bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of the hoof bacterial communities in feedlot cattle affected with digital dermatitis, foot rot or both using a surface swab technique
Authors: Wong Nicholas S. T. , Malmuthge Nilusha , Gellatly Désirée , Nordi Wiolene M. , Alexander Trevor W. , Ortega Polo Rodrigo , Janzen Eugene , Schwartzkopf-Genswein Karen , Jelinski Murray
Published: January 2024

Background

Lameness is defined as altered or abnormal gait due to dysfunction of the locomotor system, and is a health issue of feedlot cattle, having major economic, labour, and welfare implications. Digital dermatitis (DD—a lesion of the plantar surface of the foot) and foot rot (FR—affects the interdigital cleft) are common infectious causes of lameness in feedlots. These hoof lesions can occur alone or in combination (DD + FR) in the same hoof. A total of 208 hoof swabs were collected from three commercial feedlots located in southern Alberta. Every lesion sample was matched with a corresponding control skin sample taken from a healthy contralateral foot. Control skin samples were also collected from cattle with no lesion on any feet. Bacterial communities of three types of hoof lesions (DD, DD + FR, FR) and healthy skin were profiled using 16S amplicon sequencing.

Results

Alpha diversity analysis revealed a lower bacterial diversity on DD and FR lesions compared to control skin. Beta diversity analysis showed that bacterial communities of DD, FR, and DD + FR lesions were distinct from those of the control skin. While the impact of feedlot was minimal, lesion type contributed to 22% of the variation observed among bacterial communities (PERMANOVA-R = 0.22,P < 0.01). Compared to the corresponding control skin, there were 11, 12, and 3 differentially abundant (DA) bacterial genera in DD, DD + FR, and FR lesions, respectively.

Conclusions

The bacterial community description of a DD + FR lesion is a novel finding. Not only did lesions lead to altered bacterial communities when compared to healthy skin, but the composition of those communities also differed depending on the hoof lesion. The 16S amplicon sequencing of surface swabs has significant value as a research tool in separating different hoof lesions and can provide additional insights to the polybacterial etiology of DD and FR in feedlot cattle.
Horizontal transverse isotropy anisotropic parameter inversion via azimuthal seismic velocity anisotropy and its application to anisotropic 3D in-situ stress estimation
Authors: Cao Huan , Zhao Yang , Xian Chenggang , Tang Hengyu , Yan Lanlan , Shuai Da , Zhang Lele , Shen Yinghao , Li Shichang
Published: January 2024

Anisotropic parameter inversion in horizontal transverse isotropy (HTI) media plays an important role in predicting the fracture density and the anisotropic in-situ stress for unconventional reservoirs. The current industry practice is to use the azimuthal PP-wave reflection coefficient to estimate the HTI anisotropic parameters. Based on the linear slip theory, we develop an innovative approach that uses azimuthal P-wave phase velocity to calculate HTI anisotropic parameters, which presents superiority over the conventional azimuthal PP-wave reflection coefficient inversion. Specifically, we first verify that the azimuthal P-wave phase velocity is for the HTI elliptical fitting than the azimuthal PP-wave reflection coefficient using the analytical formulations. Second, we sort the prestack wide-azimuth data into offset vector tile sectors and perform amplitude-variation-with-offset inversion at each azimuth. Third, we apply an elliptical fitting to the obtained azimuthal P-wave phase velocities to estimate the HTI anisotropic parameters, fracture density, and fracture direction. Fourth, based on the HTI mechanical earth model, we formulate a cost-effective 3D in-situ stress estimation method using the obtained elastic parameters and fracture compliance. Finally, field examples from the Zhaotong area, China, demonstrate that the estimated fracture density and anisotropic in-situ stress are more accurate and have higher resolution compared with conventional methods. The dominant stress regime in the study area is a strike-slip faulting regime with a governing orientation of northeast–southwest and presents good alignments with well logs, which demonstrates the reliability and accuracy of our method for predicting fracture density and anisotropic in-situ stress.
Health-related quality of life (HRQoL) in patients with metastatic colorectal cancer (mCRC) treated with sotorasib and panitumumab (pmab) versus trifluridine/tipiracil (T/T) or regorafenib (rego) in CodeBreaK 300.
Authors: Modest Dominik Paul , Fakih Marwan , Salvatore Lisa , Esaki Taito , Paez Lopez-Bravo David , Taieb Julien , Karamouzis Michalis , Ruiz-Garcia Erika , Kim Tae Won , Kuboki Yasutoshi , Meriggi Fausto , Cunningham David , Yeh Kun-Huei , Cremolini Chiara , Tran Qui , Chan Emily , Chao Joseph , Majer Istvan Matyas , Pietrantonio Filippo
Published: January 2024

10

Background: CodeBreaK 300 (NCT05198934) is a phase 3, multicenter, randomized, open-label study, evaluating sotorasib 960 mg (soto960) + pmab, sotorasib 240 mg (soto240) + pmab against investigator’s choice T/T or rego in patients with chemorefractory KRAS G12C-mutated mCRC. The study met its primary endpoint and demonstrated statistically significant improvement in progression-free survival with both doses of sotorasib. This analysis evaluated patient-reported outcomes (PROs) as secondary and exploratory endpoints in CodeBreaK 300. Methods: Change in PRO scores from study baseline through week 8 was compared for soto960+pmab and soto240+pmab vs the control group using a mixed effect model for repeated measures. PRO instruments included the Brief Fatigue Inventory, the Brief Pain Inventory, and the European Organisation for Research and Treatment of Cancer Core 30-item Quality of Life questionnaire. Time to deterioration (TTD) were assessed using Kaplan-Meier plots and Cox proportional hazard models. All analyses were conducted on patients with baseline and at least one post-baseline PRO score. Results: 160 pts were randomized 1:1:1 to soto960+pmab (n=53), soto240+pmab (n=53), or T/T or rego (n=54). Compliance rates for PRO assessments were high (>83%) and similar across the three treatment groups. Least square (LS) mean changes from baseline in fatigue at its worst, pain at its worst, physical functioning (PF), and global health status (GHS)/QoL favored the two sotorasib dose groups (Table). The 95% confidence intervals (CI) suggested improvement in pain at its worst and PF for both sotorasib dose groups, and improvement in GHS/QoL for the soto960+pmab group versus the control group. TTD hazard ratios < 1 indicated a trend in delayed deterioration for patients treated in both sotorasib dose groups. The 95% CIsuggested delays with respect to fatigue at its worst and PF for the soto240+pmab group. Conclusions: In CodeBreaK 300, both doses of sotorasib resulted in better HRQoL and a trend to decreased risk of deterioration vs the control group. In addition to improved clinical outcomes, these findings provide further evidence on the benefit of soto+pmab in patients with chemorefractory mCRC. Clinical trial information: NCT05198934 . [Table: see text]
A retrospective analysis of the prognostic impact of KRAS G12D mutation in patients with RAS-mutated metastatic colorectal cancer.
Authors: Hirose Toshiharu , Matsuguma Kunihito , Hirano Hidekazu , Okita Natsuko Tsuda , Shoji Hirokazu , Takashima Atsuo , Kato Ken
Published: January 2024

105

Background: KRAS is an oncogene that is mutated in about half of all metastatic colorectal cancers (mCRC). Recently, a novel therapy targeting KRAS G12C mutation has demonstrated promising efficacy for advanced solid tumors, including mCRC. A therapy targeting KRAS G12D mutation is also under development and promising efficacy is expected. However, the prognostic impact of the KRAS G12D mutation in patients with mCRC is still unclear. Methods: We retrospectively reviewed the medical records of patients with mCRC harboring RAS mutation who received first-line chemotherapy between January 2013 and December 2022 at our hospital in Japan. We compared the survival outcomes between patients with KRAS G12D mutation (G12D group) and those with non- KRAS G12D mutations (non-G12D group) in terms of progression-free survival (PFS) and overall survival (OS), using the Kaplan–Meier method and the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were estimated by univariate and multivariate Cox regression analysis. Results: A total of 340 patients were included in this study. The main RAS mutations were KRAS G12D in 80 patients (23.4%), KRAS G12V in 72 (21.2%), KRAS G13D in 43 (12.6%) and KRAS G12C in 16 (4.7%). There were 80 patients in the G12D group and 260 in the non-G12D group. Patient backgrounds did not differ significantly in terms of age (median 61/63), sex (male 49%/48%), performance status (PS0 32%/32%), site of primary tumor (right 33%/32%), number of metastatic sites (3≤ 28%/23%), treatment regimen (doublet 90%/92%, triplet 3%/4%), or first line bevacizumab (yes 81%/79%). Median PFS was 9.2 months (95%CI: 7.8-12.2) in the G12D group vs. 11.5 months (95%CI: 9.2-13.1) in the non-G12D group (HR 0.97 [95%CI: 0.73-1.28]; p=0.81). Median OS was 25.8 months (95%CI: 18.8-39.8) vs 32.9 months (95%CI: 28.5-36.1) (HR 0.84 [95%CI: 0.60-1.19]; p=0.33). Second-line treatment was administered in 55 (69%) vs 192 (74%) patients in the G12D and non-G12D group, respectively. Conversion surgery was performed in 4 (5%) vs 18 (7%) patients in the G12D and non-G12D group, respectively. Multivariate analysis adjusted for PS, sex, age, site of primary tumor, number of metastatic sites and treatment regimen showed no significant differences in PFS and OS between the G12D and non-G12D groups. Conclusions: The KRAS G12D mutation did not show a detrimental prognostic impact on PFS and OS compared to KRAS non-G12D mutations in patients with RAS-mutated mCRC.
Refining first-line treatment decision in RAS wildtype (RAS-WT) metastatic colorectal cancer (mCRC) by combining clinical biomarkers: Results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).
Authors: Holch Julian Walter , Ohnmacht Alexander , Stintzing Sebastian , Heinrich Kathrin , Westphalen Benedikt , Weiss Lena , von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Kaiser Florian , Heintges Tobias , Kahl Christoph , Kullmann Frank , Scheithauer Werner , Link Hartmut , Hoeffkes Heinz-Gert , Moehler Markus H. , Modest Dominik Paul , Menden Michael , Heinemann Volker
Published: January 2024

13

Background: Optimal patient selection for first-line treatment targeting epithelial growth factor receptor (EGFR) in RAS-WT mCRC is based on primary tumor sidedness (PTS) with anti-EGFR being the preferred option for patients with left-sided mCRC (LC). Right-sided mCRCs (RC) are preferentially treated in combination with bevacizumab targeting vascular endothelial growth factor (VEGF). Here, improvement in patient selection was evaluated by combining clinical biomarkers beyond PTS using the randomized phase III trial FIRE-3. Methods: FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC. Besides PTS, further clinical biomarkers were evaluated in pairwise combinations using Cox regression models and model-based recursive partitioning with Weibull models to predict treatment benefit of either treatment arm regarding overall survival (OS): age, sex, liver-limited disease status (LLD) and baseline carcinoembryonic antigen serum level (CEA). The resulting P-values of second-order interactions were adjusted using Holm-Bonferroni correction. The model with the best test statistics and P-value was chosen for further evaluations. Results: In 400 patients with RAS-WT mCRC, a model combining PTS and LLD status best predicted treatment outcome of either treatment arm (c-index = 0.603, p=0.005). Here, a significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was evident in patients with LC/non-LLD (HR 0.62, p=0.02) compared to LC/LLD (HR 0.83, p=0.40). In patients with RC, FOLFIRI/Bev was significantly associated with increased OS compared to FOLFIRI/Cet when patients suffered from non-LLD (HR 2.09, p=0.010). However, patients with RC/LLD rather had a benefit from FOLFIRI/Cet compared to FOLFIRI/Bev (HR 0.59, p=0.218). Conclusions: Combining clinical biomarkers PTS and LLD status might improve optimal patient selection for targeted first-line treatment in RAS-WT mCRC. Validation in further data sets is warranted. Clinical trial information: NCT00433927 .
The interaction of radiotherapy and dual inhibition of BET and HAT/p300 in colorectal cancer.
Authors: Pennock Michael Matthew , Pandey Sanjay , Wahlestedt Claes , Guha Chandan , Kuang Chaoyuan
Published: January 2024

146

Background: Colorectal cancer (CRC) is characterized by extensive DNA methylation at the promoters of tumor suppressor genes and enhanced activity of histone modifying proteins such as histone acetyltransferases (HATs) or histone readers such as bromodomain and extra-terminal domain (BET) proteins. BET inhibition has been associated with the reduced expression of DNA repair proteins and therefore can be used in combination with radiotherapy (RT) and chemotherapy. In the current study, we have evaluated the therapeutic potential of a clinical stage (phase 1) dual BET and CBP/p300 inhibitor, EP31670 (EP), in combination with RT. Methods: HCT116 CRC 2-D cultures were treated with EP 4 hours before RT. After pretreatment with EP (0, 0.1, 0.5, 1, 2, 5, and 10µM), cells were irradiated with various doses (0, 2, 4, 6, and 8Gy) of RT (300-kv x-rays). Crystal violet (CV) assay at 48 hours post RT was used to determine growth inhibition and viability between the various drug, RT, and combination groups. Synergy between treatments was evaluated by estimating the combination index (CI) values via mass-action law CompuSyn calculations using CV data. CI values of <1 from the growth inhibition assay suggested that EP synergized with RT for enhanced cytotoxicity in HCT116 CRC cells. Flow cytometry was used to assess DNA damage (γH2Ax), apoptosis and total death (Annexin V-PI assay), cell cycle analysis, and proliferation (EdU). Results: There was a significant dose-dependent increase in the residual DNA damage at 6 hours (8Gy + EP 0.5µM vs. 8Gy, p<0.0001) and 24 hours (8Gy + EP 0.5µM vs. 8Gy, p=0.002) for combination therapy over RT alone. Four-hour treatment with EP promoted G2 cell-cycle arrest (8Gy + EP 0.5µM vs. 8Gy, p<0.001) and significantly reduced the number of HCT cells in S-phase (8Gy + EP 0.5µM vs. 8Gy, p<0.001) and proliferation (EdU) of the HCT cells (8Gy + EP 0.5µM vs. 8Gy, p=0.0003) compared to RT alone. There was a significant increase in apoptotic cells the combination group (8Gy + EP 0.5µM vs. EP 0.5µM, p=0.008) when compared to the unirradiated cells. The combination group also showed significant increase in the total death compared to RT alone (8Gy + EP 0.5µM vs. 8Gy, p=0.03) at the G1-S checkpoint. Conclusions: EP31670 enhanced RT-induced growth arrest, reduced proliferation, and enhanced cell death in HCT116 CRC cells in synergy with the RT. Additional preclinical studies, in vivo studies, and eventual clinical studies can be conducted to further exploit this synergistic interaction.
Genome-wide DNA methylation status to predict the efficacy of modified (m)-FOLFOXIRI plus cetuximab as initial treatment for RAS wild-type metastatic colorectal cancer: A biomarker study of the DEEPER trial (JACCRO CC-13AR).
Authors: Ouchi Kota , Tsuji Akihito , Shiozawa Manabu , Kawai Takashi , Yasui Hisateru , Ota Hirofumi , Kochi Mitsugu , Manaka Dai , Ohori Hisatsugu , Miyake Toru , Yamaguchi Tatsuro , Matsuura Masato , Sagawa Tamotsu , Makiyama Akitaka , Wakamura Kunihiko , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi , Ishioka Chikashi , Sunakawa Yu
Published: January 2024

152

Background: Genome-wide DNA methylation status (GWMS) has been shown to be a predictor of therapeutic response to anti-EGFR antibody therapies. This study investigated the association between GWMS and clinical outcomes of first-line chemotherapy with anti-EGFR or anti-VEGF antibody agents for metastatic colorectal cancer (mCRC). Methods: Tumor tissues of mCRC patients registered in the JACCRO CC-13AR (clinical trial number: UMIN000018412) were analyzed for GWMS and were classified into low-methylated colorectal cancer (LMCC) and high-methylated colorectal cancer (HMCC). Clinical data were obtained from the randomized phase II trial, DEEPER trial (JACCRO CC-13) [NCT02515734], in which patients were randomly assigned to m-FOLFOXIRI plus cetuximab (CET) arm and m-FOLFOXIRI plus bevacizumab (BEV) arm for treatment. Progression-free survival (PFS), overall survival (OS), depth of response (DpR), and response rate (RR) were analyzed according to GWMS for each treatment arm. Results: One hundred thirty-seven out of 227 patients enrolled in the JACCRO CC-13AR were analyzed. Of these, 122 (89.1%) and 15 (10.9%) were classified in the LMCC and HMCC, respectively; 66 were assigned to the CET arm including 7 HMCCs, and 54 were assigned to the BEV arm including 8 HMCCs. In the CET arm, PFS and OS of the LMCC were significantly longer than those of the HMCC (median PFS 14.3 vs. 4.0 months, hazard ratio [HR] 0.11, 95% CI: 0.05–0.29, P<0.01; median OS 42.7 vs. 13.6 months, HR 0.04, 95% CI: 0.01–0.13, P<0.01). There were no differences in DpR and RR between the LMCC and the HMCC (median DpR 58.1% vs. 46.7%, P=0.45), although RR of the LMCC was numerically higher than that of the HMCC (71.2% vs. 42.9%, P=0.13). In contrast, in the BEV arm, there were no differences in PFS, DpR, and RR between the two groups (median PFS 16.1 vs. 12.2 months, P=0.08; median DpR 48.3% vs. 53.9%, P=0.99; RR 73.0% vs. 75.0%, P=0.91). However, OS of the LMCC was significantly longer than that of the HMCC (median OS 48.9 vs. 24.2 months, HR 0.39, 95% CI: 0.16–0.95, P=0.03). Conclusions: This study showed that GWMS may be a prognostic marker for initial treatment in RAS wild-type mCRC. Also, GWMS correlates to the survival outcomes of m-FOLFOXIRI plus CET as initial treatment for RAS wild-type mCRC. Clinical trial information: 000018412 .
Clinical utility of serial circulating tumor DNA (ctDNA) to identify acquired resistance to anti-EGFR antibodies in metastatic colorectal cancer (mCRC).
Authors: Loree Jonathan M. , Bubie Adrian , Eluri Madhulika , Parseghian Christine Megerdichian , Overman Michael J. , Zhang Nicole , Drusbosky Leylah , Kopetz Scott , Raghav Kanwal Pratap Singh
Published: January 2024

158

Background: Real-world evidence informing on the value of incorporating serial ctDNA into clinical practice is lacking. We aimed to explore the utility of serial ctDNA for identifying mechanisms of resistance and new targets for patients (pts) receiving anti-EGFR therapy for mCRC. Methods: We retrospectively reviewed 2801 pts with mCRC who had ≥1 alteration detected on a Guardant360 assay (Guardant Health) and subsequently had serial ctDNA assessments with known intervening therapies. We compared detection of new MAPK pathway alterations ( RAS/EGFR/BRAFV600 SNV or indel, MET or ERBB2 amplification) among patients who initially lacked these alterations by whether patients received anti-EGFR antibody alone (panitumumab or cetuximab), in combination with chemotherapy, or if they had never received an anti-EGFR antibody between ctDNA assays. Patients with a subsequent ctDNA assay after therapy initiation were included for analysis of acquired alterations. Results: Of 2801 pts, 1308 (47%) harbored ≥1 MAPK alteration in their first ctDNA timepoint and were excluded from analysis. Of the remaining 1493 without a MAPK alteration prior to therapy, 588 (39.4%) had a MAPK alteration detected in a subsequent ctDNA timepoint. Among 447 of 1493 pts (31.8%) with subsequent exposure to anti-EGFR antibodies, acquisition of a MAPK alteration occurred in 229/447 (51.2%). This was more common (OR 2.01. 95% CI 1.61-2.51, P<0.0001) than in patients without exposure to anti-EGFR antibodies (359/1046 [34.3%]). Acquired MAPK alterations were more common among those receiving single agent antibodies (42/66, 63.6%) than anti-EGFR plus chemotherapy (187/381, 49.1%) (OR 1.82, 95% CI 1.05-3.08, P=0.030). Patients with anti-EGFR antibody exposure were found to have higher blood TMB scores in the first assay after treatment compared to patients treated with chemotherapy alone (11.5 vs. 8.8 mut/MB, respectively; P=0.001), with no significant blood TMB difference between those receiving single agent anti-EGFR versus anti-EGFR plus chemotherapy (median 12.4 vs. 11.5 mut/MB; P=0.52). Patients who acquired MAPK alterations after anti-EGFR therapy had higher blood TMB scores compared to patients who did not acquire MAPK alterations (median 14.3 vs 8.6 mut/MB, respectively; p<0.0001). Conclusions: In this large cohort of pts with mCRC and treatment information, we demonstrate serial ctDNA identified a large proportion of patients acquiring resistance alterations that may impact response to future therapies. These results suggest serial ctDNA analysis may provide additional molecular insights for patients receiving anti-EGFR therapy and inform future anti-EGFR rechallenge strategies.
Clonal hematopoiesis of indeterminate potential (CHIP), treatment outcomes and adverse events in gastrointestinal cancers: A pooled analysis of clinical trial and real-world data.
Authors: Krishnan Tharani , Solar Vasconcelos Joao Paulo , Titmuss Emma , Topham James Thomas , Schaeffer David F. , Karsan Aly , Lim Howard J , Ho Cheryl , Gill Sharlene , Kennecke Hagen Fritz , Jonker Derek J. , Chen Eric Xueyu , Renouf Daniel John , O'Callaghan Christopher J. , Loree Jonathan M.
Published: January 2024

169

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

17

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

176

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

180

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

183

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

19

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

201

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

217

Background: Colorectal cancer (CRC) is the third most common cancer in the United States with studies showing increasing incidence of Young-Onset CRC, defined as cases occurring in individuals 50 years old or younger. Separately, the WNT Signaling Pathway and its subsequent mutation can result in sustained activation and, therefore, unregulated cell proliferation which has been well described in colorectal cancers. Loss of function in APC, AXIN1, AXIN2, GKS3B, and RNF43 can each act to dysregulate WNT signaling, contributing to cancer development. In this study, we aimed to conduct a comprehensive, molecular evaluation of the WNT signaling pathway in colorectal cancer within age-specific cohorts with onset of CRC at 50 years old or less versus greater than 50 years old. Methods: We used published individual patient-level data of 6286 patients with colorectal cancer (CRC) from the 16 CRC datasets included in the cbioportal database. The WNT pathway alterations, including APC, AXIN1, AXIN2, GKS3B and RNF43 mutations were considered to define the WNT mutant CRC cohort. The presence of WNT alterations according to the age (50 years old or younger vs. over 50 years) were evaluated using Chi-square tests. The association between primary tumor distribution (colon vs. rectal) and age were evaluated across patients with and without WNT pathway alterations. The effect of WNT pathway alterations on the overall survival and survival after the metastatic stage was evaluated with Kaplan-Meier survival curves. A type-I error level of 5% (p<0.05) was considered the threshold limit for statistical significance. Results: A total of 2,630 individuals were identified with relevant clinical and molecular information. When comparing WNT alteration patterns between young-onset CRC (< 50 years old) and CRC in cohort >50 years old, there was no statistically significant difference (p-value .215). Analysis of common individual mutations in APC, AXIN1, AXIN2, GKS3B and RNF43 also showed similar incidences across age groups. However, we identified WNT alterations were significantly more common in rectal cancers compared to colon cancer, being found in 75.9% of rectal cancer cases, regardless of age groups (p-value <0.00001). Additionally, individuals identified to have WNT alterations were found to have improved survival with a median overall survival of of 58.19 months versus a median of 41.72 months in those without. Conclusions: Overall, no significant differences were found in WNT alteration expression between Young-onset CRC versus CRC in individuals over the age of 50. However, across all age groups, WNT alterations were frequently found in rectal cancers. Furthermore, these WNT alterations were associated with better outcomes.
First-line pembrolizumab (pembro) plus chemotherapy (chemo) for advanced esophageal cancer: 5-year outcomes from the phase 3 KEYNOTE-590 study.
Authors: Shah Manish A. , Sun Jong-Mu , Shen Lin , Kato Ken , Enzinger Peter C. , Adenis Antoine , Doi Toshihiko , Kojima Takashi , Li Zhigang , Kim Sung-Bae , Cho Byoung Chul , Mansoor Wasat , Li Shau-Hsuan , Sunpaweravong Patrapim , Alsina Maqueda Maria , Buchschacher Gary L , Wu Jimin , Shah Sukrut , Bhagia Pooja , Metges Jean-Philippe
Published: January 2024

250

Background: First-line (1L) pembro + chemo significantly improved survival versus placebo (pbo) + chemo in patients (pts) with advanced esophageal cancer after a median follow-up of 22.6 mo in the randomized phase 3 KEYNOTE-590 study (NCT03189719). We report 5-yr follow-up data. Methods: Eligible pts had locally advanced/metastatic adenocarcinoma or squamous cell carcinoma of the esophagus (ESCC), or Siewert type I gastroesophageal junction adenocarcinoma; measurable disease per RECIST v1.1; and ECOG PS 0 or 1. Pts were randomized 1:1 to receive pembro 200 mg or pbo IV every 3 weeks for ≤35 cycles both with chemo (5-fluorouracil [≤35 cycles] and cisplatin [≤6 cycles]). Primary end points were OS in pts with ESCC and PD-L1 CPS ≥10 and OS and PFS per RECIST v1.1 by investigator in all pts, pts with ESCC regardless of PD-L1, and pts in the ITT population with CPS ≥10. Secondary end points included ORR and DOR per RECIST v1.1 by investigator and safety. Pt-reported outcomes will also be presented. Data cutoff was July 10, 2023. Results: Overall, 749 pts were randomized to receive pembro + chemo (n = 373) or pbo + chemo (n = 376). Median time from randomization to data cutoff was 58.8 mo (range, 49.2-70.6). A total of 701/740 pts (94.7%) discontinued treatment; most commonly due to progressive disease (n = 449; 60.7%). ORR and DOR by pt population are provided (Table). In the ITT population, median OS was 12.3 mo for pembro + chemo and 9.8 mo for pbo + chemo (HR 0.72 [95% CI 0.62-0.84]); 5-yr OS rates were 10.6% and 3.0%, respectively. Median PFS was 6.3 mo for pembro + chemo and 5.8 mo for pbo + chemo (HR 0.64 [95% CI 0.54-0.75]); 5-yr PFS rates were 5.5% and 0%, respectively. Grade 3-5 treatment-related AEs occurred in 266 (71.9%) pts in the pembro + chemo arm and 250 (67.6%) pts in the pbo + chemo arm. Treatment-related AEs led to death in 9 (2.4%) and 5 (1.4%) pts in the pembro + chemo and pbo + chemo arms, respectively. Conclusions: After 5 yrs, use of pembro + chemo showed durable efficacy versus pbo + chemo, with no new safety concerns in pts with untreated advanced esophageal cancer. Long-term results continue to support 1L pembro + chemo for advanced esophageal cancer. Clinical trial information: NCT03189719 . [Table: see text]