bluuebunny/crossref_metadata_2025 huggingface dataset:
Antitumor activity of intraperitoneal (IP) paclitaxel to mucinous appendiceal adenocarcinoma in orthotopic patient-derived xenograft model.
Authors: Ito Ichiaki , Yousef Abdelrahman M.G. , Dickson Princess A , Fournier Keith F. , Fowlkes Natalie Wall , Shen John Paul Y.C.
Published: January 2023

151

Background: Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which only few preclinical models exist for drug discovery. These tumors are commonly treated with chemotherapy like those for colorectal cancer despite clear evidence that the two cancers are distinctly different in their clinical behavior and molecular profiles. Taxanes such as paclitaxel (PTX) and docetaxel have been used in the systemic treatment of gastric cancer with peritoneal metastases. IP administration of PTX has been considered a promising treatment for eliminating peritoneal metastasis, as IP delivery of PTX can attain a higher drug exposure in the peritoneal cavity with reduced systemic toxicity because of high local concentrations over a long period of time due to its hydrophobic property. The purpose of this study was to test the efficacy of IP PTX treatment in orthotopic AA PDX models. Methods: AA tumors TM00351, PMP-2 and PMCA-3 were implanted in the peritoneal cavity of NSG mice. PDX models were treated with PTX (6.25, 12.5 or 25.0 mg/kg, IP) with weekly (3 weekly treatments and 1 week off, for two cycles) or biweekly (biweekly treatments for up to 12 weeks) schedule. The peritoneal tumor burden was monitored by MRI. Solid tumor size was evaluated by modified peritoneal Response Evaluation Criteria In Solid Tumors (mpRECIST) method using ImageJ software and mucinous tumor volume was quantified by OsiriX Lite software. Results: TM00351, taken from a high-grade tumor (Grade 3), formed mucin-rich solid tumors with mucinous ascites. PDX models PMP-2 (Grade 2) and PMCA-3 (Grade 3), both with GNASR201C mutation, had a mucinous phenotype similar to GNAS mutant appendiceal tumors in humans. Weekly 25.0 mg/kg of IP PTX treatment reduced AA tumor growth of TM00351 (77.9% reduction vs. control), PMP-2 (98.6% reduction vs. control), and PMCA-3 (85.6% reduction vs. control). Similarly, biweekly 25.0 mg/kg of IP PTX treatment was effective on PMCA-3 (66.2% reduction vs. control). Survival of PMCA-3 PDX mice was significantly improved by 12.5 mg/kg (p=0.0254, log-rank test) and 25.0 mg/kg (p=0.0038) of IP PTX. At 25.0 mg/kg IP PTX treatment induced 12.0% body weight loss of PMCA-3 PDX mice 1 week after the treatment. Lower doses of IP PTX treatment, 6.25 and 12.5 mg/kg, did not induce significant body weight loss or any noticeable adverse effects on mice. Comparing the efficacy of IV to IP administration, neither 6.25 or 12.5 mg/kg of IV PTX reduced growth of PMCA-3, 25.0 mg/kg of IV PTX was lethal to mice shortly after administration. Conclusions: IP PTX is a therapeutically active for mucinous AA tumors.
Colorectal cohort analysis from the Intraperitoneal Chemotherapy After Cytoreductive Surgery for Peritoneal Metastasis (ICARuS) clinical trial.
Authors: Nash Garrett Michael , Garcia-Aguilar Julio , Paty Philip , Gonen Mithat , Foote Michael Bonner , Chung Sebastian , Mohamed Mostafa , Aguirre Nicole , Weiser Martin R. , Rassam Rachel , Guillem Jose G. , Smith Jesse Joshua , Pappou Emmanouil , Wei Iris H , Momtaz Parisa , Gollub Marc J , Vakiani Efsevia , Shia Jinru , Saltz Leonard B. , Cercek Andrea
Published: January 2023

160

Background: ICARuS is a randomized phase II, multicenter trial to evaluate the relative efficacy of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with mitomycin C vs. Early Postoperative Intraperitoneal Chemotherapy (EPIC) with floxuridine (FUDR), after cytoreductive surgery (CRS), for the treatment of peritoneal metastases (PM) from colorectal (CRC) or appendiceal cancer (AC). PRODIGE7 results failed to demonstrate benefit of HIPEC therapy after complete gross resection of CRC PM, prompting termination of CRC accrual and early cohort analysis. Methods: Patients with isolated, confirmed PM were eligible for 1:1 randomization to CRS plus HIPEC with mitomycin C or CRS plus EPIC with FUDR. Patients were stratified by recent systemic chemotherapy and disease (AC vs. CRC). The trial was originally powered to evaluate 212 patients for a 20% gain in a primary endpoint of 3-year progression free survival (PFS: HR = 1.75). Results: Seventy-five CRC patients were included between 4/2013 and 12/2018 for HIPEC (N = 40) or EPIC (N = 35) treatment. Baseline characteristics were well balanced. After a median follow up of 36 months, the median PFS was 7.7 months (95% CI: 6.3-11.1) in the HIPEC arm and 8.8 months (95% CI: 7.1-21.9) in the EPIC arm, HR = 0.69 (95% CI: 0.42-1.14) p = 0.14. In the 42 left-sided primary cancers, the median PFS was 8.4 months (95% CI: 6.4-17.7) in the HIPEC arm and 12.5 months (95% CI: 8.1-NR) in the EPIC arm, HR = 0.60 (95% CI: 0.29-1.22) p = 0.14. In the 33 right-sided primary cancers, the median PFS was 6.5 months (95% CI: 5.5-14.1) in the HIPEC arm and 8 months (95% CI: 5.8-24.1) in the EPIC arm, HR = 0.80 (95% CI: 0.39-1.64) p = 0.53. PFS was significantly better in the EPIC arm among patients with BRAF wildtype (WT) tumors and patients with higher PM burden (PCI > 7). There was no difference between HIPEC and EPIC in the primary toxicity endpoint of complications grade 3 or above (23 vs. 34%, p = 0.3). Conclusions: Three-year PFS did not significantly differ between treatment arms. The lack of survival benefit of HIPEC in the entire cohort and in subset analysis is consistent with the findings of PRODIGE7. ICARuS remains open to accrual for AC. These data support further investigation of the potential benefit of EPIC with CRS in carefully selected patients with CRC PM. Clinical trial information: NCT01815359 .
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.
Use of circulating tumor DNA (ctDNA) for early assessment of treatment response in patients with advanced colorectal cancer (aCRC): A real-world (RW) analysis.
Authors: Kasi Pashtoon Murtaza , Weipert Caroline , Nguyen Tim , Liao Jiemin , Zhang Nicole , Forbes Shaun , Gordon Sean , Tan Benjamin R.
Published: January 2023

246

Background: Data suggests that changes in ctDNA quantity correlate with response to therapy in patients with advanced solid malignancies. However, there is little consistency on how to calculate and interpret such changes. Here, we apply a clinically-validated molecular response algorithm to a RW cohort of patients with aCRC to further evaluate its ability to assess treatment outcomes. Methods: We queried the Guardant INFORM database, which comprises aggregated commercial payer health claims and de-identified records from patients with comprehensive ctDNA testing via Guardant360 (G360) from September 2018-March 2022. Patients with aCRC who received G360 within 15 weeks prior to new treatment initiation (any line of therapy) and a second test 3-15 weeks after treatment initiation were retrospectively evaluated using the G360 Response algorithm. Cox proportional hazards (CPH) were used for RW time to next treatment (TTNT), time to treatment discontinuation (TTD), and overall survival (rwOS) analyses. Patients categorized as molecular responders had a >50% decrease in mean variant allele fraction (VAF) ratio from pre-treatment to on-treatment. Gender, age, line of therapy (LOT) and comorbidities were included as covariates. Median TTNT, TTD, and rwOS were calculated by Kaplan Meier. Results: Of 185 aCRC patients with eligible MR results, 65% received chemotherapy +/- VEGF, 21% received regimens containing anti-EGFR monoclonal antibodies, and 14% received other therapies. 43% of aCRC patients were classified as molecular responders, 42% were non-responders, and 15% were not evaluable by the algorithm due to no/low ctDNA at one or both timepoints. 16% of patients cleared their ctDNA on treatment (i.e., ctDNA became undetectable). Molecular responders had significantly longer TTNT (median 10.1 months vs 6.1 months; HR p < 0.005), TTD (median 5.2 Months vs 3.9 months, HR p=0.041), and rwOS (not reached vs 17.8 months, HR p=0.017). Conclusions: Patients with aCRC classified as molecular responders, as calculated by this algorithm, had prolonged time on treatment and overall survival. Compared to tumor markers, ctDNA has a short half-life, which can allow for early response assessment, as shown by our study. These findings are relevant for clinical care, with future potential to allow for adaptive clinical trial design. [Table: see text]
Plasma-only multiomic minimal residual disease (MRD) testing in 2,000 consecutive patients with colorectal cancer (CRC).
Authors: Pedersen Katrina Sophia , Tan Benjamin R. , Zuo Xiaotong , Kiedrowski Lesli A. , Bucheit Leslie
Published: January 2023

28

Background: Use and impact of circulating tumor DNA (ctDNA) testing for MRD detection has been infrequently reported outside clinical trials. We report clinical use of a validated plasma-only multi-omic MRD assay in a large, unselected CRC cohort, including clinically annotated cases. Methods: The first 2,000 US patients (pts) with documented stage (stg) and Guardant Reveal MRD test results since clinical launch in Feb 2021 were queried; all tests per pt were analyzed (data cut-off: July 2022). Pts could be enrolled in a post-operative program (POP, up to 3 tests 3-16 weeks post-resection) or a surveillance program (SP, after treatment) for recurrent tests; pts could also have one-time tests. Programs were analyzed for stg II/III only. Clinical factors were extracted from test requisition forms; pts from Siteman Cancer Center had additional data extracted from medical records. Results: 1994 pts met criteria for analysis with median age of 64 (range 21-95); 1,112 (56%) were male. ctDNA was detected in 27%, with detection increasing by stg (Table). 30% of positive samples were detected by methylation only, a 43% increased detection over genomic only analysis. 505/544 positive pts had >1 test: 20% had ctDNA first detected on a subsequent test, a 25% increase when testing serially. Most stg II/III pts were tested in the SP. Stg II pts tested POP had a median turnaround time of 10 days (range 6-42); 96% had results prior to 12 weeks post-resection. In the annotated subgroup of 28 pts (65 tests), 8/28 (28%) had ctDNA detected. 13 pts had rectal- and 15 had colon cancer. 11/28 (39%) were stg II, 13 (46%) stg III, 4 (14%) stg IV. 26/28 had surgery, 7/13 rectal pts had neoadjuvant chemotherapy and/or radiation prior to ctDNA testing. 8 (29%) pts recurred. At data cut-off, assay sensitivity to predict or confirm recurrence was 80% (95%CI: 44.4-97.5%), specificity 100% (95%CI: 81.5-100%), PPV 100%, NPV 90% (95%CI:72.26-96.9%). Two pts with recurrence and negative ctDNA had their last test >6 months prior to recurrence. Testing informed clinical decision-making in 11 (39%) pts to proceed with systemic therapy (5), repeat scans sooner (2), proceed with biopsy (1), or confirm recurrence (3). Conclusions: Through real-word data, we confirm prior studies showing multi-omic plasma-only MRD testing has high sensitivity and specificity for recurrence and now show use of the assay in clinical decision-making. Notably, methylation analysis and serial testing both improved detection of MRD and impacted clinical care. These findings should continue to be studied in larger cohorts and randomized trials. [Table: see text]
Neo-AEGIS (Neoadjuvant Trial in Adenocarcinoma of the Esophagus and Esophago-Gastric Junction International Study): Final primary outcome analysis.
Authors: Reynolds John V. , Preston Shaun R. , O'Neill Brian , Lowery Maeve Aine , Baeksgaard Lene , Crosby Thomas , Cunningham Moya , Cuffe Sinead , Griffiths Gareth Owen , Roy Rajarshi , Falk Stephen , Hanna George , Bartlett Frederick R. , Parker Imelda , Alvarez-Iglesias Alberto , Nilsson Magnus , Piessen Guillaume , Risum Signe , Ravi Narayanasamy , McDermott Raymond S.
Published: January 2023

295

Background: The optimum combination curative approach to locally advanced adenocarcinoma of the esophagus and esophago-gastric junction (AEG) remains controversial, specifically whether multimodal therapy or perioperative chemotherapy is superior. Neo-AEGIS was designed as the first randomized clinical trial (RCT) to directly compare the multimodal CROSS regimen (carboplatin/paclitaxel, 41.4Gy radiation therapy) with a modified MAGIC (epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)) regimen (pre-2018) and more latterly the FLOT (docetaxel, 5-FU, leucovorin, oxaliplatin) regimen. Methods: 377 patients with cT2-3N0-3M0 AEG were randomly assigned to CROSS or peri-operative chemotherapy (ECF/ECX/EOF/EOX pre-2018, FLOT option 2019/20) at 24 sites (Ireland, UK, Denmark, France, Sweden). The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. This was modified after the first futility analysis (70 events) to a non-inferiority margin of 5% for peri-operative chemotherapy. Secondary end points included toxicity, pathologic measures of response, and postoperative complications as per the Esophageal Complications Consensus Group (ECCG) definitions and Clavien-Dindo severity grade. Results: Of 362 evaluable patients, 178 CROSS, 184 MAGIC/FLOT (157/27), 90% were male, median (range) age 64 (35-83), 84% were cT3, and 58% cN1. At a median (range) follow up of 34.2 (0.43-111.8) months, there were 186 deaths, 91 CROSS and 95 MAGIC/FLOT arm, with 3-year estimated survival probability of 57% (95% CI 49,64) and 55% (95% CI 47,62), respectively [(HR 1.03 (95%CI. 0.77-1.38))]. Conclusions: This RCT reveals no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy in the primary outcome of overall survival, notwithstanding greater proxy markers of local tumor response in the CROSS arm. Oncologic and operative outcomes were consistent with optimum modern benchmarks. These data strongly suggest non-inferiority and support equipoise in clinical decision making in modern practice. Clinical trial information: NCT01726452 . [Table: see text]
Analysis of concordance between microsatellite instability by next generation sequencing (NGS-MSI) and mismatch repair deficiency by immunohistochemistry (IHC-MMR) in >28,000 colorectal tumors.
Authors: Ali-Fehmi Rouba , Oberley Matthew James , Kraus Harris , Herzog Thomas J , Karnezis Anthony , Antonarakis Emmanuel S. , Kasi Pashtoon Murtaza , Farrell Alex Patrick , Xiu Joanne , Swensen Jeffrey , Spetzler David , Abraham Jim , Korn Wolfgang Michael , Bryant David
Published: January 2023

30

Background: The use of immune checkpoint inhibitors (ICI) in MSI-H/MMRd CRC patients has profoundly changed the treatment landscape in the metastatic setting; the most recent NICHE-2 trial showed 100% response rate in MSI-H/MMRd locally advanced CRC patients treated with neoadjuvant ICI, further highlighting the importance of identifying these patients accurately to enhance patient care. Here we report the concordance of NGS-MSI and IHC-MMR from a very large cohort of CRC tumors and study the molecular characteristics and clinical outcomes of these patients. Methods: A total of 28,105 CRC tumors were analyzed by NGS (592 genes, NextSeq or WES, NovaSeq) and IHC. MMRd was defined as complete loss of ≥1 IHC stains (MLH1, MSH2, MSH6, or PMS2) and proficient (MMRp) as any positive staining for all four proteins. MSI status was determined from over 7,000 target microsatellite loci covered by NGS. Central pathology review (CPR) of MMR IHC was done on 73 cases with discordant MMR/MSI results. Real-world overall survival was obtained from insurance claims and calculated from either tissue collection or treatment start to last contact; Kaplan-Meier estimates were calculated for molecularly defined patients. Results: For CRC tumors with NGS and IHC, 28031/28105 were concordant (99.74%), 0.09% were MMRd/MSS, and 0.2% were MMRp/MSI-H. After CPR, 23/24 (96%) of MMRd/MSS cases and 46/49 (94%) of MMRp/MSI-H were confirmed. Of the 46 post-CPR MMRp/MSI-H CRC samples, 52% had ≥1 pathogenic missense mutation in including MLH1/PMS2/MSH2/6 or MLH3, MSH3, PMS1 or POLE. Of the 23 post-CPR MMRd/MSS CRC samples, 38% had MLH1 loss, 91% PMS2 loss, no MSH2 loss and 9% MSH6 loss. When comparing clinical outcomes with concordant MSS/MMRp tumors, concordant MSI-H/MMRd patients had significantly longer OS (HR=1.131 [95% CI: 1.02-1.254], p<0.001) and post-ICI survival (HR= 2.695 [95% CI: 1.932-3.76], p<0.001). Compared to MSS/MMRd tumors (N=21), MSI-H/MMRp (N=29) trends to have longer OS (HR=2.163, [95% CI: 0.939-4.983], p=0.064) and insufficient ICI-treated patients were available for analysis. Conclusions: Here we report from >28,000 CRC tumors that the concordance of IHC-MMR/NGS-MSI is 99.74%. Clinical outcome from a large cohort of patients show NGS is not inferior compared to IHC in identifying patients with MSI-H/MMRd. The additional lens that NGS-MSI offers is of value in identifying CRC patients who may benefit from ICI therapy. [Table: see text]
Real-world outcomes with front-line doublet versus triplet chemotherapy in advanced gastroesophageal adenocarcinoma.
Authors: Sama Shashank , Nevala-Plagemann Christopher Duane , Smith Jarrod , Pappas Lisa M. , Haaland Benjamin , Garrido-Laguna Ignacio
Published: January 2023

313

Background: Current guidelines recommend an upfront cytotoxic doublet with or without targeted therapy or immunotherapy for the management of patients with advanced gastroesophageal adenocarcinoma (aGEA).While evidence for the superiority of combination chemotherapy over single agent chemotherapy has been well established, the comparison of two drug versus three drug regimens has been less definitive. This study analyzed a large real-world database to compare clinical outcomes between doublet and triplet approaches in the frontline setting. Methods: The nationwide de-identified Flatiron Health electronic health record (EHR)-derived database was reviewed for patients with aGEA treated with a first line (1L) cytotoxic doublet or triplet irrespective of combination targeted therapy between 2011 and 2022. Patients who received non-standard chemotherapy combinations or did not have a visit or medication order within 90 days of advanced stage diagnosis were excluded. Kaplan Meier and Cox proportional hazards models were used to compare overall survival outcomes between groups. Overall survival was considered as time from the 1L therapy to death with censoring for loss to follow up. Results: 5375 patients with aGEA who met inclusion criteria, 4415 (82%) received doublet chemotherapy and 960 (17%) received triplet in the 1L. Median OS (mOS) for those receiving a doublet was 11 months (95%CI 10-11) similar to those receiving a triplet (11 months, 95% CI 10-12). A Cox proportional hazards model controlling for potential confounding variables of gender, race, smoking status, disease site, as well as HER2 and PDL1 status did not show a significant difference in outcomes between the two groups (HR 0.9, 95%CI 0.8-1). A subgroup analysis comparing FLOT with FOLFOX/CapeOx demonstrated an improved mOS with FLOT (13 mo vs 10 mo; 95%CI 11-15 vs 9-10). This benefit was sustained in a multivariable analysis which demonstrated an increased risk of death with FOLFOX/CapeOX compared to FLOT (HR 1.2, 95% CI 1-1.4). Conclusions: Consistent with prior studies, this real-world study did not identify a significant difference in survival outcomes with 1L triplet compared to doublet chemotherapy in aGEA. When limiting analysis to modern chemotherapy regimens however this data does suggest that a survival benefit may exist with the use of FLOT when compared to FOFOX/CapeOX. This finding would need to be further evaluated in prospective trials incorporating immunotherapy and targeted therapy prior to widespread recommendation.
Treatment selection and outcomes of locally advanced esophageal cancer in octo- and nonagenarians: Is a curative intent multimodal approach feasible?
Authors: Ahmed Nabeel , Tankel James , Asselah Jamil , Alcindor Thierry , Alfieri Joanne , David Marc , Najmeh Sara , Cools-Lartigue Jonathan , Spicer Jonathan , Mueller Carmen L. , Ferri Lorenzo
Published: January 2023

333

Background: Neoadjuvant therapy followed by en bloc surgical resection affords the highest rates of survival from locally advanced esophageal cancer (LAEC) and represents the standard of care. However, patients of advanced age may not be offered this approach due to concerns over toxicity/tolerability. The outcomes of different treatment modalities for patients aged 80 and above with LAEC are not well described. Methods: A retrospective, single center, cohort analysis was performed on a prospectively maintained comprehensive esophageal cancer database. Between 2010-20, all patients ≥80yrs with locally advanced esophageal/GEJ cancer (cT2-4a, Nany, M0) were identified and outcomes stratified according to the following treatment categories: Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT) followed by surgery; definitive CRT (dCRT); upfront surgery; palliative CT or RT; or best supportive care (BSC). Data presented as median(range). Univariate analysis used for clinicopathological data (*p<0.05). Survival was compared with log rank analysis (Mantel Cox). Results: 79 patients ≥80 yrs with LAEC were identified. Median age was 83yr (80-97) and Charlson comorbidity index=7 (6-10). Most were cT3 (73%), cN- (56%) and adenocarcinoma (62%). Treatment approaches included: neoadjuvant (nCT(n=11)/nCRT(N=5)) + surgery (16/79(20%)); surgery alone (19/79 (24%)); dCRT (12/29(15%)); palliative RT or CT (24 + 3/79(34%)); BSC (5/79(6%)). Neoadjuvant consisted of nCT (FLOT=4; carbo-taxol =4; FOLFOX=2; CP+pembro=1) and nCRT (CROSS=5) and most received the intended full treatment/cycles (10/16:63%). Surgery was performed in 35 (age=82(80-96)), with major complications (grade 3-5) in 13/35 (37%) and 90-day mortality in 3/35(8.5%). Overall Survival for the entire cohort was 58% (1yr) and 19% (3yr), but highest with nCT/nCRT+surgery (94%/46%)*, followed by surgery alone (68%/39%), dCRT (58%/8%), palliative treatment (40%/4%), and BSC (0%/0%). Curative intent treatment (nCT/nCRT/surgery/dCRT) had significantly increased 1 and 3-yr survival compare to palliative treatment (76%/31% vs 34%/3.3%)*. Conclusions: Multimodal standard of care treatment, including surgical resection, of locally advanced esophageal cancer in octo/nonagenarians is feasible and safe in a subset of this high-risk population and associated with improved outcomes compared to other approaches. Age alone should not bias against curative-intent treatment in elderly patients with esophageal cancer.
Lower risk of metabolic syndrome and fatty liver in gastric cancer survivors: A propensity score-matched analysis.
Authors: Park Hyojin
Published: January 2023

334

Background: With the recent development in cancer treatments, the number of cancer survivors is rapidly increasing. Thus, evaluation and management of accompanied comorbidities as well as survival itself have become important issues in cancer survivors. The aim of this study was to investigate the prevalence and risk of metabolic syndrome (MetS) and fatty liver in gastric cancer (GC) survivors compared with that in non-cancer (NC) subjects. We also analysed the risk for metabolic dysfunction-associated fatty liver disease in GC survivors compared with that in NC subjects. Methods: In this cross-sectional study, participants who visited Gangnam Severance Hospital from 2014 to 2019 for health check-ups were enrolled. After age- and sex-matched 1:4 propensity score matching, 119 GC survivors and 476 NC subjects were included. GC survivors were divided into operated gastric cancer survivors (OpGC) (n=95) and non-operated survivors (non-OpGC) (n=24). MetS was diagnosed by metabolic components and FL was assessed by ultrasonography. Results: MetS was observed in 21.0% of GC survivors and 30.5% of NC subjects, and in 13.7% of OpGC survivors and 50.0% of non-OpGC survivors. FL was observed in 25.2% of GC survivors and 37.6% of NC subjects, and in 21.1% of OpGC survivors and 41.7% of non-OpGC survivors. After adjusting for age, sex, MetS risk was significantly lower in OpGC survivors (odds ratio [OR] = 0.377, 95% confidence interval [CI]: 0.200-0.711, P=0.003). FL risk was significantly lower in OpGC survivors (OR = 0.467, 95% CI: 0.267–0.816, P=0.007), but not in non-OpGC survivors, compared with NC subjects. Risk of metabolic dysfunction-associated fatty liver disease was significantly lower in OpGC survivors (OR = 0.412, 95% CI: 0.233–0.729, P=0.002) compared with NC subjects. Conclusions: OpGC survivors showed a lower risk of MetS and FL compared with NC subjects. These associations can be explored to ensure timely medical intervention in GC survivors.