bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolomic differences in young-onset versus average-onset colorectal adenocarcinoma.
Authors: Jayakrishnan Thejus , Farha Nicole , Mariam Arshiya , Rotroff Daniel Miller , Aucejo Federico , Barot Shimoli V , Conces Madison , Nair Kanika G. , Krishnamurthi Smitha S. , Schmit Stephanie , Liska David , Khorana Alok A. , Kamath Suneel Deepak 
Published: June 2023

3510 Background: Novel deleterious effects of environmental exposures may play a role in the rising incidence of young-onset colorectal cancer (yoCRC). We used metabolomics to assess differences between yoCRC and average-onset CRC (aoCRC), in comparison to healthy controls, which may provide insight into the pathogenesis and suggest any exposure risks. Methods: Patients with stage I-IV CRC and healthy controls were identified from prospective biobanks and categorized based on age < 50 years (yoCRC or young controls) or age > 60 years (aoCRC or older controls). Plasma metabolites were profiled using GC-TOF mass spectrometry. Differential abundance of metabolites was investigated using unadjusted and adjusted logistic regression. Metabolic pathway analysis was performed using Metaboanalyst 5.0. All p-values were adjusted for multiple testing (false-discovery rate, FDR p < 0.20 considered significant). Results: The study population comprised 170 CRC patients (66 yoCRC and 104 aoCRC) and 49 healthy controls (34 young and 15 old). Association analyses revealed four differentially abundant metabolites: citrate (FDR p = 0.04), cholesterol (0.14), and two unidentified metabolites (UM). Metabolic pathways significantly altered in yoCRC vs. aoCRC included: carbohydrate metabolism (citrate cycle, FDR p = 0.04), carbohydrate biosynthesis (glyoxylate and dicarboxylate metabolism, FDR p = 0.004), amino-acid metabolism (alanine, aspartate, and glutamate metabolism, FDR p = 0.01, arginine biosynthesis, FDR p = 0.02, and amino-acid t-RNA biosynthesis, FDR p = 0.03). There were no significant metabolomic differences between young and old controls. Significant associations on survival analysis included: adipic acid with aoCRC (HR = 3.1, 95% CI = , 1.7-5.6, FDR p = 0.13, unadjusted analysis) suggesting worse survival with higher levels and 4-hydroxyhippuric acid with the whole cohort (HR = 0.4, 95% CI = 0.3-0.7, FDR p = 0.05, adjusted analyses) indicating better survival with higher levels. Conclusions: We identified significant differences in the citrate cycle - a core pathway of cellular metabolism associated with colorectal cancer. Metabolomic differences in pathways of carcinogenic significance (aspartate) and environmental exposures (arginine and dietary red meat) were also noted, suggesting potential relationships with younger age of CRC onset. [Table: see text]
Adjuvant systemic chemotherapy with or without hepatic arterial infusion of floxuridine in patients following colorectal cancer liver metastases resection (HARVEST): A prospective, randomized controlled trial.
Authors: Li Yu-hong , Wang De-Shen , Gu Yang-Kui , Wen Lei , Ren Chao , Wu Xiao-Jun , Yuan Yun-Fei , Li Bin-Kui , Zheng Yun , Ding Pei-Rong , Wang Zhi-Qiang , Pan Zhi-Zhong , Chen Gong , Li Li-Ren , Lu Zhen-Hai , Tan Qiong , Wan De-Sen , Xu Rui-Hua 
Published: June 2023

3516 Background: Several retrospective studies have previously demonstrated that a combination of adjuvant systemic chemotherapy and hepatic arterial infusion (HAI) could benefit patients following colorectal cancer liver metastases (CRLM) resection. This prospective clinical study aimed to determine whether adding HAI to adjuvant systemic chemotherapy could reduce the risk of recurrence following CRLM resection. Methods: The HARVEST study is an investigator-initiated, prospective, randomized controlled trial investigating the efficacy and safety of adjuvant intravenous chemotherapy with or without HAI floxuridine (FUDR) in CRLM patients that underwent liver metastasectomy. Patients in the systemic chemotherapy plus HAIC arm (HAI group) received systemic FOLFOX (q2w) plus HAI (FUDR, d1-14, q4w) for up to 6 months, while the systemic chemotherapy group without HAI (non-HAI group) received intravenous FOLFOX only. The primary study endpoint is the relapse-free survival in the modified intention-to-treat (mITT) population. Blood samples at different time points were also collected and circulating tumor DNA (ctDNA) was tested for NPY and SEPT9 methylation. Results: The study was prematurely terminated due to FUDR production halt in China. Ninety-two patients were randomized and seventy-seven patients (38 in the HAI group and 39 in the non-HAI group) were eventually included in our mITT analysis. After a median follow-up of 35.8 months, there were 22 (57.9%) and 25 (64.1%) recurrences in the HAI and non-HAI groups, respectively. The median relapse-free survival was 20.0 months in the HAI group and 11.7 months in the non-HAI group (p = 0.14; HR 0.65; 95% confidence interval [CI] 0.37 to 1.16). No significant difference was found in terms of overall survival between the two groups (p = 0.461). Our subgroup analysis revealed that patients with multiple liver metastases (p < 0.01) and RAS/BRAF mutation (p < 0.01) could benefit from adjuvant HAI treatment. Based on ctDNA status, patients with positive postoperative ctDNA methylation benefited from adjuvant HAI treatment (p < 0.01), while those with negative postoperative ctDNA methylation status (p = 0.95) did not. Chemotherapy-related adverse events were comparable between the two groups. Conclusions: Adjuvant chemotherapy intensification using HAI did not significantly reduce recurrence following CRLM resection. However, patients with multiple liver metastases, RAS/BRAF mutation and those with positive postoperative ctDNA might benefit from adjuvant HAI treatment. Clinical trial information: NCT03500874 .
Sustained organ preservation in patients with rectal cancer treated with total neoadjuvant therapy: Long-term results of the OPRA trial.
Authors: Verheij Floris S , Omer Dana Mohamed Rashid , Williams Hannah , Buckley James T , Lin Sabrina T , Qin Li-Xuan , Thompson Hannah M , Yuval Jonathan B , Gollub Marc J , Wu Abraham Jing-Ching , Saltz Leonard B. , Garcia-Aguilar Julio ,   on behalf of the OPRA Consortium
Published: June 2023

3520 Background: The preliminary results of the OPRA trial demonstrated that a substantial number of patients with locally advanced rectal cancer treated with total neoadjuvant therapy (TNT) could achieve organ preservation. Although most tumor regrowths seem to occur within the first 3 years, longer follow-up is needed to assess the ongoing risk of regrowth. Here, we report the long-term organ preservation rate and oncologic outcomes of the OPRA trial. Methods: A prospective, multi-institutional phase II trial, in which patients with stage II or III rectal cancer were randomized to receive either induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients underwent reassessment for treatment response 8-12 weeks after TNT. Patients who achieved a complete or near-complete response after finishing TNT were offered a watch and wait approach (WW). Those with incomplete response were recommended total mesorectal excision (TME). We report 5-year disease-free survival (DFS), organ preservation (defined as TME-free survival), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS) for each treatment group. We also compared DFS between patients who underwent upfront TME after restaging and patients who underwent TME after tumor regrowth. All analyses followed the intention-to-treat principle and groups were compared using the log-rank test. Results: Of the 324 patients randomized, 158 were assigned to the INCT-CRT group and 166 to the CRT-CNCT group. Median follow-up was 56 months; 85 DFS events were observed. The rates of 3- and 5-year DFS, TME-free survival, LRFS, DMFS and OS are listed in the Table. In total, 80 of the 225 (36%) patients who started WW developed a regrowth; 94% occurred within 2 years and 99% occurred within 3 years. The rate of TME-free survival at 5 years was significantly higher for CRT-CNCT (54%) than in INCT-CRT (39%). 5-year DFS was similar for patients who underwent TME after restaging (61%) compared to patients who underwent TME after regrowth (62%, p = 0.86). Conclusions: In patients with rectal cancer treated with TNT and WW, the majority of tumor regrowths occur in the first 2 years, and regrowth after 3 years is vanishingly rare. Salvage TME for tumor regrowth during WW appears to offer similar outcome to immediate TME after incomplete response to TNT. Distant metastases remain the most frequent cause of treatment failure, with similar rates in the two treatment groups. Clinical trial information: NCT02008656 . [Table: see text]
Association of positive ctDNA-based minimal residual disease assays during surveillance and undiagnosed concomitant radiographic recurrences in colorectal cancer (CRC): Results from the MD Anderson INTERCEPT program.
Authors: Dasari Arvind , Bent Alisha Heather , Alfaro-Munoz Kristin , Huey Ryan W , Johnson Benny , Lee Michael Sangmin , Morelli Maria Pia , Morris Van K. , Overman Michael J. , Parseghian Christine Megerdichian , Raghav Kanwal Pratap Singh , Shen John , Willis Jason , Newhook Timothy E. , Uppal Abhineet , You Y. Nancy , Konishi Tsuyoshi , Chang George J. , Kopetz Scott , Wolff Robert A. ,   MD Anderson INTERCEPT
Published: June 2023

3522 Background: Observational cohorts have shown that detection of circulating tumor DNA (ctDNA)-defined minimal residual disease (MRD) following curative intent therapy has very high specificity and positive predictive value for future radiographic recurrence with a lead time of over 9 months. However, such data have not incorporated rigorous clinical evaluation for concomitant recurrence, nor have they established the clinical utility of MRD monitoring after completion of curative intent therapy. Methods: Pts with stages II-IV CRC (6/1/19 - 12/31/22, data cutoff) treated with curative intent at MD Anderson Cancer Center were evaluated with a tumor-informed MRD assay (Signatera, Natera), as part of the institutional INTERCEPT program that aims to integrate MRD-based testing into CRC clinical care. Surveillance visits including scans and tumor markers were performed per established guidelines. ctDNA was recommended post-operatively and q3m with each surveillance visit. Pts and providers were informed of the results and subsequent clinical courses including additional radiologic testing for ctDNA+ MRD tests were tracked. Results: 1259 pts were included in the INTERCEPT program (median 57y, [21-93]; 55% male; stage% I-III/IV 69/31; colon/rectum% 61/39), with 1049 pts tested after curative intent surgery. Of these, 159/1049 pts (15%) had ctDNA+; distribution of pts, % (+ve/total) from time of such surgery in m was: 0 - 3 (54.6/43.8); 3-6 (21.3/30); 6-12 (24/33.2). Of the pts with ctDNA+ after surgery, 49 pts (32%) were ctDNA+ prior to or during adjuvant therapy and 86 (57%) during surveillance. Of the 86 pts who were ctDNA+ during surveillance, imaging revealed concomitant new metastases in 46 (53%); i.e. only 40 (47%) were true MRD+. A total of 191 imaging studies were done (range 1-4) within 90d of the initial ctDNA+ including 99 as routine surveillance concurrent with ctDNA testing and 92 as additional follow up based on results. Of 40 pts with true MRD, majority (27 pts, 67.5%) were enrolled onto ongoing MRD trials ( https://crcmrd.com/ ). Conclusions: Our experience provides support for the feasibility of incorporation of MRD testing as part of routine surveillance. ctDNA+ results trigger a high rate of reflex imaging and, as a result, 53% of ctDNA+ patients have concomitant new radiographic findings. While clinical trials are feasible in true MRD+ pts, eligibility criteria for these trials need to be carefully specified about adequate radiographic evaluation.
Pathological analysis of tumor microenvironmental features using deep learning to predict survival of colon carcinomas.
Authors: Sinicrope Frank A. , Nelson Garth D. , Saberzadeh Ardestani Bahar , Yan Dongyao , Shanmugam Kandavel , Alberts Steven R , Shi Qian , Pai Rish , Segovia Diana I 
Published: June 2023

3527 Background: Advances in deep learning may improve the ability to evaluate and quantify pathological features in solid tumors to improve prediction of patient disease-free survival (DFS). We used an artificial intelligence (AI) algorithm to quantify morphological features in the tumor microenvironment of stage III colon cancers. Methods: We analyzed digitized stage III colon carcinomas (N = 402; 382 met QC) from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy that included all available tumors with dMMR and a randomly selected cohort of pMMR tumors (median follow-up 60 months) [NCCTG N0147; Alliance for Clinical Trials in Oncology]. Fifteen morphological features were extracted using the QuantCRC algorithm that segments images into carcinoma (low-grade, high-grade, signet ring cell), stroma (immature, mature, and inflammatory), mucin, tumor/stroma ratio, tumor budding/poorly differentiated clusters (TB/PDC), necrosis, smooth muscle, fat, and tumor-infiltrating lymphocytes (TILs) and tumor area (mucin, epithelium and TB/PDC). Analysis of AI-derived features with clinical variables, molecular alterations ( BRAF/KRAS), and DFS were examined using Kaplan-Meier methodology and multivariable Cox regression. Results: Among the 15 AI-derived morphological features, the following differed significantly between dMMR (n = 191) and pMMR (n = 189) whereby dMMR tumors had lower mature stroma, but higher inflammatory stroma and tumor, higher tumor grade and increased mucin, TB/PDCs, signet ring cells, and TILs (all p< 0.05). Among dMMR tumors, multivariable analysis revealed that tumor area [mucin, epithelium and TB/PDC] (HR adj 0.45, 95%CI (0.24, 0.84), p:0.01, [Q2/3 vs Q1]) and N stage were the only significant and independent prognostic variables. Among pMMR tumors, multivariable analysis identified that tumor budding/poorly differentiated clusters (TB/PDCs) (HR adj 0.20, 95%CI (0.06, 0.61), p:0.01, [Q1 vs Q4]) was the strongest prognostic variable and the only morphological feature that was significantly associated with DFS along with age, N stage and T stage. Conclusions: Using AI, we can extract and quantify distinct morphological features in tumor sections that differ between dMMR and pMMR and multivariately, can significantly and robustly enhance prognostication within each MMR group. Among pMMR tumors, tumor budding/poorly differentiated clusters was the strongest predictor of DFS. Support: NIH U10CA180821, U10CA180882, U24CA196171, R01 CA210509 (to FAS). Study NCCTG N0147 received funds from Sanofi https://acknowledgments.alliancefound.org . ClinicalTrials.gov Identifier: NCT00079274 Key words Artificial Intelligence; Tumor Microenvironment; Colonic Neoplasms; Disease-free survival.
HER2 testing in the MOUNTAINEER trial: Analysis of treatment response based on central HER2 assessment using IHC/ISH and NGS.
Authors: Strickler John H , Cercek Andrea , Ng Kimmie , Siena Salvatore , Andre Thierry , Van Cutsem Eric , Wu Christina , Paulson Andrew Scott , Hubbard Joleen M. , Coveler Andrew L. , Fountzilas Christos , Kardosh Adel , Kasi Pashtoon Murtaza , Lenz Heinz-Josef , Ciombor Kristen Keon , Elez Elena , Stecher Michael , Cronin Pauline , Bieda Mark , Bekaii-Saab Tanios S. 
Published: June 2023

3528 Background: Tucatinib (TUC) is a highly selective HER2-directed TKI approved by the FDA in combination w/trastuzumab (Tras) for treatment (tx) of pts w/ RAS wild-type HER2+ unresectable or metastatic colorectal cancer (mCRC) that has progressed following tx w/ fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. There are currently no established best practices for HER2 testing/interpretation in mCRC. Here we present results of central HER2 testing across multiple platforms and response to tx for MOUNTAINEER pts treated w/ TUC + Tras based on central HER2 status. Methods: MOUNTAINEER (NCT03043313) enrolled pts w/ local HER2+ mCRC using ≥1 method: IHC, ISH, and/or NGS testing; retrospective central assessment of HER2 status was performed on multiple platforms. Pts in cohorts A+B were treated w/ TUC + Tras; pts in cohort C were treated w/ TUC monotherapy. Confirmed objective response rates (cORRs) using RECIST v1.1 per BICR, DOR, and PFS were calculated for pts treated w/ TUC + Tras based on each central testing method. Results: 114 pts were enrolled in cohorts A (n = 45), B (n = 39), and C (n = 30) w/ HER2+ tumors per ≥1 local testing method. Of samples submitted for central testing for Cohorts A and B, 70 per IHC/FISH, 50 per tissue NGS, and 71 per blood NGS had evaluable results. In all cohorts, there was 81.0% (95% CI, 68.6-90.1) agreement between blood and tissue NGS, 92.6% (95% CI, 83.7-97.6) between IHC/FISH and tissue NGS, and 79.5% (95% CI, 69.2-87.6) between IHC/FISH and blood NGS. In cohorts A and B, pts w/ HER2+ tumors by central IHC/ISH had a mDOR of 16.4 months (95% CI: 10.6-25.5) and mPFS of 10.1 months (95% CI: 4.2-15.2). cORR was 41.1% to 47.7% for the 3 assays. Detailed HER2 results are presented in the Table. Conclusions: Percent agreement of HER2 status was highest w/ tissue-based platforms. Detection of HER2 amplification by ctNDA NGS is useful; however, pts w/o HER2 amplification should be confirmed w/ a tissue-based assay. HER2 status by all 3 platforms predicted tx response to TUC + Tras. cORR in IHC2+/ISH+ was numerically lower but remained clinically relevant. These data support use of the above methods to identify HER2+ mCRC patients that may benefit from TUC + Tras. Clinical trial information: NCT03043313 . [Table: see text]
Chemotherapeutic sensitivity in colorectal cancer expressing low RNA of wild type homologous recombination genes.
Authors: Walden Daniel , Deshmukh Sachin , Batalini Felipe , Zheng-Lin Binbin , Wu Sharon , Xiu Joanne , Caughey Bennett Adam , Strickler John H , Korn Wolfgang Michael , Lou Emil , Ahn Daniel H. , Wu Christina , Goel Sanjay , Shields Anthony F. , Bekaii-Saab Tanios S. 
Published: June 2023

3531 Background: Homologous recombination deficient (HRD) colorectal cancer (CRC) has improved overall survival (OS) when exposed to DNA damaging agents (DDA) oxaliplatin (OX) and irinotecan (IR). However, this OS benefit is only observed in HRD mutated CRC. Low expression of wild type (WT) BRCA1 RNA displays prolonged OS in ovarian cancer; this finding has not been investigated in CRC or outside BRCA. We investigate if low expression of WT HR genes is associated with prolonged OS in response to DDA. Methods: A total of 12,860 CRC patients tumor biopsies were analyzed by next-generation sequencing (592, NextSeq; WES, WTS NovaSeq). Patients with HRD mutations and MSI-H were excluded (N = 935). 11,925 patients were included in the analysis. A total of 11 core ( BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11, NBN, PALB2, RAD50, RAD51, RAD51B) and 7 related ( BAP1, WRN, DNMT3A, ERCC1, FANCA, FANCF, RECQL4) HR genes were analyzed. Samples were classified by RNA expression percentiles within the studied cohort. Real world OS was extracted from insurance claims and calculated using Kaplan-Meier estimates for molecularly defined cohorts from first of OX or IR to last contact. Results: OS benefit is seen in low RNA expression (bottom 10%) compared to high expression (top 10%) of all core WT HR genes except RAD51B, BARD1 and BRCA2 in response to IR. We observe a progressively longer OS with lower associated RNA expression in response to DDA. OS of nearly 7 years was observed in low expressing BRCA1 and RAD51 following IR exposure and 4.5-year OS benefit when compared to high expression of these genes. OS benefit in response to OX was less robust but significantly prolonged in BRCA1 and BRIP1 (Table). Patients harboring HRD mutations had similar OS to WT HR RNA low (bottom 10%) in response to OX (HR = 0.75; p = 0.1) and IR (HR = 0.82; p = 0.36). Conclusions: Here we report a novel subclass of CRC defined as patients with low RNA expressing WT HR genes that exhibit differential sensitivity to DDA. Significantly longer survival is noted in CRC with low expression BRCA1, RAD51 and BLM, while post-OX survival was significantly prolonged with low expression of BRCA1, BRIP1 and FANCA. Further characterization of sensitive HR genes will better predict DDA sensitivity and impact treatment sequencing. [Table: see text]
Circulating tumor DNA in plasma as an early predictor for pathological lymph node involvement and (neo-)adjuvant chemotherapy in patients with colon cancer.
Authors: Raunkilde Louise , Andersen Rikke Fredslund , Hansen Torben , Jensen Lars Henrik 
Published: June 2023

3532 Background: Postoperative chemotherapy is standard for colon cancer patients with pathological lymph node involvement (pN+). If the presence of pN+ could be accurately predicted prior to surgery, the initiation of neoadjuvant chemotherapy could potentially reduce the presence of micrometastasis and enhance survival. The objective of this study was to assess the utility of preoperative methylated circulating tumor DNA (meth-ctDNA) as a predictive marker for pN+ and its clinical value as a marker for the initiation of neoadjuvant chemotherapy. Methods: The clinical data of 203 colon cancer patients (stage I-III) was collected from the Colorectal Cancer Database established at Danish Colorectal Cancer Center South, Vejle Hospital, Denmark. Patients were randomized into a discovery and a validation cohort. Plasma collected preoperatively was analyzed for three different meth-ctDNAs (Neuropeptide Y, Galactose-3-O-Sulfotransferase 3, and KN Motif and Ankyrin Repeat Domains 1) by droplet digital PCR (ddPCR). Results: Based on analysis of the discovery cohort, samples were considered positive if two or more of the three methylation markers had at least three positive droplets in the ddPCR analysis. 40% of patients in the discovery cohort and 46% of patients in the validation cohort were considered positive. When using meth-ctDNA as a diagnostic tool to predict pN+, the sensitivity and specificity in the discovery cohort were 42% and 61% respectively. In the validation cohort the values were 54% and 59%, respectively. AUC was < 60% in both cohorts. Meth-ctDNA was associated to clinical tumor (T)- and node (N)-category in both cohorts (p≤0.01). Four-year disease free survival (DFS) in patients with and without detectable meth-ctDNA was 60% and 90% in the discovery cohort (p = 0.01), and 62% and 78% in the validation cohort (p = 0.04). Meth-ctDNA remained the strongest prognostic factor of DFS in the multivariate analysis compared to clinical T- or N-category, gender and age (p = 0.065, HR 2.46, 95% CI 1.03-5.88), however not statistically significant. Four-year overall survival (OS) in patients with and without detectable meth-ctDNA was 75% and 95% in the discovery cohort (p = 0.006), and 78% and 91% in the validation cohort (p = 0.02). In the multivariate analysis, meth-ctDNA was the strongest prognostic factor of OS compared to clinical T- or N-category, gender and age (p = 0.016, HR 4.54, 95% CI 1.32-15.6). Conclusions: The preoperative measurement of meth-ctDNA was not found to be a clinically significant predictor of pN+ or a reliable indicator for the initiation of neoadjuvant chemotherapy. Nonetheless, the results showed that preoperative ctDNA is a powerful prognostic indicator, suggesting that randomized controlled trials should be conducted to determine the efficacy of neoadjuvant chemotherapy in colon cancer patients with preoperative detectable ctDNA.