bluuebunny/crossref_metadata_2025 huggingface dataset:
Interim safety and efficacy data of [
212
Pb]VMT-α-NET in somatostatin receptor 2 (SSTR2) expressing neuroendocrine tumors (NETs).
Authors: Wahl Richard L. , Anthony Lowell Brian , Solnes Lilja B. , Mehr Samuel H. , Baratto Lucia , Hanna Alaa , Yang Wenjing M. , Keefe Stephen Michael , Halfdanarson Thorvardur Ragnar
Published: January 2025

668

Background:
After the approval of 177Lu DOTATATE, a new generation of radiopharmaceutical therapies (RPT) utilizing alpha-emitting radiometals is being developed as front-line therapies for advanced NETs with the hope of higher clinical efficacy. In this Phase I study, [
212
Pb]VMT-α-NET, a novel targeted alpha radionuclide therapy (TAT) to SSTR2, is being evaluated in SSTR2-expressing NETs tumors in patients with no prior PRRT treatment. Here we present interim safety and the first efficacy results from dose escalation cohorts 1 and 2.
Methods:
In this first-in-human dose-escalation study, safety, PK, and efficacy of [
212
Pb]VMT-α-NET were investigated in a population of well-differentiated adult NETs of any grade which progressed after prior standard of care therapy as assessed by RECIST v1.1 (NCT05636618). No patient may have received prior
177
Lu-DOTATATE or PRRT. The dose escalation design includes four cohorts, 3 mCi, 5 mCi, 7.5 mCi and 10 mCi based on a Bayesian modified toxicity probability interval (mTPI-2) design. Subjects in cohorts 1 and 2 underwent dosimetry evaluations using the therapeutic surrogate [
203
Pb]VMT-a-NET. Therapeutic [
212
Pb]VMT-a-NET was administered for 4 cycles Q8W in combination with reno-protective amino acids. The DLT assessment period is defined as the first 6 weeks of cycle 1. The primary objectives include the evaluation of safety and tolerability, the PK and RP2D of [
212
Pb]VMT-a-NET as well as ORR as assessed by RECIST 1.1 criteria.
Results:
The current data cut occurred on September 19
th
, 2024. A total of 9 patients were enrolled (2 in cohort 1 and 7 in cohort 2). Median exposure for cohort 1 was 2.5 mCi (2.5 mCi, 2.5 mCi) and for cohort 2 was 5.1 mCi (4.7 mCi, 5.2 mCi). No DLTs were observed. Two grade 3 AEs occurred in Cohort 2 (diarrhea, syncope). The most frequent related TEAE were alopecia, fatigue, anemia, lymphopenia and nausea (all grade 1 or 2). One subject in Cohort 2 was discontinued due to progressive disease. Landmark PFS at 9 months is 89%. ORR is not yet mature and will be shown at the time of the meeting. Safety Monitoring Committee (SMC) meeting was held on July 17
th
, 2024, recommended dose escalation to cohort 3 at 7.5 mCi. No nephrotoxicity was reported in either cohort.
Conclusions:
[
212
Pb]VMT-α-NET is safe up to 185 MBq (5 mCi) dose level, and the SMC supported dose escalate to cohort 3 at 277.5 MBq (7.5 mCi) following a mandated FDA review in fall. Cohort 2 remains open for dose level expansion. Early efficacy results demonstrate encouraging progression-free survival.
Clinical trial information: NCT05636618
.
Characteristics and outcomes of patients with early-onset versus average-onset small bowel neuroendocrine tumors.
Authors: Grewal Udhayvir Singh , Patel Rishi , Semprini Jason , O'Rorke Michael , Dillon Joseph S. , Chandrasekharan Chandrikha
Published: January 2025

670

Background:
The global incidence of early-onset gastrointestinal cancers (GI) is increasing. Although patients with more common early-onset GI cancers, e.g. colorectal cancer, often present with more advanced disease and experience relatively worse outcomes; the characteristics and treatment outcomes for less common early-onset small bowel neuroendocrine tumors (SBNETs) have yet to be explored.
Methods:
We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with SBNETs (2004-2021), using ICD-0-3 SEER histology codes (8240/3, 8241/3, 8243/3, 8244/3, 8249/3, 8246/3). Patients with poorly differentiated histology were excluded. We used the chi-square test to compare categorical variables between early-onset SBNETs (EO-SBNETs, aged 30-49 years) and average-onset SBNETs (AO-SBNETs, aged ≥ 50 years) patients. Overall survival was estimated using the Kaplan-Meier method followed by application of the log-rank test to assess for differences in survival. A multivariable Cox regression analysis included early onset of disease, sex, race/ethnicity, marital status, urban/rural residence, prior treatments, and disease extent as covariates. All tests were conducted with a significance threshold of p < 0.05 using RStudio.
Results:
A total of 3,713 patients were included, of which, 925 (25%) were EO-SBNETs. Compared to AO-SBNETs, EO-SBNETs patients were more likely to be females (51.1% vs 46.7%, p=0.02), non-Hispanic Black (20.8% vs 17.6%, p=0.04), Hispanic (13.6% vs 8.8%, p<0.0001) and less likely to be non-Hispanic White 60.8% vs 69.9%, p<0.0001). There were no differences in stage at diagnosis between the EO-SBNETs and AO-SBNETs, i.e,, localized disease (33.5% vs 31.0%, p=0.15), regional spread (41.9% vs 42.8%, p=0.64) and distant metastatic disease (20.9% vs 21.9%, p=0.50). There were no differences in receipt of surgical resection (90.5% vs 89.1%, p=0.25) or chemotherapy (5% vs 6.3%, p=0.15) comparing EO-SBNETs and AO-SBNETs respectively. In a multivariate cox regression analysis, early onset was associated with a significantly better overall survival (HR=0.49, 95% CI 0.41-0.59, p<0.0001).
Conclusions:
With this first of its kind analysis, significantly superior overall outcomes among EO-SBNETs despite no differences in stage and receipt of surgery establishes age at diagnosis as a significant prognostic factor for SBNETs. Further studies investigating the role of factors such as differences in tumor biology and patient preferences in receipt of other therapies besides surgery are needed.
A retrospective study of the prognostic value of early induction of S-1 postoperative adjuvant therapy for pancreatic cancer.
Authors: Yukutake Aki , Adachi Tomohiko , Kinoshita Ayaka , Imamura Hajime , Hamada Takashi , Matsushima Hajime , Hara Takanobu , Soyama Akihiko , Eguchi Susumu
Published: January 2025

689

Background:
The usefulness of oral S-1 administration as adjuvant therapy (AC) after pancreatic cancer surgery has been demonstrated (1). Our study also suggested the importance of maintaining relative dose intensity or postoperative early induction (2). In a large Japanese data set, a comparison of induction before and after the postoperative 10 weeks showed a worse prognosis in the group which started 10 weeks after surgery (3). However, the number of patients of which early induction is possible are gradually increasing with recent improvements of surgical outcomes. In the present study, we retrospectively evaluated the survival benefit of AC which was started within 2 weeks after surgery.
Methods:
129 patients with invasive pancreatic cancer who underwent radical surgery from January 2018 to May 2023 were enrolled in this retrospective study. The patients were divided into the following groups: 46 (36%) underwent induction within 2 weeks, 56 (43%) within 3-6 weeks, 13 (10%) after 7 weeks, and 14 (10%) without AC (4 with low renal function, 4 with deteriorating physical condition after surgery, 4 with not desired, and 2 with comorbid disease treatment). The background of each group was as follows (Described in the following order; induction within 2 weeks after surgery: 3-6 weeks: after 7 weeks: without AC), age 71: 71: 71: 78 (n.s.), pancreatic head cases 52: 68: 69: 50% (n.s.), BR cases 35: 23: 8: 21% (n.s.), NAC performed 86: 38: 15: 29% (p < 0.001), preoperative CEA ≥ 5.0ng/ml 24: 23: 8: 21% (n.s.), preoperative CA19-9 ≥ 37U/ml 48: 52: 54: 64% (n.s.), PV/SMV reconstruction 20: 16: 31: 14% (n.s.), postoperative complications (Clavien Dindo ≤3) 0: 16: 31: 43% (p < 0.001), Pathological stage 2 or higher 83: 65: 77: 79% (n.s.).
Results:
The need for reduction of S-1 dosage was 87: 89: 92% of the patients (n.s.), and the 6-month completion rate was 70: 71: 61% (n.s.). Median overall survival duration in each group was as follows: not reached: 49.5: 35.5: 48.6 months, and 1-year postoperative recurrence-free survival was 73: 66: 45: 71%, median recurrence free survival time was 34.0: 20.8: 10.3: 12.1 months, and induction within 2 weeks after surgery group significantly improved the recurrence-free survival in comparison with the group of after 7 weeks (p < 0.05). No significant factors were detected in multivariate analysis.
Conclusions:
These results suggest that early induction of AC as a result of improvement of surgical outcomes would contribute to postoperative recurrence-free survivals. 1. Uesaka et al, Lancet, 2016. 2. Matsushima et al. Anticancer Res, 2022. 3. Tomimaru et al, J Gastroenterol, 2023.
Perioperative versus adjuvant therapy in resectable pancreas cancer.
Authors: Wang Tianyi , Mills Jamie N , Ellsworth Brandon , Griffith Brian , Gunchick Valerie , Enzler Thomas , Crysler Oxana V. , Cuneo Kyle , Nathan Hari , Lawrence Theodore Steven , Zalupski Mark , Cho Clifford , Sahai Vaibhav , Bednar Filip
Published: January 2025

703

Background:
Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer death in the United States with a 5-year survival rate of 13%. Recurrence rates are high following resection and optimization of neoadjuvant and adjuvant therapy remains under investigation, with the hypothesis that neoadjuvant/perioperative therapy may convert borderline resectable tumors to resectable and prevent progression of micro-metastases in the postoperative setting. Our study evaluates patient outcomes and models predictive and prognostic markers to assist with clinical decision-making in consideration of neoadjuvant therapy for resectable and borderline resectable pancreatic cancers.
Methods:
We performed a single-institution retrospective analysis of patients who underwent pancreatic resection between January 1, 2016 and December 31, 2020 (n=532). We excluded patients with unresectable disease or a non-PDAC diagnosis. Analysis of the remaining patients (n=175) was performed using automated and manual chart review, basic statistical comparisons with T-tests or Chi-squared tests, Kaplan-Meier Survival analyses, and Cox Proportional Hazard Testing using intention to treat analysis.
Results:
There were no significant differences (p>0.05) the presenting demographics between the adjuvant (AJ, n=97) and neoadjuvant/perioperative (NP, n=76) groups. Patients were more likely to have a history of pancreatitis, a risk factor for PDAC development, in the NP group (p=0.0153). Patients in the AJ group included patients who ultimately did not receive the recommended adjuvant therapy for various reasons (n=25) and had overall worse performance status (p=0.004) and received less chemotherapy overall compared to the NP cohort (p=0.0003). Adjuvant therapy was more likely to be gemcitabine with capecitabine (n=37, p=0.0007) in the AJ group and gemcitabine with nab-paclitaxel (n=11, p=0.0018) in the NP group. In the neoadjuvant setting, 62% of patients received FOLFIRINOX and 28% received gemcitabine with nab-paclitaxel. Patients in the NP group were more likely to receive radiation (p=0016), including 6 patients who received neoadjuvant radiation. Median overall survival (33.9 [28.8-43.8] versus 38.2 [28.2-47.8] months) and progression free survival (21.1 [18.1-34.2] versus 16.6 [11.7-23.6] months) were not significantly different between the AJ and NP groups, respectively.
Conclusions:
These results demonstrate similar presenting characteristics between patients with resectable PDAC treated in a period when general practice shifted from adjuvant therapy to a neoadjuvant/perioperative approach. Although patients treated neoadjuvantly received more chemotherapy overall and the chemotherapy regimens differed between the groups, patients had similar outcomes in the two groups.
Effect of dose adjustments on overall survival (OS) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX: A post hoc analysis of NAPOLI 3.
Authors: Patel Anjan J , Laursen Ashley Ann , Cockrum Paul , Liu Yutong , Surinach Andy , Rhodes Whitney , Zhang Li , Li Jia , Maxwell Fiona , Wainberg Zev A. , O'Reilly Eileen M.
Published: January 2025

716

Background:
NALIRIFOX is approved by the US Food & Drug Administration and European Medicines Agency for the first-line treatment of adults (no upper age limit) with mPDAC. Approval was based on the results of NAPOLI 3 (NCT04083235), in which NALIRIFOX demonstrated significant improvements in OS (primary outcome) and progression-free survival compared with nab-paclitaxel plus gemcitabine. In this exploratory post-hoc analysis of NAPOLI 3, we examined the impact of NALIRIFOX dose adjustments on OS in patients treated in North America.
Methods:
Patients (N = 770) with confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m
2
+ oxaliplatin 60 mg/m
2
+ leucovorin 400 mg/m
2
+ 5-fluorouracil 2400 mg/m
2
(NALIRIFOX) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m
2
and gemcitabine 1000 mg/m
2
on days 1, 8 and 15 of a 28-day cycle. In this analysis, liposomal irinotecan dose reductions, delays, and exposure were examined descriptively in patients who received NALIRIFOX at centers in North America. OS was evaluated using Kaplan–Meier methods; no statistical tests were performed.
Results:
Overall, 120 patients were randomized to receive NALIRIFOX at centers in North America (intention-to-treat [ITT] population) and 112 received treatment (safety population). Dose adjustments (dose reductions and dose delays) occurred in a higher proportion of patients presenting with longer OS. Patients with the longest duration of liposomal irinotecan exposure and highest cumulative dose had the longest OS.
Conclusions:
This finding suggests that tolerability-guided dose modification of liposomal irinotecan does not adversely affect efficacy outcomes and suggests a path forward to further optimize the OS of patients with mPDAC receiving NALIRIFOX.
Clinical trial information: NCT04083235
.
MEK inhibitor-based therapy in metastatic pancreatic adenocarcinoma with
KRAS
G12D or
KRAS
G12V alteration.
Authors: Yohay Stephanie , Ying Grace , Auckley Elizabeth , Aldakkak Mohammed , Thalji Samih Z , Vakili Parnian , Grahl Justin , Mayer Bradley , Shahjehan Faisal , Low Soon Khai , Evans Douglas B. , Christians Kathleen K. , Seo Yongwoo David , Erickson Beth , Hall William Adrian , McFall Thomas , Kurzrock Razelle , George Ben , Kamgar Mandana
Published: January 2025

726

Background:
Up to 95% of pancreatic ductal adenocarcinomas (PDAC) are driven by oncogenic alterations in the
KRAS
gene, with
KRAS
G12D (40%) and
KRAS
G12V (30%) mutations being the most common. However, in most cases,
KRAS
alterations are accompanied by alterations in other tumor suppressors such as
TP53
,
CDKN2A/B
, and
SMAD4
. Therefore, targeting
KRAS
alone may not be sufficient for effective treatment of PDAC . As part of the MCW-Master-PREDICT (NCT05802069) observational study, we evaluated the effectiveness of MEK inhibitor (MEK-inh)-based therapy, tailored to the unique molecular alterations of each patient’s tumor, in treating metastatic PDAC (mPDAC) with
KRAS
G12D or
KRAS
G12V alterations.
Methods:
From April 2022 to December 2023, 19 patients (
KRAS
G12D=10 (53%),
KRAS
G12V=9 (47%)) were treated with MEK-inh-based therapy. Comprehensive genomic profiling was performed using Tempus xT (648 genes) in 15 patients (79%), FoundationOne (324 genes) in 4 patients (21%), and STRATA (429 genes) in 1 patient. The genomic characteristics, matched therapies, and treatment outcomes are provided (Table).
Results:
Of the 19 patients, 11 (58%) were female. The median age at the initiation of MEK-inh-based therapy was 67 years. Six (32%) patients received MEK-inh-based therapy as first or second-line treatment, while 13 (68%) patients were treated in the third to fifth-line. Among the 19 patients, the median overall survival (mOS) and median progression-free survival (mPFS) from the initiation of MEK-inh-based therapy were 5 and 2 months, respectively. The mOS from the time of MEK-inh-based therapy was 5.1 months for
KRAS
G12D, and 4.7 months for
KRAS
G12V (P=0.87). The mPFS from the time of MEK-inh-based therapy was 2.3 months for
KRAS
G12D and 1.4 months for
KRAS
G12V (P=0.12). Among all 19 patients, 4 (21%) patients had mPFS above 4 months (
KRAS
G12V=1,
KRAS
G12D=3; 4.1, 4.3, 4.7, 9.9 months).
Conclusions:
The efficacy of MEK-inh-based therapy was limited in the late-line treatment of mPDAC for patients with
KRAS
G12D and
KRAS
G12V mutations. The potential role of MEK inhibitors in earlier lines of therapy, and their combination with
KRAS
inhibitors, requires further prospective evaluation.

Tumor alterations and matched therapies.

Altered gene
KRAS G12V(N=9)
KRAS G12D(N=10)
Patients matched(N=19)
Type of matched therapy

KRAS G12D/V

9 (100%)
10 (100%)
19 (100%)
MEK inhibitor

TP53

7 (78%)
8 (80%)
8 (42%)
VEGF/VEGR inhibitor*

CDKN2A/B

8 (89%)
5 (50%)
9 (47%)
CDK4/6 inhibitor**

SMAD4

3 (33%)
4 (40%)
4 (21%)
MEK inhibitor + (EGFR or pan-HER inhibitor) ***

*PMID: 27466356; **PMID: 33472910; ***PMID: 36127339, PMID: 24625091.

N= number of patients.
Chemotherapy selection for advanced or metastatic pancreatic cancer using machine learning models trained with multi-center datasets.
Authors: Kim Moonho , Choi Gyucheol , Cheon Jaekyung , Yoo Changhoon , Koo Jamin
Published: January 2025

738

Background:
Several factors must be considered when selecting the chemotherapeutic regimen for advanced or metastatic pancreatic cancer. The decision between FOLFIRINOX and Gemcitabine/Nab-paclitaxel (GnP) as the first-line therapy is challenging, as survival is influenced by the efficacy and toxicity profiles of these treatments, along with individual patient characteristics and therapeutic vulnerabilities. This study aims to facilitate the selection of an appropriate first-line regimen for advanced or metastatic pancreatic cancer by employing machine learning (ML) methods trained on multi-center datasets.
Methods:
Our study is based on a cohort of 191 patients who underwent systemic chemotherapy for advanced or metastatic pancreatic cancer at the Gangneung Asan Hospital and Asan Medical Center in South Korea between 2014 and 2023. The dataset consisted of 17 types of demographic and clinical characteristics, as well as time-course of response and survival outcomes. We divided the cohort into training and test groups (4:1) in a stratified manner. ML models predicting overall survival (OS) were trained on the former group using the CatBoost method. The models utilizing a minimal subset of variables were selected with respect to ROC-AUC during 5-fold cross validation. A patient was classified as having high risk to a therapy when the predicted probability of death following treatment initiation was above the threshold value as determined during training of the respective model.
Results:
The median age of the entire cohort was 62 years, with 64% being male. The ML models achieved ROC-AUCs of 0.81 and 0.82 when predicting early death within 12 months following the initial administration of FOLFIRINOX or GnP, respectively. The predictive accuracies of the models were 0.77 and 0.80 for the unseen datasets from the two treatment groups, respectively. The median OS of the high- versus low-risk groups of FOLFIRINOX predicted by the ML models were significantly different (9 vs 15 months, P <0.0001), with a hazard ratio (HR) of 2.8. Similarly, the median OS of the high- and low-risk groups of GnP were significantly different (9 vs 18 months, P <0.01, HR of 2.5). We observed that 27% of the patients predicted as high risk to FOLFIRINOX therapy were predicted as low risk to GnP and vice versa for 32% of the patients predicted as high risk to GnP therapy.
Conclusions:
We developed ML models to compute the probability of early death following FOLFIRINOX or GnP therapy from routinely collected data of the patients with advanced or metastatic pancreatic cancer. After confirming robust predictive performance with multi-center datasets, we believe that these models may assist clinicians in selecting a first-line regimens, potentially enhancing personalized treatment strategies for this challenging disease.
Telotristat ethyl to promote weight stability in patients with advanced pancreatic cancer.
Authors: Gbolahan Olumide B. , Babadi Elham , McPherson Tarrant , Coleman Kathleen , Switchenko Jeffrey , El-Rayes Bassel F. , Alese Olatunji B. , Shaib Walid Labib
Published: January 2025

747

Background:
Cachexia a key feature of pancreatic ductal adenocarcinoma (PDAC), affects up to 80% of patients (pts), and is associated with worse outcomes. Serotonin, due to its tumorigenic potential and effect on gut function may contribute to weight loss in PDAC. Telotristat ethyl (TE) inhibits serotonin production and improves gut motility dysfunction. We developed a phase II trial to evaluate the impact of TE on the weight of patients with metastatic PDAC (mPDAC) receiving first-line chemotherapy.
Methods:
Treatment-naïve pts with mPDAC who had lost at least 10% of baseline weight (Group 1) received gemcitabine and nab-paclitaxel (GnP) in combination with TE (250mg administered orally three times a day). Pts with < 10% weight-loss were recruited in Group 2 and received chemotherapy without TE. Serum serotonin was collected monthly during the study. The primary endpoint was weight stability, evaluated as % weight change at 3 months compared to baseline, with a goal of < 5% decrease. A key secondary endpoint was change in serotonin levels at 3 months compared to baseline. The groups were analyzed independently.
Results:
We enrolled 22 pts, 14 in group 1 (planned 40) and 8 in group 2 (planned 40). The median age was 70 years (IQR 62-75), majority were male (n = 15; 68%) and 11 (50%) were Black. Mean weight at treatment start was 77.9 kg (SD 19.16) group 1, and 90.6kg (SD 24.71) group 2. Mean serotonin level at baseline was 165.07 ng/ml (SD 60.49) group 1, and 296.9 ng/ml (SD 166.65) group 2. Mean % weight change over 3 months in group 1 was -2% (90% CI -5.2 to 1.3, P < -5% = 0.0595). Mean change in group 2 was -5.6% (90% CI -9.4 to -1.7%, P < 5% = 0.53). At 3 months, the median change in serotonin level in group 1 was -37.8% (IQR -59.1 to -13, P = 0.064) and -42.6% (IQR-57.8 to -29.9, P = 0.016) for group 2. Adverse events (AE) were consistent with known AE for GnP and TE. The median overall survival was 10.7 months (95% CI 5.4-16.9) group 1 and 12.2 (95% 6.1 to 21.4) group 2, HR 1.41 (95% CI 0.57 to 3.52 P = 0.46).
Conclusions:
Among pts with mPDAC and cachexia, the addition of TE to chemotherapy led to weight stabilization. These pts experienced 2% weight loss on average during the study (the upper limit of the CI just crossed -5% at -5.2%). The average weight loss was 5.6% in those who did not receive TE suggesting a signal of activity. A larger study is warranted to evaluate the role of TE in the management of cachexia in mPDAC. Funded by Lexicon Pharmaceuticals (NCT03910387).
Clinical trial information: NCT03910387
.
Spatially resolved protein profiling in pancreatic adenosquamous carcinoma.
Authors: Kardosh Adel , Sears Rosalie C. , Xia Zheng , Sasatomi Eizabaru M , Mau Brian , Brody Jonathan R , Wong Melissa , Lopez Charles D. , Chen Emerson Yu-sheng , Pegna Guillaume Joe , Franca Cristiane M , Muschler John , Pucilowska Joanna , Goodyear Shaun M.
Published: January 2025

760

Background:
Pancreatic adenosquamous carcinoma (PASC) is a rare histopathological type of pancreatic cancer that is more aggressive than pancreatic ductal adenocarcinoma (PDAC). Although PASC has a unique tumor biology and poorer prognosis, there are no guidelines for differentially treating PASC patients, and its rarity makes it significantly understudied. We used Nanostring GeoMX digital spatial profiling (DSP) to provide a targeted proteomic characterization of key tumor-promoting proteins in PASC and PDAC.
Methods:
FFPE tissue from PASC (n=10 primary, n= 4 met) and PDAC (n=21 primary, n=5 met) cases were analyzed using the DSP platform. Sections were stained with an 82-protein cocktail of antibodies conjugated to UV-photocleavable DNA barcodes. A pan-cytokeratin morphology marker was used to select tumor regions of interest (ROI) and inferred surrounding stromal (i.e., pan-CK negative) ROIs. UV excitation of the defined ROIs was used to release the DNA barcodes and were quantified on the NanoString nCounter system. For PASC, squamous enriched ROI were inferred from corresponding p40 IHC. Corresponding clinical and mutational status for all cases were abstracted from medical records.
Results:
TP53 (PDAC, 80%; PASC, 83%) and KRAS (PDAC, 76%; PASC, 100%) were the most prevalent mutations
.
In comparing the tumor ROIs of PASC and PDAC (all cases), DSP-assessed global expression and activation of EGFR-MAPK signaling is significantly increased in PASC, whereas PI3K-AKT signaling is significantly decreased. Compared to PDAC, EGFR expression and phosphorylation (p-EGFR), as well as p-MEK1, are significantly increased in PASC. PASC showed significantly lower levels of PLCG1 and INPP4B, while the majority of other AKT signaling effectors were unchanged. For DNA damage response signaling, PASC showed significantly higher levels of p-ATM, p-CHK2, and p21, but not p-ATR. Likewise, expression of oncoproteins c-MYC and BCL6 were significantly increased in PASC (vs. PDAC).
Conclusions:
Given that the normal pancreas lacks squamous cells, their histological presence is a uniquely aberrant feature that can be used to guide deep spatially-resolved interrogation of complex cellular and molecular programs. Our preliminary findings show that regions of squamous cell differentiation within PASC have intrinsically higher levels of active EGFR signaling. With emerging RAS-targeted agents poised to alter the treatment landscape, high EGFR signaling in PASC suggest a possible compensatory resistance mechanism that may require additional targeting. Likewise, reliance on ATM signaling highlights this as preferential target for DDR-directed therapies. Building on these results with additional multiomic assays will inform strategies for improving the management of patients with PASC.
Investigation of the association of
CTRB2
exon 6 deletion with time to progression and overall survival in pancreatic ductal adenocarcinoma.
Authors: Siddiqui Zafar A , Jazieh Khalid , Hoskins Jason , Rabe Kari G. , Antwi Samuel O , Sicotte Hugues , Carlson Erin E. , Oberg Ann L. , Connellly Katelyn , Carr Ryan Michael , Amundadottir Laufey
Published: January 2025

770

Background:
Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and limited treatment options. A 584 bp deletion in
CTRB2
, which impairs chymotrypsin B2 function, has been linked to increased PDAC risk. This study investigates the impact of this deletion on progression and survival outcomes in patients with PDAC.
Methods:
There were 633 patients in whom
CTRB2ex6
deletion was genotyped; 263 patients received chemotherapy and had time to progression (TTP) information. TTP was calculated from diagnosis date until earliest of 1) progression date (event), 2) surgery, death, or next chemotherapy date (competing risk), or 3) date last known to be alive (censor). Overall survival (OS) was calculated for the cohort from diagnosis until date of death (event) or date last known to be alive (censor). TTP was analyzed using cumulative incidence methods accounting for competing risks; OS was analyzed using Kaplan-Meier methods. Cox proportional hazard models adjusted for age and sex were used to test associations and compute hazard ratios (HR) and 95% confidence intervals (CI).
Results:
Median TTP in those with
CTRB2ex6
deletion negative carrier status (n=209) was 1.3 years vs 5.9 years for those with positive carrier status (n=54). Estimated 3-year progression rates were 54.2% for patients with no
CTRB2ex6
deletions, 43.7% for patients with one deletion (n=48), and 33.3% for patients with two
CTRB2ex6
deletions (n=6). TTP was not associated with
CTRB2
deletion carrier status (HR: 0.8, 95% CI: 0.6-1.3). Median OS for
CTRB2ex6
deletion negative carriers (n=514) was 1.0 year vs 0.9 years for positive carriers (n=119); within deletion carriers, heterozygous carriers (n=110) had a median OS of 0.9 years, and homozygous carriers (n=9) had a median OS of 2.6 years. OS was not associated with
CTRB2
deletion carrier status (HR: 1.0, 95% CI: 0.9-1.3).
Conclusions:
Although we did not detect statistically significant differences in TTP and OS by
CTRB2ex6
deletion carrier status, there was an interesting trend toward longer TTP and OS in the small number of patients who carried homozygous
CTRB2ex6
deletions. Larger studies are warranted to validate these findings.
Exploring predictive factors for detecting KRAS mutations in pancreatic cancer using liquid biopsy.
Authors: Furukawa Takaaki , Fukada Ippei , Hayashi Naomi , Takamatsu Manabu , Sato Yoichiro , Maegawa Yuri , Hirai Tatsuki , Mie Takafumi , Okamoto Takeshi , Takeda Tsuyoshi , Sasaki Takashi , Ozaka Masato , Takahashi Shunji , Sasahira Naoki
Published: January 2025

782

Background:
Liquid biopsy offers an alternative to tissue specimens for comprehensive genetic profiling. However, circulating tumor DNA is sometimes insufficient to detect genomic alterations in pancreatic cancer (PC). The detection rate of KRAS mutations was reportedly increased in PC with liver metastasis. In contrast, the predictive value of CA19-9 levels, the timing of liquid biopsy, or the type of liquid biopsy for detecting KRAS mutations remains unclear. We investigated whether these factors could be predictive of detecting KRAS mutations in PC.
Methods:
From September 2021 to August 2024, we retrospectively reviewed patients with PC who underwent liquid biopsy.
Results:
A total of 106 patients were enrolled (median age: 64 years, male: 66). Patient characteristics were as follows: tumor status: locally advanced: 10, metastatic: 90, recurrence: 6; metastatic site: liver: 51, lung: 26, lymph nodes: 20, peritoneum: 38, others: 7; number of metastatic sites: 1: 63, 2: 25, ≥3: 8; treatment line at liquid biopsy: 1: 21, 2: 77, 3:8; median CA19-9 level: 1053.4 U/mL; type of liquid biopsy: FoundationOne Liquid CDx (FL): 75 or Guardant360 (G): 31. The overall rate of KRAS mutations was 47%, with a median variant allele frequency of 0.83 [range:0.1-71.0]. The patterns of KRAS mutations were as follows: G12D: 23, G12V: 18, G12R: 4, and others: 14. The detection rate of KRAS mutations varied by the follows factors: metastatic site: liver: 65%, other organs: 44%; number of metastatic sites: ≥2: 47%, <2: 48%; CA19-9 level: ≥2,000 U/mL: 68%, <2,000: 38%; timing of liquid biopsy: 1st line: 42%, ≥2nd line: 67%; types of liquid biopsy: FL: 49%, G: 42%. In multivariate analysis, liver metastasis and CA19-9 level ≥2,000 U/mL were identified as independent factors associated with improved detection of KRAS mutations. In PC with these two factors, the detection rate of KRAS mutation increased to 76%.
Conclusions:
Our findings indicate that liver metastasis and CA19-9 levels above 2,000 U/mL are predictive factors for detecting KRAS mutations in PC through liquid biopsy.
Management trends and outcomes of appendiceal cancers: A National Cancer Database study.
Authors: Esparham Ali , Whittington Jennifer , Agriantonis George , Shafaee Zahra
Published: January 2025

810

Background:
Appendiceal tumors encompass a variety of histological types that exhibit different behaviors. The current study aimed to investigate and compare overall survival, predictive factors for overall survival, and management of histological variations of appendiceal tumors.
Methods:
The National Cancer Data Bank (NCDB) database (2004–2020) was evaluated to include patients with appendiceal tumors histologies including goblet cell adenocarcinoma (GCA), neuroendocrine neoplasm (NEN), non-mucinous adenocarcinoma (NMA), and mucinous adenocarcinoma (MA). Univariate and multivariable analyses were conducted.
Results:
The GCA, MA, NEN, and NMA groups consist of 6,111, 16,471, 19,199, and 11,065 patients, respectively. The NMA and NEN groups had significantly lowest and higher overall survival compared to other types (p<0.001 for both) (GCC: 143.27 (140.23-146.30), MA: 111.91 (109.996-113.832), NEN: 170.88 (168.56-173.20), and NMA: 101.399 (99.132-103.666) months). The independent predicting factors of worse overall survival were age (HR: 1.03 (1.03-1.04)), black race (HR: 1.24 (1.08-1.43), ref: white race), fourth median income (HR: 0.84 (0.74-0.96), ref: first median), Charleson index comorbidity score (HR: 1.3 (1.22-1.38)), lymphovascular invasion (HR: 1.28 (1.15-1.42)), pathologic stage 2 (HR: 1.32 (1.12-1.57)), stage 3 (HR: 1.99 (1.66-2.40)), stage 4 (HR: 4.20 (3.47-5.07)), ref: stage 1, intraoperative systemic therapy (HR: 0.52 (0.39-0.70)), positive surgical margin (1.55 (1.39-1.73)), number of positive lymph nodes (HR:1.06 (1.05-1.07)), moderately differentiated tumors (HR:1.43 (1.25-1.63)), poorly differentiated (HR: 1.94 (1.69-2.24)), undifferentiated (HR: 1.48 (1.14-1.91)), ref: well differentiated, and NMA type (HR:1.30 (1.10-1.55)). Furthermore, in terms of type of surgery, significantly higher patients of GCA (54.6%) and NMA (55.2%) groups underwent subtotal colectomy compared to other groups. Regarding systemic therapy, significantly higher patients of MA group received intraoperative, and both neoadjuvant and adjuvant therapy compared to other groups. Also, NEN group had significantly higher patients who underwent surgery with laparoscopic approach compared to others.
Conclusions:
This study reveals that different types of appendiceal tumors have distinct characteristics in regard to overall survival outcomes and treatment approaches. NENs showed the highest survival rates, while NMAs had the lowest. These results underscore the need for personalized treatment strategies for each tumor type to improve patient outcomes.
Risk of second primary cancer among patients with a first primary appendiceal adenocarcinoma.
Authors: Holowatyj Andreana Natalie , Goldberg Richard M , Washington Mary Kay , Murphy Caitlin C.
Published: January 2025

819

Background:
Incidence rates of rare appendiceal cancers are increasing across the United States. Although this is suggestive of a growing population of appendiceal cancer survivors over time, the risk of second primary cancers specific to patients with a first primary appendiceal adenocarcinoma remains unknown.
Methods:
We conducted a population-based study of adults (age ≥18 years) diagnosed with a first primary appendiceal adenocarcinoma from 1992 to 2021, using data from the Surveillance, Epidemiology, and End Results (SEER) Program. We estimated cumulative incidence of second primary cancer, defined as any primary cancer diagnosed at least 3 months after appendiceal adenocarcinoma, with Fine and Gray methods to account for the competing risk of death. For comparison to the general population, we also estimated standardized incidence ratios [SIRs], or the observed number of second cancers relative to the expected number based on age-, sex-, and race-specific incidence rates.
Results:
A total of 5,827 adults diagnosed with a first primary appendiceal adenocarcinoma (mean age 58.0 years; 51.8% female; 68.5% non-Hispanic White) were identified during the study period, of whom 418 developed a second primary cancer. The most common types of second primary cancer were prostate (17.7%), colorectal (14.4%), female breast (10.5%), lung (8.4%), and melanoma (6.0%). At 10 and 20 years after appendiceal adenocarcinoma diagnosis, the cumulative incidence of second primary cancer was 7.5% (95%CI 6.8%-8.4%) and 11.7% (95%CI 10.5%-12.9%), respectively. Cumulative incidence significantly differed by sex (p<0.01) and age at appendiceal adenocarcinoma diagnosis (early-onset [age<50]
vs
late-onset; p<0.01). For example, at 10 years post-diagnosis, the cumulative incidence of second primary cancer was 6.4% (95%CI 5.4%-7.4%) for females and 8.8% (95%CI 7.6%-10.1%) for males. The overall SIR for any second primary cancer was 1.12 (95%CI, 1.02-1.23)—corresponding to 14.8 excess cancers per 10,000 person-years. SIRs for common types of second primary cancers were: 1.07 (95%CI 0.84-1.35) for prostate, 2.12 (95%CI 1.63-2.70) for colorectal, 0.91 (95%CI 0.68-1.19) for female breast, 0.81 (95%CI 0.58-1.09) for lung, and 1.20 (95%CI 0.79-1.73) for melanoma.
Conclusions:
Approximately one in every 13 adults diagnosed with a first primary appendiceal adenocarcinoma in the United States will be diagnosed with a second primary cancer within 10 years. After diagnosis of an appendiceal adenocarcinoma, patients have a 12% excess incidence in second primary cancers and double the excess incidence in second primary colorectal cancers compared to the general population. Implementation of cancer prevention and early detection strategies (e.g., colonoscopy screening, genetic testing) for patients with an appendiceal adenocarcinoma is a clinical priority.
A phase 1/2 study evaluating the safety and efficacy of autologous TAC T cells in subjects with claudin 18.2+ advanced solid tumors.
Authors: Dumbrava Ecaterina Elena , Iqbal Syma , Turcotte Simon , Botta Gregory P. , Schlechter Benjamin L. , Ku Geoffrey Yuyat , Hosein Peter Joel , Saibil Samuel , Gavriliuc Miriam , Apostolopoulou Maria , Giwa Mobolaji , Moss Kara M. , Murugappan Swaminathan , Sohal Davendra
Published: January 2025

828

Background:
Claudin18.2 (CLDN18.2) is a tight junction protein found in gastric epithelial cells. It can become abnormally expressed in gastric cancer and other solid tumors, rendering it a candidate for targeted therapy. There are no approved therapeutic agents against CLDN18.2. The T cell antigen coupler (TAC) technology modifies T cells
ex vivo
, allowing cytotoxicity of tumor cells by co-opting the natural T cell receptor. TAC T cells demonstrate a safer profile than chimeric antigen receptor T cells. TAC01-CLDN18.2 is an autologous T-cell product comprising T cells expressing CLDN18.2 TAC.
Methods:
In this first-in-human study (NCT05862324), subjects will undergo leukapheresis and may receive bridging anticancer therapy during cell manufacturing. Prior to TAC01-CLDN18.2 infusion, subjects will undergo lymphodepletion chemotherapy. In Phase I, TAC01-CLDN18.2 will be administered at increasing doses (3 cohorts) in adult subjects with ≥2 lines of prior therapy (1 for subjects with pancreatic ductal adenocarcinoma (PDAC)) using the classic 3+3 dose escalation study design. CLDN18.2 expression levels will be determined centrally using a validated clinical trial assay. Dose-limiting toxicities (DLTs) will be assessed up to 28 days after the infusion. A second dose may be administered according to preidentified clinical and safety criteria. In Phase II, dose expansion groups will evaluate the efficacy, safety, and pharmacokinetics of the optimal TAC01-CLDN18.2 dose, with the option of redosing. Indications will include gastric and esophageal adenocarcinoma (group A), PDAC (group B) and ovarian and non-small cell lung cancer (group C) in subjects with <4 lines of prior therapy.
Results:
The first two dose cohorts of Phase I have been completed, with no reported dose-limiting toxicities (DLT). All of the TAC-related adverse events were low-grade. No cytokine release syndrome was reported. One subject in cohort 2 experienced a grade 1 neurotoxicity, which resolved the same day without intervention. Six subjects reported a total of 6 serious adverse events, none related to TAC01-CLDN18.2. An 83.3% disease control rate was observed at first tumor assessment (Day 29). One subject in cohort 1 with heavily pre-treated PDAC (3 prior lines) with high CLDN18.2 expression has an ongoing, confirmed partial response. The subject received a second dose and is still on treatment (6 months).
Conclusions:
Treatment with the lower doses of TAC01-CLDN18.2 is safe and shows promising clinical activity in a heavily pre-treated cancer population. Treatment of cohort 3 has begun.
Clinical trial information: NCT05862324
.
CK2 expression gastrointestinal cancer: Exploring clinical characteristics and cancer genetics.
Authors: Wilson Nicholas , Figueroa Cristián , Kreber Isabelle , Dominguez Isabel M. ,   Dominguez
Published: January 2025

834

Background:
The expression of protein kinase CK2 subunits (CSNK2A1, CSNK2A2, CSNK2A3, and CSNK2B) in gastrointestinal cancers has not been fully characterized. In this study, we seek to evaluate how changes in CK2 subunit expression are associated with GI cancer clinical characteristics and genetics.
Methods:
Data analysis was performed with data from The Cancer Genome Atlas (TCGA). R version 4.2.2 was used for analysis. We provide an analysis of several cancer cohorts looking at CK2 subunit expression, as well as cancer mutations, copy number alterations, and clinical characteristics.
Results:
From the TCGA datasets containing mRNA expression data, we assessed hepatocellular carcinoma (n=361), colorectal adenocarcinoma (n=339), gastric adenocarcinoma (n=306) and diffuse type gastric adenocarcinoma (n=69), pancreatic adenocarcinoma (n=169), esophageal adenocarcinoma (n=89) and squamous cell carcinoma (n=95), and cholangiocarcinoma (n=36). We explored associations between CK2 subunit expression and GI cancer-specific known driver mutations, of which we report the following significant findings (p < 0.05 for all). Mutations in TP53 were associated with increased expression of CSNK2A1 in hepatocellular carcinoma and stomach adenocarcinoma, increased CSNK2A2 in colorectal adenocarcinoma, and CSNK2B in colorectal adenocarcinoma, pancreatic adenocarcinoma, and stomach adenocarcinoma. Mutations in KRAS were associated with increased expression of CSNK2A1 and CSNK2B in pancreatic adenocarcinoma. Mutations in BRAF were associated with decreased expression of CSNK2A2 and CSNK2B in colorectal adenocarcinoma. We also noted significant changes in CSNK2 subunit expression when looking at mutations and copy number alterations in signaling pathways such as Wnt, NOTCH, PI3K, TGFβ, and more. We also explored associations between CK2 subunit expression and GI cancer clinical characteristics, of which we report the following significant findings (p < 0.05 for all). In colorectal adenocarcinoma, increased CSNK2A2 expression was associated with lymph node invasion and advanced clinical stage. In hepatocellular carcinoma, increased CSNK2A1 and CSNK2A3 expression was associated with greater tumor grade, tumor size, and more advanced clinical staging. Increased CSNK2A2 expression was associated with greater tumor size, more advanced clinical staging, and vascular invasion. Increased CS2NKB expression was associated with increased tumor grade, size, and vascular invasion. In pancreatic adenocarcinoma, increased CSNK2A3 expression was associated with a worse response to the first treatment course.
Conclusions:
Our results suggest that changes in protein kinase CK2 expression are associated with different cancer clinical characteristics as well as cancer-specific mutations and signaling pathways.
Gender imbalance in colon cancer screening rates in Texas: A population-based cohort study.
Authors: Rodriguez Vazquez Jorge , Sukhera Ahmed Bashir , Erazo Gloria , Mathew Merry , Ullah Mosffa , Ogedegbe Oboseh John , Sanchez Asley , Garza John
Published: January 2025

92

Background:
Males have a higher risk of acquiring Colorectal Cancer (CRC) than females. In Texas, males are diagnosed with CRC more than females, regardless of race or ethnicity. Texas CRC screening compliance rates are lower than the national average of 72.2%. It is important to understand the gender trends in screening to apply more specific strategies.
Methods:
We used the Texas Outpatient Public Use Data File (TOPUDF), a deidentified and publicly available statewide dataset, to conduct a population-based cohort study of outpatient colon cancer screenings of residents age 45 -74 years old at hospitals and ambulatory surgery centers during 2021. Colon cancer screenings were identified using Current Procedural Terminology (CPT) and Healthcare Common Procedure Coding System (HCPCS) codes. We queried the National Cancer Institute Surveillance, Epidemiology and End Results Program (SEER) for age grouped populations in 2021 stratified by gender, race, age group, and county of residence. We calculated age-adjusted outpatient colon cancer screening rates per 100,000 population (AASRs) using the direct standardization method based on the age group weights from the 2000 standard US population. Confidence intervals for AASR were derived by estimating the standard error as the AASR divided by square root of number of colon cancer screenings. The statistical significance of the difference between female and male AASR were tested by comparing the intersection of 95% confidence intervals (95% CI) for the individual rates. Subgroup analyses included age group, rural
vs
urban residence, and race/ethnicity.
Results:
A total 514,601 outpatient colon cancer screenings were included in the study of which 275, 189 (53.5%) were for female residents. During 2021, 51.1% of state residents age 45-74 years old were female. The overall statewide AASR in 2021 was 6071.5 (95% CI 6054.6 – 6088.4)) with the female AASR (6282.1 [95% CI 6258.1 – 6306.0]) significantly higher than the male AASR (5847.7 [95% CI 5823.9 – 5871.5]). For residents aged ≥ 45 years the statewide AASR was 5580.8 (95% CI 5565.5 – 5596) with the female AASR (5735.2 [95% CI 5715.9 – 5754.4]) significantly higher than the male AASR (5429.8 [95% CI 5410.1 – 5449.6]). Female residents had higher AASR amongst White, Black, and Hispanic race/ethnicity groups with the largest difference observed for Blacks; female AASR 5843.9 (5777.7 - 5910.1)
vs
male AASR 4733.5 (4668.5 - 4798.5). The difference between male and female outpatient screening rates was significant among both rural and urban residents.
Conclusions:
Despite a clear relationship between male gender and CRC, females have a higher rate of colon cancer screening. The Black population has the largest gender difference among race/ethnicity groups.