bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex differences in the colorectal tumor immune microenvironment.
Authors: Seitz Elizabeth , Tsai Ya-Yu , Melas Marilena , Lindsey Sidney S. , Walker Christopher P , Bonner Joseph D. , McDonnell Kevin , Idos Gregory , Greenson Joel K , Rennert Gad , Moreno Victor , Gruber Stephen B. , Schmit Stephanie
Published: January 2025

283

Background:
Males have increased risk and mortality rates of colorectal cancer (CRC) compared to females, but the reasons for these disparities are not well understood. Immune responses differ by sex, and a robust T cell response is an important prognostic indicator in CRC. We hypothesized that females exhibit a stronger CRC-associated T cell response, contributing to reduced mortality in females compared to males.
Methods:
The study cohort included 2,751 incident CRC patients (1,337 female; 1,414 male) from a population-based case-control study. T cell receptor (TCR) abundance and clonality were quantified using immunoSEQ, and a gastrointestinal pathologist scored tumor-infiltrating lymphocyte counts per high-powered field (TILs/hpf). We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between T cell metrics and sex, adjusting for age, anatomic site, and microsatellite instability (MSI) status. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals for the association between sex and 5-year all-cause and CRC-specific survival, adjusting for known prognostic indicators. We also conducted a formal test for interaction between sex and T cell features in relation to survival outcomes.
Results:
There were no associations between sex and TCR abundance (OR=1.05, 95% CI=0.98-1.13, p=0.14), TCR clonality (OR=0.99, 95% CI=0.91-1.06, p=0.72), or TILs/hpf (OR=1.05, 95% CI=0.88-1.25, p=0.60). We observed no differences in overall or disease-specific five-year survival between males and females. Further, the associations between T cell responses and survival did not significantly differ by sex.
Conclusions:
In a well-powered analysis, no robust sex differences were observed in the CRC immune microenvironment or in the relationship between T cell infiltration and CRC outcomes. The high burden of CRC and the emergence of immunotherapy as an important therapeutic approach suggest a need for further research investigating immunological sex differences in the setting of treatment response.

Summary of associations between the colorectal tumor T cell response and sex.

T cell Features
Odds Ratio(Female vs. Male)
Lower 95% CI
Upper 95% CI
P Value

TCR Abundance
1.05
0.98
1.13
0.14

TCR Clonality
0.99
0.91
1.06
0.72

TILs/hpf* <2
1.05
0.88
1.25
0.60

*A total of 99 patients (45 female; 54 male) with missing TILs/hpf data were excluded from the regression analysis.
The prevalence and prognostic significance of
KRAS G12C
mutation in metastatic colorectal cancer.
Authors: Lutz Joseph , Khamis Mohamed , Alkharabsheh Omar , Sahin Ibrahim Halil , Khushman Moh'd M.
Published: January 2025

289

Background:
Kristen rat sarcoma virus (
KRAS
) mutations are reported in 40-45% of colorectal cancer (CRC), and they are associated with poor prognosis.
KRAS G12C
mutation is reported in 3-4% of CRC patients and may be associated with worse prognosis compared to
RAS non-G12C
mutations. Here, we explored the prevalence and prognostic significance of
KRAS G12C
mutation compared to
RAS non-G12C
and
BRAF V600E
in a cohort of CRC patients from a tertiary cancer center in the United States (US).
Methods:
The cBioCancer Genomics Portal was used to obtain genomic data. The prevalence of
KRAS
G12C
mutation,
RAS non-G12C
(
KRAS
G12D,
KRAS
G13D,
KRAS
G12V,
KRAS
A146T,
KRAS
G12A,
KRAS
G12S,
KRAS
G13C,
KRAS
V14I,
KRAS
Q61H,
KRAS
G12R,
KRAS
Q61R,
KRAS
K117N,
NRAS Q61K
,
NRAS Q61R
,
NRAS Q61L
,
NRAS Q61H
,
NRAS G13D
,
NRAS G13C
NRAS G13R
NRAS G12D
,
NRAS G12C
,
NRAS G12V,
NRAS G12V
and
NRAS G60V
) mutations and
BRAF V600E
mutations was calculated. The median overall survival (mOS) was explored in CRC (MSK, Cancer Cell 2018 cohort). Patients in this cohort were not treated with
KRAS G12C
targeted therapy. Survival analysis was performed using the Kaplan-Meier method with log-rank test comparisons.
Results:
In this cohort of patients with stage IV CRC (N=1134), the prevalence of
KRAS G12C
mutation in patients with stage IV CRC was 3.1%. In patients with
RAS non-G12C
mutations,
BRAF V600E
mutation, and
RAS/BRAF V600E
wild-type (WT), the prevalence was 41.7%, 7.5%, and 47.7% respectively. The mOS in
KRAS G12C
mutation,
RAS non-G12C
mutations,
BRAF V600E
mutation, and
RAS/BRAF V600E
WT was 65 months (m), 55m, 19m and 105m respectively. Compared to
RAS non-G12C
, the mOS of CRC patients with
KRAS G12C
was (65m vs 55m, p=0.54) . Compared to patients with
BRAF V600E
mutation, the mOS was better in patients with
KRAS G12C
(65m vs. 19m, p <0.0001) and in patients with RAS non-G12C (55m vs. 19m, p <0.0001).
Conclusions:
The prevalence of
KRAS G12C
mutation in this cohort was relatively similar to other reports at 3.1%. Consistent with several other reports, there was no statistically significant difference in the mOS between patients with
KRAS G12C
mutation and patients with
RAS non-G12C
mutations. Patients with BRAF V600E mutations had worse mOS compared to patients with
KRAS G12C mutation
and
RAS non-G12C
mutations. The reported high mOS in this cohort is possibly due to selection bias (patients able to afford and receive treatment at this tertiary center).
Adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations and overall mortality among adults with colorectal cancer in a multiethnic cohort study.
Authors: Asiimwe Edgar , Tolstykh Irina , Chan June M. , Kenfield Stacey A , Wilkens Lynne , Le Marchand Loic , Haiman Christopher , Cheng Iona , Van Blarigan Erin
Published: January 2025

29

Background:
High adherence to AICR recommendations on diet, adiposity, and physical activity is associated with improved survival among adults with colorectal cancer (CRC). However, over 80% of participants in existing studies self-reported as non-Hispanic White (NHW). We studied the association between adherence to AICR recommendations and overall mortality among adults with CRC in a multiethnic cohort.
Methods:
This prospective analysis used data from the Multiethnic Cohort (MEC) study. The MEC is a racially/ ethnically diverse cohort of over 200,000 participants residing in Hawaii and Los Angeles. Lifestyle behaviors in the MEC were assessed by questionnaire at enrolment/Q1 (1993-1996) and periodically over follow-up. We included those with incident CRC before completing Q3 (2003-2008). Follow-up was from Q3 survey completion to December 2019. The main exposure was the standardized AICR score [0-7 points] at Q3. The primary outcome was overall mortality; CRC-specific mortality was secondary. We used multivariable Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CIs).
Results:
There were 1127 adults diagnosed with CRC prior to Q3. Of these, 1079 (95.7%) had non-missing data on the AICR score and comprised our study population. Median (IQR) age at diagnosis was 69 (62-75); median (IQR) follow-up was 12.2 (0.1-16.4) years. There were 489 (45.3%) women. By self-reported race/ethnicity, there were: 153 (14.2%) Black/African Americans, 453 (42.0%) Japanese Americans, 79 (7.3%) Latinos, 165 (15.3%) Native Hawaiians, and 229 (21.2%) NHWs. Only 48 (4.4%) adults had high adherence (AICR≥5 points). Those in the highest category of AICR scores (AICR≥4.5) had statistically significant lower risk of overall mortality relative to those in the lowest category (AICR≤2.5) (HR: 0.64, 95% CI, 0.47-0.89). A similar (but non-statistically significant) association was observed with CRC-specific mortality [HR (high vs low): 0.70, 95% CI, 0.31-1.60]. Those who increased their score between Q1&Q3 had lower overall mortality (HR: 0.87, 95% CI,0.79 - 0.96). Similar trends were observed in stratified analysis by race/ethnicity; however, statistical power was limited.
Conclusions:
High adherence to AICR recommendations was associated with lower risk of overall mortality in this multiethnic population of adults with CRC. Efforts to increase adherence to AICR recommendations in this population are needed.
5-hydroxymethylcytosine as a liquid biopsy biomarker in colorectal cancer.
Authors: Maher Christopher , Navadkar Netra , Liao Muheng , Crutcher De'Vana , Mudd Jacqueline L. , Coruh Ceyda , Guler Gulfem , Ning Yuhong , Chowdhury Shimul , Rozycki Emily , Ly Amy , Levy Samuel , Fields Ryan
Published: January 2025

291

Background:
5-hydroxymethylcytosine (5hmC) is an epigenetic modification which regulates gene expression and is associated with active transcription. The optimization of 5hmC sequencing in cell-free DNA (cfDNA) could therefore enable assessment of gene activity through a liquid biopsy. We aimed to investigate the 5hmC landscape of colorectal cancer (CRC) in plasma-derived cfDNA to evaluate the potential of 5hmC modifications as a liquid biopsy-based biomarker of CRC.
Methods:
Genome-wide 5hmC modifications were analyzed with a low-input whole-genome 5hmC sequencing method based on selective chemical labeling in cfDNA from 72 CRC patients and 70 healthy samples. Differential 5hmC analysis between CRC and healthy samples was conducted using DESeq2 (padj < 0.05 and log2FC <= -1 and >=1). Low-pass whole genome sequencing (LP-WGS) was performed on all cfDNA samples. Tumor fraction was estimated using ichorCNA to classify samples into high ct-fraction (>=0.1) and low ct-fraction (<0.1) groups. Nucleosome profiling was performed on LP-WGS to reveal chromatin accessibility patterns. Elastic Net Regression (ENR) was applied to identify changes in 5hmC levels for classifying samples as cancerous or healthy.
Results:
Differential cfDNA 5hmC levels of 139 genes distinguished high ct-fraction CRC (n=16) and healthy samples (n=70). Although the remaining CRC samples (n=56) had similar ct-fractions as the healthy samples, as estimated by ichorCNA, we found a differentially hydroxymethylated gene signature could discriminate between these low ct-fraction CRC and healthy samples. Nucleosome profiling analysis with LP-WGS in cfDNA was used to identify active transcriptional drivers of the genes with increased 5hmC levels. The analysis revealed increased chromatin accessibility near the binding sites for the transcription factor caudal-related homeobox transcription factor 2 (
CDX2
), a master transcriptional regulator of intestinal cell fate and cancer, in CRC patients relative to healthy samples. Corroborating this,
CDX2
and its downstream targets had increased 5hmC levels in cfDNA in CRC relative to healthy samples, consistent with colorectal-derived tumor DNA in CRC plasma samples.
Conclusions:
Genes with differential 5hmC levels in cfDNA can discriminate CRC and healthy samples. Our 5hmC signature identified CRC samples that did not harbor copy number gains or losses; which is typically used to estimate ct-fraction and routinely included in targeted ctDNA sequencing assays. Integration of 5hmC and LP-WGS can be used to identify gene activation in disease. In the context of CRC, CDX2 displayed increased chromosome accessibility in the promoters of its target genes which in turn displayed increased 5hmC levels. Further studies are aimed at optimizing and validating 5hmC-based biomarkers throughout patient treatment.
UGT1A1 mutation rates in a minority-rich comprehensive cancer center: A retrospective pharmacogenomic study.
Authors: Mo Christiana , Kuang Chaoyuan , Moon Jee-Young , Zhang Chenxin , Raj Srilakshmi , Bteich Fernand , Saenger Yvonne M. , Laderian Bahar
Published: January 2025

294

Background:
Irinotecan is a widely used and effective treatment for various gastrointestinal malignancies. Its toxic metabolite, SN-38, is inactivated by UDP glucuronosyltransferase-1A1 (UGT1A1). However, variability in individual clearance of irinotecan and SN-38 can cause unpredictable toxicities. Mutations in the
UGT1A1
gene reduces enzyme activity, resulting in dose-limiting neutropenia and diarrhea, hospitalizations, treatment delays, and dose reductions. The best characterized germline variant is a polymorphism in the UGT1A1*28 allele, but data in underrepresented groups remains particularly lacking.
Methods:
We conducted a retrospective cohort study of patients who were treated at our minority-rich academic medical center. A total of 63 patients with gastrointestinal malignancies were tested for the UGT1A1*28 polymorphism. Data for irinotecan treatment course, related toxicities, and dose reductions was available for 41 patients. Analysis was performed using Fisher’s exact test, one-way ANOVA, and Welch’s two-sample test.
Results:
73% (n = 46) of patients were identified with the UGT1A1*28 polymorphism, including 63% (n = 29) with heterozygous genotype and 36.9% (n = 17) with homozygous genotype. There were significantly more patients of UGT1A1*28 polymorphisms carriers in the African American and Hispanic population as compared to the white population (p = 0.001, 0.01 respectively). The polymorphism frequency was 0.66 in the African American group [95% CI (0.49 – 0.81)], 0.48 in the Hispanic group [95% CI (0.34 – 0.62)], and 0.06 in the white group [95% CI (0.001 – 0.30)]. The frequency was significantly lower in the white population when compared to all other races (p-value = 0.0002), to African American (p- value < 0.001), and to Hispanic (p-value = 0.003) populations. There were higher rates of overall toxicities of any grade in the heterozygotes (76%) and homozygotes (64%) when compared to the wild-type group (56%). 55% (n = 6) of the homozygous and 48% (n = 10) of the heterozygous patients developed G1-G4 neutropenia, as compared to the 22% (n = 2) of the wild-type patients.
Conclusions:
Ethnic differences are known to exist in UGT1A1*28 polymorphism, with the prevalence being significantly higher in African and Caucasian populations. Historical data based on large-scale genotyping report allele frequencies of 0.42 in African/African American, 0.37 in Hispanic American, and 0.29 in Europeans. Our local population has a higher rate overall in both the African American and Hispanic populations with significantly higher rates than the white population. Patients with the UGT1A1*28 polymorphism experienced more toxicities and neutropenia of any grade.
UGT1A1
genotyping is not routinely performed in patients initiating irinotecan treatment, however it may prove to be beneficial in certain demographics with higher rates of UGT1A1*28 polymorphisms.
Real-world treatment patterns, healthcare resource utilization (HCRU), and costs in newly diagnosed patients with rectal cancer (RC) in the United States (US).
Authors: Moore-Schiltz Laura , Solem Caitlyn T , Tkacz Joseph , O’Donnell Sean
Published: January 2025

295

Background:
RC constitutes 30% of colorectal cancer cases, the fourth most common cancer in the US, and is associated with a substantial economic burden. This retrospective claims analysis examined patient (pt) characteristics, all-cause and RC-related HCRU, and costs in pts who received surgery, radiotherapy (RT), or systemic therapy (ST) for RC.
Methods:
Medicare Fee-for-Service and MORE
2
Registry claims data were used to select pts with RC (RC cohort) and matched, non-RC controls (non-RC cohort). Pts with RC were required to have a diagnosis of RC in the primary position of ≥1 inpatient claim or in any position of ≥2 outpatient claims between Jan 1, 2016, and Dec 1, 2021, and ≥1 claim for an RC surgery, RT, or ST after diagnosis. Pts (aged ≥18 y) also needed to have continuous enrollment for 12 months preceding and minimum 30 days following the treatment index date (earliest RC treatment claim). Non-RC controls were matched to pts with RC on birth year, sex, payer type, and Deyo-Charlson Comorbidity Index (DCI). All-cause HCRU and costs (per pt per month [PPPM]) were compared for the RC and non-RC cohorts.
Results:
A total of 20,953 pts were included in each cohort (median age, 70 y; 52.5% male; median DCI, 1.0 in both cohorts). Median follow-up time was 24 months. In the RC cohort, 88.5% of pts underwent ≥1 surgery after RC diagnosis and 51.3% had ≥4 surgeries during follow-up. Colonoscopy and biopsies (59.4%), total mesorectal excision (47.7%), and proctectomy (45.2%) were the most frequent surgeries/procedures. RT was used as neoadjuvant and adjuvant therapies in 21% and 15.7% of pts, respectively; 5-fluorouracil was the most common neoadjuvant (12.7%) and adjuvant (20.9%) ST. Among nonsurgical pts (11.5%), 72.8% were treated with RT and 49.9% with 5-fluorouracil; a small proportion received immunotherapy (pembrolizumab, 1.2%; nivolumab, 0.7%). All-cause HCRU was significantly greater (
P
<0.001) in the RC cohort vs the non-RC cohort (proportion of pts with ≥1 claim for physician office/clinic visit, 81.3% vs 73.6%; emergency room visits, 68.7% vs 45.3%; hospitalization, 71.1% vs 25.9%). The mean all-cause costs PPPM were $6043 for the RC cohort vs $1538 for the non-RC cohort (
P
<0.001); mean RC-related costs PPPM were $3119. Outpatient and inpatient services were the main cost drivers in the RC cohort, accounting for 57.1% and 36.6% of all-cause expenditure, respectively, and 58.1% and 40.5% of RC-related expenditure.
Conclusions:
Most pts newly diagnosed with RC received standard of care surgical treatment, often with neoadjuvant or adjuvant RT or ST. All-cause HCRU was significantly greater for pts with RC vs those without RC; all-cause costs were almost 4 times higher, with about half of these costs related to RC and driven by outpatient services and hospitalizations. These results show a high economic burden and a need for additional treatments for pts with RC.
Man versus machine: Comparative analysis of ChatGPT’s colon cancer guidance and expert opinion.
Authors: Ojha Sujata , Sessions William Steele , Goodgame Boone
Published: January 2025

299

Background:
AI Chatbots, such as ChatGPT, are increasingly being utilized across various aspects of society, including healthcare. Despite this growing usage, their role within the field of oncology remains underdeveloped. The objective of this study is to evaluate ChatGPT’s ability to accurately respond to patient inquiries regarding colon cancer by comparing its responses to assessments from expert clinical oncologists.
Methods:
Ten comprehensive questions were compiled by reviewing commonly asked questions from reputable sources, including the American Society of Colon & Rectal Surgeons, Mount Sinai, the National Cancer Institute, Mayo Clinic, and the American Cancer Society. The questions were categorized into two categories based on their content: General Oncology Characteristics (covering symptoms, screening, and prevention) and for Diagnosis & Treatment. These questions were then entered into ChatGPT, with prompts designed to simulate patient inquiries. The AI-generated responses were subsequently evaluated by oncology experts using a 5-point Likert scale to assess their accuracy and relevance, with scores reflecting the experts' level of agreement with the answers.
Results:
On a five-point Likert scale, with 1 representing "strongly disagree" and 5 representing "strongly agree," the mean score was 4.72. ANOVA analysis was performed and there was no statistically significant difference in the mean score across all raters (p = 0.221). However, ratings between the two categories were statistically significant (p=0.034).
Conclusions:
This study demonstrates that ChatGPT can provide accurate and relevant responses to patient inquiries about colon cancer, as assessed by medical oncology experts. With an average rating of 4.72 on a 5-point Likert scale, ChatGPT’s responses closely align with expert opinion, particularly for general characteristics category which included symptoms, prevention, and screening. However, responses related to diagnosis and treatment showed a statistically significant difference between expert opinions and AI, indicating that the experts agreed less with this component of AI's responses. These findings highlight the potential of AI chatbots in supplementing patient education in oncology, though further research is necessary to explore its limitations and expand its clinical utilities.
Demographic predictors of multi-target stool DNA test completion in an underserved primary care population: A retrospective analysis.
Authors: Ganguly Arup , Paladiya Ruchir , Vergara Cunegundo
Published: January 2025

30

Background:
Colorectal cancer screening remains crucial for early detection, with multi-target stool DNA(Exact Sciences, Madison, WI, USA) serving as a non-invasive option. However, adherence to test completion may vary across different demographic groups. This study aims to assess the association between patient demographics and the completion of Cologuard testing in an underserved primary care population in order to further explore the disparities that exist.
Methods:
We conducted a retrospective analysis of 12071 eligible patients, aged 45-75, across Hartford Healthcare Primary Care Clinics across Connecticut, USA, between November 2022 and April 2024 for whom an order for this test was placed. Demographic data including gender, age, English proficiency, and insurance status(public/private vs no insurance) were analyzed. The outcome of interest was whether patients had results available within 120 days of placing the order. Logistic regression was used to examine the relationship between these variables and the likelihood of Cologuard test completion.
Results:
11704(96.9%) of all patients were insured. Among insured patients, 6945 (59.9%) had results available, while 4759 (41.1%) did not have results at the 120 day mark. Among uninsured patients, 46 (12.5%) had results, while 321 (87.5%) did not. Insured patients were more likely to have test results available compared to uninsured patients (OR = 10.184, 95% CI: 7.460-13.901, p < 0.01). 10977(90.9%) patients were English proficient. They were more likely to have results compared to Non-English proficient patients (OR = 3.474, 95% CI: 3.038-3.972, p < 0.01). Gender was not a significant predictor of test completion (OR = 0.964, 95%CI: 0.895-1.039, p = 0.341), and older age demonstrated a small, non-significant effect (OR = 1.004, p = 0.094), with a test for non-linearity confirming a linear relationship between age and test completion (p = 0.162).
Conclusions:
Insured status and English proficiency are significant predictors of Cologuard test completion in this primary care cohort and are more likely complete testing. These findings underscore the need for targeted interventions to increase colorectal cancer screening adherence, particularly among this population.
Comprehensive analysis of socioeconomic and clinical factors contributing to treatment delay in early-onset colorectal cancer.
Authors: Tanariyakul Manasawee , Acoba Jared David
Published: January 2025

32

Background:
The prevalence of early-onset colorectal cancers (EOCRC) is rising globally. Disparities in social determinants of health can delay access to treatment and impacting outcomes. This study aims to analyze factors influencing time from diagnosis to treatment among EOCRC patients in a racially diverse population, considering tumor factors and sociodemographics.
Methods:
We analyzed EOCRC data from patients diagnosed between 2000 and 2022 at Queen’s Medical Center in Honolulu, Hawaii. Time from diagnosis to treatment for Asians, Whites, and Native Hawaiian or Other Pacific Islanders (NHOPI) was assessed using the Kaplan-Meier Method. Cox proportional hazards regression models were used to identify predictors, adjusting for clinical and pathological factors.
Results:
A total of 379 patients were analyzed. NHOPI were more like to be underinsured compared to Whites and Asians. In the unadjusted Cox model, underinsured/uninsured status, older age, unknown stage, left sided, and rectal locations were associated with delayed treatment. After adjustment, underinsured/uninsured status, older age, and rectal location remained significant predictors of delayed treatment.
Conclusions:
EOCRC patients with underinsured/uninsured status, age, and rectal tumor location are significantly associated with delayed in cancer treatment. While age was statistically significant, its clinical impact appears minimal. The need for a multidisplinary approach and additional preoperative staging in rectal cancer may explain treatment delays even after adjustment. Improving treatment accessibility and reducing delays, especially for underinsured EOCRC patients, is important.

Univariate and multivariate analysis of time from diagnosis to treatment.

Univariate
Multivariate

HR (95% CI)
p-value
HR (95% CI)
p-value

Insurance
-
-
-
-

Private insurance
-
-
-
-

Underinsured/Uninsured
0.692 (0.545-0.878)
0.003
0.706 (0.55-0.906)
0.006

Race

White
-
-
-
-

Asian
0.912 (0.696-1.195)
0.503
0.817 (0.619-1.077)
0.151

NHOPI
0.749 (0.548-1.025)
0.071
0.779 (0.562-1.08)
0.134

Age
0.978 (0.96-0.997)
0.021
0.968 (0.949-0.987)
0.001

Histopathology grade

Grade 1&2
-
-
-
-

Grade 3&4
1.046 (0.798-1.371)
0.746
1.083 (0.813-1.441)
0.587

Stage

1
-
-
-
-

2
1.022 (0.718-1.456)
0.902
1.071 (0.744-1.539)
0.713

3
1.227 (0.896-1.682)
0.203
1.387 (0.997-1.931)
0.052

4
0.964 (0.673-1.381)
0.842
1.039 (0.716-1.507)
0.842

Unknown
0.631 (0.406-0.981)
0.041
0.748 (0.473-1.182)
0.213

Sex

Male
-
-
-
-

Female
1.029 (0.836-1.267)
0.785
1.072 (0.868-1.325)
0.518

Microsatellite status

Stable
-
-

Unstable
1.074 (0.616-1.875)
0.8

Not done/Unknown
1.259 (1.004-1.577)
0.046

Location of Tumors

Right
-
-
-
-

Left
0.631 (0.468-0.851)
0.003
0.735 (0.535-1.011)
0.058

Rectal
0.43 (0.317-0.582)
<0.001
0.448 (0.327-0.613)
<0.001

NHOPI: Native Hawaiians and Other Pacific Islanders. HR: Hazard Ratio CI: Confidence Interval.
Intraperitoneal and intravenous paclitaxel plus S-1 versus intravenous paclitaxel plus S-1 in gastric cancer patients with peritoneal metastasis: Results from the multicenter, randomized, phase 3 DRAGON-01 trial.
Authors: Yan Chao , Yang Zhongyin , Shi Zheng , Lu Sheng , Shi Min , Nie Mingming , Chen Jian , Wu Dan , Mou Yiping , Xu Yunyun , Wang Yanong , Liu Xiaowen , Cao Hui , Gu Jiayi , Yu Jiren , Liu Kai , Liu Xinchun , Zhang Jun , Yin Kai , Zhu Zhenggang
Published: January 2025

327

Background:
The optimal chemotherapeutic regimen for gastric cancer with peritoneal metastasis remains undefined. We evaluated the efficacy and safety of intraperitoneal and intravenous paclitaxel plus S-1 (NIPS Group) versus paclitaxel plus S-1 (PS Group) in gastric cancer patients with peritoneal metastasis.
Methods:
In this multicenter, randomized, controlled, phase 3 trial, patients were recruited from 9 cancer centers in China. Eligible patients were aged 18~75 years with an Eastern Cooperative Oncology Group performance status of 0~1, histologically confirmed gastric adenocarcinoma, peritoneal metastases from gastric cancer requiring definitive diagnosis by laparoscopy, without gastric outflow tract obstruction and intestinal obstruction, no prior treatment with chemotherapy, radiation therapy, targeted therapy or immunotherapy. Eligible patients were randomly assigned (2:1) to receive either intravenous paclitaxel at 50 mg/m² and intraperitoneal paclitaxel at 20 mg/m² on days 1 and 8, along with oral S-1 at a dose of 80 mg/m² on days 1~14, or intravenous paclitaxel at 70 mg/m² on days 1 and 8, along with oral S-1 at 80 mg/m² on days 1~14. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all participants. A sample size of 238 patients was calculated to provide 80% power with a one-sided alpha of 0.1, accounting for a 10% dropout rate. Survival was analyzed using Kaplan-Meier curves and compared with the log-rank test. Cox regression was used for multivariate analysis. A
P
-value < 0.05 was considered statistically significant.
Results:
From May 10, 2017, to March 9, 2022, 246 patients were screened and 222 were included in the modified intention-to-treat population, of whom 148 patients were assigned to the NIPS Group and 74 to the PS group. As of data cutoff (March 9, 2024), the median survival time was 19.4 months (95% CI, 17.1~22.9), in the NIPS group and 13.9 months (95% CI, 10.3~16.1) in the PS group (HR = 0.66; 95% CI 0.49 - 0.88;
P
= 0.005). The 1-year and 2-year overall survival rates were 69.6% and 37.2% in the NIPS group, compared to 54.1% and 20.3% in the PS group. The most common grade 3~4 adverse events were leukopenia (21.7% in the NIPS group, and 24.7% in the PS group) and neutropenia (19.9% in the NIPS group, and 23.4% in the PS group). No treatment-related deaths were reported.
Conclusions:
Intraperitoneal and intravenous paclitaxel plus S-1 significantly improved the overall survival compared to intravenous paclitaxel plus S-1 in gastric cancer patients with peritoneal metastasis, with manageable toxicity. Clinical trial information: ChiCTR-IIR-16009802.
Safety and efficacy of first-line nivolumab plus chemotherapy for HER2-negative advanced gastric cancer in real-world patients: Updated analysis.
Authors: Shimozaki Keitaro , Fukuda Koshiro , Ooki Akira , Nakayama Izuma , Yoshino Koichiro , Udagawa Shohei , Fukuoka Shota , Osumi Hiroki , Ogura Mariko , Wakatsuki Takeru , Takahari Daisuke , Shinozaki Eiji , Chin Keisho , Yamaguchi Kensei
Published: January 2025

341

Background:
Based on the results of CheckMate-649 and ATTRACTION-4, nivolumab plus chemotherapy is the new standard of care as first-line treatment for patients with HER2-negative advanced gastric cancer (AGC) regardless of PD-L1 combined positive score (CPS) status in Japan. This study aimed to evaluate the safety and efficacy of this regimen in real-world patients with HER2-negative AGC with a longer follow-up.
Methods:
In this single-institutional retrospective study, patients with HER2-negative AGC who were treated with first-line nivolumab plus chemotherapy between September 2021 and April 2024 were consecutively enrolled and evaluated. Early tumor shrinkage (ETS) was defined as ≥20% tumor reduction at 8 ± 2 weeks.
Results:
Of 151 patients, median age was 66 years (range, 27–83); 58% were male; 81% had diffuse-type histology; the peritoneal metastasis was seen in 60%; PD-L1 CPS of <1, 1≤/<5, 5≤ was 30%/41%/29%; deficient mismatch repair and/or high microsatellite instability was 7%. At a median follow-up of 14.2 months, the median overall survival (OS) and progression-free survival (PFS) were 21.7 months (95% confidence interval [CI] 14.4–26.2) and 7.7 months (6.4–9.6), respectively. The median OS according to CPS subgroups (<1, 1≤/<5, 5≤) were 21.7 / not reached (NR) /25.0 months, respectively (log-rank P = 0.55). In patients with measurable lesions at baseline according to RECIST ver 1.1, the objective response rate and disease control rate were 62% and 87%, respectively, with a complete response rate of 10%. In the exploratory analysis by ETS, both median PFS and OS were significantly longer in the ETS group compared to the non-ETS group (PFS, NR vs. 6.2 months; hazard ratio [HR] 0.35; 95% CI 0.17–0.68; P = 0.001) (OS, 25.0 vs. 11.7 months; HR 0.44; 95% CI 0.20–0.93; P = 0.03). The immune-related adverse events (irAEs) of any grade were observed in 26% (grade 3–4 irAEs 12%), whereas no treatment-related death was documented.
Conclusions:
The updated analysis suggests that first-line nivolumab plus chemotherapy provides benefit in real-world patients with HER2-negative AGC regardless of PD-L1 status, and suggests that the magnitude of ETS may predict a significant impact on the duration of survival.
The association of antibiotic use and survival among patients receiving first line immunotherapy-based treatment for advanced gastroesophageal cancers.
Authors: Balmaceda Nicole Baranda , Hu Junxiao , Alami Vida , Davis S. Lindsey , Leal Alexis Diane , Lentz Robert William , Robinson Hannah Ruth , Baiyee Toegel Emily , Lieu Christopher Hanyoung , Messersmith Wells A. , Ueberroth Benjamin Edward , Hayden Alexander , Kim Sunnie S.
Published: January 2025

349

Background:
The advent of immune checkpoint inhibition (ICI) has improved the survival for patients with gastroesophageal cancer (GEC). It is vital to understand the relationship between the tumor microenvironment and the ability of the immune system to prevent and eliminate cancer cells. Antibiotics (abx), frequently used in patients on cancer-directed therapy, can alter gut microbiota leading to dysbiosis and altered immune responses. Some research shows its use is associated with decreased ICI efficacy in RCC, NSCLC, and melanoma. The goal of our study is to investigate the association of abx timing and survival with 1L ICI-based treatments for advanced GEC.
Methods:
The retrospective, multicenter analysis used the Flatiron Health deidentified electronic health record-derived database of real world (rw) patients with advanced esophageal, GEJ, and gastric cancers (EC/GEJC/GC) who received ICI +/- chemotherapy (chemo) as 1L therapy. Abx exposure was defined by antibiotic use from 42 days before to 42 days after starting ICI. The cox proportion hazards models were used to compare rw overall survival (OS) and progression-free survival (PFS) across exposure groups.
Results:
A total of 990 patients were included for the main group analysis with comparison of survival and abx usage and timing: 876 did not receive abx, 58 received abx within 42 days after starting ICI, and 56 received abx within 42 days prior to starting ICI. The median age was 66 with 44.4% EC, 33.5% GC, and 22% GEJC. The majority of patients had adenocarcinoma (87.9%). The unadjusted OS HR for abx (within 42 days) before ICI was 0.99 (0.68-1.46, p=0.971) and (within 42 days) after ICI was 1.56 (1.11-2.19, p=0.011), suggesting worse OS with abx use after ICI initiation. HR trended towards worse PFS for those receiving abx after 1L ICI [1.36 (0.97-1.90 p= 0.073)]. In subgroup analysis, the negative effect of starting abx after 1L ICI over abx before ICI was more prominent in those receiving ICI monotherapy compared to those receiving chemo/ICI.
Conclusions:
Our study identifies a poorer survival association of abx administration after 1L ICI-based therapy for advanced GEC, primarily driven by ICI monotherapy.

Main group comparison between abx usage and timing: OS

Abx Use/Timing
n (%)
HR

No
876 (88.5)

Yes, after 1L IO
58 (5.9)
1.56 (1.11-2.19, p=0.011)

Yes, before 1L IO
56 (5.7)
0.99 (0.68-1.46, p=0.971)

Subgroup comparison between abx usage and timing by treatment type

Chemo + IO: OS
Yes, after 1L IO
44 (6.9)
1.32 (0.88-1.98,p=0.177)

Yes, before 1L IO
38 (6.0)
1.01 (0.62-1.65, p=0.964)

IO monotherapy: OS
Yes, after 1L IO
12 (4.9)
2.64 (1.38-5.06, p=0.003)

Yes, before 1L IO
12 (4.9)
1.09 (0.53-2.23, p=0.810)
Prognostic and biological divergence of upper gastrointestinal adenocarcinomas.
Authors: Dang Arun , Pan Minggui , Stover Jack , Huang Tina , Tong Meng , Jiang Chen , Habel Laurel A. , Achacoso Ninah , Bien Jeffrey , Solorzano-Pinto Aleyda V , Tse Pamela , Chung Elaine , Felsher Dean W. , Fisher George A. , Thomas Sachdev P.
Published: January 2025

350

Background:
Esophageal (EAC), gastroesophageal junction (GEJ) or gastric (GAC) adenocarcinoma share similar etiologies and treatment approaches. However, it is not clear if they possess similar or different prognostic and biological characteristics. We aimed to examine overall survival (OS) in associations of the common genomic alterations with these three anatomically closely linked adenocarcinomas.
Methods:
Eligible patients had recurrent or de novo metastatic GAC, GEJAC or EAC whose tumors had undergone next generation sequencing (NGS) performed from November 2017 to December 2023. We used Cox regression modeling to examine the association between GAC, GEJAC, EAC and OS, adjusting for demographics, performance status, Charlson comorbidity index, receipt of chemotherapy, and HER2 overexpression or amplification (HER2 positive),
p53
(mutp53
)
,
KRAS
(mutKRAS),
CDKN2A
,
PIK3CA
co-mutations and
MYC
amplification.
Results:
Of 875 total eligible patients, 173 had EAC, 276 had GEJAC and 426 had GAC. GEJAC had substantially better OS than EAC (HR = 0.68, [95% CI, 0.54-0.86]), and modestly better OS than GAC (HR = 0.85, [95% CI, 0.67-1.09]). HER2 positivity was associated with substantially better OS among EAC (HR = 0.62; [95% CI, 0.40-0.96]) and GEJAC (HR = 0.59; [95% CI, 0.38-0.87]) but not among GAC (HR = 0.98; [95% CI, 0.78-1.23]) patients. In addition, p53 gain-of-function versus non-gain-of-function mutations were associated with substantially worse OS among GAC (HR = 1.41; [95% CI, 0.98-2.01]) but not among EAC or GEJAC. MutKRAS was associated with substantially worse OS among EAC (HR = 1.81; [95% CI, 1.10-2.99]) but not among GEJAC or GAC. Surprisingly,
MYC
amplification was associated with dramatically better OS among EAC (HR = 0.19; [95% CI, 0.08-0.42]) but substantially worse OS among GEJAC (HR = 1.98, 95% CI, 1.14-3.40]) and GAC (HR = 1.75; [95% CI, 1.10-2.80]).
Conclusions:
GEJAC, EAC and GAC possess substantially different OS that appears differentially associated with HER2 status, mutp53, mutKRAS and
MYC
amplification. These results suggest distinct prognostic and biological characteristics of these three anatomically closely linked adenocarcinomas that could have important implications in clinical practice and on further investigations on their biological and topological mechanisms.
Results of a multicenter retrospective cohort study evaluating the safety and efficacy of FTD/TPI plus ramucirumab in advanced gastric cancer (HGCSG2302).
Authors: Yoshikawa Ayumu , Nakamura Takeaki , Sawada Kentaro , Ishiguro Atsushi , Motoo Iori , Sonoda Yuki , Suzuki Kazuhiro , Nakatsumi Hiroshi , Hosokawa Ayumu , Ishii Takahiro , Ito Ken , Nakamura Michio , Hatanaka Kazuteru , Meguro Takashi , Sogabe Susumu , Sasaki Yusuke , Nakano Shintaro , Muranaka Tetsuhito , Yuki Satoshi , Komatsu Yoshito
Published: January 2025

351

Background:
In advanced gastric cancer, trifluridine/tipiracil (FTD/TPI) is one of the standard treatments for later-line chemotherapy. Ramucirumab (RAM), an anti-VEGFR-2 monoclonal antibody, has shown promising efficacy in combination with FTD/TPI in phase II studies conducted in Japan, suggesting that this combination could improve treatment outcomes. However, there remains a paucity of real-world clinical data comparing the efficacy and safety of FTD/TPI monotherapy and FTD/TPI plus RAM combination therapy in general clinical practice.
Methods:
This retrospective analysis to evaluate safety and efficacy included patients with gastric cancer who were received FTD/TPI plus RAM combination therapy or FTD/TPI monotherapy between August 2019 and March 2023 at 21 institutions.
Results:
164 patients were analyzed, 38 patients in the RAM combination group and 126 in the FTD/TPI monotherapy group. The distribution of treatment lines (third/fourth/fifth) was 10/13/15 in the RAM group and 26/54/46 in the monotherapy group, respectively. RAM had been previously administered to 34 patients (89.5%) in the RAM group. Objective response rate and disease control rate were 11.1% / 55.6% (OR 2.0, 95% C.I. 0.84-4.77, p=0.126) in the RAM group and 5.5% /38.5% (OR 2.0, 95% C.I. 0.84-4.77, p=0.126) in the monotherapy group, respectively. Median progression-free survival (PFS) was 3.5 months in the RAM group and 2.1 months in the monotherapy group (HR 0.69, 95% C.I. 0.49-1.02, p=0.06), respectively. Median overall survival (OS) was 8.4 months in the RAM group and 5.8 months in the monotherapy group (HR 0.82, 95% C.I. 0.54-1.25, p=0.350), respectively. Grade 3 neutropenia was reported in 48.6%/52.4% (p=0.707), and there were no significant differences in other adverse event profiles between the two groups. Additionally, in the RAM group, a comparison between patients receiving standard dosing (2 weeks on/2 weeks off; n=7) and those on biweekly dosing (1 week on/1 week off; n=24) showed no notable differences in efficacy or safety.
Conclusions:
FTD/TPI plus RAM combination therapy showed a trend toward prolonged PFS compared to FTD/TPI monotherapy, but no significant difference in OS.
Impact of prior nivolumab use on the efficacy of second-line taxane-based chemotherapy in advanced gastric or esophagogastric junction adenocarcinoma.
Authors: Sano Momoko , Hirose Toshiharu , Yamaguchi Shotaro , Hirano Hidekazu , Okita Natsuko Tsuda , Shoji Hirokazu , Takashima Atsuo , Kato Ken
Published: January 2025

352

Background:
Taxane-based chemotherapy remains the standard second-line treatment after first-line treatment including anti-PD-1 antibody therapy for patients with advanced gastric or esophagogastric junction adenocarcinoma (GA/EGA). The CheckMate 649 trial suggested that prior use of nivolumab in the first-line setting was associated with longer progression-free survival (PFS) with subsequent treatment. However, there have been few reports on the difference in efficacy of taxane-based chemotherapy as second-line treatment with or without prior nivolumab use in the real-world setting.
Methods:
We retrospectively reviewed the medical records of patients with advanced GA/EGA who received solvent-based paclitaxel or nanoparticle albumin–bound (nab)-paclitaxel chemotherapy regimens as second-line treatment after first-line platinum-based chemotherapy between January 2018 and August 2024. We divided the patients into two groups: those who received nivolumab with the first-line chemotherapy (Nivo group) and those who did not (non-Nivo group). PFS and overall survival (OS) were estimated using the Kaplan–Meier method and compared between the two groups using 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 115 patients were included: 27 patients in the Nivo group and 88 in the non-Nivo group. Patient backgrounds did not differ significantly in terms of age (median 67/67 years), sex (male 59%/57%), performance status (PS; ≥2 11%/15%), site of primary tumor (EGA 11%/9%), number of metastatic sites (≥3 33%/18%), and ramucirumab use (yes 82%/82%). For the taxane regimens, nab-paclitaxel-based treatment was significantly more common in the non-Nivo group (11.1% /55.7%, p<0.001). There was a tendency toward longer PFS in the Nivo group compared with the non-Nivo group (median 4.2 months [95%CI 2.8-6.0] vs. 2.3 months [95%CI 2.0-3.0], HR 0.65 [95%CI 0.40-1.03]; p=0.067.) The objective response rate was numerically higher in the Nivo group compared with the non-Nivo group (29.4% vs. 17.6%, p=0.315). OS was not significantly different between the Nivo and non-Nivo groups (median 9.6 months [95%CI 4.9-NA] vs. 6.6 months [95%CI 5.5-10.8], HR 0.92 [95%CI 0.52-1.64]; p=0.785). In the non-Nivo group, 64 patients (73%) received subsequent chemotherapy, and 63 patients (72%) received nivolumab. Multivariate analysis identified prior use of nivolumab was a favorable prognostic factor for PFS (HR 0.55 [95%CI 0.31-0.97]; p=0.039). However, prior use of nivolumab did not show a significant benefit for OS (HR 1.09 [95% CI: 0.56-2.13]; p = 0.802).
Conclusions:
Prior use of nivolumab in first-line platinum-based chemotherapy had a positive impact on PFS with taxane-based second-line chemotherapy in advanced GA/EGA.
Q-TWiST analysis of pembrolizumab plus trastuzumab and chemotherapy for patients with metastatic HER2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma in the KEYNOTE-811 trial.
Authors: Rha Sun Young , Revil Cedric , Valderrama Adriana , Wang Liya , Andre Manon , McCarthy Grant , Young Kate
Published: January 2025

354

Background:
In the phase 3 KEYNOTE-811 trial (NCT03615326), first-line pembrolizumab plus trastuzumab and chemotherapy (pembrolizumab group) statistically significantly improved PFS and OS versus placebo plus trastuzumab and chemotherapy (placebo group), with manageable safety, in patients with metastatic HER2-positive G/GEJ adenocarcinoma, while maintaining HRQoL, specifically in patients with PD-L1 combined positive score (CPS) ≥1 tumors. The objective of this analysis was to assess quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) for patients treated in the KEYNOTE-811 trial.
Methods:
Q-TWiST is a measure of survival weighted by health states utility values. The analysis categorized survival time into 3 health states: time with grade ≥3 adverse events (toxicity [TOX]) and time without symptoms or toxicities (TWiST)—both before disease progression or death—and relapse (REL), defined as time from disease progression to death. Q-TWiST was calculated as the restricted mean survival time spent in each state, with a weighted health state utility for that state. Average utility weights were derived based on pooled EQ-5D-5L scores using the US mapping algorithm and standardized base case utility weights. Relative gains in Q-TWiST of ≥10% and ≥15% were “clinically important” and “clearly clinically important,” respectively, as reported in the literature. Treatment difference 95% CIs were generated using the nonparametric bootstrapping method. Data are reported for patients with PD-L1 CPS ≥1 tumors. The data cutoff date was March 20, 2024.
Results:
At the maximum follow-up of 63 months, patients in the pembrolizumab group had a 2.36-month (95% CI, −0.24 to 4.56) longer restricted mean time in TOX (6.98 vs 4.63 months), a 3.40-month (95% CI, −0.44 to 7.45) longer restricted mean time in TWiST (12.03 vs 8.62 months), and a 1.45-month (95% CI, −5.84 to 3.09) shorter restricted mean time in REL (8.87 vs 10.32 months) versus the placebo group. For the restricted mean Q-TWIST at month 63, based on the US mapping algorithm, the difference between the pembrolizumab and placebo groups favored the pembrolizumab group by 3.90 months (95% CI, 1.30 to 6.72), representing a 16.57% relative Q-TWiST gain. Based on the standardized base case utility weights, the difference also favored the pembrolizumab group by 3.86 months (95% CI, 1.47 to 6.67), representing a 16.38% relative Q-TWiST gain.
Conclusions:
Pembrolizumab plus trastuzumab and chemotherapy produced a clearly clinically important improvement in quality-adjusted survival time based on Q-TWiST analyses compared with placebo plus trastuzumab and chemotherapy in patients with previously untreated metastatic HER2-positive G/GEJ adenocarcinoma with PD-L1 CPS ≥1.
Clinical trial information: NCT03615326
.