bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating tumor DNA (ctDNA) dynamics and clinical outcome in metastatic colorectal cancer (mCRC) patients (pts) undergoing front-line chemotherapy.
Authors: Ghidini Michele , Hahne Jens Claus , Senti Chiara , Tomasello Gianluca , Ratti Margherita , Heide Timon , Garrone Ornella , Cortellini Alessio , Passalacqua Rodolfo , Valeri Nicola 
Published: January 2023

175 Background: The potential of monitoring circulating tumor DNA (ctDNA) dynamics to guide clinical decisions in metastatic colorectal cancer (mCRC) patients (pts) treated with I and II line systemic anti-cancer therapy (SACT) has not been widely tested. Methods: 862 serial plasmas were collected 4-weekly from baseline (BL) until disease progression in 75 mCRC pts undergoing SACT. ctDNA was tested using a custom (RMH GI; 20 genes) or a commercial (Roche Avenio; 77 genes) ctDNA next generation sequencing (NGS) panel. White blood cells were sequenced to rule out clonal hematopoiesis. Whole exome sequencing (WES) was performed on tissue biopsies. ctDNA normalization was defined as ≥99% clearance after 1 month of therapy (Mo1) in the 3 variants with the highest allele frequency in BL ctDNA. Results: 83 paired samples from 75 pts were available for analysis (for 8 pts, I and II line bloods were available). 12 pairs (14.4%) showed no variants in either BL or Mo1. In the remaining 71 comparisons (65 pts), 37 (52.1%) showed ctDNA normalization at Mo1. Among normalized pts there was a higher proportion of cases with a baseline ECOG performance status (PS) 0-1 (97.3% vs 82.4%, p = 0.0362) in comparison to non-normalized pts, whilst no other clinic-pathologic characteristics, including age, sex, prior primary tumor resection, sidedness, RAS/RAF genotype, type of regimen and number of metastatic sites were significantly associated with ctDNA dynamics. Pts with normalized ctDNA had significantly longer overall survival (OS), 45.6 months (95% confidence interval [CI]: 30.0 - not reached, 14 events) and progression-free survival (PFS), 13.9 months (95%CI: 11.2-18.3; 30 events) compared to non-normalized pts [OS = 22.6 months (95%CI: 16.6-31.2, 24 events) (Log-rank p = 0.01) and PFS = 10.7 months (95%CI: 7.53-13.8; 32 events) (Log-rank p = 0.036) respectively]. In addition, pts with normalized ctDNA had higher overall response rate (ORR) of 72.9% (27/37 responses; 95%CI: 53.0-84.1) compared to 38.2% (13/34 responses; 95%CI: 22.1 – 56.4) in non-normalized pts. In a multivariate model, ctDNA normalization was confirmed as an independent predictor of decreased risk of death (hazard ratio [HR] 0.47, 95%CI: 0.23-0.96; p = 0.04) and higher probability of achieving an objective response from front-line treatment (odds ratio [OR] 3.03, 95%CI: 1.08-8.49; p = 0.0351). Only 23/50 (46%) of variants detected in ctDNA were detected by WES in paired tissues in 12 pts for whom liquid/solid biopsy was available. Conclusions: ctDNA monitoring represents an early indicator of benefit from systemic therapy in mCRC pts. A significant fraction of variants detected in ctDNA was not detected in paired tissues.
ctDNA-based fusion detection for advanced colorectal cancer with a partner-agnostic assay.
Authors: Barnett Reagan , Gnerre Sante , Willis Jason , Overman Michael J. , Raghav Kanwal Pratap Singh , Parseghian Christine Megerdichian , Dasari Arvind , Morelli Maria Pia , Johnson Benny , Eluri Madhulika , Drusbosky Leylah , Kopetz Scott , Morris Van K. 
Published: January 2023

186 Background: Actionable mutations can predict therapeutic benefit in patients with advanced malignancies, though clinical relevance of fusion testing for advanced colorectal cancer (aCRC) remains undefined. Identification of fusions from circulating tumor DNA (ctDNA) has previously been restricted to defined oncogenic fusion partners. To improve the sensitivity for fusion detection, we evaluated a partner-agnostic fusion analysis from ctDNA of patients with aCRC. Methods: De-identified data from Guardant Health was reviewed for 18,558 patients with aCRC who underwent ctDNA NGS testing by Guardant360 (Redwood City, CA) between 2017-2022. Fusion results were analyzed with a partner-agnostic bioinformatic approach. A fusion was defined as “clonal” if the variant allele frequency (VAF) ratio exceed ≥50% of highest somatic VAF, and “subclonal” if < 50% maxVAF. Microsatellite instability (MSI) status [MSI-high (bMSI-H) or microsatellite stable (bMSS)] and anti-EGFR exposure signature were determined using prior methods. Associations between fusion occurrence and coexisting alterations were performed using Fisher’s exact test. Results: Fusions were detected in 221 (1.2%) of patients with aCRC. 258 activating fusions were detected in 187 patients; FGFR3 (N = 59, 23%), RET N = 55, 21%), BRAF (N = 43, 17%), and ALK (N = 41, 16%) were most frequent. There were 71 previously unreported fusions in 28 additional patients; RET (N = 16; 23%), MET (N = 15, 21%), and BRAF (N = 11; 15%) were most prevalent. Clonal fusions occurred in 7% (18/258) of all activating fusions; RET (5/18, 28%) and FGFR3 (3/18, 17%) were most common and associated with bMSI-H status relative to bMSS (27% vs 4%, OR 8.165, 95% CI 2.332-33.99; p = 0.0076). Clonal fusions occurred less commonly in samples with a prior EGFR signature (OR 0.22, 95% CI 0.05-0.997, p = 0.049). Most detected fusions were subclonal including ALK, FGFR1-3, MET, RET and ROS1. Conclusions: Highly specific partner-agnostic fusion detection is feasible to increase sensitivity of ctDNA assay performance. Oncogenic fusions occurred in ~1% of all patients with aCRC. Clonal fusions as oncogenic drivers were infrequent and associated with bMSI-H status. Subclonal fusions were more common and occur in a setting consistent with prior exposure to anti-EGFR therapies. Reporting fusion partners and clonality from ctDNA may guide oncologists on the appropriate context for consideration of fusion-directed treatments.
HER2 testing in colorectal cancer: Concordance analysis between breast and gastric scoring algorithms from the MOUNTAINEER trial.
Authors: Cercek Andrea , Ng Kimmie , Strickler John H , 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 , Feng Wentao , Bekaii-Saab Tanios S. 
Published: January 2023

198 Background: HER2 overexpression/amplification (HER2+) occurs in 3%-5% of patients (pts) w/ metastatic colorectal cancer (mCRC). Rates of HER2+ can increase to ~10% in pts w/ RAS/BRAF wild-type mCRC tumors. The MOUNTAINEER trial (NCT03043313) evaluated the efficacy and safety of the investigational combination of tucatinib with trastuzumab in pts with HER2+ and RAS wild-type mCRC. Established regional guidelines for mCRC recommend HER2 testing and HER2-directed treatment options; however, there is currently no established best practice for HER2 testing and interpretation in mCRC. Here, we present data from a concordance analysis comparing breast and gastric HER2 testing algorithms in the mCRC setting. Methods: The MOUNTAINEER trial enrolled pts w/ HER2+ mCRC identified using ≥1 method: tissue-based local immunohistochemistry (IHC), in situ hybridization (ISH), and/or next-generation sequencing (NGS) testing. Archival or fresh tumor tissue was submitted to a sponsor-designated central laboratory for confirmatory HER2 testing w/ IHC/FISH per the package insert of the FDA approved assay and scored by both the breast and gastric algorithms for HER2 IHC. A positive result per the breast scoring criteria for IHC requires circumferential membrane staining for HER2, while the gastric criteria allows for circumferential, basolateral, or lateral staining patterns. Results: A total of 114 pts were enrolled with HER2+ tumors per ≥1 local testing methods; 69 pts were HER2+ by NGS, 46 by IHC 3+, and 36 by ISH. Of 105 pts who had tissue available for central HER2 testing w/IHC/FISH, 98 had valid HER2 results; 82/98 (83.7%) of pts had tumors centrally confirmed as HER2+ using both the breast and gastric algorithms. Tissue samples from pts in the MOUNTAINEER trial had 100% concordance between breast and gastric algorithms in HER2 status and 99% concordance in HER2 IHC score. Conclusions: Central pathology testing using both the breast and gastric criteria showed high concordance between these two commonly used algorithms. A high central confirmation rate of local HER2+ results was also observed. These data support the use of either the breast or gastric algorithms to identify HER2+ mCRC tumors until an FDA-approved HER2 assay is available for mCRC. Clinical trial information: NCT03043313 . [Table: see text]
Comparative analyses of intratumoral microbiome with diet in patients with early- vs late-onset colorectal cancer.
Authors: Green Myra E. , Weinberg Benjamin Adam 
Published: January 2023

208 Background: Early-onset colorectal cancer (CRC) is a growing public health problem with an incidence rate increase of 7.9% in individuals aged 20-29, 4.9% in those aged 30-39, and 1.6% in those aged 40-49 during 2004-2016. The etiology of this rise is not well established, but there is emerging evidence that the intra-tumoral microbiome may be implicated. We sought to categorize the interaction between diet and intra-tumoral microbiome in early- vs. late-onset CRC. Methods: Intra-tumoral microbiome data were collected from patients enrolled in a retrospective/prospective study of early ( < 45 years) vs. late-onset (≥ 65 years) CRC. Formalin-fixed paraffin-embedded tumor samples were microdissected for tumor vs. non-tumor, then DNA was extracted and analyzed using 16S ribosomal gene sequencing. The DHQ3 diet questionnaire was used to ascertain diet history for a period of 12 months prior to diagnosis. Twelve bacteria of interest were selected for analysis based on increased prevalence and known potential association with CRC. Diet groups of interest for analysis included high-risk groups: fried foods, red meat, and alcohol. Results: A subset of 3 bacteria were further analyzed, Bacillus sp., Fusobacterium nucleatum, and Moraxella osloensis, based on relation to the group of patients diagnosed with CRC before the age of 45 (N = 8) and after age 65 (N = 12). Bacteria of interest had a similar prevalence in early- (38%, 3/8) and late-onset patients (33%, 4/12). Fifteen of the 20 patients had one or more of the bacteria of interest present. 71% (5/7) of both early- and late-onset patients who had Bacillus present had no alcohol in their diets. 100% (4/4) of the late onset patients with Bacillus present all had the same diet pattern: no tree nuts, high amounts of potato chips, no alcohol, and no red meat. 83% (5/6) of the early onset patients with 1 or more bacteria present had a high amount of potato chips in their diets. 80% (4/5) patients who had none of the bacteria of interest present also had no red meat in their diet. All early- and late-onset patients with Moraxella had a diet that consisted of more high-risk food groups, in particular potato chips. Conclusions: There were no significant differences in intra-tumoral microbiome in patients with early- vs. late-onset CRC. However, there may be an association between certain bacteria and high-risk diets. Results were limited by a small sample size, and further research should be done to better understand the relationship between intra-tumoral microbiome and diet.
Identification and characterization of four bacteriome- and mycobiome-derived subtypes in tumour and adjacent mucosa tissue of colorectal cancer patients.
Authors: Salvucci Manuela , Poynter Liam , Mirnezami Reza , Carberry Steven , O'Byrne Robert , Alexander James , Lambrechts Diether , Veselkov Kirill , Kinross James M. , Prehn Jochen 
Published: January 2023

214 Background: The bacteriome and mycobiome, collectively referred to as the microbiome, is a key player in CRC pathogenesis, progression and response to chemotherapy, radiotherapy and immunotherapy. Microbial modulation and exacerbation in CRC is likely attributable to alterations of composition and diversity of the microbiome rather than to a single microbial species. We therefore systematically investigated alterations in the bacteriome and mycobiome of CRC patients in tumours and matched adjacent mucosa resulting in the identification of microbiome-based subtypes associated with host clinico-pathological and molecular characteristics. Methods: We estimated bacterial and fungal composition from RNA sequencing experiments using a validated subtractive method ( PathSeq) in in-house and publicly available cohorts. We evaluated the quality of the microbial estimates with two sets of orthogonal analysis determining i) the agreement with composition from an independent method and ii) retrieval of expected clinically-relevant microbial signatures. Diversity and composition of bacteriome and mycobiome of tumour and adjacent mucosa, and resulting subtypes were computationally deconvoluted using > 10,000 samples. Results: The bacteriome of tumours had higher dominance and lower ɑ-diversity compared to matched adjacent local and distant mucosa. Tumours were enriched with Proteobacteria (Gammaproteobacteria class), Fusobacteria (including Fusobacterium Nucleatum species) and Basidiomycota fungi (Malasseziaceae family). Tumours were depleted of Bacteroidetes (Bacteroidia class), Firmicutes (Clostridia class) and Ascomycota (Sordariomycetes and Saccharomycotina). Tumours and adjacent mucosa samples were classified into 4 microbial subtypes, termed C1 to C4, based on the bacteriome and mycobiome composition. The bacterial Propionibacteriaceae, Enterobacteriaceae, Fusobacteriaceae, Bacteroidaceae and Ruminococcaceae along with the fungal Malasseziaceae, Saccharomycetaceae and Aspergillaceae were among the key families driving the microbial subtyping. Microbial subtypes were associated with distinct tumour histology and patient phenotypes and served as independent prognostic marker for disease-free survival. Key associations between microbial subtypes and alterations in host immune response and signalling pathways were validated in the TCGA pan-cancer cohort. The microbial subtyping demonstrated stratification value in the pan-cancer settings beyond merely representing differences in survival by cancer type. Conclusions: This study demonstrates the translational potential of microbial subtyping in CRC patient stratification, and provides avenues to design tailored microbiota modulation therapy to further precision oncology.
Predicting recurrence in patients with stage II and III colon cancer: Validation cohort and long-term follow-up of the experimental cohort.
Authors: Viñal David , Martinez-Perez Daniel , Martínez-Recio Sergio , Gutiérrez-Sainz Laura , Ruiz-Gutierrez Iciar , Jiménez-Bou Diego , Peña-Lopez Jesus , Alameda-Guijarro Maria , Martin-Montalvo Gema , Rueda-Lara Antonio , Garcia-Leal Andrea , Zwisler Patricia , Palacios Maria Elena , Custodio Ana B. , Feliu Jaime , Rodriguez Salas Nuria , Ghanem Ismael 
Published: January 2023

215 Background: The prognosis of stage II and III colon cancer is heterogeneous and current staging system do not accurately predict recurrence. We previously reported a score that was able to select a subgroup of patient with excellent prognosis ( https://doi.org/10.1016/j.annonc.2022.04.177 ). Here we present long-term follow up of the experimental cohort and the results of the validation cohort. Methods: We included patients with pathologically confirmed diagnosis of stage II and III colon cancer at Hospital Universitario La Paz. The experimental cohort included patients from October 2016 to September 2020. The validation cohort included patients from October 2020 to August 2021. Our prognostic score assigns 1 point for each of the following features: T4, N2, R1 and high tumor budding. Patients with a score of 0 as compared to those with ≥1 had an excellent prognosis regardless AJCC TNM staging. We assess the time to recurrence (TTR) between both groups in the experimental and validation cohort. Results: Baseline characteristics of the experimental cohort (n = 304) were reported previously. 135 (44%) and 169 (56%) patients had a score of 0 and ≥1, respectively. After a median follow up of 45 months, 81 recurrences and 96 deaths were observed. Median TTR was not reached in either cohort (score 0 vs ≥1; P < 0.001), with a hazard ratio (HR) for recurrence of 0.13 [confidence interval (CI)95%: 0.05 to 0.32; P < 0.001]. At 24 months, 95% and 73% of the patients were recurrence free in the score 0 and ≥1 groups, respectively. Within the validation cohort (n = 86), thirty-eight (44%) patients had a score of 0 and 48 (56%) of ≥1. After a median follow up of 19 months, 14 recurrences were observed, all of them in patients with score ≥1. Mediant TTR was not reached in either cohort (P < 0.001), with a HR for recurrence of 0.14 (IC95%: 0.00 – 1.07, P = 0.05). At 12 months, 100% and 78% of the patients were recurrence-free in the score 0 and ≥1 groups, respectively. When assessing TTR according to AJCC TNM stage, we found similar TTR between patients with stage II (n = 45) and III (n = 41) (not reached in either cohort; P = 0.16), with a HR for recurrence of 0.47 (CI95%: 0.15 to 1.40; P = 0.17). At 12 months, 90% and 86% of the patients with stage II and III were recurrence-free. Conclusions: In this study, we validate a prognostic score that identifies a subgroup of patients with localized colon cancer with an excellent prognosis regardless of their TNM stage.
Characteristics of immune-infiltrating cells in the tumor microenvironment of appendiceal cancer with peritoneal disease.
Authors: Strach Madeleine Cornelia , Yeung Nicole , Lin Hui-Ming , Ansari Nabila , Koh Cherry , Shin Joo-Shik , Kench James , Horvath Lisa , Mahon Kate Lynette 
Published: January 2023

217 Background: Appendiceal cancers (AC) are rare, associated with peritoneal metastases, and respond poorly to current systemic treatments. There are limited studies on the characteristics and prognostic impact of infiltrating immune cells within the tumour microenvironment (TME) of AC with peritoneal metastases. Infiltrating immune cells are associated with survival outcomes and predict the effectiveness of immunotherapies in solid tumours. Different definitions have been developed to describe infiltrating immune cells and associated structures such as tertiary lymphoid aggregates (TLS). The aim of our study was to describe the immune TME in patients with AC peritoneal metastases to understand mechanisms of sensitivity and resistance to chemoimmunotherapies. Methods: Fresh tissue was collected during cytoreductive surgery from consenting patients with AC with peritoneal disease (Jul 2020-Feb 2022). Uncultured Day 0 tissues were fixed in formalin prior to paraffin embedding (FFPE). Haematoxylin and eosin (H&E) staining was performed on sections of FFPE tissue. Sections were evaluated by light microscopy for the presence of immune cells based on morphological appearance. Patterns of infiltrating immune cells were classified based on location (peritumoural, intratumoural, perimucinous, stromal), and aggregation (none, immature, mature). Immune cells forming aggregates were counted and the diameter of aggregates measured using QuPath. Results: We evaluated 25 patients with AC peritoneal disease during the study period. Immune cells were detected in tissues from all except 3 patients; 16 cases (78 immune areas) were low grade (LG) disease of primary appendiceal mucinous neoplasms, and 6 cases (29 immune areas) were high grade (HG) from primary appendiceal adenocarcinomas (Table). Immune cell aggregates had a median diameter of 209 mm (75-491) and median cell count of 892 cells (46-6490). Conclusions: This study represents the first formal description and characterisation of infiltrating immune cells in appendiceal cancer peritoneal metastases. Perimucinous immune cells were not observed in HG disease despite presence of mucin. Intratumoural immune cells were not observed in LG disease, consistent with these tumours being more resistant to chemotherapy. We plan ongoing work correlating the immune features with clinical outcomes alongside immunohistochemical and transcriptomic characterisation of the aggregates. [Table: see text]
Source of funding and enrollment disparities in the inclusion of minorities in colorectal clinical trials: A systematic review and meta-analysis.
Authors: Ayaz Ahsan , Naqvi Syed Arsalan Ahmed , Islam Mahnoor , Ikram Waleed , Raza Umar , Riaz Anum , Khakwani Kaneez Zahra Rubab , Ijaz Hafsah , Sonbol Bassam Bassam , Jin Zhaohui , Riaz Irbaz Bin 
Published: January 2023

23 Background: Identification of factors associated with enrollment disparities in clinical trials can narrow cancer care inequities. Funding source can influence minority representation in clinical trials. Therefore, we aimed to assess the impact of funding sources on enrollment disparities in colorectal (CRC) clinical trials. Methods: CRC phase II/III randomized controlled trial (RCTs) identified through MEDLINE and EMBASE from each database’s inception through 2022 were considered eligible. Trial level enrollment incidence ratios (EIR) were computed; defined as the ratio of trial proportions of a gender, age, or racial/ethnic subgroup category and the global incidence in the corresponding gender/age subgroup (from the global burden of disease database), or the US-population-based incidence in the corresponding racial/ethnic subgroup (from SEER 21 database). EIRs were then meta-analyzed using a random-effects model for each funding source category (US- government, industry, others). Temporal trends were analyzed using a univariate meta-regression. Results: Using data from 287 RCTs, women were significantly under-represented in the industry sponsored trials (EIR: 0.85 [95% CI: 0.83 - 0.88]) but not in US-government sponsored trials (0.92 [0.84-1.00]). A total of 87 RCTs reported age proportions; older adults (above 65 years) were significantly under-represented in the industry sponsored (0.84 [0.74-0.96]) and as well as in US-government sponsored CRC trials (0.52 [0.44-0.61]). Only 56 and 15 trials reported race and ethnicity, respectively. Limited data on racial/ethnic enrollment revealed significant under-representation of Black (0.45 [0.36 -0.57]) and Hispanic (0.45 [0.31-0.66]) patients across industry sponsored CRC trials. In contrast, no significant disparity was observed in the inclusion of Asian race in the industry sponsored trials. The number of US-government sponsored trials reporting racial/ethnic subgroups were small ( < 10) which precluded any meaningful statistics. Trends show that the representation of women has improved ( P: 0.02) while the representation of Black ( P: 0.007) and Hispanic patients ( P: 0.04) has worsened over the last three decades in industry sponsored CRC trials. Conclusions: The reporting of race/ethnicity is suboptimal in CRC trials especially in those sponsored by US government. Older adults may be under-represented regardless of funding source. Women, Blacks and Hispanics may be under-represented in industry sponsored CRC clinical trials. While representation of women appears to be improving, representation of Black and Hispanic patients has worsened in industry sponsored CRC clinical trials over the last three decades.