bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential effect of the gut microbiome on tumour response to anti-cancer treatment in patients diagnosed with pancreatic ductal adenocarcinoma.
Authors: Dean Andrew Peter , Comito Olivia Rose , Yusoff Ian , Rao Samarth , Johansson Mikael , Navadgi Suresh , Webber Laurence , Watanabe Yuki
Published: January 2025

757

Background:
Chemotherapy is the standard of care for pancreatic ductal adenocarcinoma (PDAC), however, recent research has identified bacteria in the human gut microbiome that may influence patient response to chemotherapy. These bacteria are also present in faeces, and are thought to be representative of the bacteria in the pancreatic ductal system. Preliminary studies have suggested that patients with more advanced PDAC demonstrate lower levels of Firmicutes, and higher levels of Proteobacteria. Additionally, research has shown bacteria in the Firmicutes phylum possess several anti-cancer properties, which may improve patient treatment response, meanwhile, Gammaproteobacteria (Proteobacteria phylum), have been shown to attenuate gemcitabine efficacy and worsen treatment response.
Methods:
This prospective study involved 14 participants with locally advanced PDAC. Participants received combinations of Gemcitabine, Nab-Paclitaxel, and durvalumab (immunotherapy). Participant tumours were assessed every 8 weeks using radiological imaging according to RECIST v1.1, and serum CA19-9 levels were analysed monthly. Gut microbial profiling was completed on stool samples taken pre-treatment using PacBio HiFi full-length 16S rRNA sequencing.
Results:
16S rRNA sequencing identified that of the 4 patients that died due to disease progression, 3 patients had a low Firmicutes abundance, and a high Proteobacteria abundance. The rother patient demonstrated low levels of Actinobacteriota and Bacteroidota, and a low bacterial diversity. One participant showed a significant increase in CA19-9 (1066.7%), and exhibited a low abundance of Actinobacteriota and Bacteroidota, a high abundance of Proteobacteria, and a low diversity. 5 participants demonstrated a significant treatment response (according to CA19-9 and RECIST analysis), with 4 patients showing a high Firmicutes abundance, high levels of Actinobacteriota or Bacteroidota, and low levels of Proteobacteria. The remaining patient demonstrated a low abundance of Firmicutes and Proteobacteria, yet, displayed the highest abundance of Actinobacteriota and Bacteroidota.
Conclusions:
This exploratory study suggests an association between microbial composition and treatment response, with Firmicutes potentially being associated with an improved treatment response, and Proteobacteria with a worsened response. We believe this study to be one of the first to explore correlation of microbiome with clinical treatment response in PDAC.
Genomic analysis of paired primary and metastatic pancreatic ductal adenocarcinoma tumors.
Authors: McIntyre Caitlin A , Rudneva Vasilisa , Richards Allison L. , Park Wungki , Jarnagin William R. , Donoghue Mark , O'Reilly Eileen M.
Published: January 2025

758

Background:
The genomics of pancreatic ductal adenocarcinoma (PDAC) have been increasingly understood allowing for improvements in treatment, yet the clinical relevance of PDAC evolution is less well studied. The aim of this study is to evaluate genomic differences and clinical correlations between primary pancreatic tumors and paired metastases using a targeted sequencing panel.
Methods:
Patients who underwent surgical resection for PDAC with recurrent disease who had targeted genomic sequencing of both the primary tumor and a metastasis were included. Genomic alterations were determined using a panel of cancer-related genes (MSK-IMPACT). OncoKB was used to annotate driver alterations. MATH scores were used to quantify intratumoral heterogeneity. Comparison between paired samples was performed and association with clinical variables was assessed.
Results:
There were 55 patients included; 20% (n=11) received neoadjuvant therapy, 91% (n=50) had adjuvant therapy and 36% (n=20) had adjuvant radiation. The most common sites of metastasis sequenced were lung (36%, n=20), liver (35%, n=19) and local (13%, n=7). There was concordance between the first site of recurrence and site sequenced in 93% (n=51) of cases with a median time between resection and biopsy of recurrence of 25 months. The most commonly altered genes are
KRAS
(96%),
TP53
(83%),
CDKN2A
(40%),
SMAD4
(25%) and
RNF43
(13%). The majority of alterations are shared between the primary tumor and metastasis. Clonal mutations were defined as cancer cell fraction (CCF) >0.8. The majority of shared mutations are clonal; 52% of mutations are clonal in both the primary and metastasis, and clonality is preserved in 76% of shared mutations in metastases. The most commonly shared alterations are in driver genes and the majority are clonal-
TP53
(80%),
KRAS
(78%),
CDKN2A
(77%) and
SMAD4
(64%). The proportion of clonal mutations among drivers is higher than variants of unknown significance (p=0.005). There are 31 mutations private to the metastasis in 19 patients, 12 of which are clonal (39%). Mutations private to the metastasis are more common in patients who received adjuvant systemic therapy (p=0.035); however this was not seen when comparing patients who received adjuvant radiation to those who did not (p=0.38). MATH scores are higher in the metastasis as compared to the primary in all patients (p=0.0096), including those who received adjuvant treatment (p=0.002), indicating increased intratumoral heterogeneity in metastases.
Conclusions:
A targeted sequencing panel demonstrates that the majority of driver mutations are clonal and preserved between the primary tumor and metastasis. Additional private mutations and increased intratumoral heterogeneity are noted in metastasis, and our data suggests that this may be associated with exposure to systemic therapy.
Predictive methylation signature for gemcitabine sensitivity in pancreatic ductal adenocarcinoma: A pathway to personalized treatment.
Authors: Sherpally Deepak , Jeepalyam Sravan , Puram Harshitha , Manne Ashish
Published: January 2025

768

Background:
Gemcitabine (Gem) is a key drug used in chemotherapy regimens for treating pancreatic ductal adenocarcinoma (PDA). Identifying a biomarker to predict patient response to Gem could be crucial in personalizing treatment selection between Gemcitabine and fluorouracil (5-FU)-based therapies, thereby improving patient outcomes. We hypothesize that DNA methylation changes in genes linked to Gem resistance may serve as surrogates for the expression of corresponding proteins, thereby predicting treatment outcomes in patients with PDA receiving this therapy.
Methods:
We curated a 93-gene panel through a literature review spanning from January 1970 to April 2024. The proteins encoded by these genes have demonstrated either preclinical evidence (from cell line or mouse models) or clinical evidence (from tissue-based studies) of affecting the response to Gem in PDA. We evaluated the prognostic significance of methylation at specific CpG (cytosine-phosphate-guanine) sites within these genes using data from The Cancer Genome Atlas (TCGA) database, focusing on patients who had received Gem (106 /184 patients). We utilized elastic net multivariate analysis to analyze survival and created Kaplan-Meier plots based on our gene panel to estimate overall survival (OS). We compared RNA and gene expression levels for the clinically significant gene signatures between normal (NT) and PDA tissues using TNMplot.com, a web-based tool developed from data in the Gene Expression Omnibus of the National Center for Biotechnology Information (NCBI-GEO), TCGA, Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories. This tool employs Mann-Whitney or Kruskal-Wallis tests to determine statistical significance.
Results:
We identified an 8-CpG site methylation signature across eight genes, distinguishing a high-risk subgroup within the Gem-treated cohort in the TCGA database. Patients exhibiting methylation at specific CpG sites in this signature experienced significantly worse OS, with median survival times of 20.35 months compared to 49.38 months (p=0.0068). Additionally, the RNA expression (fold change: 2.11, p=2.12e-55) and gene expression (fold change: 1.42, p=3.14e-18) of these genes were markedly higher in PDA tissues compared to normal tissues. Notably, the candidate genes in our signature do not overlap with those used to classify PDA into classical versus basal subtypes. In an ongoing study, we are also investigating methylation changes of these candidate genes in the blood (cell-free DNA) of PDA patients.
Conclusions:
We present a signature that can predict Gem sensitivity or resistance in patients with PDA. This signature serves as a critical first step toward personalizing treatment strategies.
More isn't always better: Expanding and refining prognostic methylation signatures for pancreatic ductal adenocarcinoma.
Authors: Sherpally Deepak , Jeepalyam Sravan , Puram Harshitha , Manne Ashish
Published: January 2025

769

Background:
In our previous study, we developed protein-informed methylation signatures from a chemoresistance gene panel (RGp, n=122) curated from the literature, identifying 28 signatures with strong prognostic value in The Cancer Genome Atlas (TCGA) pancreatic ductal adenocarcinoma (PDA) database. To enhance the clinical utility of this panel, we incorporated methylation changes from genes with known prognostic (PGp) and diagnostic (DGp) significance in PDA to form a composite gene panel (CGp-PDA) and repeated our analysis. We hypothesized that epigenetic changes in these genes reflect protein expression and that deriving signatures from them could help identify patients at risk of treatment failure.
Methods:
We assembled a composite gene panel (CGp-PDA) of 206 genes (122 RGp + 26 PGp + 82 DGp) through a literature review spanning from January 1970 to April 2024. These PGp and DGp genes are unique, as cell-free DNA methylation changes in them have established prognostic and diagnostic value, respectively in PDA. The same cohort of pancreatic ductal adenocarcinoma (PDA) patients (n=184) from our previous study was analyzed. We applied elastic net multivariate analysis to calculate survival outcomes and generated Kaplan-Meier plots using our gene panel, optimizing values for 𝛼 and λ over 100 iterations.
Results:
Our analysis identified 20 signatures with cytosines followed by a guanine residue (CpG) site in genes from our panel. The number of CpG sites in these signatures ranged from 3 to 4248. The most effective signature featured 17 CpG sites (22 months [m] vs. 67m, p=0.03), followed by signatures with 3 (16m vs. 49m, p=0.009) and 12 (17m vs. 36m, p=0.02) CpG sites. The 4248 CpG site signature demonstrated the poorest prognostic value among the signatures (17m vs. 21m, p=0.01). Some signatures included multiple CpG sites within a single gene. Notably, KCNH2 reappeared in several signatures, as in the prior study. Expanding our RGp to CGp-PDA did not produce more (20 vs. 28) signatures or improved prognostic value.
Conclusions:
Targeted methylation signatures, supported by robust preclinical or translational evidence of their impact on treatment resistance, can be clinically valuable for informing treatment selection and prognosis. We may need to shift our focus from machine learning-based broad methylation or transcriptomic analyses to more targeted investigations.
p53 pathway genes' mutations as prognostic factors in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A single center study.
Authors: Trovato Giovanni , Barone Diletta , Spring Alexia , Minucci Angelo , Chiofalo Laura , Perazzo Serena , Ceccarelli Anna , Di Francesco Linda , Cosmai Antonia , Messina Gloria , Preziosi Alessia , Giaco' Luciano , Bensi Maria , Bagalà Cinzia , Tortora Giampaolo , Salvatore Lisa
Published: January 2025

771

Background:
Mutations (muts) in oncosuppressor genes have been associated with poor prognosis in different solid tumors. This study aims to evaluate the prognostic impact of p53 pathway muts in mPDAC pts.
Methods:
For each mPDAC pt enrolled in this study a FFPE tumor tissue specimen was collected and Next Generation Sequencing (NGS) was performed by TSO500HT assay (DNA [523 genes], RNA [55 genes]). Primary endpoint was overall survival (OS). The Kaplan–Meier method was used to estimate efficacy outcome; log-rank test, Peto-Peto test and Cox-regression model were used to compare the differences, considering a statistically significant
p
value < 0.05.
Results:
A total of 149 mPDAC pts were enrolled; TP53 was mutated in 115/149 (77.2%) pts, CDKN2A in 28 (24.3%), CDKN2B in 8 (5.3%), ATM in 6 (4%), TP53BP1 and MDM2 in 2 pts each (1.3%) and ATR in 1 (0.7%). No mutations were found in MDM4, CHEK1 and CHEK2 genes. Overall, 121 (81.2%) pts had at least one mutation in a gene of p53 signaling pathway (p53sigmut) and 28 pts (19.8%) had none (p53sigwt). The most frequent TP53 alterations were single nucleotide variations (SNVs): R175 (10 pts-8.7%), R248 (9 pts-7.8%) and R273 (8 pts-7%); 27 TP53 muts (18.1%) occurred in exon 7, 26 (17.4%) in exon 5, 19 (12.8%) in exon 8 and 13 (8.7%) in exon 4. Median OS (mOS) was 15 months (mos) (CI 95%: 12.8-18.2) in TP53 mutated pts vs 24.3 mos (CI 95%: 17.3-Not reached) in TP53 wt pts, p=0.03. The site of TP53 alteration was correlated with pts’ survival: mOS was 34.9 mos (CI 95%: 31-Nr) in exon 4-mutated pts, 16.9 mos (CI 95%: 11.2-21.2) in exon 7-mut, 13.8 mos (CI 95%: 11.2-17.8) in exon 5-mut and 10.7 mos (CI 95%: 8.2-Nr) in exon 8-mut, p= 0.018. CDKN2A mutations were also associated with survival: mOS was 17.9 mos (CI 95%: 15.9-24.1) in wt pts vs 13.4 (CI 95%: 10.7-22.2) in mutated pts, p= 0.04. CDKN2B, ATM, TP53BP1, MDM2 and ATR mutations were not associated with OS. Overall, patients with at least one mutation in one of the genes of p53 pathway had a mOS of 15 mos (CI 95%: 12.8-18.2) vs 19.6 months (mos) (CI 95%: 17.3-Not reached) in p53sigwt patients. In terms of comutations, TP53 wt pts had a higher frequency of KRAS mutations: 94% vs 64.5%, p<0.001.
Conclusions:
Our study suggests an important prognostic role of p53 signaling muts in mPDAC pts; wt pts resulted in a longer OS than mutated pts, although some mutations seem to be associated with a longer survival. Further studies are needed to investigate these findings, including an in-depth analysis of structural proteogenomic.
Analysis of serum and urine miRNAs as biomarkers of cancer cachexia in pancreatic cancer.
Authors: Okada Mao , Kondo Shunsuke , Igawa Yukiko Shimoda , Yoshida Tatsuya , Havelka Milos , Yamaguchi Hiroki , Ando Yoriko , Mikami Motoki , Ichikawa Yuki , Yamamoto Noboru
Published: January 2025

773

Background:
Cancer cachexia (CC), characterized by anorexia, weight loss and skeletal muscle wasting, is a common complication in patients (pts) with pancreatic cancer (PC). The association of CC with treatment-related toxicity and decreased quality of life has been reported. Although CC is believed to result from systemic inflammation and cancer-induced metabolic changes, the underlying mechanisms remain poorly understood. Early diagnosis of CC is particularly challenging, highlighting the need for reliable biomarkers. We analyzed microRNAs (miRNAs) in serum and urine as potential biomarkers for the early detection of CC in PC.
Methods:
Clinical information, along with serum and urine samples were collected from pts with PC treated at the National Cancer Center Hospital, Tokyo, from March 2022 to March 2024. CC diagnosis according to Fearon et al: (1) ≥5% weight loss in 6 months, (2) ≥2% weight loss in individuals with a BMI of <20 kg/m², or (3) ≥2% weight loss in pts with sarcopenia. In this study, pts were considered to have CC if they met the definition of CC at enrollment or within six months. Serum and urine extracellular vesicle (EV) miRNA profiles were sequenced by NGS and compared by means of counts per million (CPM). Differential expression of miRNAs between pts with and without CC was investigated by DEseq2.
Results:
Of the 84 enrolled cases, 73 had sufficient sample volume for NGS assay. After excluding 4 cases with low miRNA read counts and 10 cases with unknown CC status, 59 cases were analyzed. CC was present in 41 pts (69%). Patients’ background was as follows (CC/no CC); median age 70 [IQR:62–75]/ 67 [63–69], male 21/9 pts, cStage {I (7/0), II (1/0), III (18/5), IV (15/13)} pts, median BMI (21.7 [IQR:19.6–24.0]/21.8 [20.7–22.4]) kg/m2, respectively. There were 141 common miRNA species between serum and urine samples, 81 miRNAs unique to serum and 33 unique to urine. The correlation between the common miRNAs was moderate (R = 0.60). No significant differences in miRNA expression were observed between pts with and without CC in serum samples. In urine samples, miR-141-5p was significantly downregulated (log2FoldChange = -0.667, padj = 0.0463), while miR-146b-5p was significantly upregulated (log2FoldChange = 1.03, padj = 0.0463) in pts with CC compared to those without.
Conclusions:
The results of this study suggest that urine is a suitable biofluid for detecting CC in patients with PC, as differentially expressed miRNAs were not observed in serum. However, the mechanism underlying the superiority of urine over serum in detecting CC remains unclear and should be addressed in future studies.
Personalized ctDNA monitoring to assess the recurrence of early stage pancreatic cancer after surgery.
Authors: Du Juan , Zou Lu , Sha Hui-zi , Tong Fan , Ni Jiayao , Chen Jingjing , Bai Xinyuan , Tang Haochen , Kong Xiang , Liu Yaru , Wang Chengyi , Hu Meizhen
Published: January 2025

774

Background:
Up to 80% of patients with resected pancreatic cancer recur within 2 years. Here, we assessed the feasibility and accuracy of a personalized, tumor-informed circulating tumor DNA (ctDNA) test for early warning of recurrence risk during long-term surveillance.
Methods:
This study retrospectively analyzed 43 patients who underwent radical surgery for pancreatic cancer between November 2021 and June 2023 at the Comprehensive Cancer Centre of Drum Tower Hospital, Clinical Cancer Institute of Nanjing University. A personalised panel was constructed to detect ctDNA in plasma based on whole-exon mutation information from tumour tissue. A total of 139 ctDNA samples were obtained from periods including postoperative, during adjuvant therapy, and post-treatment.
Results:
Until the last follow-up time (May 13, 2024), a personalised ctDNA monitoring panel was successfully constructed for 35 (81.4%) stage I-III patients with a median follow-up of 11.82 months (range: 2-17.8 months). A total of 16 patients experienced recurrence within 15.7 months (range: 5.4-30 months), with a median lead time from first positive ctDNA to imaging recurrence of 3.6 months (range: 1-9.3 months). ctDNA positivity was detected in 25.8% (8/31) of ctDNAs at the landmark time point (postoperative prior to adjuvant therapy), with a positive predictive value (PPV) of 75% (6/8) and a negative predictive value (NPV) of 69.6% (16/23). Patients with positive ctDNA at the landmark time point had inferior DFS (6.9 months vs undefined. HR 3.955, P=0.007) and OS (15 months vs undefined. HR 5.599, P=0.001) compared to those with negative ctDNA. When integrating longitudinal time points, PPV and NPV were 68.2% (15/22) and 91.7% (11/12), respectively. For all 16 relapsed patients, the sensitivity of positive ctDNA detected longitudinally was 93.75% (15/16). The ctDNA-MRD status at longitudinal time points had a more significant difference with DFS (undefined vs 12.6 months. HR 5.096, P=0.002) and OS (undefined vs 21 months. HR 6.487, P=0.038).
Conclusions:
Personalized ctDNA surveillance is effective in identifying high recurrence risk after pancreatic surgical resection. Long-term longitudinal warning of arbitrary ctDNA positivity suggests a recurrence probability of up to 93.75%; therefore, full ctDNA dynamic monitoring is essential. And ctDNA monitoring will be further used to guide the decision-making in the clinic to prolong patient survival.
Correlation of tumoral collagen width with overall survival and tumoral collagen straightness with distant recurrence-free survival in patients with pancreatic ductal adenocarcinoma.
Authors: Marwaha Alexander , Dhamija Kriti , Kim Rachel , Dileo Rachel , Yin Yue , Hassan Abdulahi , Monga Dulabh K. , Landau Michael
Published: January 2025

779

Background:
Quantitative measurements of fibrillar collagen characteristics has been shown to correlate with survival in several types of malignancy. The aim of this study was to determine whether these characteristics correlate with survival in pancreatic ductal adenocarcinoma.
Methods:
Patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma at an Allegheny Health Network hospital between 1/1/2019 and 12/31/2023, and for whom archived formalin-fixed paraffin-embedded tumor tissue was available, were included in the study. Clinical and pathologic characteristics were collected from the patient's electronic medical record. Survival data included overall survival (OS), local recurrence-free survival (RFS), and distant RFS. One section of tumor per patient was stained with Picrosirius Red and a representative digital image was obtained with a camera attached to a microscope at 100x magnification. Each image was analyzed with CT-FIRE software to determine averages of collagen fiber width, length, straightness, and angle. Descriptive statistics were initially computed. Log-rank tests were also conducted to compare the OS rate and RFS rate between four different groups (width, length, straightness, angle). Each group was divided into high and low groups, using the mean as cutoff. In the end, multivariate Cox regression was conducted by controlling the confounders including sex, perineural invasion, lymphovascular invasion, and presence of lymph node metastasis to examine the hazard ratios of OS, local RFS, and distant RFS for the four collagen fiber metrics. All statistical analyses were performed via SAS 9.4 under alpha level .05.
Results:
One hundred three patients met the inclusion criteria. Based on the results of log-rank test, OS was significantly different between high and low collagen width groups,
p
= .0251. The lower width group had higher survival rate than the upper width group. Also, distant recurrence-free survival was significantly different between high and low collagen straightness groups,
p
= .0053. The lower straightness group had higher distant RFS rate than upper group. The results of multivariate Cox regression were consistent with the Kaplan-Meier curves. Compared to the high collagen width group, the low collagen width group had a 57% lower chance of dying, hazard ratio = 0.43, 95% CI [0.23, 0.78],
p
= .0056. The low collagen straightness group had a 60% lower chance of distant recurrence than the high collagen straightness group, hazard ratio = 0.40, 95% CI [0.19, 0.85],
p
=.0163.
Conclusions:
Quantitative collagen fiber metrics could help identify patients with resected pancreatic adenocarcinoma who are at risk of earlier death and distant recurrence.
Comparison of mutational landscape in primary and metastatic pancreatic tumors.
Authors: De La O Jean-Paul , Hoag Jess R , Basu Gargi D. , Starodynov Arthur , Deem Angela , Kundranda Madappa N.
Published: January 2025

781

Background:
Genomic profiling has brought to the forefront the clinical relevance of intratumoral heterogeneity. Oncogenic
KRAS
mutation is the most common driver event in pancreatic ductal adenocarcinoma (PDAC), but little is known about how
KRAS
alteration may cooperate with other genetic lesions to support dissemination and growth of metastatic disease. Therefore, an improved understanding of molecular events affecting the clinical course of
KRAS
-altered PDAC is needed to identify biomarkers of early disease and expand the repertoire of targeted therapies.
Methods:
We retrospectively analyzed tissue samples from PDAC patients using the OncoExTra tumor-normal whole exome and whole transcriptome test between April 2018 and May 2024. The prevalence of actionable somatic alterations was determined overall and by specimen location (primary vs. metastatic). Fisher’s exact test with FDR-based correction for multiple testing was used to identify co-alterations with
KRAS
and 19 DNA damage response (DDR) gene alterations.
Results:
PDAC samples from 434 patients (51.2% female; mean age 65.4±10.9 years) were analyzed.
KRAS
alterations were detected in 369 (85.0%) samples: 198 (45.6%) primary and 239 (55.1%) metastatic.

KRAS
G12D

(32.7%) and

KRAS
G12V

(29.5%) were the most common
KRAS
mutations. The frequency of
KRAS
alterations was 85.9% and 84.5% in primary and metastatic samples, respectively.
TP53
alterations occurred in 68.2% samples overall and in 64.6% and 71.1% of primary and metastatic samples, respectively. Examination of co-alterations in
KRAS
-altered versus
KRAS
-WT samples uncovered enrichment of
TP53
alterations in
KRAS
-altered (277 samples, 75.1%) compared to
KRAS
-WT samples (19 samples, 29.2%) (
p
<0.001). Also,
BRAF
mutations and
SND1:BRAF
fusions exclusively occurred in metastatic
KRAS
-WT samples, although the number of events was small (
n
=4 and
n
=2, respectively). We also found that
MTAP
was significantly co-altered in metastatic
KRAS
-WT samples (n=6, 16.2%) compared to
KRAS
-altered samples (6 samples, 3.0%) (
p
=0.004). A total of 21.9% of all PDAC samples had an alteration in at least 1 DDR gene. No associations were observed between
KRAS
alteration status and alteration in DDR genes. However,
TP53
alterations were more frequent in non-DDR-altered samples (
p
<0.001), while
CDKN2B
alterations were enriched in DDR-altered samples (
p
=0.025).
Conclusions:
We observed expected rates of alterations in known PDAC driver genes and uncovered higher co-occurrence of
KRAS
and
TP53
alteration in metastatic samples. Additionally,
TP53
alterations were less frequent in DDR-altered samples. Our findings suggest that a number of therapy approaches including BRAF, WEE1, PARP, and KRAS inhibitors as well as epigenetic modulators, alone or in combination, could improve clinical outcomes in PDACs with specific mutational profiles.
Cohort-level patient-derived organoid assays and prediction of clinical trial outcomes in PDAC.
Authors: Ronteix Gustave , Bouteiller Jean , Gryspeert Anna-Rose , Boileve Alice , Jerome Cartry , Mathieu Jacques RR , Bedja Sabrina , Ducreux Michel Pierre , Jaulin Fanny
Published: January 2025

785

Background:
Clinical trials are one of the major barriers in contemporary drug development. Improving the number of therapeutic solutions for patients whilst limiting the financial burden of healthcare systems will require dramatically improving clinical trial success rates. Functional assays based on patient-derived organoids (PDO) are a promising new tool for derisking clinical development of new therapies, but their use has been limited due to small cohort sizes and the absence of systematic validation studies.
Methods:
We have assembled a collection of 70 demographically relevant PDAC PDOs. Each PDO was screened with a 22-drug panel including standard of care, chemotherapies and targeted therapies. Using a best-in-class patient response prediction model we generate cohort scale estimations of overall response rates (ORR) and progression-free survival (PFS). The estimations are compared with data from published clinical trials to determine the validity of the approach.
Results:
The PDOs exhibit representative treatment histories in terms of number of lines of treatment (mean = 1.60) and treatment types (prior treatment types: folfirinox = 68.6%, gemcitabine = 50%). All the organoids’ mutational profile, past patient treatments and subsequent responses to future lines were analyzed and compared to the distributions observed in the clinic. The cohort-level drug efficacy on our PDO collection matches retrospective clinical trial ORRs reported in the literature. Furthermore, our preclinical assay predicts the relative performance of drugs in different clinical trial arms.
Conclusions:
We report that large-scale PDO-based assays predict clinical ORR and PFS with best-in-class accuracy. This work shows that well-characterized PDO collections can be used to improve the success rates of clinical studies for new potential treatments in PDAC.
Disparities in clinical trial enrollment among LGBTQ+ individuals and its impact on cancer treatment and management: A systematic review.
Authors: Chitkara Akshit , Anamika Fnu , Khosla Atulya Aman , Batra Akshee , Patel Rushin , Bai Sakshi , Deshpande Sohiel , Singh Rohit
Published: January 2025

805

Background:
There is a significant gap in oncologic research, which arises from the exclusion of LGBTQ+ individuals from cancer clinical trials, compromising the development of personalized cancer therapies and limiting the generalizability of findings. Despite known health disparities in this population, including higher cancer risk factors and unique psychosocial stressors, data on clinical trial participation remains sparse. This study aims to elucidate the extent of underrepresentation of LGBTQ+ individuals in cancer clinical trials and examine its impact on treatment efficacy, safety, and overall management.
Methods:
We conducted a systematic review of literature and clinical trial databases, including PubMed, ClinicalTrials.gov, and other registries, focusing on cancer trials from 2010 to 2024. We extracted data on LGBTQ+ enrollment, analyzed demographic inclusivity criteria, and identified barriers to participation. Subgroup analyses evaluated the correlation between LGBTQ+ representation and treatment outcomes, considering variables such as trial design, recruitment strategies, and data collection on sexual orientation and gender identity. The review also examined policy changes and inclusivity initiatives aimed at improving trial access for this community.
Results:
The review identified a significant underrepresentation of LGBTQ+ individuals in cancer trials, with sexual orientation and gender identity data reported in only 6.2% of trials. Structural and sociocultural barriers, including heteronormative trial designs, lack of inclusive recruitment strategies, and pervasive discrimination, were frequently cited as impediments. Trials that included LGBTQ+ participants rarely conducted stratified analyses to assess differential treatment responses, leading to a paucity of data on drug safety, efficacy, and toxicity profiles specific to this population. The absence of these data may contribute to suboptimal therapeutic decision-making and potential adverse outcomes in clinical practice.
Conclusions:
The substantial underrepresentation of LGBTQ+ individuals in cancer clinical trials impairs the ability to develop inclusive, evidence-based oncology care. Addressing this gap requires systematic changes, including the integration of sexual and gender minority data collection, implementation of LGBTQ+-specific recruitment frameworks, and stratified analyses of treatment outcomes. Enhancing trial inclusivity will not only improve the external validity of oncologic research but also support the development of tailored therapeutic approaches that address the unique needs of LGBTQ+ cancer patients, ultimately advancing health equity in cancer care.
Association between skeletal muscle morphometrics and overall survival among older adults with gastrointestinal cancers.
Authors: Doshi Apoorva , Saad Omar , Martin Landon , Williams Grant Richard , Giri Smith
Published: January 2025

808

Background:
Older adults with gastrointestinal (GI) cancers face a higher risk of treatment toxicities and adverse survival outcomes. However, the variability in these outcomes remains poorly understood. Age-related changes, including the progressive loss of skeletal muscle and gain in adipose tissue, contribute to this heterogeneity. Recent studies highlight an association between skeletal muscle gauge (SMG) and overall survival (OS) in older cancer patients, but its relevance among those with GI cancers is unclear.
Methods:
We included adults aged ≥ 60 years with newly diagnosed GI cancers, enrolled in the University of Alabama at Birmingham (UAB) Cancer and Aging Resilience Evaluation (CARE) registry between October 2017 and April 2024. Skeletal muscle index (SMI; skeletal muscle area in m²/height in cm) and skeletal muscle radiodensity (SMD; Hounsfield units) were derived from single-slice computed tomography (CT) staging scans at the third lumbar vertebra (L3) using validated methods. SMG was calculated as the product of SMI and SMD, reported in arbitrary units (AU). Participants were followed until death or the study cutoff date of July 10, 2024. Kaplan-Meier survival analysis was used to estimate OS by SMG status (low: < median; high: ≥ median). Cox proportional hazards models were employed to assess the relationship between SMG and OS, adjusting for age, sex, race/ethnicity, and cancer stage.
Results:
A total of 568 patients were included in the study, with a median age at diagnosis of 68 years (interquartile range, IQR: 64-74), 55% male, 73% non-Hispanic White, and 43% were diagnosed with Stage IV disease. Colorectal (33%) and pancreatic (27%) cancers were the most common diagnoses. The median SMG was 1,529 AU (IQR: 1,151–1,967). Over a median follow-up of 60 months, 367 patients (64%) died. Median OS was 19 months for those with low SMG and 26 months for those with high SMG (log-rank test, p < .05). After adjustment for confounders, SMG remained independently associated with OS (adjusted Hazard Ratio: 0.678 per IQR increase; 95% CI: 0.57– 0.807; p < .001), indicating that each IQR increase in SMG is associated with a decrease in all-cause mortality risk by 32.2%.
Conclusions:
Skeletal muscle gauge, an integrated measure of SMI and SMD, is significantly associated with improved survival among older adults with GI cancers. Further research is needed to determine whether SMG has a causal impact on survival in this population.
Patient-reported outcomes in GI cancer: Leading change to meet the needs of the gastrointestinal cancer community.
Authors: Raymond Martha , Simonetta Margaret-Ann
Published: January 2025

813

Background:
According to the World Health Organization International Agency for Research on Cancer, globally gastrointestinal (GI) cancers account for 1 in 4 cancer cases and 1 in 3 cancer deaths, with an estimated 4.8 million new cases and 3.4 million GI cancer deaths reported annually. Understanding the global burden of GI cancers and the importance of understanding the real-world impact of a GI cancer diagnosis, the GI Cancers Alliance (GICA) conducted a 12-month patient-reported outcomes (PRO) research initiative that included a workshop at the 2023 American Society of Clinical Oncology (ASCO) annual meeting. In addition, our PRO research was published in the Journal of Clinical Oncology (J Clin Oncol 42, 2024 suppl 3; abstr 731) with a poster presented at the 2024 ASCO Gastrointestinal Cancers Symposium.
Methods:
Based on our 2022-2023 PRO research of 1,122 patients highlighting the unmet needs and critical gaps in services of the GI cancers community, we developed a series of follow-up initiatives. Nutrition education 17%, biomarker/precision medicine education 19%, patient-centered care education 11% and caregiver support 16% were four of the highest levels of unmet need based on our global research. Subsequently, in 2023 we created the ‘GI Cancers Patient & Caregiver Advisory Board’ representing all GI cancers. The board hosts educational forums supporting patients and caregivers throughout the care continuum. Our pilot nutrition program launched at the 2024 ASCO annual meeting, consisting of in-person and online video components, and an extensive nutrition guide with recipes tailored for GI cancer patients. In 2024, we partnered with our gastric cancer advocates to develop ‘Test Your Biomarkers’ enhancing education and awareness of biomarker testing and precision medicine.
Results:
Implementing direct patient feedback from our published research, we are creating actionable solutions to unmet needs and gaps in services. Our ‘Patient & Caregiver Advisory Board’ continues to amplify the patient and caregiver voice participating in global engagement opportunities. GICA provided 10,000 nutrition guides to community oncology centers, and our online messaging reached 250,000 individuals across digital platforms and partner websites in the first three months from launch. In the first six months of the ‘Test Your Biomarkers’ campaign our messaging reached 1.7 million individuals across all digital platforms, campaign, and partner websites.
Conclusions:
Our PRO research provides the roadmap for new initiatives and programming to meet the needs of our GI cancer community. The GI Cancers Alliance will proceed to collaborate with our 100+ partner organizations to activate change by targeting the needs of our patient community while eliminating critical gaps in services. By doing so, we will continue to provide greater patient impact through the amplification of the patient voice.
The efficacy of anamorelin in gastrointestinal cancer with cancer cachexia: Single center experience.
Authors: Suzuki Yuka , Takashima Atsuo , Hirose Toshiharu , Shoji Hirokazu , Hirano Hidekazu , Okita Natsuko Tsuda , Kato Ken
Published: January 2025

815

Background:
Cancer cachexia is a catabolic syndrome that causes weight loss and loss of appetite in cancer patients. Anamorelin (ANAM) is an oral drug approved in Japan to treat cancer cachexia by selectively activating ghrelin receptors. There is limited real-world data available on the efficacy of ANAM for patients with gastrointestinal cancer. We assessed its efficacy and identified associated clinical features.
Methods:
We retrospectively collected data from medical records and questionnaires on gastric and colorectal cancer patients who received ANAM between April 2021 and March 2023. We evaluated the change in body weight, appetite, and oral intake from the time of initiation of ANAM. We judged the responder who gained more than 0.5 kg in body weight, improved appetite, and increased oral intake, respectively. The association between clinical features and the responders was also assessed using multivariate logistic regression analysis.
Results:
72 patients were included in this study. Characteristics of the patients: median age: 68 years old (range 38-85), male/female: 35/37, gastric/colorectal cancer: 39/33, PS 0-1/2 or more: 63/9, median body mass index (BMI): 18.0 kg/m
2
(range 12.3-27.9), number of prior chemotherapy regimens 1/2/3 or more: 17/22/33, ascites none/mild/moderate/severe: 42/19/7/4, median serum albumin levels (Alb): 3.2 g/dl (range 2.0-4.2). The median treatment duration of ANAM was 47.5 days (3-450 days). 57 patients (79.2%) continued ANAM for more than 3 weeks, and 9 patients for more than 12 weeks. The main reasons for discontinuation were progressive disease (39.7%), ineffective (12.7%), effective (11.1%) and adverse events of ANAM (11.1%). 33 patients (45.8%) gained weight, 41 patients (56.9%) improved appetite and 34 patients (47.2%) increased oral intake. There was a correlation found between BMI ＜ 18.0 kg/m
2
and the responders (OR 3.43, p = 0.041).
Conclusions:
In this study, 68.0% of patients who received ANAM for showed response, that is, gained body weight, or improved appetite, or increased oral intake. And these observations suggested that BMI was associated with effects of ANAM. Further studies involving more patients needed.
Evaluating the clinical benefits of anti-cancer drugs approved by Food and Drug Administration for gastrointestinal neoplasms for the past two decades.
Authors: Jamal Fares , Sahvan Oudai , Bekaii-Saab Tanios S. , Sonbol Mohamad Bassam
Published: January 2025

820

Background:
The number of FDA-approved anticancer drugs have increased in recent years with a more use of surrogate endpoints. However, it is unclear whether the same trend applies to GI cancers. Therefore, we aimed to evaluate the trend in FDA-approved GI cancer drugs over the past two decades and the associated clinical benefit.
Methods:
The FDA’s online database was searched for drugs approved for GI cancers from 2006 until 2024. Primary and secondary endpoints along with trial characteristics were extracted. ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) was assessed by two blinded investigators with a third resolving disagreements. We divided the study into period A (01/2006-12/2014) and period B (01/2015-08/2024).
Results:
Since 2006, FDA approved 62 regimens for GI cancer based on 70 trials, mostly (n= 45;72.6%) in period B. Most trials (n=44) were phase III with only 26 phase II: 22 single arm, and 4 randomized. All the 22 single-arm phase II trials were approved in period B with two randomized phase II trials approved in each period. Approvals based on phase III trials dropped by 33.5% (from n=15 to n=29) between the two periods. Half (n=34) of the approvals were based on overall survival (OS) benefit, while the use of objective response rate (ORR) as an endpoint has increased from 11.8% (n=2) in period A to 45.3% (n=24) in period B. Quality of life (QoL) was assessed only in 27% of the studies and found benefit only in 22.7%. The mean gain in OS was similar across both periods; 2.3 months [1.2-4.7]. Out of the 19 accelerated approvals, 17 were in period B, of which 23% (4/17) were based on secondary endpoint, 18% (3/17) were withdrawn, and 59% (10/17) received full approval. Substantial clinical benefit (ESMO score 4-5) was seen in 11.8% of the trials in period A and 19.6% in period B, with 17.4% overall from 2006-2024.
Conclusions:
Despite rising FDA approvals for GI cancer drugs since 2006, only 17.4% demonstrated substantial clinical benefit based on ESMO-MCBS. Recent approvals rely more on single-arm phase II studies and ORR, often without OS or QoL benefit. These trends underscore the need for more rigorous clinical trials that prioritize meaningful endpoint to ensure that new therapies provide real clinical value to the patient.
Annual incidence of colorectal cancer among patients with average risk in the United States between 2017 and 2023.
Authors: Stieber Brad , Greene Mallik , Le Quang Anh , Mou Joshua , Sakthisivabalan Lakshya , Lynch Danielle , Ozbay A Burak , LeMaster Joseph , Stukalin Igor , Anderson Joseph , Limburg Paul J.
Published: January 2025

83

Background:
Colorectal cancer (CRC) is the second most common cause of cancer-related mortality and third most common cancer in the United States. In 2021, 141,902 new cases of CRC were reported. With recent increases in early onset of CRC incidence, a shift in patterns amongst various demographics has been observed. Together with an estimated 60% increase in burden of CRC globally, it is important to continuously assess the nationwide incidence rates and monitor the changing patterns. In this study, we examined the annual incidence rates of CRC in average risk adults using a large national claims database and report patterns of incidence based on various demographic characteristics.
Methods:
CRC diagnoses were retrospectively identified from a large national claims database, which covers over 165 million lives and is representative of the U.S. population, for each calendar year during the study period from 2017 to 2023. Individuals aged 45 to 75 years, with an average risk of CRC before each index calendar year were included in the study. Individuals were required to be continuously enrolled in the same health plan for at least 1 year prior to and 1 year following the index year. Annual CRC incidence rates per 100,000 people were calculated for each year from 2017 to 2023 within various subgroups based on baseline demographics.
Results:
Overall, annual CRC incidences remained consistent during the study period with 186.86 (95% CI, 184.87-188.86) cases in 2017 and 183.40 (95% CI, 181.32-185.5) cases in 2023 per 100,000. Among younger adults aged 45-49 years, the annual CRC incidence increased by 66% from 2017 (92.04 cases/100,000) to 2023 (153.12 cases/100,000). Conversely, annual CRC incidence decreased by 25% between 2017 (328.52 cases/100,000) and 2023 (244.93/100,000) in older adults aged 65-75 years. Over the study period, CRC incidence in men was higher than women with an overall rate ratio (RR) of 1.206 (95% CI, 1.122-1.297). African American adults had higher CRC incidence than White Americans with an overall rate ratio (RR) of 1.216 (95% CI, 1.152-1.283).
Conclusions:
Based on this large study of national claims data, CRC incidence rates remained relatively stable in the total population among average-risk patients from 2017 to 2023. The continuing increase in recommended CRC screening utilization showed a decreased incidence rate in the older population, while observing increased incidences among younger patients.
A comparative study of dosage strategies in HIPEC: BSA-based vs fixed dose methods.
Authors: Multani Harsimran Kaur
Published: January 2025

832

Background:
Peritoneal metastases commonly occur in ovarian, gastric, and colorectal cancers, significantly contributing to patient morbidity and mortality. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is a promising approach for managing peritoneal surface cancers. This procedure involves cytoreductive surgery to remove visible tumors, followed by the perfusion of heated chemotherapy (41-42°C) directly into the peritoneal cavity. HIPEC addresses the limitation of systemic chemotherapy, which often fails to penetrate the peritoneal cavity effectively. HIPEC dosing may either be a flat-fixed dose or be calculated based on Body Surface Area (BSA). BSA can be determined using three methods: actual BSA (based on weight and height), ideal BSA (based on sex and height), and adjusted BSA (considering lean and fat mass).
Methods:
A retrospective chart review was conducted on 151 metastatic cancer patients at UVMMC. Patient BMI, weight, and height at diagnosis were collected to calculate BSA values (actual, adjusted, and ideal) for estimating a hypothetical chemotherapy dosage. Statistical analysis using SPSS involved linear mixed models and paired t-tests to compare Mitomycin-C dosages between a fixed dose (40 mg) and a BSA-derived dose (30 mg/m²).
Results:
The average dosage of Mitomycin-C differed significantly depending on whether the dose was calculated using actual, adjusted, or ideal BSA. The largest discrepancy in dosage was observed between the actual BSA method and the flat-fixed dose, with an average difference of 16 mg. The smallest difference in dose was between the adjusted and ideal BSA methods. When stratifying by BMI, the greatest variation in Mitomycin-C dosage was found among overweight and obese patients (BMI ≥ 25). For these patients, the average dosage difference between the flat fixed dose and the actual BSA dose was 20 mg. In comparison, in patients with a BMI under 18.5 (underweight) the actual BSA dose was comparable to the fixed dose.
Conclusions:
Different institutions utilize a variety of dosing strategies for the HIPEC procedure. Differences in BSA calculation methods and perfusate volumes (literature values of 2, 3 and 4 L is most common) contribute to the complexity of establishing standardized dosing. The significant dosing variations observed, especially in overweight and obese patients, are of concern, as 70% of the U.S. population has a BMI ≥ 25. Our study demonstrates significant variability in HIPEC chemotherapy dosing, especially among patients with higher BMI. The discrepancy between BSA-based methods and flat-fixed doses may impact treatment efficacy and toxicity. Standardizing dosing approaches is important to ensure consistent therapeutic outcomes and patient safety.