorts. Herein, we characterized the prevalence of the different KRAS variants and its impact on clinicopathological features and outcomes. Methods: A retrospective review of patients with metastatic PDAC and a known KRAS mutation status who underwent next-generation sequencing (NGS) from liver biopsy was performed. Descriptive statistics analyzed the differences in clinicodemographic features by presence and type or absence of KRAS variants. Kaplan-Meier method was used to assess overall survival (OS). Cox regression was used to study the relationship between KRAS variants and OS when confounding factors were adjusted. Results: 50 pts with PDAC diagnosed at a single community-based institution between 2011-2018 were evaluated. Median age at diagnosis was 68 years (24-80 range), 68% were male, and 76% presented with metastases. Most (86%) tumors harbored KRAS mutations. The most frequent variants were G12V (44%), G12D (37%), G12R (9%), Q61R (5%), G12C (2%), Q61H (2%). Sex (p=0.03) and tumor differentiation (p=0.04) varied according to mutation status and KRAS variant subtype. However, no significant difference was observed in age, race, smoking status, location of primary, and performance status (PS) in KRAS variants. Overall, median OS in months was 8.9 (95% CI 6.7-14.3) for KRAS mutated patients and 11.2 (95% CI 2.1-33.5) for patients with WT. Among patients with KRAS mutations, median OS in months by variant was as following: G12V 9.6 (95%CI 6.6-17.2), G12D 8.4 (95%CI 3.9-15.4), G12R 8.2 (95%CI 1-20.8), and Q61R 11.8 (95%CI 1.3-22.3). However, these differences did not reach statistical significance (p=0.72). In multivariable analyses, female sex (HR 0.16, 95% CI 0.03-0.81, p=0.03) and no receipt of chemotherapy (38.5 95% CI 2.1-698.50, p=0.01) were significant predictors of death. KRAS mutation variant type was not an independent predictor of death. Conclusions: No significant difference was observed in metastatic PDAC with KRAS mutations compared to WT. However, numerical difference in OS were observed among the various KRAS mutation type. Hence, larger studies are needed to better define the effect of KRAS type on outcomes.
Quality of educational YouTube videos related to pancreatic cancer: Analysis of patient-focused and NCI-designated cancer center videos.
Authors: Didier Alexander , Fang Lauren , Stiene Jennifer , Ud Din Shabab , Spencer Caleb , Hamouda Danae M.
Published: January 2023

756

Background: The incidence of pancreatic cancer among young adults has sharply risen over the past decade. Young adults often utilize online educational media, such as YouTube videos, for information about their disease. These may be subject to a high degree of bias and misinformation; previous analyses have demonstrated low quality of other cancer-related YouTube videos. Thus, we sought to determine if patients can rely on YouTube videos for accurate information about pancreatic cancer, and we compared relevant YouTube videos with those published by NCI-designated cancer centers (CCs). Methods: We designed a novel search query and inclusion/exclusion criteria based on published studies evaluating YouTube user tendencies. These criteria were used to identify videos most likely watched by patients, which composed our “Patient-Focused” (PF) group. We compared PF videos with those uploaded by CCs by manually searching each CC’s affiliated YouTube and applying the same inclusion/exclusion criteria. Data were summarized by descriptive statistics. Videos were evaluated based on two well-known criteria, the DISCERN and JAMA tools, as well as a tool published by Sahin et al to analyze the contents of colorectal cancer videos. A score of ≥ 6 on the Sahin scale correlated with high quality information. We used t-test and Chi-squared test to analyze differences between groups. Results: 39 videos met inclusion criteria within the PF sample and 19 videos within the CC sample, total sample of 58 videos. The PF sample had mean Sahin scores of 4.24 ± 2.21, DISCERN scores of 2.15 ± 0.47, and JAMA scores of 1.77 ± 0.60. CC videos had mean Sahin scores of 3.84 ± 2.70, DISCERN scores of 2.25 ± 0.63, and JAMA scores of 2.00 ± 0.0. Perceived speakers’ ethnicity was 75% White (n=77), 21% Asian (n=21), and 4% Hispanic (n=4). There were no Black speakers. Most videos uploaded were fair or poor quality. 16.4% (n=27) were of average or high quality by the Sahin criteria, with 1 video receiving a perfect score. 9.6% (n=5) and 90.4% (n=47) were average or high quality by DISCERN and JAMA criteria, respectively. 8.6% (n=5) of videos discussed palliative care and 10.3% (n=6) discussed staging. Independent samples t-test revealed no significant differences between PF and CC videos for the Sahin criteria (p=0.429) and DISCERN criteria (p=0.387). The mean JAMA score was higher for CCs (2.0 ± 0.0) than the PF group (1.8 ± 0.6) (p=0.001). Chi-squared test revealed that CC and PF videos had similar speaker ethnic diversity (p=0.381). Conclusions: Educational pancreatic cancer YouTube videos demonstrate low to moderate quality information with limited speaker ethnic diversity. Given ongoing trends in the spread of misinformation through social media, CCs and other patient educators should be mindful of their role in producing high quality, comprehensive information for patients and their caregivers.
Metachronous colorectal cancers in Icelandic MSH6 and PMS2 Lynch syndrome carriers in 1955-2017: A population-based study.
Authors: Haraldsdottir Sigurdis , Andresdottir Arna Kristin , Einarsson Haukur , Jonsdottir Hildur , Snaebjornsson Petur , Bjornsson Einar Stefan , Jonasson Jon G.
Published: January 2023

76

Background: The prevalence of Lynch syndrome in Iceland is the highest described so far or 1:226 with three founder mutations, one in MSH6 and two in PMS2, and was first reported in 2017. Lynch syndrome predisposes carriers to colorectal cancer and metachronous primaries. Most data on metachronous colorectal cancer reflects on MLH1 and MSH2 carriers and is not well described in MSH6 and PMS2 carriers. The purpose of this study was to examine the cumulative incidence of metachronous colorectal cancer in Icelandic Lynch syndrome carriers diagnosed with colorectal cancer from 1955-2017. Methods: This retrospective study included all individuals with pathogenic variants in mismatch repair genes identified in a nationwide genotype database and a colorectal cancer diagnosis in the Icelandic Cancer Registry from 1955-2017. DeCODE genetics has collected extensive genotypic information on the Icelandic population sequencing the whole genomes of 49,708 Icelanders and imputing genotypes into 116,573 Icelanders whose DNA had been genotyped with SNP chips. Cancer information was obtained from patient charts and cause of death obtained from the Cause of Death Register. All polyp pathology was accessed in the pathology registry and reassessed by two pathologists. Results: A total of 65 individuals developed colorectal cancer during the study period with 34 (52.3%) PMS2 carriers and 25 (38.5%) MSH6 carriers. The cumulative incidence of metachronous colorectal cancer was low or one case (1.5%) in an MSH2 carrier with a median follow-up time of 58 months (Q1 8.0, Q3 167.0, range 0-365 months) in the cohort. Only two (3.1%) individuals, one with MSH2 and one with MSH6 pathogenic variants, underwent a total colectomy. Median age at first colorectal cancer diagnosis was 63 years (Q1 54.0, Q3 72.5, range 28-94). Thirty-one (47.7%) individuals had polyps resected during the study period with adenomas (67.1%) being the most common. Significantly more MSH6 carriers had a history of advanced adenomas as compared to PMS2 carriers (36.0 % vs 11.8%, p = 0.026). Five-year colorectal cancer survival was 81.4% for PMS2 carriers and 71.5% for MSH6 carriers. Conclusions: The incidence of metachronous colorectal cancer was zero in Lynch syndrome carriers with MSH6 or PMS2 pathogenic variants from 1955-2017 despite these individuals not undergoing rigorous Lynch syndrome screening. This would support performing segmental colectomies and following European screening guidelines for MSH6 and PMS2 carriers in Iceland.
Demographic and regional trends of gastrointestinal (GI) cancer mortality in adolescents and young adults (AYA) in the US, 1999-2019.
Authors: Hussaini S. M. Qasim , Blackford Amanda L. , Sedhom Ramy , Gupta Arjun
Published: January 2023

786

Background: There is an alarming rise in incidence of GI cancers in AYAs that face unique social challenges in navigating their healthcare and receiving guideline-concordant care. There is limited data on mortality trends in this understudied group. We investigated age-adjusted mortality rates (AAMRs) in young adults with GI cancer. Methods: We utilized the CDC WONDER database to analyze deaths among young adults aged 15 to 44 years from GI cancer (ICD 15-26) from 1999 to 2019. We calculated AAMRs per 100,000 and stratified by sex, race/ethnicity, census, and urban metro (population >1,00,000), medium/small (50,000 – 999,999) or rural area (<50,000) per NCHS Classification Scheme. We used Joinpoint regression software (v4.9) to establish annual percentage change (APC) trends. Results: Between 1999 and 2019, there were 73,954 deaths from GI cancer in young adults (39% female, 16% Hispanic, 20% non-Hispanic Black, 16% rural, 42% Southern-located, 52% colorectal, and 17% each pancreatic, hepatobiliary, and gastric cancers). Overall AAMR over study period was 3.3. Among subgroups, the AAMR was higher in men (3.9), non-Hispanic Black adults (4.6), and rural areas (3.7). Time analysis by year showed overall stability or slight decrease in AAMRs between 1999-2009, followed by an increase from 2009-2019. This was especially notable in Hispanic individuals. Earlier increases in AAMR were noted in rural (since 2004) and Midwestern (since 2001) locations. Highest AAMRs were noted in Southern states (Mississippi, Kentucky, West Virginia, and Alabama). Compared to our younger cohort, older adults (45+) had expectedly higher but recorded significantly better AAMR improvements during study period. Conclusions: Mortality rates for AYAs with GI cancers remained relatively stable from 1999 to 2009, but have since risen, with significant sociodemographic and regional variation. These data highlight the need to better understand risk factors (diet, environmental, and other), screening trends, and variation in receipt of guideline-concordant care to ensure appropriate and equitable risk reduction and cancer management in AYAs.[Table: see text]
Continuous maintenance (Maint) capecitabine (Cape) dosing for colorectal (CRC) and pancreatic cancers (PC): A single-institution, retrospective, real-world study.
Authors: Mukherji Reetu , Yin Chao , Weinberg Benjamin Adam , Alqahtani Ali , Hameed Rumaisa , Barcellos Anna , Connole Maegan , Perelgut Chelsea , Fortuin Josephine , Marshall John
Published: January 2023

789

Background: Cape is an oral fluoropyrimidine (FP) used as maint therapy in CRC and PC. While the standard FDA dosing is 1250 mg/m2 twice daily (BID) for 14 days followed by 7 days off in a 21-day cycle, there are variations across institutions as to the preferred schedule. To improve tolerability and convenience, our institution adopted a “continuous” dosing schedule where cape is taken BID Monday-Friday (M-F) with a treatment break on Saturday and Sunday. Here, we describe our institution’s experience with continuous maint dosing in advanced CRC and PC patients (pts) and explore real-world outcomes. Methods: Pts ≥ 18 years of age treated with continuous maint cape (+/- bevacizumab) after any line of therapy for stage 4 CRC/PC or locally advanced PC between 1/2016-12/2020 were identified in the COTA real-world database. The final study population included 35 PC and 85 CRC pts. Pt characteristics were analyzed descriptively and progression-free survival (PFS) was calculated using Kaplan Meier methods. Results: Among the 35 PC pts, the median age was 66 years (IQR: 61-73), 57.1% were females, and 65.7% were Caucasian. Among the 85 CRC pts, the median age was 54 years (IQR: 47-66), 47.1% were females, and 55.3% were Caucasian. Most PC (71.4%) and CRC (57.7%) pts were initially prescribed a total daily cape dose of 2 g (range 0.5-4 g). Dose adjustments, including dosage/schedule changes, occurred 11 times amongst PC and 36 times amongst CRC pts, and the leading cause was toxicity (72.7% in PC, 55.6% in CRC). Among PC pts, 14.3% had a dose reduction, 3% had a dose increase, and 11.4% switched to an alternative dosing schedule. Among CRC pts, these rates were 32.9%, 12.9%, and 9.4%, respectively. The leading cause of maint discontinuation was progression of disease (POD) (55.6% in PC, 59.3% in CRC). Additional outcomes are summarized in the table. Conclusions: Although maint FP is an established standard of care, it is often underutilized due to inherent inconveniences and toxicities associated with FDA cape dosing or intravenous FP therapy. The PFS reported here using a continuous cape dosing (predominantly starting at 2 g daily dosing) was in range with those previously reported in PC/CRC 1st-line maint studies using FDA cape dosing or intravenous FP. The rates of cape discontinuation attributed to toxicity we report may be confounded by not controlling for the treatment setting. We argue fixed cape dosing (1 g BID) M-F should be considered a standard maint regimen based on efficacy, convenience, tolerability, and feasibility of dose adjustments.[Table: see text]
Prevalence of UGT1A1 polymorphisms in gastrointestinal cancer: A single-institutional retrospective study.
Authors: Jiang Bei , Daboul Nour , Hafez Maria , Wen Sijin , Heise Crystal , Safi Danish , Abonofal Abdulrahman , Uchida Emma , Malla Midhun
Published: January 2023

797

Background: UGT1A1 gene polymorphisms are heterogeneously distributed among ethnicities and varying geographical regions. Patients with UGT1A1*6 and UGT1A1*28 polymorphisms have an increased risk of grade 3-4 neutropenia and diarrhea from irinotecan due to poor metabolism. This study evaluated the prevalence of UGT1A1 polymorphisms in the cancer patients in a large tertiary cancer center in the Appalachian region, in order to develop individualized institutional guidelines on the utility of UGT1A1 testing in chemotherapy dose management. Methods: This retrospective study evaluated all patients with gastrointestinal (GI) malignancies who underwent UGT1A1 testing prior to chemotherapy initiation between 1/1/2020 and 6/30/2022 at West Virginia University. All patients within this disease sub-specialty who were eligible for chemotherapy were tested for UGT1A1 *6 and UTG1A1*28 polymorphism via PCR based pharmacogenomic evaluation using OneOme RightMed comprehensive testing. Patients were excluded if they were tested for genetic alterations specifically due to previous treatment intolerances. Prevalence of the alterations along with demographic characteristics of patients are reported. Results: UGT1A1 genotyping was performed in 278 patients prior to initiating chemotherapy and 12 patients were excluded due to insufficient sample. A total of 266 patients met the inclusion criteria. The median age was 66 years (IQR: 26-92). Males constituted a higher proportion of the population compared to females (M: F = 147: 119). Colon (n-81; 30.5%) and pancreatic (n-80; 30%) cancers were the predominant GI malignancies. Fifty five percentage of patients (n-146) had metastatic disease. The distribution of the UGT1A1 variant genotype is showed in the table below. Conclusions: The prevalence of heterozygous and homozygous of UGT1A1*28 polymorphism in GI cancer patients in the Appalachian region is 51.5%, consistent with the reported literature. Homozygous and heterozygous UGT1A1 *28 alterations constituted 13.2 and 38.3% respectively. Data collection for pre-emptive chemotherapy dosage adjustments and adverse events is ongoing to integrate testing for UGT1A1 polymorphism routinely for all GI malignancies cancer patients starting irinotecan chemotherapy.[Table: see text]
The efficacy and safety of ripretinib in Chinese patients with advanced gastrointestinal stromal tumors: A multicenter, retrospective study.
Authors: Yang Weili , Qian Haoran , Yang Litao , Wang Pengfei , Qian Hailong , Chu Binbin , Liu Zhuo , Sun Jingyu , Wu Dan , Sun Lifeng , Zhou Wenqiang , Hu Jingwei , Chen Xiaolei , Shou Chunhui , Ruan Lingxiang , Yu Jiren
Published: January 2023

800

Background: Ripretinib is a switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits KIT and platelet-derived growth factor receptor α (PDGFRA) kinase signaling. Ripretinib demonstrated favorable therapeutic efficacy and safety in clinical trial settings and was approved for advanced GIST who have received prior treatment with three or more TKIs. Here, we report the efficacy and safety of ripretinib in Chinese patients with advanced GIST in a multicenter, retrospective study. Methods: Patients with advanced GIST who received ripretinib in ZheJiang province were included and analyzed. The primary endpoint was progression-free survival (PFS) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 GIST-Specific Standard. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of therapy (DOT), safety and overall survival (OS). Exploratory endpoint was the predominant genotype for ripretinib treatment. Results: 23 patients were enrolled, while 21 patients were included in the study. The median number of prior lines of therapy was 3 (range, 0-4). The site of primary tumor was predominantly the small intestine (52.38%) and 47.62% of patients with ECOG performance status≥2. Median PFS was 7.1 months (95% CI, 4.9-NA), the ORR and DCR were 9.52% and 85.71%, respectively. Median duration of therapy was 7.3 months (range, 1.8-12). For patients on ≥fourth-line therapy, the median PFS was 9.2 months (95% CI, 4.6-NA), the ORR and DCR were 7.14% and 100%, respectively. Shorter interval between the end of the latest TKI and ripretinib therapy was correlated with longer median PFS and OS (P = 0.021 and P = 0.009, respectively). In univariate analysis, patients with KIT exon 9 mutation had a shorter PFS than patients without KIT exon 9 mutation (hazard ratio, 3.692; 95% CI, 1.109 to 12.294; P = 0.033). Patients with KIT exon 17/18 mutation had a longer PFS (hazard ratio, 0.097; 95% CI, 0.011 to 0.871; P = 0.037). Ripretinib was associated with a favorable safety profile, grade 3 treatment-emergent adverse events (TEAEs) were recorded in 5 patients. No grade 4 or 5 TEAEs were recorded. Conclusions: The ECOG performance status of the patients that received ripretinib in this study is poor. Ripretinib can provide clinical benefit in advanced GIST in real-world China with a favorable safety profile. Immediately switch from the latest TKI to ripretinib after progression will prolong the survival of the patients.
Prevalence and genomic landscape of BRAF alterations across gastrointestinal cancers.
Authors: Driscoll David , Wang Min , Alyaqoub Fadel S. , Udhane Sameer S. , Szelinger Szabolcs , Jalkanen Aimee , Hall David W. , Hoag Jess R , LoBello Janine R. , Baehner Frederick L. , Thakkar Snehal Govind , Basu Gargi D.
Published: January 2023

806

Background: BRAF V600E mutations can lead to activation of the MEK/ERK pathway. The combination of dabrafenib plus trametinib was recently FDA-approved for use in these BRAF V600E altered unresectable or metastatic cancers. BRAF non-V600 alterations also increase phosphorylation of MEK and ERK and are potential candidates for MEK/ERK inhibitors. Here we examine the frequency of BRAF mutations and their genomic background across GI cancers. Methods: The Oncomap ExTra genomic profiling assay utilizes tumor-normal, whole-exome, whole-transcriptome DNA and RNA sequencing to identify somatic alterations in tumors. The assay detects single-nucleotide substitutions, indels, copy number alterations, alternative transcripts, and gene fusions. Tumor mutational burden (TMB) and microsatellite instability (MSI) are also assessed. The frequency of BRAF and other gene alterations were identified across all GI cancers. Reported BRAF alterations were limited to those linked to an FDA approved therapy, clinical trial eligibility, and those deemed significant from review of the literature. Results: A total of 1927 patients with GI cancers were assayed between April 2018 to July 2022. The BRAF gene was mutated in 85 (4.4%) patients, which included 53 (2.8%) that were V600E and 32 (1.5%) that were non-V600, representing 37.6% of BRAF mutations. Colorectal and small bowel cancers had the highest frequencies of BRAF mutations at 7.6% and 7.1% respectively, and the frequency was lower in other GI cancers (0-2.3%). In addition to BRAF V600E, other mutations occurred across the kinase domain, including D594 (0.6%), K601E (0.3%), G466 (0.3%) and G469 (0.2%). BRAF fusions were found in 1 CRC and 2 pancreatic cancer cases. BRAF mutational status (altered versus not) was significantly associated with mutations in several other genes. In addition, BRAF status was significantly associated with TMB-high and MSI-high. Conclusions: Analysis of whole-exome and whole transcriptome sequencing data found actionable BRAF mutations in 4.4% of GI cancer patients, 37.6% of whom had BRAF mutations not at V600. Several biomarkers were significantly associated with BRAF alterations. Assays that are limited to DNA sequencing, or to targeted gene panels, may not detect mutations and fusions that could aid in therapy selection and prognosis. [Table: see text]
The Wnt signaling pathway in gastrointestinal cancers.
Authors: Gatalica Zoran , Dogruluk Turgut W , Noel Pawan , Dombrowski Susan M. , Hong Lenny , Barbi Michelle , Chandrasekaran Thiruppavai , Basu Gargi D. , Hall David W. , Hoag Jess R , Kundranda Madappa N.
Published: January 2023

807

Background: Activation of the Wnt signaling pathway leads to increases in β-catenin levels, which subsequently increases transcription of various genes, including those involved in cell proliferation. Dysregulation of the Wnt signaling pathway has been observed in numerous gastrointestinal (GI) cancers. Here we examine Wnt pathway activation across all GI cancers by investigating alterations in certain genes of the Wnt pathway, which may identify patients eligible for clinical trials. Methods: The Oncomap ExTra genomic profiling assay utilizes tumor-normal, whole-exome, whole-transcriptome DNA and RNA sequencing to identify somatic alterations in tumors. The assay detects single-nucleotide substitutions, indels, copy number alterations, alternative transcripts, and gene fusions. Alterations in genes that activate Wnt signaling and their frequency across all GI cancers was determined. Results: A total of 1928 patients assayed April 2018 to July 2022 were included. The Wnt signaling pathway was activated in 922 (47.8%) patients. Wnt pathway activation varied substantially across GI cancers, from 81.1% in colorectal cancer (CRC) to 3.4% in anal cancer. APC was the most commonly altered gene in CRC, small bowel and biliary carcinomas. CTNNB1 was predominant in liver (41.2%), MEN1 in neuroendocrine (14.6%), and RNF43 in gastric (9.4%) cancer. Of 921 patients with alterations in the Wnt pathway, 5.2% had a co-mutation in another Wnt pathway-related gene. RSPO2/3 fusions were found in 4 CRC, 1 stomach, 1 biliary, and 1 small bowel cancer and were mutually exclusive with other alterations in the Wnt pathway. Conclusions: Wnt signaling is activated in about half of all GI cancers, and APC alterations are the most frequently observed. Whole transcriptome profiling allowed us to identify RSPO2/3 fusions, which also contribute to activation of the Wnt pathway. Wnt activation appears to be a particularly important in CRC, with 81.1% of CRC having a Wnt pathway alteration. Our results highlight the therapeutic potential of targeting the abnormal Wnt/β-catenin signaling pathway in GI malignancies. [Table: see text]
Factors associated with weekend emergency department visits in patients with GI cancer.
Authors: Parekh Jay , Lee Victor , Yerlikaya Aslihan , Abraham Soniya , Park Henry Soo-Min , Stein Stacey , Jairam Vikram
Published: January 2023

813

Background: Gastrointestinal (GI) cancers account for highest ED revisits among cancer patients. Weekend ED visits are also associated with higher mortality. We aimed to analyze factors associated with weekend ED visits among GI cancer patients. Methods: Nationwide Emergency Department Sample (NEDS) database was queried from 2009 to 2017 for ED visits with GI primary tumor. ED visits were characterized by demographic, socioeconomic factors, hospital characteristics and primary cancer. Univariate and multivariate logistic regression were performed. Data was analyzed using Stata. Results: From 2009 to 2017, 6,862,077 ED visits associated with GI cancer were analyzed and 1,811,111(26.4%) visits were on weekend. Weekend visits were associated with increased in-hospital mortality (odds ratio [OR] 1.06; 95% Confidence Interval [CI] 1.04-1.). Weekday mortality was 3.8%, while weekend was 3.9%. Weekend visits were negatively associated with presentation in 2013-2017 as compared to 2009-2012 (OR 0.96; 0.95-0.97), Northeast hospitals (OR 0.89; 0.88-0.91) compared to Midwest, teaching hospital status (OR 0.96; 0.95-0.97) compared to non-teaching and metastatic cancer (OR 0.96; 0.95-0.97) compared to non-metastatic cancers. Compared to colon, weekend admissions were also negatively associated with anorectal (OR 0.96; 0.95-0.98) and hepatobiliary cancers (OR 0.96; 0.95-0.98). Conclusions: Presentation between 2013 to 2017, teaching hospital status, Northeast hospitals and metastatic stage were associated with fewer weekend ED visits. These findings could be potentially explained by increased and primary care utilization. There was a statistically significant association between mortality and weekend admissions, however the absolute difference was only 0.1%. Possible explanations include potential differences in staffing, interventions and procedures over the weekends compared to weekdays. In comparison to colon, anorectal and hepatobiliary cancer patients are less likely to have weekend ED visits while pancreatic cancer patients are more likely to have weekend ED visits. Our findings may help GI oncologists identify patients at risk of weekend ED visits.[Table: see text]
Severe enterocolitis with capecitabine (CAPE) is not a predictor of gastrointestinal (GI) toxicity with infusional 5-fluorouracil (5-FU)–based regimens: An institutional analysis.
Authors: Parish Marie , Cox Ronald , Shreenivas Aditya V. , Mahipal Amit , Chakrabarti Sakti
Published: January 2023

89

Background: Enterocolitis is a potentially fatal toxicity of CAPE. The safety of infusional 5-FU-based regimens in patients developing severe enterocolitis with CAPE is not well established in the literature. Methods: After institutional review board approval, a database search identified patients who received infusional 5-FU-based regimens between January 2015 and July 2022 in a tertiary care cancer center after experiencing severe CAPE-induced enterocolitis, defined as the presence of grade 3 or higher diarrhea and features of enterocolitis on computed tomography (CT) scan. Data on patient characteristics, grade of CAPE-induced diarrhea, clinical course, details of 5-FU-based regimens administered after recovery, and outcomes were collected by retrospective electronic chart review. Results: Among the 791 patients treated with CAPE during the study period, 27 (3.4%) developed grade 3 or higher diarrhea, and 15 of these 27 patients (1.9%) had evidence of enterocolitis on CT scan. All patients were treated with supportive measures. All but 1 patient recovered fully; 1 patient died due to a condition unrelated to CAPE toxicity. After complete recovery, 7 patients aged 46 to 69 years (median, 68 years) received FOLFOX (oxaliplatin and infusional 5-FU). The time interval between recovery from CAPE-induced enterocolitis and the start of infusional 5-FU ranged from 4 to 20 weeks (median, 12 weeks), with 3 patients starting 5-FU within 4-5 weeks of recovery. Standard dose 5-FU (2400 mg/m2 over 46 hours) was given to 2 of the 7 patients; the remaining 5 patients received 50% to 80% of the standard dose at the beginning of treatment, but eventually tolerated the standard dose. All patients tolerated 5-FU infusion without experiencing any grade 2 or higher 5-FU induced GI toxicity. Conclusions: Most patients developing severe enterocolitis with CAPE recover fully with appropriate supportive measures. Infusional 5-FU-based regimens appear to be safe in this patient group. Severe CAPE-induced enterocolitis should not preclude the use of infusional 5-FU-based regimens, especially in curative-intent settings such as adjuvant therapy.
Toxicities and outcomes of neoadjuvant treatment in elderly patients with locally advanced rectal cancer: A scoping review.
Authors: Hamed Ruba Ahmed Mohammed , Korpanty Greg , Kella Dervla
Published: January 2023

91

Background: Neoadjuvant treatment (NAT) followed by surgery has become the standard treatment for locally advanced rectal cancer (LARC). This scoping review aims to assess the toxicity and outcomes of the currently available NAT of rectal cancer in elderly patients with age-associated frailty. Methods: Six thousand seventy-nine records were identified on Ovid Medline, Embase, Cochrane database, and CINAHL. Two independent reviewers screened the articles. Fifteen articles were identified through a hand search. Articles on NAT in LARC in elderly patients were included. Results: Thirty-three studies from 2005 to 2022 met inclusion criteria, including 27 retrospective reviews, 4 clinical trials (Phase 1 and 2) and 2 prospective studies; 5 were multicentred. The median age of the sample was 70-75 in 24 studies and 76-83 in 11 studies. One study examined only patients above 80. Twenty-four studies examined NAT with long course concurrent chemoradiotherapy (LCCRT), 5 examined both LCCRT and RT alone, 3 examined short-course radiotherapy (SCRT), one examined SCRT with sequential chemotherapy (CT), and one study examined neoadjuvant CT followed by LCCRT. Concurrent CT with 5 FU-based treatments was given in 23 studies with either intravenous or oral, and oxaliplatin was added to 5 FU in 10 studies. Interruption of concurrent treatment was reported with dose reduction, delay or discontinuation in 26 studies. Diarrhea, nausea/vomiting and radiation dermatitis were reported as significant side effects (G3 -4), with G3-4 diarrhea reported in 18 studies. Haematological toxicities were very frequent, with a 20-60% rate in the studies. No dose interruption of RT was required in the three studies that included only SCRT, except for one patient. The study on CT followed by LCCRT showed that CT was completed in 82% and LCCRT in 76% of patients. A preliminary result of PRODIGE 42-GERICO 12 NACRE, a randomised trial comparing SCRT with chemoradiotherapy (CRT), showed that 14% of patients in the CRT arm did not receive all of the planned treatment compared to 0% in SCRT arm, and the 6 months death rate was 10.0% in CRT arm and 3.92% in SCRT. Conclusions: Toxicities are frequently reported with Neoadjuvant LCCRT in the elderly and lead to treatment interruption. SCRT is well tolerated and probably associated with better survival (pending final results of the NACRE trial). Studies in this scoping review are over-represented by retrospective studies, and we suggest that future clinical trials focus on elderly patients to investigate treatment strategies with fewer toxicities.
LEANOX: Lean body mass normalization of oxaliplatin-based chemotherapy for patients with stage III colon cancer treated in adjuvant setting: Impact on oxaliplatin-induced sensitive neurotoxicity—A multicenter phase II randomized trial.
Authors: Assenat Eric , BEN Abdelghani Meher , Monnier Maeva , Perrier Herve , Khemissa Faiza , Desgrippes Romain , Galais Marie-Pierre , Rinaldi Yves , Lepage Come , Tetreau Raphael , Senesse Pierre
Published: January 2023

92

Background: Adjuvant chemotherapy is the current worldwide standard of care for stage III colorectal cancer (CRC) but it leads to significant neurotoxicity. We have shown in 2 cohorts of CRC patients treated with Oxaliplatin (Ox) that Ox-due neuropathy occurred in patients receiving an excess of 3.09 mg Ox/ kg Lean Body Mass (LBM). The aim of this trial was to determine whether the Ox dose adaptation based on the LBM index can reduce neurotoxicity, in patients treated for a stage III CRC. Methods: LEANOX is a randomized phase II multicentre study in patients eligible for an Ox regimen as adjuvant chemotherapy for CRC. Patients without sarcopenia (LBM index <3.09mg/kg, group 1) received a dosage of Ox according to Body Surface Area (BSA) (85 mg/m²).Patients with sarcopenia (LBM index ≥3.09mg/kg) were randomized in 2 groups, group 2: dosage of Ox according to BSA (similar to group 1) and group 3: a dosage of Ox according to LBM (3.09 mg Ox/ kg LBM). Randomization (1:1) was stratified by center, age and weight loss. The primary endpoint was the percentage of patients without grade ≥2 neurotoxicity during the first 6 cycles of adjuvant Ox-based chemotherapy. The study required 108 randomized patients (bilateral α=0.05, 80% power) to compare the primary endpoint between groups 2 and 3 with P2=55% and P3=80%. Secondary endpoints included time to onset of grade≥2 chronic cumulative neurotoxicity, duration of the chronic cumulative neurotoxicity, cumulative Ox doses that can be delivered without reaching the dose-limiting chronic neurotoxicity, tolerance, disease free survival, overall survival and quality of life. Results: A total of 160 patients were included in 18 french centers: 33 in group 1, 64 in group 2 and 63 in group 3. Median age was 63 years, 52.5 % male, 89.3 % OMS 0 and tumoral stage was T3 (57.5%), T4 (33.8%), N1 (60.6%) and N2 (38.1%). Grade 3-4 AE events occurred in 58.0% in group 2 and 59.7% in group 3. The percentage of patients without experiencing grade ≥ 2 of neurotoxicity during the first 6 cycles of adjuvant Ox-based chemotherapy was 43.9% in group 2 vs 67.2% in group 3 (p=0.01). Conclusions: We wish to avoid severe adverse reactions to Ox regimen by personalization of cancer chemotherapy. Clinical trial information: NCT03255434 .
Impact of dose adjustment of fluoropyrimidines on toxicity in patients with DPD-deficient colorectal cancer: A single-center experience.
Authors: Martinez-Perez Daniel , Ghanem Ismael , Rosas-Alonso Rocio , Arias Pedro , Rodriguez-Novoa Sonia , Borobia Alberto , Viñal David , Ruiz-Gutierrez Iciar , Jiménez-Bou Diego , Rodriguez Salas Nuria , Feliu Batlle Jaime
Published: January 2023

94

Background: Fluoropyrimidines (FPs) are the chemotherapy backbone for most patients with CRC. FPs are metabolized by dihydropyrimidine dehydrogenase (DPD). Current guidelines recommend measuring DPD activity before chemotherapy administration to adjust the initial dose and thus prevent high-grade toxicity. However, the clinical impact of this strategy is still understudied. We aim to study the efficacy and toxicity of FPs dose modifications according to DPD activity in patients with CRC. Methods: We retrospectively identified all the CRC cancer patients treated with FPs between January 2017 and July 2021 and with DPD activity assessment at Hospital Universitario La Paz, Madrid, Spain. Clinical characteristics and tolerability were collected. Two cohorts were stablished according to its DPD activity, patients with a normal DPD metabolism (DPD wild-type patients) and patients with a diminished metabolism of FPs (DPD deficient patients). Results: A total of 249 CRC patients were included in this study. Sixteen patients (6,4%) were DPD deficient, and 15 of them (94%) received initially 50% of the recommended standard dosing of FPs (increasing to 75% in following cycles if well tolerated) according to guidelines. Forty percent of non-DPD deficiency started FPs at 75% of the standard initial dose due to frailty. Two toxic deaths were observed in the DPD-wild-type cohort, none in the DPD deficient cohort. Clinico-pathological characteristics of patients and their toxicity according to each cohort are depicted in the table. No significant differences in G3/4 toxicity between both groups (40% and 37% in the DPD-wild-type and DPD-deficient cohort, respectively). Diarrhea G3/4 was numerically more present in the DPD-deficient group (25% vs 12%, respectively). Conclusions: Overall, DPD genotype-guided FP treatment in DPD deficient patients with CRC may prevent high-grade toxicity. Diarrhea might still be higher in this group despite dose modifications, so careful surveillance and early treatment should be considered in these patients. [Table: see text]