bluuebunny/crossref_metadata_2025 huggingface dataset:
Digesting danger: A two-decade study exploring the association between food processing and colon cancer.
Authors: Katsnelson Elise , Jin William
Published: January 2025

87

Background:
Dietary patterns play a significant role in cancer prevention and progression, yet the specific association of food processing with colon cancer remains largely under-investigated. The NOVA classification system categorizes foods by their level of processing, providing a unique way to examine this relationship. Colon cancer remains a leading global health concern, and emerging evidence points to diet as potential contributors. This study explores associations between NOVA-classified foods and colon cancer, offering new insights into the role of food processing in cancer development.
Methods:
Survey data from the NHANES database (from 1999 to 2018) was probed for demographic and clinically relevant data, and day one food journals were converted into NOVA classifications. Participants aged 20 and older were included for analysis, including those with and without colon cancer (n=339 and 47615, respectively). Independent two-sample t-tests were conducted to compare the mean proportion of daily energy consumption of various NOVA food categories between the two groups, and a Benjamini-Hochberg correction was applied to adjust for multiple comparisons at p<0.05. Sensitivity analyses were performed using total grams and percent total caloric intake as inputs. Subgroup analyses were conducted via a logistic regression model including BMI, age, ethnicity, gender, education, country of birth, and military service.
Results:
Individuals with colon cancer had higher intake of ham and salted meats (NOVA 3, adjusted p=0.028) compared to those without cancer. Conversely, individuals without cancer consumed more legumes (NOVA 1, adjusted p=0.028), oils (NOVA 2, adjusted p=0.023), and “other processed foods” that did not fall into a specific processed food category (NOVA 3, adjusted p=0.038). Subgroups analyses revealed a greater association with colon cancer for age greater than 50 and non-hispanic White ethnicity.
Conclusions:
To our knowledge, this is the only study at this scale that evaluates colon cancer prevalence in the context of dietary behaviors stratified by level of industrial processing. The significant associations between ham and salted meats consumption, age greater than 50, and non-Hispanic White ethnicity with increased cancer prevalence highlight the impact of dietary and demographic patterns on colorectal carcinogenesis. Additional studies are needed to confirm these hypotheses in the prospective setting.
Multi-target stool-DNA test for colorectal cancer screening and effects on health and economic outcomes compared to blood-based tests: Influence of adherence.
Authors: Vahdat Vahab , Ebner Derek W. , Dore Michael , Fendrick A. Mark , Estes Chris , Kisiel John B. , Limburg Paul J.
Published: January 2025

88

Background:
There are an estimated 60 million individuals in the US who are not up-to-date with average-risk colorectal cancer (CRC) screening, as screening rates and adherence have remained stubbornly below the national target of 80%. Efforts are ongoing to improve CRC screening performance and participation, including the development of new blood-based tests. Despite high expectations for these tests, performance remains lower than other guideline-recommended strategies, particularly with respect to advanced precancerous lesion (APL) sensitivity. We conducted a simulation study of estimated clinical and economical outcomes for CRC screening with a blood-based test (at perfect adherence) compared to the multi-target stool-DNA (mt-sDNA) test (at published adherence rates).
Methods:
Utilizing CRC-AIM, a calibrated and validated microsimulation model, CRC screening outcomes were calculated for 1 million average-risk individuals screened between ages 45-75 years with triennial blood-based versus mt-sDNA testing. CRC and APL sensitivity and specificity inputs were derived from two large clinical validation studies for these screening modalities: ECLIPSE (NCT04136002) and DeeP-C (NCT01397747), respectively. To demonstrate the maximum benefits and burdens of blood-based screening, adherence to initial screening and follow-up colonoscopy after a positive blood test was modeled at 100%, while real-world adherence estimates of 65.6% were used for the mt-sDNA test. Outcomes of interest included life years-gained (LYG) and CRC cases missed by the blood-based test compared to the stool-based test, additional treatment costs imposed by theblood-based test, and additional CRC-related deaths per 1 million screened.
Results:
Compared to triennial screening with mt-sDNA at real-world adherence, blood-based screening at perfect adherence resulted in a higher number of incident (n=18,464) and fatal (n=6,483) CRC cases that would been avoided with the mt-sDNA test. Over a lifetime, screening with blood-based tests required 1,276,310 more tests (21% more) and 52,942 additional follow-up colonoscopies (7% more) compared to mt-sDNA screening. This increased testing burden did not generate additional benefits and instead reduced life-years gained by 67,645 per 1 million screened, resulting in an additional $1.6 billion in treatment costs compared to the mt-sDNA strategy.
Conclusions:
Data from this CRC-AIM modeling study show that even with perfect adherence, blood-based screening yields inferior clinical and economic benefits compared to mt-sDNA screening, due to suboptimal APL detection with the former test.
Impact of COVID-19 on colorectal cancer screening using Medicare Centers for Medicare and Medicaid Services (CMS) claims data.
Authors: Lim Soyun , Lee Tae Hoon , Jang Sekwon
Published: January 2025

91

Background:
When COVID-19 pandemic started in 2020 in the US, the Centers for Medicare and Medicaid Services (CMS) recommended that all non-urgent procedures, including screening colonoscopies, be delayed until pandemic stabilization. This was done to prevent the spread of the virus via colonoscopy since the presence of the virus in fecal samples has been reported in infected patients. Little is known of the impact of COVID-19 on the number of colorectal cancer (CRC) screening performed in the US.
Methods:
We utilized the Centers for Medicare & Medicaid Services Database which provides Medicare claims data for 2013-2022. We searched “Medicare Physician & Other Practitioners - by Geography and Service” using CPT code for colonoscopy(G0121, G0105), fecal occult blood test (FOBT; G0328, 82270), stool-based gene analysis (81528), sigmoidoscopy (G0104), and barium enema (G0120) and collected the number of CRC screening claims at national level and calculated the year-over-year (YOY) change.
Results:
The number of CRC screening claims in the US from 2013 to 2022 is listed (Table). The total number of CRC screening claims increased an average of 0.5% YOY from 2014 to 2019 then decreased 23.4% in 2020. From 2014 to 2019, the average YOY change in colonoscopy, FOBT, stool-based gene analysis, sigmoidoscopy, and barium enema claims were -0.5%, -6.0%, 58.7%, 8.1%, and -6.0%, respectively whereas in 2020, the rates were -27.5%, -25.0%, -14.4%, -25.3%, and -1.7%, respectively. The total number of CRC screening claims in year 2021 and 2022 increased from 2020, however, was still lower than 2019.
Conclusions:
CRC screening claims decreased in the US in 2020 likely due to COVID-19 and not yet returned to pre-pandemic levels.

Number of CRC screening claims in the US from 2013 to 2022.

Screening test
2013
2014
2015
2016
2017
2018
2019
2020
2021
2022
　

Colonoscopy
759,883
736,400
743,873
765,974
767,063
755,806
736,247
533,972
685,439
707,672
　

FOBT
1,307,054
1,263,602
1,161,214
1,130,130
1,085,777
996,016
897,993
673,614
646,550
556,950
　

Stool-Based Gene analysis
　
　
　
123,748
231,765
335,459
482,761
413,224
497,748
536,348
　

Sigmoidoscopy
2,666
2,316
3,254
3,390
3,835
3,784
3,975
2,968
3,893
3,680
　

Barium enema
107
93
80
116
128
97
58
57
44
65
　

Total CRC screening
2,069,710
2,002,411
1,908,421
2,023,358
2,088,568
2,091,162
2,121,034
1,623,835
1,833,674
1,804,715
　

Data are expressed in numbers (N).

CRC; colorectal cancer; FOBT; fecal occult blood test.
Cost-effectiveness of blood-based colorectal cancer screening: A simulation model incorporating real-world longitudinal adherence.
Authors: Yay Donderici Elifnur , Forbes Shaun P. , Zhang Nicole , Schafer Greg , Raymond Victoria M. , Das Amar , Eagle Craig , Talasaz AmirAli , Grady William M.
Published: January 2025

93

Background:
Colorectal cancer (CRC) is a predominant cause of cancer-related mortality worldwide. Regular screening improves outcomes. However, despite there being many U.S. Preventive Services Task Force (USPSTF) recommended CRC screening options, many people elect not to use any of them. Most cost-effectiveness models assume perfect (100%) adherence initially and over time (longitudinally), which is implausible as approximately one-third of eligible individuals are not up to date with CRC screening. Our study evaluates the cost-effectiveness of Shield, an FDA-approved blood-based CRC test, while incorporating real-world adherence.
Methods:
The CAN-SCREEN (Colorectal cANcer SCReening Economics and adherENce) model is a validated, discrete-event simulation model designed to evaluate the clinical and economic outcomes of CRC screening strategies under real-world adherence scenarios. We simulated individual lifetime outcomes for a cohort of 10,000 people beginning screening at age 45, running 4,000 trials per cohort. We conducted a cost-effectiveness analysis using the CAN-SCREEN model, and compared the Shield blood-based test administered every three years to no screening. Costs were calculated from a healthcare perspective and adjusted to 2023 US dollars. Shield was considered cost-effective if the incremental cost-effectiveness ratio (ICER) was below $100,000 per quality-adjusted life-year (QALY) gained. The analysis also assessed the maximum price Shield could maintain while remaining cost-effective.
Results:
Compared to no screening, Shield increased the number of QALYs by 154 per 1,000 individuals and raised costs by $7.5 million per 1,000 individuals at its commercial test cost. With an incremental cost of $48,662 per QALY gained, Shield was found to be cost-effective relative to no screening at $100,000 cost per QALY willingness-to-pay threshold. Furthermore, the unit cost of Shield can be as high as $3,241 and $4,942 to be considered cost-effective at $100,000 and $150,000 per QALY gained, respectively.
Conclusions:
This study used the CAN-SCREEN model to compare Shield, an FDA-approved blood-based CRC screening test, against no screening, finding that Shield is cost-effective. With about one-third of the U.S. population not up to date on CRC screening, Shield's noninvasive approach offers a promising, cost-effective solution to increase adherence and reduce CRC mortality.

Economic outcomes of Shield against no screening using CAN-SCREEN model.

Intervention
Test Unit Cost
QALYs/Person
Cost ($)/Person
Cost ($)/QALY Gained vs No screening

No Intervention
-
15.269
$6,312.18
-

Shield
$1,495
15.423
$13,786.72
$48,662

Shield
$3,241
15.423
$21,672.34

$100,000.00

Shield
$4,942
15.423
$29,352.42

$150,000.00
dMMR/MSI tumour occurrence during follow-up of patients with Lynch syndrome treated with immune checkpoint inhibitors for a metastatic digestive cancer between 2015 and 2024: A retrospective monocentric cohort.
Authors: Pellat Anna , Loisel Camille , Dardenne Antoine , Andre Thierry
Published: January 2025

96

Background:
Immune check point inhibitor(s) (ICIs) transformed the prognosis of patients with metastatic dMMR/MSI cancers especially for patients with Lynch syndrome (LS). The aim of our study was to describe a population of LS carrier patients treated with ICI(s) for metastatic digestive cancer, specifically assessing the risk of developing metachronous cancer.
Methods:
We collected data of 93 patients with LS, treated by ICI(s) for a metastatic digestive tumour. These patients were selected from the “immunoMSI” patient cohort, which included all patients presenting with a MSI and/or dMMR digestive cancer treated with ICI(s) between February 2015 and April 2024 in the medical oncology department of Saint-Antoine Hospital (Paris, France). Our primary outcome was the cumulative risk of metachronous MSI/dMMR cancer; secondary outcomes included cumulative risk and time to de novo colorectal polyps, as well as PFS and OS under ICI(s). We performed a cox model to assess the association of predefined variables with OS and PFS under ICI(s).
Results:
Patients most frequently carried a germline pathogenic variant on the
MSH2
(or
EPCAM
) gene (47%) or on the
MLH1
gene (30%). The majority presented with colorectal cancer (CRC) as their primary cancer (83%), followed by small intestine tumours (6%), stomach and pancreatic cancers (4%) and bile duct cancer (1%). Median age at cancer index was 62 years-old (26-77). A total of 12 out of 93 patients presented metachronous cancers during or after treatment with ICI(s). Ten of these metachronous cancers were dMMR or within the LS spectrum (urothelial n=4, CRC n=2, bilio-pancreatic n=1 and 3 skin cancers including 2 kerato-acanthomas). All patients who developed a metachronous cancer had a complete or partial response under ICI(s) for the index cancer. During a median follow-up of 47.8 months, 44 patients had colonoscopies and a total of 17 patients (39,5 %) developed pre neoplastic colorectal polyps. In multivariate analysis, PS ≥ 2 and age ≥ 70 years were associated with poorer OS with HRs of 6.3 (95% CI [1.5-25.9], p=0.01) and 5.5 (95% CI [1.6-18.9], p=0.006) respectively.
Conclusions:
Our results show that ICI(s) for patients with LS treated for an MSI/dMMR metastatic digestive cancer can still develop metachronous cancers and pre neoplastic polyps, which underlines the importance of maintaining dedicated follow-up after ICI(s) treatment in this population.
Short-course radiation(SCRT) followed by 6 cycles of cadonilimab plus mFOLFOX6 as neoadjuvant therapy for patients with locally advanced rectal cancer (LARC): A multicenter, single arm, phase II trial (NeoCaCRT).
Authors: He Wan , Huang Jun , Liao Guixiang , Li Wenwen , Shen Jing , Fu Yuxiang , Tang Na , He Fang , Zhao Yandong , Liu Zhimin , Shi Lishuo , Pei Fengyun , Yao Qijun , Zhong Xiaoling , Zhong Keli
Published: January 2025

LBA210

Background:
Preoperative chemoradiotherapy (CRT) followed by
total mesorectal excision
(TME) is recommended for mismatch repair-proficient (pMMR) or microsatellite stability(MSS) LARC. Recent studies have shown that anti-PD-1/PD-L1 in combination with CRT can improve pathological complete response (pCR) compared to CRT in the neoadjuvant setting. This trial aims to investigate the efficacy and safety of SCRT followed by cadonilimab, a first-in-class anti-PD-1/CTLA-4 bispecific antibody, plus mFOLFOX6 in patients (pts) with LARC.
Methods:
Eligible pts aged 18-79 years with pMMR/MSS, nonmetastatic, stage cT3-4N0 or cT1-4N1-2 rectal adenocarcinoma located below the peritoneal reflection were enrolled and given SCRT (25Gy/5F) followed by 6 cycles of cadonilimab (6mg/kg, q2w) plus mFOLFOX6. The primary endpoint was pCR. Secondary endpoints included clinical complete response (cCR), major pathological response (MPR), disease-free survival (DFS), overall survival (OS), safety and quality of life. The exploratory endpoint explored potential biomarkers related to response.
Results:
From April 2023 to May 2024, 27 pts were enrolled and received at least 1 dose of treatment. As of data cutoff date of October 20, 2024,median follow-up was 9.7 months (IQR 5.4–18·8)，and all pts received study treatment, and 24/27(88.9%) underwent R0 resections (one delayed surgery due to chemotherapy-related pneumonia, while the other two were assessed unresectable). The primary endpoint was met with a pCR of 37%(10/27)(95% CI, 19.4%–57.6%) and MPR of 55.6%. A cCR of 22.2%(6/27) was observed, and among them, 83.3%(5/6) still received local excisions. The T downstaging was observed in 59.3%(16/27) while N downstaging in 66.7%(18/27). Grade 3–5 adverse events occurred in 5 (18.5%) of 27 pts; the most common were diarrhea (ten [37%]),nausea (ten [37%]) and fatigue (ten [37%]), and neutropenia (seven [26%]). Drug-related serious adverse events occurred in eight (30%) of 27 patients. No new safety signal was identified.
Conclusions:
In pts with pMMR/MSS LARC, neoadjuvant SCRT with cadonilimab plus mFOLFOX6 resulted in promising pCR rates with intolerable toxicities. Follow up continues. These data deserve further investigations in a phase III randomized trial.
Clinical trial information: NCT05792735
.
NRG-GI008: Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-North America).
Authors: Lieu Christopher Hanyoung , Yu Guan , Kopetz Scott , Puhalla Shannon L. , Lucas Peter C. , Sahin Ibrahim Halil , Deming Dustin A. , Philip Philip Agop , Hong Theodore S. , Rojas-Khalil Yesenia , Loree Jonathan M. , Wolmark Norman , Yothers Greg , George Thomas J. , Dasari Arvind
Published: January 2025

TPS310

Background:
Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC.
Methods:
In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines
v
serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox
v
more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate
v
delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox
v
FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Current accrual (as of 9-20-2024): 500/1,912.
Clinical trial information: NCT05174169
.
A randomized phase II clinical trial evaluating the safety and efficacy of initial dose adjustment of zolbetuximab plus chemotherapy in patients with HER2-negative and CLDN18.2-positive unresectable advanced or recurrent gastric, gastroesophageal junction cancer or esophageal adenocarcinoma (GENTLE-Z).
Authors: Okunaka Mashiro , Furuoka Momoka , Wakabayashi Masashi , Furuya Hideki , Bando Hideaki , Shitara Kohei , Nakayama Izuma
Published: January 2025

TPS504

Background:
Zolbetuximab, a monoclonal antibody targeting CLDN18.2, was recently approved in Japan for patients with HER2-negative/CLDN18.2-positive metastatic gastric or gastroesophageal junction cancer (mGC/GEJC). On-target GI toxicities such as nausea and vomiting are commonly observed during first infusion, occasionally leading to early treatment discontinuation. Effective management of these toxicities is essential for the successful use of zolbetuximab in clinical practice. This study aims to assess whether omitting the loading dose in the first cycle can reduce zolbetuximab-related GI toxicities without compromise efficacy
.
Methods:
GENTLE-Z is a prospective, open-label, multi-intuitional, randomized phase II trial designed to compare the safety and efficacy of fixed-dose of zolbetuximab without loading dose vs. the standard zolbetuximab dose in combination with first-line mFOLFOX6 or CAPOX for patients with HER2-negative/CLDN18.2-positive mGC/GEJC. Patients are randomly assigned (1:1) to receive either a fixed dose of zolbetuximab (400 mg/m
2
q2w or 600 mg/m
2
q3w) or standard zolbetuximab regimen (800 mg/m
2
loading dose followed by 400 mg/m
2
q2w or 600 mg/m
2
q3w) with chemotherapy. The primary endpoint is the vomit-free rate during cycle 1, and secondary endpoints include efficacy outcomes such as objective response rate, progression-free survival and overall survival. The sample size is set based on the hypothesis that omitting loading dose will improve the vomit-free rate from 50% to 75%. The planned sample size is 86 patients, with a one-sided alpha error of 5% and power of 75%, over an estimated enrollment period of 1.5 years. Enrollment has been ongoing since September 2024 across 55 sites in Japan. This trial is registered in Japan Registry of Clinical Trials (jRCTs031240347). Clinical trial information: jRCTs031240347.
Valemetostat and trastuzumab deruxtecan (T-DXd) in previously treated advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric cancer or gastro-esophageal junction (GEJ) adenocarcinoma.
Authors: Shitara Kohei , Enzinger Peter C. , Mohapatra Avani , Janjigian Yelena Y.
Published: January 2025

TPS508

Background:
Valemetostat tosylate (valemetostat), a novel and selective dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, has demonstrated clinical efficacy and tolerability in multiple hematologic cancers (200 mg orally [PO] once daily [QD]). EZH2 inhibition by valemetostat is expected to upregulate DNA/RNA helicase Schlafen 11 expression and sensitize tumor cells to DNA damaging agents such as topoisomerase I inhibitor antibody–drug conjugates (ADCs). Topoisomerase inhibitors cause DNA strand breaks, which may synergize with valemetostat. HER2 gene amplification or protein expression has been associated with gastric cancer (GC) and GEJ adenocarcinoma. Patients with HER2+ locally advanced or metastatic gastric adenocarcinoma who progress after first line treatment have poor prognosis and limited therapeutic options. T-DXd is approved globally for HER2+ locally advanced or metastatic GC previously treated with a trastuzumab-based regimen. This study evaluates the clinical activity and safety of valemetostat in combination with T-DXd in patients with GC or GEJ adenocarcinoma as part of a Master Protocol trial evaluating valemetostat in combination with ADCs in solid tumors.
Methods:
This global, phase 1b, multicenter, open-label Master Protocol study (NCT06244485) will enroll ~ 70 patients per sub-protocol in multiple regions, including the US and Japan. The gastric cohort enrolls patients with previously treated advanced or metastatic HER2+ GC or GEJ adenocarcinoma. The dose-escalation (Part 1) will determine the recommended dose for expansion (RDE), combining valemetostat 50–200 mg PO QD with T-DXd 5.4 or 6.4 mg/kg intravenously every 3 weeks. The dose-expansion (Part 2) will assess the efficacy of valemetostat + T-DXd at the RDE. Primary endpoints include safety and tolerability in Part 1 and the objective response rate in Part 2. Secondary endpoints include response duration, progression-free and overall survival, pharmacokinetics, and HER2 expression by immunohistochemistry and in situ hybridization with clinical response. An interim futility analysis will be performed when 20 patients are enrolled with ≥ 6 months of follow-up.
Clinical trial information: NCT06244485
.
A multicenter, open-label, first-in-human study of TYRA-200 in advanced intrahepatic cholangiocarcinoma and other solid tumors with activating
FGFR2
gene alterations (SURF201).
Authors: Rodon Ahnert Jordi , Roychowdhury Sameek , Ellis Haley , Blanco Fernando F. , Burn Timothy , Davis Jennifer Michelle , Balcer Alex , Zalutskaya Alena , Kelley Robin Kate
Published: January 2025

TPS646

Background:
Approved Fibroblast Growth Factor Receptor (FGFR) inhibitors have demonstrated clinical benefit in locally advanced or metastatic cholangiocarcinoma harboring oncogenic
FGFR2
fusions or other rearrangements. However, the emergence of acquired resistance mutations limits the clinical activity and duration of responses to currently available inhibitors. TYRA-200 is an orally bioavailable FGFR1/2/3 inhibitor designed to specifically address these clinically observed acquired resistance alterations in
FGFR2.
Methods:
SURF201 is a single arm, multicenter, open-label, first-in-human, dose escalation and expansion study designed to investigate TYRA-200 in patients (pts) with advanced intrahepatic cholangiocarcinoma and other solid tumors with primary activating
FGFR2
gene alterations and on-target acquired known
FGFR2
resistance mutations. The study is being conducted in two parts. Part A dose escalation uses an i3+3 design and is evaluating the safety, tolerability, and the pharmacokinetic profile of TYRA-200. Part B dose expansion will further characterize the safety profile and evaluate the preliminary anti-tumor activity of TYRA-200 by RECIST v1.1 in pts with unresectable locally advanced/metastatic intrahepatic cholangiocarcinoma who have previously received an FGFR inhibitor(s) and have developed acquired
FGFR2
kinase domain resistance mutations. The study is currently planned for approximately four centers in the US and is actively enrolling (NCT06160752).
Clinical trial information: NCT06160752
.
A first-in-human phase I trial with antibody drug conjugate ADCT-701 in neuroendocrine tumors and carcinomas.
Authors: Del Rivero Jaydira , Glod John , Magee Tamika , Cooper Kimberley , Rivero Anna , Lanfranconi Tea , Patel Rashmika , Figg W Douglas , Pommier Yves , Widemann Brigitte C. , Roper Nitin
Published: January 2025

TPS672

Background:
Neuroendocrine neoplasms (NENs) consist of neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), which are rare malignancies found in various anatomical sites, including the gastrointestinal tract, pancreatic islets, lungs, and adrenal glands. Poorly differentiated NECs are classified as high-grade carcinomas that bear resemblance to small-cell lung cancer (SCLC). Treatment for poorly differentiated NECs typically follows small-cell carcinoma guidelines, utilizing platinum-based regimens; however, these patients experience a high risk of relapse and demonstrate a limited response to additional systemic therapies. Adrenocortical carcinoma (ACC) is another rare malignancy associated with a median survival of approximately 14.5 months post-diagnosis, and advanced disease management options show limited efficacy. Currently, no targeted therapies have demonstrated significant effectiveness for this condition. Preclinical investigations have indicated that Delta-like non-canonical notch ligand 1 (DLK1) is expressed in various neuroendocrine neoplasms, including ACC, SCLC, neuroblastoma, pheochromocytoma, and paraganglioma. ADCT-701, a humanized antibody targeting DLK1, has shown potential in suppressing tumor growth and enhancing survival across multiple cancer models expressing this marker.
Methods:
This Phase I dose escalation study (NCT06041516) aims to enroll adult patients with histologically or cytologically confirmed neuroendocrine neoplasms or malignant ACC with evaluable disease, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Participants will be part of a dose-finding trial. A 3+3 design is utilized to assess up to ten different dose levels of ADCT-701. Dose escalation continues unless dose-limiting toxicities occur, the maximum tolerated dose (MTD) is reached, or an optimal dose is established. The primary endpoint of the study is to ascertain the recommended phase 2 dose of ADCT-701 in patients with neuroendocrine neoplasms or malignant adrenocortical carcinoma. Secondary endpoints will assess safety, preliminary tumor activity, response rate, overall survival, pharmacokinetics, and the immunogenicity profile of ADCT-701. The trial aims to enroll up to 70 evaluable patients across a maximum of 10 dose levels. For further details, please refer to clinical trial information NCT06041516.
Clinical trial information: NCT06041516
.
Phase II study of olaparib in patients with advanced pancreatic acinar cell carcinoma.
Authors: Skorupan Nebojsa , Arda Efsun , Kozlov Serguei , Alewine Christine Campo
Published: January 2025

TPS789

Background:
Pancreatic Acinar Cell Carcinoma (PACC) is a rare and biologically distinct subtype of pancreatic cancer, representing 0.5-1% of all pancreatic malignancies, with a median overall survival of 15-20 months. Significant serum CA 19-9 elevation is uncommon, while elevation of serum lipase is observed in at least 50% of patients. Most patients present at advanced stages and treatment with combination chemotherapies extrapolated from other GI malignancies leads to low response rates. No clinical treatment trials specific for PACC have ever been reported. PACC tumors from patients show evidence of high chromosomal instability, a hallmark of DNA repair deficiency. ID3 is ubiquitously downregulated and was recently shown to play a significant role in homologous recombination repair (HRR). Recent genomic profiling of larger PACC patient cohorts has revealed a high prevalence of mutations in HRR genes, including BRCA1, BRCA2, and PALB2. Olaparib is a Poly-ADP ribose polymerase (PARP)-1 inhibitor that has been FDA approved for treatment of BRCA-mutant HRR deficient cancers. We hypothesize that PACC will be sensitive to PARP inhibition with olaparib.
Methods:
This is an open label, single arm, single center, phase II study of olaparib in patients with advanced previously treated PACC. The primary objective of the trial is to evaluate anti-tumor activity of olaparib (objective response rate). Secondary objectives assess the safety (CTCAE v. 5.0) and alternative measures of efficacy such as clinical outcomes and blood biomarkers (disease control rate, median progression-free survival, median overall survival, best response in serum lipase). Key eligibility criteria include histologic diagnosis of PACC, receipt of at least one line of combination chemotherapy, presence of RECIST measurable disease and adequate organ and bone marrow function. A fixed dose of olaparib at 300 mg will be given orally continuously twice daily during a 28-day cycle, for up to 2 years or until disease progression or intolerable toxicities. In person visits to assess toxicity are required every 4 weeks, and response is determined through serial imaging every 8 weeks (CT or MRI). Exploratory objectives include acquisition of tumor tissue for establishment of new PACC preclinical models, assessment of genetic alterations through genetic mapping technique, assessment of HRR-related gene products as a predictive biomarker, assessment of ID3 protein levels, and assessment of treatment response to tumor profile. Up to 13 evaluable participants will be enrolled. Three participants have been enrolled as of Sep 19, 2024.
Clinical trial information: NCT05286827
.
Randomized phase II trial of olaparib + pembrolizumab vs olaparib alone as maintenance therapy in patients with metastatic pancreatic cancer with germline BRCA1 or BRCA2 mutations: SWOG S2001 NCT04548752.
Authors: Chung Vincent , Guthrie Katherine A. , Pishvaian Michael J. , Lowy Andrew M. , Sohal Davendra , Reiss Kim Anna , Sanford Nina Niu , Allegra Carmen , Colby Sarah , O'Reilly Eileen M. , Chiorean E. Gabriela , Philip Philip Agop
Published: January 2025

TPS793

Background:
Olaparib was approved in 2019 as maintenance therapy for gBRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression-free survival (mPFS) with olaparib compared to placebo (7.4 vs 3.8 months) for platinum sensitive gBRCA1/2+ mPDA pts. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Results of the phase 2 pembrolizumab and olaparib (POLAR) maintenance trial in patients with germline or somatic BRCA1/2 or PALB2 mutations responding to platinum-based chemotherapy for at least 4 months was presented at ESMO 2024. In 33 patients, a 35% overall response rate with 90% disease control rate at 6 months was observed. S2001 is an important randomized study to better define the impact of the combination.
Methods:
S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. Key eligibility criteria include: mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing and progression-free after receiving at least 4 months of platinum-based chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin +/- nab-paclitaxel). One cycle of gemcitabine and nab-paclitaxel is allowed while waiting for germline testing. Zubrod performance status (PS) 0 or 1 pts are eligible. Pts are stratified according to first line chemotherapy, PS 0 vs 1, and disease status after 1st line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha = 0.10, this design requires 78 evaluable pts with a total sample size of 88 pts. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support: NIH/NCI grants U10CA180888 and U10CA180819, U10CA180821 and U10CA180868.
Clinical trial information: NCT04548752
.
EQUITY GI: A prospective study to enhance quality, inclusivity, and trial participation in Black patients with gastrointestinal cancer.
Authors: Chakrabarti Sakti , Sadri Navid , Lumish Melissa Amy , Bajor David L. , Conces Madison , Selfridge J. Eva , Fu Pingfu , Mahipal Amit
Published: January 2025

TPS843

Background:
Black individuals, including African Americans, experience a disproportionate cancer burden and exhibit the lowest survival rates among all racial groups for gastrointestinal (GI) cancers. The EQUITY GI study seeks to address the significant health disparities encountered by Black patients with GI cancers in the areas of biomarker testing, evidence-based care, clinical trial participation, and health literacy. Our central hypothesis postulates that a comprehensive approach—encompassing appropriate biomarker testing, ensuring evidence-based treatments, support for clinical trial participation, and health literacy initiatives—is essential to effectively mitigate health disparities among Black patients with GI cancers.
Methods:
The primary objective of this study is to promote equitable care for Black patients with GI cancers by ensuring appropriate biomarker testing and the delivery of evidence-based care. The secondary objectives include promoting clinical trial participation and enhancing health literacy. The specific goals are to increase the rate of evidence-based care, including biomarker testing, to ≥80%, increase the clinical trial enrollment rate from 5% to 15%, and improve the Cancer Health Literacy Test-30 (CHLT-30) score by 30%. Following a comprehensive assessment of the care gap, several initiatives will be implemented: 1. Tracking biomarker testing through a clinical information tracking tool (EQUITY-GI Oncotracker), 2. Providing guidance to treating providers through a molecular tumor board, 3. Facilitating referrals for clinical trials through navigators, and 4. Implementing health literacy interventions measured by CHLT-30 score. We aim to enroll 200 patients over 18 months. With this expected enrollment, the power to detect a ≥60% absolute improvement in the biomarker testing rate (from the current 20% to the expected ≥80%) is over 98%, using a two-sided chi-square test with a significance level of 0.05. To demonstrate an improvement in the clinical trial enrollment rate from 5% to 15%, 18 black patient will be required to get enrolled in a clinical trial through the referrals generated from the current project. To detect a 30% improvement in the mean CHLT-30 score (17 to 22) following health literacy interventions, at least 120 patients will be required, using a two-sided paired t-test with a significance level of 0.05.
A phase 1/2 study to evaluate CHM-2101, an autologous cadherin 17 (CDH17) chimeric antigen receptor (CAR) T cell therapy for the treatment of relapsed or refractory gastrointestinal cancers.
Authors: Eads Jennifer Rachel , Morelli Maria Pia , Olson Daniel , Litten Jason Blair , Astrow Stephanie H. , Pelster Meredith
Published: January 2025

TPS844

Background:
Patients with advanced gastrointestinal (GI) malignancies have poor prognoses and limited treatment options. Cadherin 17 (CDH17) is a cell membrane-associated protein important for GI cell-cell interactions that is expressed in proximity to epithelial tight junctions. In some GI malignancies, CDH17 expression is also expressed diffusely across the cancer cell membrane, thus providing access to CDH17 directed CAR T-cells. CHM CDH17 is a third generation autologous CAR T-cell product candidate that was designed to target and eradicate CDH17+ solid tumors. Notably, expression of CDH17 varies across indications in the cancer setting CDH17– TABLE 1.
Methods:
Clinical Trial NCT06055439 is a seamless Phase 1/2 clinical trial of autologous CHM CDH17 CAR T-cells for patients with advanced gastric cancer (GC), colorectal (CRC) cancer or neuroendocrine tumors (NETs) of the midgut or hindgut. As CDH17 expression in GC is heterogenous, GC subjects will be screened for CDH17 expression. In preparation for receiving CDH17 CAR T-cells, subjects receive 3-days of lymphodepleting intravenous (IV) chemotherapy (fludarabine and cyclophosphamide). The Phase 1 portion of the clinical trial uses a 3+3 dose escalation and a starting dose of 50 million CAR-T cells in a single IV infusion. Decisions regarding dose escalation/de-escalation are based on real-time dose-limiting toxicity evaluation during the first 28 days of treatment during dose escalation. After establishing a recommended Phase 2 dose, three indication-specific Simon 2-Stage cohorts will be initiated in (1) GC (2) CRC and (3) NETs of the midgut or hindgut to further characterize the safety and assess the efficacy of CHM CDH17 CAR T-cells. This is an ongoing first-in-human multi-center clinical trial of CHM CDH17, a CDH17 directed autologous CAR T-cell product candidate, enrolling subjects with advanced GI cancers that express CDH17.
Clinical trial information: NCT06055439
.

Expression of CDH17 in selected gastrointestinal cancer indications.

Indication
Sample size
CDH17Expression %*

Colorectal cancer
821
96%

Neuroendocrine tumors of the midgut and hindgut
119
97%

Gastric cancer
1,409
64%

*Expression of total tumors tested for CDH17 by immunohistochemistry (CHM data on file).
Estrogen Receptor Signaling Alters Sperm DNA Methylation Landscape in Adult Male Rats
Authors: Khambata Kushaan , Raut Sanketa , Parte Priyanka , Balasinor Nafisa H
Published: January 2025

Estrogen through its receptors, ERα and ERβ, regulate various aspects of spermatogenesis and male fertility. Because the sperm epigenome is an important contributing factor to male fertility, we evaluated the effects of estrogen signaling activation through the ERs on sperm DNA methylome in adult rats. Whole genome-bisulfite sequencing in caudal sperm DNA was performed. The differentially methylated CpG (DMC) sites were validated by pyrosequencing, and the expression of differentially methylated genes (DMGs) was evaluated in testis by quantitative RT-PCR. Activation of ERα signaling brought about large-scale changes in the sperm DNA methylome compared to ERβ. There were 28074 DMCs and 5189 DMGs obtained after ERα agonist 4,4′,4′′-(4-Propyl-[1H] pyrazole-1,3,5-triyl) (PPT) treatment, whereas 1492 DMCs and 336 DMGs for ERβ agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN). In genic regions, most of the DMCs were intronic, followed by promoter and upstream regions. DMCs were distributed around the transcription start site and in transcription factor-binding regions, implicating their plausible role in gene expression regulation. Genes important for spermatogenesis were identified and validated which showed a similar trend of differential methylation as obtained by whole genome-bisulfite sequencing. The expression of the DMGs was also found to be altered in the testis. There was a considerable overlap (14% to 50%) of PPT DMGs with the DMGs reported to be affected in clinical conditions of male infertility. This study highlights the role of ERs in shaping the sperm epigenome and that aberrant estrogen signaling could be a contributing factor in clinical conditions of male infertility.
O-16 A CASE OF VITAMIN D-DEPENDENT RICKETS DIAGNOSED IN ADULTHOOD FOLLOWING PREGNANCY
Authors: Salva Hazal , Yavuz Dilek Gogas
Published: January 2025

Discussion

Vitamin-D (Vit-D)-dependent rickets are the result of a deficiency in 1-alpha hydroxylase. It is a rare condition that is typically diagnosed in childhood. We present a case of Vit-D-dependent rickets that was detected in adulthood after pregnancy.

Clinical Case

A 25-year-old female patient has been sent from the neurosurgical clinic to the endocrinology department for evaluation of Vit-D deficiency, which is believed to be causing muscle weakness. She experienced chronic lower back discomfort that began two years ago. She experienced challenges when going down stairs and when bending her body forward. Rest alleviated the lower back pain, whereas physical activity exacerbated it, and it did not interfere with her sleep. The weakness in the legs was there with it. There was no previous fractures or other form of physical injury. The woman's issues became evident after her pregnancy. She consulted a physician nine months postpartum, following the birth of a robust infant.

The patient's personal and family history was unremarkable. She had no smoking or drinking habits. During the physical examination, the patient stood 150cm tall and weighed 60kg. Except for left lower extremity muscle strength, which was 3-4/5 on the neurological assessment, everything else was normal. In her laboratory results; calcium 8 mg/dl (8.8-10.6), ionized calcium 3.61mg/dL (4.6-5.0), albumin 4.7 g/dl (3.5-5.2), phosphorus 2.1 mg/dl (2.5-4.5), parathormone 640 ng/L (12-88), creatinine kinase 50 U/L (0-145), alkaline phosphatase 345 U/L (33-98), 25-OH Vit-D 24.2 ug/L, leukocyte: 7100/uL, hemoglobin 11.6 gr/dl, thrombocyte 336000/uL, ALT: 6.6 U/L, osteocalsin: 65 ng/mL (11-48), 1,25-OH Vit-D level: 43.1 pg/mL (15-90).

Computed CT revealed type H vertebrae in the thoracic vertebrae, with no disease found in the lumbar, cervical, pelvic, or femur. (Figure 1). Bone density (BD): L1-L4 Z score: -2.7 BMD: 0.858; Femoral neck Z score: -2.7 BMD: 0.644. The EMG results were consistent with moderate myopathy. After one year of complaints, she became wheelchair-dependent. At that point, a neurosurgical doctor prescribed Vit-D and calcium tablets. She was able to walk again in two months and referred to our clinic two years after the initial issue.

Genetic testing revealed that CYP27b1>homozygous positive was compatible with Vit-D dependent Rickets Type 1.

During the two-year diagnostic period, the patient's height dropped from 153 cm to 150 cm. Calcitriol 0.25 mcg was administered every other day. Her calcium level: 9.4 mg/dL and phosphorus level: 2.2 mg/dL following treatment.

This type of rickets is caused by a lack of the 1-alpha hydroxylase enzyme, which is essential for Vit-D production in the kidney. Untreated patients may have muscular and bone abnormalities. It is a sickness that responds exceptionally well to treatment.Figure 1:Vertebral lateral X -ray revealed H shaped vertebrae
P-32 MANAGEMENT OF A RARE COMPLICATION IN TYPE 1 DIABETES WITH EXTREME LIVER ENLARGEMENT AND GROWTH FAILURE
Authors: Mohammed Adel Gassab , Al Waeli Dheyaa Kadhim
Published: January 2025

Clinical Case

A 21 year old single male presented with growth failure, delayed puberty, and significant liver enlargement attributed to glycogen deposition, a rare complication observed in some children and young adults with Type 1 Diabetes Mellitus (T1DM), irrespective of glycemic control.

In his initial visit (Sep 5, 2020):Height: 144 cm, Weight: 40 kg. The patient’s uncontrolled diabetes and growth failure were notable. In the follow-up visits (Oct 4, 2020 - May 20, 2024), the patient exhibited fluctuating glycemic control (HbA1c ranging from 9.7% to 12.0%), variably elevated liver enzymes (ALT and AST), and concerning lipid profiles, with triglycerides peaking at 905 mg/dL. Growth parameters remained below the expected range for age and sex, indicating persistent growth failure.

Laboratory tests highlighted uncontrolled diabetes, hypertriglyceridemia, and liver enzyme elevation. Endocrinological assessments revealed low testosterone levels with slightly altered FSH and LH, pointing to a hypogonadotropic pattern. The persistent high HbA1c levels (>10%) indicated poor glycemic control, complicating the patient’s liver condition and growth failure.

The treatment regimen focused on intensive insulin therapy to manage diabetes, using combinations of NovoRapid, Tresiba, Ryzodec (aspart+degludec), and Apidra (Glulisine insulin). Lipid profile management included Lipanthyl (Fenofibrate) and Crestor (Rosuvastatin). Nutritional support was indicated with Nutrigen syrup aiming to address growth failure and possible micronutrient deficiencies.

Despite the comprehensive management approach, challenges in achieving optimal glycemic control were apparent with the latest HbA1c at 9.7%. However, some improvement in liver enzymes and lipid profile was noted. Growth failure and delayed puberty remain significant concerns requiring ongoing multidisciplinary care.

Conclusion

This case underscores the complexity of managing rare complications of T1DM like extensive liver enlargement due to glycogen deposition, in conjunction with growth failure and delayed puberty. It highlights the necessity of an integrated therapeutic strategy focusing not only on glycemic control but also on the management of associated metabolic derangements and hormonal imbalances. Further research into targeted treatments for such rare complications is warranted.

Managing patients with T1DM who develop rare complications such as extensive liver enlargement, growth failure, and delayed puberty is challenging. A holistic and tailored approach is essential for improving patient outcomes, underlining the crucial role of continuous monitoring, adjustment of therapeutic strategies, and multidisciplinary care.