bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clonal hematopoiesis of indeterminate potential (CHIP), treatment outcomes and adverse events in gastrointestinal cancers: A pooled analysis of clinical trial and real-world data.
Authors: Krishnan Tharani , Solar Vasconcelos Joao Paulo , Titmuss Emma , Topham James Thomas , Schaeffer David F. , Karsan Aly , Lim Howard J , Ho Cheryl , Gill Sharlene , Kennecke Hagen Fritz , Jonker Derek J. , Chen Eric Xueyu , Renouf Daniel John , O'Callaghan Christopher J. , Loree Jonathan M. 
Published: January 2024

169 Background: Clonal hematopoesis of indeterminate potential (CHIP) is the acquisition of somatic mutations leading to clonal expansion of hematopoietic stem cells and is a common incidental finding in circulating tumor DNA (ctDNA). Inflammation from these cells or a reduced marrow reserve may impact treatment outcomes or adverse events. We investigated the incidence of CHIP in ctDNA from patients with gastrointestinal (GI) cancers and explored its association with outcomes and adverse events (AEs). Methods: We collected ctDNA results from a local prospective metastatic colorectal cancer (mCRC) cohort (PREDICT-L) and ctDNA data from two randomized trials: CCTG CO.26 (durvalumab + tremelimumab [D+T] or best supportive care [BSC] in mCRC) and CCTG PA.7 (gemcitabine and nab-paclitaxel [GN] with or without D+T in metastatic pancreatic adenocarcinoma [mPDAC]). CHIP+ was defined as the presence of a variant of ≥2% variant allele frequency annotated in the ctDNA report in any of the genes DNMT3A, TET2, ASXL1 and ATM, and not annotated as germline by respective sequencing platforms. The first line of treatment after ctDNA was reviewed, and grade ≥3 or dose-limiting adverse events were documented. Results: The prevalence of CHIP varied from 10% to 18% (see table). CHIP+ patients were older than CHIP- in the CO.26 cohort (p=0.011), and ECOG was higher in CHIP+ patients in the PREDICT-L cohort. There was no difference between CHIP+/- patients with regards to sex. DNMT3A was the gene most frequently mutated in all three cohorts. There was no significant difference in PFS or OS between the CHIP+/- groups, both in those treated with chemotherapy (Chemo) or immunotherapy (IO). The most common AEs were rash, GI toxicities and bleeding/clotting abnormalities. There was no significant difference in the rates of AEs between the CHIP+/- groups for those treated with Chemo or IO. Conclusions: CHIP is a common alteration in ctDNA but did not impact PFS, OS, or the chance of developing an AE. [Table: see text]
Colon cancer screening disparities among limited English proficient patients during implementation of patient navigation services.
Authors: Yao Rebecca , Jenkins Gregory , Grimm Jessica , Hill James , Agunwanba Amenah , Njeru Jane 
Published: January 2024

17 Background: Age-appropriate colon cancer screening has long demonstrated effectiveness in reducing colon cancer incidence and mortality. However, despite a gradual rise in compliance with colon cancer screening, significant disparities remain, particularly among patients with limited English proficiency (LEP). Multitarget stool DNA (MT-sDNA) testing (Exact Sciences, Madison, WI) has been available over the past decade in the United States as a lower-cost and non-invasive option for screening. In 2019, Exact Sciences began to offer patient navigation services comprising outbound phone, text, and e-mail reminders, and inbound phone support (>200 languages) with all MT-sDNA orders. In this study, we aimed to evaluate the disparity in successful MT-sDNA testing between LEP and EP patients in a time frame when patient navigation services were active. Methods: We performed a retrospective cohort study of patients 45-75 years old enrolled in the primary care setting of our institution who received an order for MT-sDNA screening during a period in which patient navigation services began to be offered. A multi-state Cox model was constructed with time to MT-sDNA or other CRC screening predicted by English proficiency accounting for age and gender. Wald tests were used to test the association of CRC screening completion and English proficiency. Rates of completion of MT-sDNA screening and other CRC screening following MT-sDNA test ordering were calculated using the Kaplan-Meier method. Results: Of the 5016 patients evaluated and referred for multitarget stool DNA testing from May 1st, 2021, and May 1st, 2022, 154 patients were of LEP, and 4862 were English proficient (EP). At 180 days following a MT-sDNA test order the rate of completion for the LEP patients was 50.2% (95% CI: 42.8-58.7%) versus 70.3% (95% 69.1-71.6%) for EP individuals (p=0.001). A small portion of individuals also completed another type of CRC screen, 3.3% for LEP and 2.5% for EP (p=0.99). Conclusions: This study is consistent with the existing research demonstrating LEP as a significant demographic group linked with decreased participation in cancer screening. Our findings indicated that despite the availability of patient navigation services, individuals with LEP were still less likely to complete an MT-sDNA test successfully when compared to those with EP. [Table: see text]
Microscopic residual disease (MRD) monitoring with circulating tumor DNA (ctDNA) across gastrointestinal (GI) malignancies.
Authors: Winters Harrison David , Sackstein Paul , Weinberg Benjamin Adam , Debnath Dipanjan , Geng Xue , Wang Hongkun , Chintalacheruvu Saavan , Marshall John , He Aiwu Ruth , Noel Marcus Smith , Mukherji Reetu 
Published: January 2024

176 Background: ctDNA is a powerful tool that can detect early evidence of tumor relapse, or MRD. There are limited studies characterizing the performance of ctDNA in non-colorectal GI cancer patients (pts). We describe the clinical outcomes of GI cancer pts who underwent real-world MRD testing at our institution. Methods: We retrospectively analyzed GI cancer pts with ≥1 ctDNA test (Natera, Inc) ordered for MRD testing between June 2020-August 2022. Descriptive statistics were used to characterize rates of ctDNA positivity (ctDNA+) and relapse rates (RR). Median relapse-free survival (mRFS) and overall survival (mOS) were calculated using Kaplan-Meier method, group comparisons by log-rank test, and hazard ratios (HR) by Cox proportional hazard models. Associations between initial mean tumor molecules per milliliter (MTM/mL) (continuous variable) and clinical factors were assessed by Kruskal-Wallis or Wilcoxon Rank-sum tests. Results: ctDNA testing was successful in 222/228 pts (table). The median follow-up was 15 months (mo) (Interquartile Range 8.6-24.7). 61/222 (27.5%) of pts had ≥1 ctDNA+ test of which 59% had relapse on their next scan obtained after a median of 40 days from the first + test. Of all relapsed pts (62/222), ctDNA detected relapse before imaging in 69.4% with a median lead time of 57 days. The positive and negative predictive values of ctDNA for relapse were 82% and 92.5%, respectively. The mRFS was 10.8 mo vs. not reached (NR) (HR 18.6; p<0.0001) and mOS 43.1 mo vs. NR (HR 5.0; p=0.002) in anytime vs. never ctDNA+ pts with similar trends in the colorectal and pancreas subgroups. Of ctDNA+ pts with >1 test, 49.2% (29/59) cleared ctDNA with 79.3% of clearances on/after therapy. Between ctDNA clearers and non-clearers, RR were 72.4% vs. 93.3%, mRFS 12.4 vs. 7.6 mo (HR 0.3; p=0.6), and mOS NR vs. 43.1 mo (log-rank test p=0.01). No significant associations existed between initial MTM/mL and tumor types (p=0.6), relapse status (p=0.2), or number of relapse sites (p=0.4). Conclusions: ctDNA is a prognostic tool able to detect early relapse with high accuracy in GI cancers. The initial MTM/mL in ctDNA+ pts did not correlate with tumor histology or relapse patterns. Pts clearing ctDNA tended to have improved outcomes; however, RRs were higher than anticipated. More pts and longer follow up will help characterize the performance of ctDNA across rarer GI subtypes. [Table: see text]
Multiomic analysis for minimal residual disease detection: Addressing challenges in stage II-III colon cancer from COSMOS-CRC-01.
Authors: Nakamura Yoshiaki , Tsukada Yuichiro , Matsuhashi Nobuhisa , Murano Tatsuro , Shiozawa Manabu , Kato Takeshi , Oki Eiji , Goto Masahiro , Kagawa Yoshinori , Kanazawa Akiyoshi , Ohta Takashi , Ouchi Akira , Bando Hideaki , Uchigata Hiroshi , Notake Chiemi , Cai Mingyang , Zhang Shile , Rich Thereasa A. , Banks Kimberly , Yoshino Takayuki 
Published: January 2024

180 Background: A considerable number of patients with stage II-III colon cancer experience disease recurrence following definitive treatment while others may receive unnecessary toxicity from adjuvant chemotherapy. Minimal residual disease (MRD) detection through ctDNA analysis can be evaluated without reliance on tissue which comes with logistic advantages and may be the only option for patients with limited tumor specimens. Methods: COSMOS-CRC-01 is an ongoing biomarker study that enrolled patients with resectable stage 0-III colorectal cancer between January 2020 and April 2021. Plasma samples and clinical data were collected 28 days post-operatively and every 3-6 months for up to 5 years alongside radiographic imaging. Samples were tested on the Guardant Reveal Infinity Oncology Platform for MRD detection. This analytically validated multiomic NGS assay interrogates >700 genes and ~15Mb of methylated regions. A bioinformatics algorithm trained for CRC detection classifies each sample as ctDNA detectable or undetectable based on a predefined statistical likelihood threshold and returns quantitative tumor fraction. The primary endpoint was time to recurrence (TTR) based on ctDNA detection status. Results: This subgroup analysis evaluated 801 post-surgical plasma samples (4mL each, median input 19ng, 96% passed QC) from 136 patients with R0 resected stage II-III colon cancer with a median follow-up of 28 months. ctDNA detection at Day 28 post-surgery and following adjuvant chemotherapy were both associated with significantly shorter TTR (p<0.0001; Table). Sensitivity with serial measurement was 80% (95% CI, 56.3-94.3%), with a median lead time of 5.3 months. Sensitivity was highest for detection of locoregional (2/2), brain (1/1), liver (7/7), or multiple (3/3) metastasis compared to isolated lung (2/4) or peritoneal (1/3) metastasis. Tumor fraction increased as expected in samples collected closer to the time of radiographic detection. Three recurred patients had KRAS G12C variants detected in ctDNA prior to recurrence, suggesting the potential of early intervention with targeted agents. Among 553 post-treatment samples from 114 non-recurred patients, sample specificity was 97.3% (95% CI 95.6-98.5%). Conclusions: We show a plasma-only genomic- and methylation-based assay to have sensitive and specific detection of MRD in stage II-III colon cancer. Serial measurement provides superior performance versus one-time measurement at Day 28 post-surgery and detects targetable variants prior to recurrence. [Table: see text]
Prediction of postoperative recurrence by integrating preoperative ctDNA levels and tumor metastasis volume in patients (pts) with colorectal cancer (CRC) with resectable lung or liver metastasis.
Authors: Oyoshi Hidekazu , Bando Hideaki , Yamashita Riu , Kageyama Shun-ichiro , Horasawa Satoshi , Nakamura Masaki , Fujisawa Takeshi , Tomizawa Kento , Motegi Atsushi , Mishima Saori , Kotani Daisuke , Taniguchi Hiroya , Oki Eiji , Takemasa Ichiro , Kato Takeshi , Nakamura Yoshiaki , Mori Masaki , Jurdi Adham A , Liu Minetta C. , Yoshino Takayuki 
Published: January 2024

183 Background: In pts with CRC, the clinical usefulness of ctDNA testing after curative resection has been strongly suggested. Prognostic biomarkers are also needed for pts with resectable metastases to identify high-risk patients who may be spared unnecessary surgery or local ablation. We aimed to create a prediction model to estimate the risk of post-operative recurrence using an integrated analysis of preoperative ctDNA level and radiographic imaging. Methods: The GALAXY study (UMIN000039205) included 645 pts with newly diagnosed or recurrent CRC with resectable metastatic lesions. Pts without liver or lung metastases and those who had received chemotherapy within 3 months prior to ctDNA measurement were excluded. We used the ratio of preoperative ctDNA levels [mean tumor molecules (MTM)/mL] to tumor metastasis volume (mL) from radiographic imaging (ctDNA/volume) to predict recurrence. Cutoff ctDNA/volume values were determined from receiver operating characteristic curves using Youden index. Pts with above and below the cutoff values were defined as high and low risk, respectively. Disease-free survival (DFS) was calculated from the date of definitive surgical resection to first recurrence or death. Results: In this cohort of 110 pts with liver metastases and 24 with lung metastases, the median follow-up was 13.2 months (range: 0.7-30.9). The cutoff values for the ctDNA/volume model were 0.837 (liver) and 0.496 (lung) MTM/mL2. Among the pts with liver metastases, the high-risk group predicted by the ctDNA/volume model had a median DFS of 14.7 months (95% CI: 6.1–not reached) versus not reached (95% CI: not reached–not reached) in the low-risk group (HR = 3.6, P = 0.021). Among the pts with lung metastases, the median DFS was 2.9 months (95% CI: 2.1–not reached) in the high-risk group versus 21.8 months (95% CI: 21.8–not reached) in the low-risk group (HR = 21.0, P < 0.0001). The high-risk group had a significantly higher cumulative recurrence at 6 months (17% and 67% in pts with liver and lung metastases, respectively) versus the low-risk group (0%, P = 0.012 and 6%, P < 0.001 in pts with liver and lung metastases, respectively) considering death as a competing risk. Conclusions: The ctDNA/volume model was able to predict postoperative recurrence in CRC pts with liver and lung metastases. Ongoing and future studies will further optimize the model by incorporating other clinicopathologic factors associated with postoperative CRC recurrence. [Table: see text]
Prevalence and predictors of aspirin/NSAID use among patients with Lynch syndrome (LS).
Authors: Singhal Sachi , Chertok Yana , Osorio Nadine , Chavez Juan Pablo , Riggs Emma D. , Daly Mary Beryl , Hall Michael J. 
Published: January 2024

19 Background: LS is among the most common hereditary cancer (CA) syndromes, underlying 3% cases of colorectal CA (CRC) and 8% CRC <50 yrs. LS patients have a high lifetime risk of CRC which is lowered by intensive colonoscopy surveillance. However, interval CRC can still develop, and adjunctive therapies like ASA and NSAIDs have been recognized for their CP benefits, with 35% risk reduction associated with sustained (>2 yrs) ASA use. Existing data are scarce on uptake of CP in LS pts, as well as patient-level factors that may impact uptake. Methods: PREVENTLynch recruited LS participants in the FoxChase Cancer Center (FCCC) Risk Registry, who were invited to complete a one-time e-survey after providing informed consent (1/2020-6/2020; IRB 20-8014). This survey was additionally provided online (PREVENTLynch-II) to US and international patients through 2 patient advocacy websites (10/2022-7/2023). Demographic/personal/familial CA history were collected. Perceived inconvenience, side effects, reassurance, and likelihood of recommending available and emerging CA prevention modalities were measured on 9-point scales (low=1; high=9). Results: 296 patients with LS completed the survey. Median age was 53 yrs [IQR 44-62], and overall CP use was 37.5%. No significant variation in CP uptake was seen based on race, age, marital status or geographic region (nationally and internationally). Personal history of cancer was reported by 56.4%, but was not associated with CP (p=0.6). Gene mutated (MLH1, MSH2, MSH6, PMS2) was not associated with CP (p=0.5).CP users vs non-users perceived greater convenience (mean 1.32 vs 1.90 respectively, p=0.02), lower concern for side effects (2.30 vs 3.61, p=0.0008), and higher perceived preventive reassurance from CP use (5.68 vs 3.93 p<0.0001). CP users were more likely to recommend CP to others (7.57 vs 4.49, p<0.0001). Conclusions: CP uptake is low among patients with LS. Patient perceptions of CP convenience, side effects and preventive benefits predicted CP uptake whereas factors such as age, sex, geographical location, gene affected and personal history of malignancy did not. This suggests a critical need for education addressing negative perceptions of CP among LS patients to improve CP uptake. [Table: see text]
Impact of KRAS codon-specific mutations on survival of patients with metastatic CRC (mCRC) treated with trifluridine-tipiracil (TAS) plus bevacizumab (Bev): A real-world analysis.
Authors: Maddalena Giulia , van der Pol Ymke , Rivers Zachary , Dasari Arvind , Rogers Jane E. , Guinney Justin , Kopetz Scott , Raghav Kanwal Pratap Singh 
Published: January 2024

201 Background: Clinical benefit and survival data utilizing later lines of therapy with TAS in metastatic CRC is limited, highlighting the need for better patient selection (Mayer, NEJM 2015). Recently, codon-specific KRAS mutations have been implicated as biomarkers for TAS treatment. KRAS G12 was associated with a lack of benefit and G13 displayed improved benefit (Van de Haar, Nat Med 2023) However, it is unknown whether this differential prognostic impact occurs on TAS + Bev which has now supplanted TAS as the standard of care (Prager, NEJM 2023). Methods: We retrospectively investigated outcomes in a cohort of 100 mCRC patients treated with TAS + Bev for ≥1 month between September 2019 and April 2023 at MD Anderson (cohort A) using institutional databases. For validation, a cohort of 205 mCRC patients from the Tempus database was used (cohort B). Mutation status was determined from tissue biopsy using clinical NGS (Beaubier, Nat Biotechnol 2019). The primary endpoint was overall survival (OS), determined by Kaplan Meier estimators and risk set adjustment methods and compared using the log-rank test. Results: Baseline characteristics were similar in the two cohorts; in cohort A, 52% (N = 52) patients were male and median age at diagnosis was 56 years (IQR:47-61y). Correspondingly, 56% (N = 93) of cohort B were male and the median age at diagnosis was 56 (IQR: 47-66y). The table shows the distribution of codon-specific RAS mutations and their OS across the two cohorts. Comparative analysis of median OS (mOS) between KRAS G12, KRAS G13 and RAS/RAF-WT subgroups showed no significant differences (p=0.06 and 0.94 for cohort A and B, respectively). Conclusions: In this cohort of mCRC treated with TAS-Bev, codon-specific KRAS mutations did not appear to predict survival benefit, unlike previously reported for TAS treated patients. Overall, KRAS G13 mutated patients appeared to have a worse outcome. Further investigations into codon-specific impact are required prior to incorporating this for patient selection for treatment. *G. Maddalena and Y. van der Pol as co-first authors. [Table: see text]
Investigating the association of WNT pathway dysregulation and young-onset colorectal cancer.
Authors: Ferrell Morgan , Guven Deniz Can , Gonzalez Cyndi , Giza Richard , Cheng Svea , Syed Masood Pasha , Magge Tara , Singhi Aatur D. , Saeed Anwaar , Sahin Ibrahim Halil 
Published: January 2024

217 Background: Colorectal cancer (CRC) is the third most common cancer in the United States with studies showing increasing incidence of Young-Onset CRC, defined as cases occurring in individuals 50 years old or younger. Separately, the WNT Signaling Pathway and its subsequent mutation can result in sustained activation and, therefore, unregulated cell proliferation which has been well described in colorectal cancers. Loss of function in APC, AXIN1, AXIN2, GKS3B, and RNF43 can each act to dysregulate WNT signaling, contributing to cancer development. In this study, we aimed to conduct a comprehensive, molecular evaluation of the WNT signaling pathway in colorectal cancer within age-specific cohorts with onset of CRC at 50 years old or less versus greater than 50 years old. Methods: We used published individual patient-level data of 6286 patients with colorectal cancer (CRC) from the 16 CRC datasets included in the cbioportal database. The WNT pathway alterations, including APC, AXIN1, AXIN2, GKS3B and RNF43 mutations were considered to define the WNT mutant CRC cohort. The presence of WNT alterations according to the age (50 years old or younger vs. over 50 years) were evaluated using Chi-square tests. The association between primary tumor distribution (colon vs. rectal) and age were evaluated across patients with and without WNT pathway alterations. The effect of WNT pathway alterations on the overall survival and survival after the metastatic stage was evaluated with Kaplan-Meier survival curves. A type-I error level of 5% (p<0.05) was considered the threshold limit for statistical significance. Results: A total of 2,630 individuals were identified with relevant clinical and molecular information. When comparing WNT alteration patterns between young-onset CRC (< 50 years old) and CRC in cohort >50 years old, there was no statistically significant difference (p-value .215). Analysis of common individual mutations in APC, AXIN1, AXIN2, GKS3B and RNF43 also showed similar incidences across age groups. However, we identified WNT alterations were significantly more common in rectal cancers compared to colon cancer, being found in 75.9% of rectal cancer cases, regardless of age groups (p-value <0.00001). Additionally, individuals identified to have WNT alterations were found to have improved survival with a median overall survival of of 58.19 months versus a median of 41.72 months in those without. Conclusions: Overall, no significant differences were found in WNT alteration expression between Young-onset CRC versus CRC in individuals over the age of 50. However, across all age groups, WNT alterations were frequently found in rectal cancers. Furthermore, these WNT alterations were associated with better outcomes.