bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival of patients with colorectal cancer (CRC) with low expression of homologous recombination proficient (HRP) genes.
Authors: Walden Daniel , Deshmukh Sachin , Batalini Felipe , Zheng-Lin Binbin , Wu Sharon , Xiu Joanne , Lou Emil , Ahn Daniel H. , Wu Christina , Goel Sanjay , Shields Anthony Frank , Spetzler David , Oberley Matthew James , Korn Wolfgang Michael , Bekaii-Saab Tanios S. 
Published: January 2023

225 Background: HR deficient (HRD) CRC has improved outcomes following exposure to DNA damaging agent (DDA) (irinotecan, IR; oxaliplatin, OX) compared to HRP CRC. Low expression of wild type (WT) BRCA1 mRNA is associated with prolonged OS in ovarian cancer; however, this finding has not been investigated in CRC or outside of BRCA. Here, we examine the effect of low expression of HR genes in HRP CRC on post-DDA survival. Methods: 12,860 CRC samples were analyzed by NGS (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq) at Caris Life Sciences (Phoenix, AZ). Samples were classified by RNA expression percentiles. 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: Post-IR survival was prolonged with low expression of ATM, CHEK2 and PALB2 in WT ATM, PALB2, and CHEK2 WT CRC, respectively (bottom vs. top 10%, bottom vs. top 25%; p<0.05). Notably, low PALB2 expression (bottom 10%) showed a 14.5-month post-IR benefit compared to high PALB2 expression (top 10%) in WT PALB2 CRC (p=0.003). Post-OX survival was not significantly prolonged with low expression of CHEK2 in WT CHEK2 CRC (bottom 10% vs top 10%, bottom 25% vs top 25%) but was with low expression of ATM (+9.7 months, p=0.02) and PALB2 (+5.6 months, p=0.03) in WT ATM and PALB2 CRC, respectively (all bottom 25% vs top 25%). Conclusions: Here we report the first findings to suggest a novel subclass of CRC defined as the low expression of mRNA of non-mutated HRD genes that exhibit sensitivity to DDA. Low expression of WT ATM, CHEK2, and PALB2 correlates with prolonged OS following IR, post-OX survival was prolonged with low expression of ATM and PALB2. Further characterization defining sensitivity of low expressing HRP genes to DDA may help guide treatment considerations in HRP CRC. [Table: see text]
Comprehensive characterization of KRAS mutations and inter-relation with primary tumor location in colorectal cancers.
Authors: Salem Mohamed E. , Kopetz Scott , Tabernero Josep , Sinicrope Frank A. , Chalabi Myriam , Tie Jeanne , Kadakia Kunal C. , George Thomas J. , Mauer Elizabeth , Macera Lisa , Chao Calvin Y. , Lonardi Sara , Van Cutsem Eric , Andre Thierry , Overman Michael J. 
Published: January 2023

231 Background: The recent development of KRAS G12C inhibitors underscores the potential to target KRAS mutations. Right-sided and left-sided colon tumors (RT and LT) exhibit different molecular features. We characterize the prevalence of KRAS-variants, interrelation with primary tumor location, and association with immune biomarkers in CRC. Methods: We retrospectively reviewed CRC tumors of all stages (with known sidedness) that underwent NGS with the Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). Bivariate analyses were performed to compare KRAS alterations, immune biomarkers, and co-mutations by tumor location. P-values comparing individual co-mutations between groups were adjusted for false discovery (FDR). Results: A total of 3,391 CRC were analyzed (RT: n = 442 [13%], transverse: n = 116 [3%], LT; n = 2,833 [84%]) of which 1486 (44%) tumors harbored KRAS mutations. Overall, KRAS mutations were more frequent in RT compared to transverse tumors and LT (52% vs 41% vs 43%, p<0.001, respectively). The most frequent KRAS mutation variants observed were G12D (29 %), G12V (22%), G13D (16%), and G12C (5.7%). There was no significant difference in the prevalence of KRAS variant types between LT and RT (p=0.5). Significant differences in genomic co-mutations with various KRAS variants were observed in the following genes: TP53, FBXW7, and NF1 (FDR- P<0.05). RT and transverse tumors were more likely have MSI-H and TMB-H (>10 mut/mb) status than LT (MSI-H: 18% vs 22% vs 2.2% and TMB-H (20% vs 22% vs 3%, P<0.001), respectively. CRC tumors harboring G13D variants were more likely to be associated with and MSI-H and TMB-H status (and 7.7% and 8.5%) compared to G12D (2.8 % and 3.9 %), G12V (1.8 % and 2.1%), and G12C (0% and 2.4%); P = 0.003 and 0.001. Conclusions: The most frequent KRAS mutation variants observed in CRC tumors were G12D, G12V, G13D, and G12C. There was no significant difference in the prevalence of KRAS variant types between tumors of the left vs right colon. CRC tumors that harbored G13D variants were significantly more likely to be associated with MSI-H and TMB-H status. [Table: see text]
Rectal cancer–specific subtyping using transcriptomics datasets derived from treatment-naive patients to assess novel prognostic signatures and key differences to CMS-based subtyping.
Authors: Prehn Jochen , Kisakol Batuhan , Matveeva Anna 
Published: January 2023

235 Background: Molecular subtyping in colorectal cancer provided novel insights into tumour heterogeneity and delivered new prognostic signatures. Existing methods (such as CMS-based subtyping) were generated without much consideration of differences in expression profiles between colon and rectal cancer tissues. Moreover, stage 2 and 3 rectal cancer patients often receive neo-adjuvant radio-chemotherapy which may impact on gene expression when determined from resection samples. Methods: We investigated possible differences between treatment-naive colon and rectal cancers at the molecular level. We collected mRNA expression profiles for rectal and colon cancer samples available from Gene Expression Omnibus (GEO) database (n=2139) and applied batch-effect correction using ComBat. Results: To explore whether CMS subtypes changed after neoadjuvant chemoradiation in rectal cancers, we analysed rectal tumour samples from 40 patients where both pre-operative biopsies and resections after chemoradiotherapy were available. More than half of samples shifted from CMS1-3 to CMS4 after patients received chemoradiotherapy. We therefore focused our further analysis on treatment-naive rectal cancers. We observed that CMS-based subtyping showed different prognostic potential in treatment-naïve colon vs. rectal cancers. Rectal cancers had significantly better disease-free survival (DFS) when assigned to CMS 2 or 4 compared to colon cancers. This suggested differences in disease biology that were not captured by CMS subtyping. We next aimed to identify molecular subtypes in rectal cancers, and identified three prevalent rectal-specific subtypes (RSS) by applying hierarchical clustering in 182 untreated rectal cancer samples. We used gene co-expression network analysis to define functional gene modules to identify these subtypes. Based on the gene modules’ signatures, we built a classifier to predict our new subtypes in different transcriptomics datasets (n=692). We observed that RSS1 had better disease-free survival (DFS), whereas RSS2 exhibited worse short-term DFS (less than 3 years) and RSS3 showed worse long-term DFS (3+ years). We discovered the deactivation of EGFR, MAPK and WNT pathways on RSS3 as well as high CD8+ infiltration and low CD4+ counts in these tumours. RSS2 exhibits low plasma cell and regulatory T-cell abundance and high activations of TGF-β, NF-κB, and TNF-α. We also observed high EMT, angiogenesis and inflammatory response in this subtype. Lastly, RSS1 showed high expression on MYC target and low activity on angiogenesis genes. Moreover, the immune and inflammatory responses were also lower than in the other subtypes. Conclusions: Rectal-specific subtypes are of prognostic importance and provide new insight into molecular disease pathways and potential targets.
Pathological features associated with lymph node disease in patients with appendiceal neuroendocrine tumors.
Authors: Rodriguez Franco Salvador , Thomas Madeline , Khomiak Andrii , Roque Assumpcao Lia , Sugawara Toshitaka , Stewart Camille , Schulick Richard D. , Del Chiaro Marco , Ahrendt Steven , Gleisner Ana 
Published: January 2023

238 Background: Appendiceal neuroendocrine tumors (ANETs) are well known for their benign and slow progression; nonetheless, the presence of lymph node metastasis has been described in up to 50% of all cases. The risk of metastasis is mainly associated with tumor size, and the role of other pathological features remains unclear. Hence, this study was designed to assess the pathologic features of ANETs associated with an increased risk of lymph node metastasis. Methods: Patients ≥18yrs of age with ANETs were identified in the National Cancer Database (NCDB) from 2004 to 2017. Groups were defined based on lymph node status as N(-) (all examined nodes were negative) and N(+) (one or more examined nodes were positive). Multivariable models using demographics and oncological features were used to identify factors independently associated with nodal metastasis (N+). Marginal effects, specifically for tumors <2 cm were also calculated. Results: A total of 2,465 cases were identified and included for data analysis. Among these, 23% had lymph node metastases, including 33 of 979 tumors <1 cm (3.4%), and 145 of 696 tumors ≥1 cm but ≤2 cm (20.8%). Tumor size, depth of tumor invasion, and presence of lymphovascular invasion (LVI) were identified as independent predictors of lymph node metastasis (p <0.001). When evaluating marginal effects, both the depth of tumor invasion and the presence of LVI were associated with increased risk of node metastasis in small tumors (<2 cm), comparable to the mere risk of node metastasis in big tumors (≥2cm). In addition, for small ANETs (<2cm), the true positive rates (TPR) of node metastasis vary according to the number of assessed lymph nodes, differing significantly between patients with at least 12 evaluated lymph nodes vs. those with less than 12 (TPR 4.7% vs. 1.6% for <1 cm [p =0.02], and 40.1% vs. 25.7% in ≤2 cm ANETs, [p <0.001]). Conclusions: In ANETs, the presence of high-risk pathological features, including LVI and tumor depth, increases the risk of node metastasis in addition to tumor size, and should be considered when selecting the optimum management and follow-up in these patients. [Table: see text]
Delta radiomic parameters for the evaluation of liver metastases in patients with colorectal cancer treated with cetuximab rechallenge plus avelumab in the CAVE mCRC study.
Authors: Martini Giulia , Nardone Valerio , Ciardiello Davide , De Chiara Marco , Troiani Teresa , D'ambrosio Luca , Napolitano Stefania , Cardone Claudia , Cremolini Chiara , Pietrantonio Filippo , Maiello Evaristo , Avallone Antonio , Cappabianca Salvatore , Ciardiello Fortunato , Reginelli Alfonso , Martinelli Erika 
Published: January 2023

241 Background: We performed a retrospective analysis of metastatic colorectal cancer (mCRC) patients enrolled in CAVE trial. Cave mCRC is a single arm, academic, multicenter, phase II trial that evaluated the efficacy of cetuximab rechallenge plus avelumab in mCRC patients. Methods: CT imaging of patients were collected and retrospectively analysed. Inclusion criteria included evidence of liver metastases that could be measured and segmented, availability of an enhanced contrast phase at baseline and restaging CT imaging (within 3 months from baseline). The gross tumor volume (GTV) of liver metastases was evaluated at both baseline and first restaging CT. Multiple texture parameters were extracted with LifeX Software, and delta-texture analysis (D-TA) was calculated as percentage variations in the two time points. Patients were divided in a training cohort (coordinating center, University of Campania “L. Vanvitelli”) and validation cohort (other centers involved in CAVE mCRC trial). Patients were further divided in responders/non-responders according to median progression free survival (mPFS). ROC curve were calculated to obtain a cut-off. Survival analysis of progression free survival (PFS) and overall survival (OS) with Kaplan-Meier method was used in the two subgroups to test the cut-off found with the methods previously described. Results: The original dataset of CAVE mCRC protocol included 77 patients. Liver metastasis were present in 55 patients (71%); after application of inclusion and exclusion criteria, a total of 42 patients were included in the current analysis. The training cohort consisted of 22 patients (for a total of 32 liver metastasis) and the validation cohort of 20 patients (for a total of 28 liver metastasis). After Bonferroni correction, the only D-TA parameters that significantly correlated with mPFS in the training cohort were EntropyHistogram (p:0,021), HomogeneityGLCM (p<0,001) and Dissimilarity GLCM (p:0,002). At multivariate analysis only HomogeneityGLCM resulted significant both in training (p:0,001, OR 0,1) and validation cohort (p:0,021, OR 0,3). ROC curves were generated and the cut-off of HomogeneityGLCM was equal to 0. Patients who developed a reduction of HomogeneityGLCM at first restaging CT scan showed a better PFS and OS (in both training and validation cohorts). Conclusions: Our results suggest that D-TA parameter such as HomogeneityGLCM is able to discriminate better survival outcomes in patient treated with cetuximab rechallenge plus avelumab, further prospective investigations are needed. [Table: see text]
Pretreatment risk prediction for distant metastasis in locally advanced rectal cancer.
Authors: Song Changhoon , Kang Byung-Hee , Kim Jae-Sung 
Published: January 2023

248 Background: Distant metastasis is the most common form of recurrence in locally advanced rectal cancer. This study aimed to identify pretreatment risk factors for distant metastases in patients with locally advanced rectal cancer. Methods: This single-institution retrospective study included 285 patients who underwent preoperative chemoradiotherapy followed by surgical resection between January 2016 and December 2020. Pretreatment clinical characteristics, MRI findings, and blood profiles were analyzed to investigate its association with distant metastasis. Results: With a median follow-up of 39 months (range: 6 - 78), 42 patients had confirmed distant metastasis (14.7%), and most distant metastasis occurred within three years (40 patients, 95.2%). In the multivariate analysis, pretreatment extramural venous invasion (EMVI, HR = 3.05, p < 0.001) and carcinoembryonic antigen (CEA) > 10 ng/mL (HR = 2.77, p = 0.002) were independent predictors of distant metastasis. Patients with no adverse factors had significantly better distant metastasis-free survival than patients with 1 or 2 adverse features (92% vs. 70% vs. 59% (p < 0.001) at 3 years). Conclusions: Pretreatment CEA and EMVI have predictive significance for distant metastasis in locally advanced rectal cancer. Our findings may help select patients who may benefit from intensified preoperative treatment, such as total neoadjuvant therapy.
A plasma-based analysis and genomic landscape of patients with high tumor mutational burden (TMB-H), microsatellite stable (MSS) colorectal cancer (CRC).
Authors: Saeed Anwaar , Barnett Reagan , Lou Emil , Madeira da Silva Luciana , Cho May Thet , Lieu Christopher Hanyoung , Fakih Marwan , Kopetz Scott , Loree Jonathan M. , Gholami Sepideh 
Published: January 2023

249 Background: An estimated 85% of CRC are microsatellite stable (MSS) and this population has limited response to immune checkpoint inhibitors (ICIs). Biomarkers are needed to identify responders. Although pembrolizumab received FDA universal approval for chemorefractory cancers with tissue TMB-H > 10 mut/Mb, it is not effective across all TMB-H cancers. We aim to identify TMB-H/MSS CRC patients that derive benefit from ICIs through analysis of circulating tumor DNA (ctDNA). Methods: We retrospectively queried Guardant Health database (2020-2022) for patients with advanced CRC who had ctDNA NGS (Guardant360, Redwood City, CA) as part of routine clinical care. The assay covers a 1Mb panel for TMB that counts synonymous and non-synonymous somatic SNVs and indels to calculate a TMB score. Co-mutations were evaluated for MSS cancers with plasma TMB-H; ≥20mut/Mb vs those with low TMB (TMB-L; < 20mut/Mb). RAS- mutated signature was defined as those harboring an activating somatic alteration in KRAS, NRAS, or BRAF. Statistical significance was calculated using Fisher’s exact test. Results: We identified 6412 CRC patients: 11% (711) TMB-H/MSS (median age 64), 69% (4426) TMB-L/MSS (median age 62), 3% MSI-H, and 17% unevaluable. When compared to TMB-L/MSS, patients with TMB-H/MSS had a significantly higher frequency of select genetic mutations, including TP53, APC, KRAS, EGFR, and PIK3CA (p < 0.001). Treatment-naïve TMB-H/MSS cancers had a higher frequency of ARID1A (p = 0.05) and TERT (p = 0.02) alterations, while those post therapy progression had higher frequency of KRAS (p = 0.02), EGFR (p < 0.001), and MAP2K1 (p = 0.002) alterations. A total of 556 (78%) CRC patients in the TMB-H/MSS cohort harbored a RAS-mutated genetic signature. Of those, 432 (78%) belonged to the post therapy progression group, likely representing adaptive clones post anti-EGFR therapy. While RAS-mutated tumors had a higher prevalence of PIK3CA (p = 0.001) and SMAD4 (p = 0.007) co-alterations, RAS-wildtype ones carried a higher frequency of ERBB2 (p = 0.068) alterations. Conclusions: We describe the genomic landscape of patients with plasma TMB-H/MSS CRC. A clinical cohort of TMB-H/MSS CRC patients identified by ctDNA and treated with ICIs will be presented.
Effect of spatial transcriptomic-derived intrinsic epithelial signatures on immune cell recruitment and behaviour in the microenvironment of colorectal cancer.
Authors: Wood Colin , Hatthakarnkul Phimmada , Leslie Holly , Legrini Assya , Cameron Andrew , Pennel Kathryn AF , Sansom Owen J , Edwards Joanne , Jamieson Nigel Balfour , Steele Colin William 
Published: January 2023

251 Background: Colorectal Cancer (CRC) remains a significant healthcare problem. Interest in the role of the Tumour Microenvironment (TME) in progression and metastasis is established, yet much remains to be learned about the mechanism of immune cell recruitment to the TME of primary and metastatic tumours. The Klintrup Makinen (KM) score measures the density of immune infiltrate to the invasive edge of tumours and is associated with good prognosis in primary CRC. Neutrophil infiltration to metastases is a poor prognostic feature suggesting phenotypic differences in the TME at primary and metastatic sites. We set out to examine epithelial determination of the TME in primary CRC. Methods: 180 patient’s primary CRC from a curated TMA underwent deep phenotyping using a multiplex-immunofluorescent panel (DAPI, Panck, CD3 (T cells), FOXP3 (T regulatory cells), CD68 (Macrophages), CD163 (Tumour associated macrophage), CD66b (Neutrophils), KI67). The Nanostring GeoMx Spatial Transcriptomic platform was used to obtain segmented (Tumour: Panck+; TME: Panck-) whole transcriptomic (18000 genes) readout from 54 matched cores from the same TMA. Results: No significant association was demonstrated between immune cell density of any cell types and clinicopathological variables including tumour side, MMR status, N-stage or survival. High KM grade was associated with high CD3 (P = 0.01) and FOXP3 (P = 0.002). Density of all immune cell types were highly corelated. Spatial transcriptomic analysis of the segmented epithelium of patients with high KM grade demonstrated over-expression of known neutrophil chemo-attractant CXCL5 (log2FC 3.76 Adj.P < 0.005). The TME compartments of cores with high CD68 and low CD163 counts were associated with adaptive immune co-ordination with high expression of CXCL13 (log2FC -2.97, Adj.P < 0.005) and CD74 (log2FC -1.42 Adj.P 0.007). IGF2 (log2FC 6.08 Adj.P < 0.005) and LCN15 (log2FC 4.96 Adj.P < 0.005) were globally over-expressed in both TME and epithelium of cores with generalised low immune infiltration. The epithelial compartment neutrophil dense cores also over-expressed IGF2 (log2FC -3.53 Adj.P 0.02). Conclusions: TMAs provide a unique opportunity for broad transcriptomic phenotyping of large numbers of patients simultaneously. The Nanostring GeoMx platform is a flexible tool which can be used in novel ways with other proteomic technologies to drive deeper analysis of the TME. CXCL5 expression in the epithelial compartment drives global immune infiltration to the TME and may be manipulated in different contexts therapeutically through CXCR2 signalling in future.
AI-powered multi-omic signature to predict treatment response of patients with colorectal cancer liver metastasis.
Authors: Kapelanski-Lamoureux Audrey , Tsamchoe Migmar , Krzywon Lucyna , Bloom Jessica , Cardin Julie , K Petrillo Stephanie , Gao Zu-hua , Jenna Sarah , Lazaris Anthoula , Metrakos Peter 
Published: January 2023

252 Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in North America with over 50% of CRC patients developing liver metastases (LM) and 90% will die from metastatic disease. CRCLM are categorized into two main histological growth patterns (HGP) lesions: Desmoplastic (DHGP) and Replacement (RHGP). We have previously published that HGPs display distinct patterns of vascularization, local invasion, growth and response to treatment. Resected CRCLM patients with predominantly DHGP metastasis (~45%) receiving anti-VEGF therapy and chemotherapy have more than double the 5-year overall survival compared to patients with RHGP (~55%) who have received the same treatment. We are therefore treating patients that will not respond and should in fact be managed differently. Currently, there are no available biomarkers or stratification tools that predict colorectal cancer liver metastasis response to therapy. Methods: In collaboration with My Intelligent Machines (MIMs’), we used a proprietary GI2 (Genetic Interaction Graph Inference) algorithm inferring genetic interactions. We developed an AI based pipeline to develop a multi-modality signature, based on blood test analysis, to identify CRCLM patients who will 1) respond to Angiogenic Inhibitor-based therapies and 2) monitor the development of drug resistance (non-responders). Results: We obtained transcriptomic (tumor tissue) as well as proteomic data (liquid biopsy: Extracellular vesicle cargo), linked to clinical data from 40 chemonaïve patients, and fed the data into MIMs platform (BioMark). The software was able to identify differentially expressed genes common to the top differentially enriched proteins leading to a robust liquid biopsy biomarker signature distinguishing DHGP and RHGP. Furthermore, our data demonstrates a unique multi-modality signature providing biological insight for therapeutic failures and/or success. Conclusions: We will use these signatures to not only predict response to treatment but also decipher the molecular mechanisms driving these two phenotypes and identify unique targets. It is expected that this knowledge will lead to optimization of current treatment strategies, allowing for a precision therapy approach to the management of metastatic disease and cost saving for the health care system.