bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of demographics, mortality outcomes and resource utilization in early-onset versus later-onset pancreatic cancer: An analysis of the US National Inpatient Sample (NIS).
Authors: Singh Sneha , Zengin Bugra , Mandal Shobha , Sangam Sangam , Khadka Sushmita
Published: January 2025

700

Background:
Pancreatic cancer is associated with higher mortality, with 5-year relative survival of 12%. Early-onset pancreatic cancer (EOPC) is relatively uncommon and is seen in 5-12% of the cases. Recent studies indicate a rising trend in the incidence of EOPC. In this study, we categorized EOPC for ages less than 50 and later-onset pancreatic cancer (LOPC) for ages above or equal to 50 years. The aim of the study is to understand difference in demographics, mortality, and resource utilization between the two sub-categories of patients admitted to acute care hospitals in the United States.
Methods:
This is a retrospective cohort study of adult patients hospitalized with pancreatic cancer as the primary diagnosis at acute care hospitals across the United States in 2021, using the National Inpatient Sample (NIS) database. International Classification of Diseases, 10th Revision (ICD-10) codes were utilized to identify patients with a primary diagnosis of pancreatic cancer. The primary outcome is comparing demographics and in-hospital mortality between EOPC and LOPC. The secondary outcomes are length of stay (LOS) and total hospitalization charges. We performed multivariate logistic regression analysis to assess in-hospital mortality, LOS, and total hospitalization charges after adjusting for potential confounders such as sex, race, Charlson comorbidity index, hospital teaching status, and hospital region.
Results:
Our study included 38,654 patients with pancreatic cancer, of which 2,242 were EOPC and 36,412 were LOPC. The majority of the baseline characteristics were similar in both groups, except that EOPC has a higher Hispanic population (16.06% versus 8.77 %, p < 0.001), higher Medicaid as the payer source (28.28 % versus 7.32%, p < 0.001), and a more significant number of patients admitted to an urban teaching hospital (89.2 % versus 85.2%, p < 0.05) compared to LOPC subpopulation. No statistically significant difference in mortality was found between the two sub-categories (odds ratio 0.97, 95 % CI 0.60-1.5). Charlson index, hospital location, hospital bed size, and hospital region are independent predictors of mortality. There was no statistically significant difference between the two sub-categories for mean length of stay and total hospitalization charges.
Conclusions:
No significant difference was observed between EOPC and LOPC regarding in-hospital mortality, total length of stay, and total hospitalization charges. Our study highlights that EOPC disproportionately affects the Hispanic population and also a greater number of EOPC patients being admitted to urban teaching hospitals. Future research is needed to understand the disproportionate effect on the Hispanic population in the EOPC group and continued research in the domain, as the incidence of early-onset pancreatic cancer is expected to rise.
Clinical outcomes and molecular characteristics of patients with locoregional ampullary carcinoma.
Authors: Eslinger Cody , Chang Isabela , Fonseca Rodrigo , Sahvan Oudai , Yee Claire I. , Truman Mia , McWilliams Robert R. , Babiker Hani M. , Pai Rish , Wu Christina , Ahn Daniel H. , Borad Mitesh , Bekaii-Saab Tanios S. , Sonbol Mohamad B.
Published: January 2025

732

Background:
Ampullary carcinoma (AC) is a rare malignancy arising from the ampulla of Vater which has a more favorable prognosis compared to other pancreatic malignancies. Current guidelines favor surgical resection followed by adjuvant therapy for average risk patients (pts), however the type of regimen as well as other perioperative treatment modalities are still being explored. The objective of this retrospective study aims to provide insight into the management of locoregional disease.
Methods:
Pathology records from Mayo Clinic (AZ, FL, MN) denoting AC between 2010 to 2024 were searched using Mayo Data Explorer and selected for retrospective review. Pt demographics, treatment courses, and next generation sequencing (NGS) data were collected. Statistical analysis was conducted using SAS version 9.04.
Results:
A total of 137 pts (62% male, n = 85) were identified with median age 66 years old. Histologic subtypes were 54% pancreatobiliary (44/81), 40% intestinal (32/81), 6% mixed (5/81), with 56 pts unknown. Stages at diagnosis were 81% resectable (111/137), 11% locally advanced (15/137), and 8% metastatic (11/137). Nearly all (93%, n = 103/111) pts with localized disease had resection with a 97% R0 resection rate (100/103). Majority (68%, n = 75/111) of resectable pts had perioperative chemotherapy with 5-FU or gemcitabine-based regimens (24%, n = 18/75 neoadjuvant vs. 76%, n = 57/75 adjuvant). Perioperative chemoradiation was given in 17% (19/111) of pts. At median follow up of 30.5 months, recurrence rates were 40% (41/103), primarily to the liver (18/41). Median recurrence free survival (RFS) was 29.3 months (95% CI 24.7 – NE). Median overall survival (OS) has not been reached. The 5-year RFS and OS rates were 0.37 (95% CI 0.25 - 0.55) and 0.69 (95% CI 0.58 - 0.82), respectively. Univariate analysis showed no difference in OS with the addition of neoadjuvant or adjuvant chemotherapy or chemoradiation. Somatic NGS testing showed pathogenic mutations in 90% of pts (63/70): 57% KRAS (36/63; 44% G12D, 19% G12V, 8% G12C, 8% G12D, 19% others); 13% homologous recombination (HR) (8/63); 6%
ERRB2
/Her2 amplification (4/63), and 5% mismatch repair (MMR) (3/63).
Conclusions:
AC has a favorable prognosis in resectable pts. However, high recurrence rates indicate the need for better systemic therapies and improved selection of pts who would benefit from these treatments. Future research should focus on refining perioperative strategies to enhance outcomes and reduce recurrence.
Surufatinib combined with TAS-102 as a late-line therapy in patients with metastatic pancreatic cancer (mPDAC): Updated results of a single-arm, phase II trial.
Authors: Zhang Dong-Sheng , Lu Yun-Xin , Liu Fu-Rong , Bai Bing , Zhang Yang , Wang Zhiqiang , Liu Yu , Chen Jian-Wen , Li Yu-Hong , Wang Feng-Hua , Guo Gui Fang , Wang Feng , Xu Rui-Hua
Published: January 2025

739

Background:
Patients (pts) with mPDAC recurrent after FOLFIRINOX and AG chemotherapies have few treatment options. Previous reports of NCT05481463 showed promising clinical benefits of surufatinib (a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) plus TAS-102 (combination of trifluridine and tipiracil hydrochloride) in recurrent mPDAC pts. Here, we report the updated results.
Methods:
This is a single-arm, phase II trial (NCT05481463). Eligible pts with histologically confirmed mPDAC, who had progressed after ≥ 2 lines of previous therapies were treated with surufatinib (250mg, qd, po, q4w) and TAS-102 (35 mg/m
2
, bid, po, days 1–5 and 8–12, q4w). The primary endpoint was progression-free survival (PFS). Key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety.
Results:
Up to Sep 18, 2024, 20 pts were enrolled (median age 58 years, male 70.0%, TNM stage IV 100.0%, ECOG PS 1 100.0%, liver metastasis 50.0%, peritoneum metastasis 50.0%). Median baseline CA19-9 level of the 20 pts was 996.7u/ml, with a range from 2u/ml to 16612u/ml. 40.0% of pts had received 3L prior therapies before enrollment and 70.0% with primary site on pancreatic body and tail. All pts had received at least one post-baseline tumor assessment (evaluable), among which ORR was 15.0% (3 PRs), DCR was 30.0% (3 PRs, 3SDs). 35.0% pts had stable or shrinking tumors. Median PFS was 2.35m (95% CI 1.91-3.94). Median OS was 6.44m (95% CI 3.81-NR). In subgroup analysis, significantly longer PFS&OS were observed in pts without liver metastasis (mPFS: 3.42m vs 2.01m, p=0.049; mOS: 9.92m vs 3.70m, p=0.026), or with ≤ 2 metastatic organs (mPFS: 3.94m vs 1.91m, p=0.005; mOS: 10.09m vs 3.81m, p=0.003). Additionally, OS was significantly prolonged in pts with baseline CA19-9 level ≤ 996.7u/ml, in contrast with those with baseline CA19-9 level more than 996.7u/ml (9.92m vs 3.70m, p=0.008). All pts experienced treatment emergent adverse events (TEAEs). Most common (≥ 10%) TEAEs (any grade) were anemia (59.1%), neutropenia (54.6%), leukopenia (50.0%), and lymphopenia (45.5%). Grade ≥ 3 TEAEs included neutropenia (31.8%), lymphopenia (13.6%), and anemia (9.1%).
Conclusions:
Surufatinib plus TAS-102 showed encouraging survival benefits and promising anti-tumor activity with acceptable toxicity in the late-line treatment of refractory mPDAC, especially in patients without liver metastasis, with ≤ 2 metastatic organs, or with baseline CA19-9 level ≤ 996.7u/ml. The results warrant further investigations in a large cohort.
Clinical trial information: NCT05481463
.
Dose-escalated radiation for locally advanced unresectable pancreatic cancer.
Authors: Moorthy Arjun K , Sckolnik Steven , Thosani Amar , Amini Albert , Borazanci Erkut Hasan
Published: January 2025

750

Background:
Patients with unresectable locally advanced pancreatic cancer have limited therapeutic options. Historical treatments have included systemic chemotherapy or palliative radiation. New advanced radiotherapy treatment techniques have allowed dose escalated ablative radiotherapy to be delivered for patients with cancer limited to the pancreas. This study retrospectively reviews the long term outcomes of patients receiving dose escalated radiation for unresectable localized pancreatic cancer.
Methods:
Patients with locally advanced unresectable pancreatic underwent neoadjuvant chemotherapy with either gemcitabine or FOLFIRINOX based regimens. When maximum response was achieved with chemotherapy or this was no longer tolerated, patients were reassessed with imaging. Patients with localized unresectable disease then proceeded to definitive dose escalated radiation with either SBRT radiosurgery (40Gy in 5 fractions) or IMRT radiation (65-70Gy in 30-35 fractions) with concurrent 5FU. Surveillance of disease was performed with CT imaging and Ca19-9 biomarker assessment.
Results:
A total of 38 patients (21 male, 17 female) underwent definitive radiation. Radiation technique was determined by treating physician based on patient anatomy, with 7 patients having SBRT and 31 IMRT/5FU. Average patient age at diagnosis was 71. All patients underwent at least 6 months of follow up and mean follow up was 14 months. At time of latest follow up, 30 patients had no evidence of local progression and 12 patients had no evidence of progression at any site. The most common side effect at last follow up was grade 2/3 duodenal ulcer experienced by 7 patients.
Conclusions:
Advances in systemic chemotherapy have increased the population of patients with locally advanced unresectable pancreatic cancer who have persistent pancreatic disease after induction chemotherapy. Definitive dose escalated radiation is a new and effective technique to provide local control in this setting. This approach is well tolerated with manageable toxicity and effective durable local control. Patients continue to experience distant disease failure despite improving local control rates, though at a lower rate than historical controls. Control of primary pancreatic malignancy with dose escalated radiation can potentially improve quality of life and function for these patients for whom additional chemotherapy or surgery is not indicated.
Effects of tumor treating fields (TTFields) with FOLFIRINOX on BRCA WT pancreatic cancer cells.
Authors: Zheng Michael , Ene Hila , Ben Meir Kerem , Gabay Hila , Dor-On Eyal , Haber Adi , Giladi Moshe , Palti Yoram
Published: January 2025

753

Background:
Pancreatic cancer remains one of the most aggressive malignancies, frequently diagnosed at the locally advanced or metastatic stage. In the advanced setting, first-line chemotherapy options include gemcitabine with nab-paclitaxel or FOLFIRINOX, a combination regimen of fluorouracil, oxaliplatin, irinotecan and leucovorin. The FOLFIRINOX regimen is however associated with greater toxicity and is hence used only in patients with good performance status. BRCA-mutated tumors seem to be more sensitive to FOLFIRINOX due to the DNA-damaging, platinum-based component of this treatment regimen. Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes crucial for cancer cell viability that have shown efficacy in preclinical pancreatic cancer models; and, in various cancer types, have been shown to reduce expression of proteins from the BRCA-dependent DNA repair pathway. The current study examined the potential use of TTFields for sensitization of BRCA wild-type pancreatic cancer cells to treatment with FOLFIRINOX.
Methods:
Human pancreatic BRCA wild-type cancer cells BxPC3 and AsPC1 were treated with TTFields (150 kHz; 0.7 and 1 V/cm RMS, respectively), using the inovitro device. FOLFIRINOX was administered to the cells at increasing concentrations, with or without co-treatment with TTFields. After 72h of treatment, cell count, colony formation, and apoptosis were measured. For mechanistical insight, gene and protein expression were evaluated following 24, 48, or 72h of TTFields treatment.
Results:
TTFields application to the pancreatic cells together with FOLFIRINOX elevated the cytotoxic, clonogenic and apoptotic effects induced by FOLFIRINOX or TTFields alone. RNA sequencing data revealed that TTFields downregulated DNA damage repair, DNA replication, and cell cycle related processes. Specifically, real-time PCR and Western blot analysis demonstrated reduced expression of several central players in the BRCA DNA damage repair pathway.
Conclusions:
TTFields application together with FOLFIRINOX in pancreatic cancer cells lacking background BRCA mutations exhibits potential improvement relative to FOLFIRINOX alone, that may be rationalized based on downregulation of key DNA repair pathways. Future studies should explore the possibility of reducing FOLFIRINOX treatment dose, potentially alleviating FOLFIRINOX-related toxicity.
MUC5AC levels as predictors of adjuvant therapy outcomes in pancreatic ductal adenocarcinoma: A study of post-surgical gemcitabine-based regimens.
Authors: Manne Ashish , Khorasanchi Adam , Sara Amir , Sheel Ankur , Yu Lianbo , Esnakula Ashwini K.
Published: January 2025

759

Background:
The role of tissue mucin 5 AC (MUC5AC) in PDA is not fully understood. In our previous work we showed that mature MUC5AC (MM) detected in the extracellular (EC) space and in apical region has better prognostic value than perinuclear immature MUC5AC (IM). Our previous research demonstrated that mature MUC5AC (MM), present in the extracellular (EC) space and apical region, offers better prognostic value than perinuclear immature MUC5AC (IM). Preclinical studies suggest that MM may confer chemoresistance to gemcitabine (Gem), commonly used in adjuvant therapy (AT) either alone or with capecitabine (Cap) or nab-paclitaxel (NP) in patients not eligible for FOLFIRINOX. This study investigates MM’s effect on outcomes in PDA patients undergoing post-surgical treatment with Gem-only, Gem-NP, and Gem-Cap.
Methods:
Formalin-fixed, paraffin-embedded tissue samples from resected PDA cases (January 2010 - June 2021) were sourced from the Ohio State University biorepository. Immunohistochemistry using monoclonal antibodies 45M1 (for MM) and CLH2 (for IM) was employed to examine cellular MM and IM expression, with H-scores calculated. Statistical analysis of progression-free survival (PFS) and overall survival (OS) was done using the log-rank test.
Results:
We had 49 patients available for analysis. The median age of the group was 66 years (range: 38 to 89) with majority Caucasians (90%) and 53% (n=26) females. AT distribution within this group was, 31 Gem-only, 7 Gem-NP, and 11 Gem and capecitabine (Cap). Median expression levels for MM and IM were both 150, and 82% (n=40) were EC-MM positive. Using the median MM H-score as a threshold (< 150 vs. ≥ 150), outcomes were evaluated within each therapy subgroup (Table).
Conclusions:
This preliminary study suggests that PDA patients with low MM expression may benefit from Gem-Cap therapy. However, larger, prospective studies are needed for definitive conclusions.

Comparing outcomes in the sub-groups.

Sub-group (n)
OS in days (p-value)
PFS in days (p-value)

MM H-score < 150 vs. ≥ 150

Gem-only (11 vs. 20)
775 vs. 1006 (0.4)
444 vs. 413 (0.4)

Gem NP (4 vs. 3)
1409 vs. 551 (0.8)
391 vs. 418 (0.5)

Gem-Cap (4 vs. 7)
not evaluable (NE) vs. 766 (0.02)
NE vs. 415 (0.01)
Treatment sequences in patients with metastatic colorectal cancer in Japan: Real-world evidence of 1
st
- to 5
th
-line treatments.
Authors: Kagawa Yoshinori , Osaka Tsuyoshi , Imamura Toshiki , Kuwabara Hiroyo
Published: January 2025

76

Background:
The development of later-line drugs for metastatic colorectal cancer (mCRC) has expanded treatment options for systemic chemotherapy in patients with mCRC. However, few studies have investigated patients who received later-line treatment in a real-world setting, and available information on treatment sequences and transition rates from early- to later-line treatments is limited.
Methods:
This was a retrospective study using hospital administrative data collected by MDV (Medical Data Vision, Tokyo, Japan) from April 2008 through February 2023 in Japan. Treatment regimens were derived from standard treatments recommended in the Japanese guidelines. The study population was determined using an algorithm from a similar study previously conducted in Japan. Our analysis focused on patients who started CRC surgery or 1
st
-line treatment after January 2017 to reflect recent late-line real-world practice. Transition rates from 1
st
- to 5
th
-line treatment were calculated, and treatment sequences were summarized using a Sankey diagram. Logistic regression was performed to identify the factors associated with the transition from 2
nd
- to 3
rd
-line treatment.
Results:
A total of 722,005 patients with a CRC diagnosis record were identified in the MDV database. Of these, 26,456 patients were included in the study population. The median age was 69 years and 61.4% of patients were male. The rates of transition to subsequent lines from 1
st
to 5
th
line ranged from 65.7% to 70.4% (1
st
to 2
nd
68.3%; 2
nd
to 3
rd
70.4%; 3
rd
to 4
th
69.9%; 4
th
to 5
th
65.7%). Among 8528 patients who received 2
nd
-line treatment, ~70% of patients (6006) continued 3
rd
-line treatment, and 30% of patients (2522) received best supportive care. Comparing these 2 patient groups, younger age (<65 years, OR: 1.50, 95%CI: 1.35-1.67; p<0.001) and longer treatment durations of 1
st
(≥180 days, OR: 1.26, 95%CI: 1.14-1.39; p<0.001) and 2
nd
(≥120 days, OR: 1.67, 95%CI: 1.52-1.84; p<0.001) lines were significant factors for 3
rd
-line treatment continuation. Prior therapy with oxaliplatin or irinotecan plus molecular targeted drugs was also associated with a higher likelihood of proceeding to 3
rd
-line treatment (OR: 1.42, 95%CI: 1.28-1.58; p<0.001).
Conclusions:
In this study, ~70% of patients were able to transition to subsequent lines at the time of each line transition. However, 30% of patients were unable to continue treatment in real-world practice. To increase treatment continuation rates and maintain patient quality of life, new treatment options and further research are necessary to meet patients’ treatment needs, especially in the later-line treatment setting where unfavorable effects from previous treatments are accumulated.
Serum mucin 5AC (MUC5AC) as a predictor of outcomes and microscopic distant metastasis in pancreatic ductal adenocarcinoma (PDA).
Authors: Manne Ashish , Bao Yonghua , Sara Amir , Sheel Ankur , Esnakula Ashwini K. , Yang Wancai
Published: January 2025

767

Background:
Our prior studies demonstrated that tissue extracellular MUC5AC (EM) detection (EM-D) is associated with early recurrence, and serum MUC5AC (sM) levels have prognostic value in resected PDA following neoadjuvant therapy. This study evaluates the predictive value of post-operative sM before adjuvant therapy (AT).
Methods:
Serum samples, collected from January 2010 to June 2021 and sourced from the Ohio State University biorepository, were analyzed using enzyme-linked immunoassays with a human MUC5AC kit (NBP2-76703). Multivariate (MV) Cox regression models quantified progression-free survival (PFS) and overall survival (OS), while Wilcoxon tests compared group differences.
Results:
Nineteen patients had serum samples available post-operative and pre-AT. The cohort's median age was 65 years (range: 48-83), predominantly Caucasian (n=18), and 58% female. Serum was collected a median of 2 weeks (range: 1-16) after surgery, with a mean sM level of 1.1 ng/mL (range: 0.42 to 3.3). Most patients (17/19) received Gemcitabine-based therapy, one received chemoradiation, and another FOLFIRINOX. Among patients, 3 had no recurrence (Nr), 10 experienced distant metastases only (mets), 3 had local recurrence only (Lr-o), and 3 had both Lr and liver recurrence (Liv/Lr). In the MV model, incorporating sM, EM-D, and AT, higher sM levels (HR=2.83, p=0.04) and negative EM-D (HR=6.85, p=0.02) were associated with increased recurrence risk, whereas AT type did not influence recurrence. Regarding OS, sM was significant (HR=2.95, p=0.04) while other factors were not. Elevated sM levels correlated with metastasis risk (mets vs. Liv/Lr vs. Lr-o vs. Nr = 1.54 vs. 0.61 vs. 0.62 vs. 0.92, p=0.01). Patients with locoregional recurrence had significantly lower sM than those with distant metastasis and no recurrence (mets vs. Liv/Lr+Lr-o vs. Nr = 1.54 vs. 0.62 vs. 0.92, p=0.005). In a separate cohort of 10 metastatic patients (mean sM of 1.8 ng/mL, range: 0.43 to 11.2), liver metastases were linked to significantly lower sM than non-liver metastases (0.54 vs. 3, p=0.02), while peritoneal metastases were associated with higher sM levels (3 vs. 0.6, p=0.04).
Conclusions:
This small study suggests that sM can serve as a biomarker for assessing outcomes and recurrence sites post resection before the initial dose of AT. Elevated sM should prompt suspicion of microscopic metastases, particularly non-liver metastases.
Frequency and incidence of oncogenic
RAS
mutations in patients with metastatic pancreatic ductal adenocarcinoma: Derived from the real-world evidence database Foundation Medicine Insights.
Authors: Pant Shubham , Kar Sumit , Lin Kevin K. , Ahler Ethan
Published: January 2025

777

Background:
Approximately 60,000 patients are diagnosed with pancreatic cancer in the United States annually, with half of all cases diagnosed at the metastatic stage.
1
The most common type, pancreatic ductal adenocarcinoma (PDAC), accounts for ~90% of all pancreatic cancers
2
and is characterized by frequent
KRAS
oncogenic mutations. Newer investigational therapeutics target HRAS and NRAS, in addition to KRAS. To comprehensively characterize the incidence of RAS mutations in patients with PDAC, we analyzed mutational frequency data from the Foundation Medicine Insights (FMI) database.
Methods:
NGS-based comprehensive genomic profiling (CGP) data from 27,298 PDAC tissue samples were accessed from the FMI database (May 7, 2024 data cut). Only ‘short variants’ in RAS genes (
KRAS
,
NRAS
, and
HRAS)
occurring at amino acid positions G12, G13, or Q61 that had a frequency 0.1% or greater were included. To estimate the number of new US cases of
RAS
-mutant PDAC, pancreatic cancer incidence estimates
3
were adjusted by the derived
RAS
mutational frequency values. All incidence estimates were rounded to the nearest 100.
Results:
Oncogenic
RAS
mutations were identified in 92% of PDAC patients, with nearly all being
KRAS
(91.8%) and the remaining
NRAS
(0.2%). No
HRAS
mutations passed our minimum frequency threshold requirement. Individual
RAS
mutations with frequency >1% included
KRAS
G12D (39.9%),
KRAS
G12V (28.6%),
KRAS
G12R (14.6%),
KRAS
Q61H (4.2%),
KRAS
G12C (1.7%), and
KRAS
Q61R (1.4%). Applying these
RAS

mutation rates to reported PDAC incidence, we estimate that ~56,000 new patients with PDAC in USA per year will have tumors harboring an oncogenic
RAS
mutation, including ~51,000 of those with a
RAS
G12 mutation specifically.
Conclusions:
Oncogenic
RAS
mutations are identified from NGS testing in nearly all patients with advanced PDAC. Both the frequency and diversity of RAS mutations in PDAC suggest that PDAC is largely a RAS-driven cancer and that targeting RAS may be useful broadly in this disease.

Mutational frequency and incidence at G12, G13, and Q61 amino acid positions in
KRAS
and
NRAS
among patients with PDAC.

RAS
G12

RAS
G13

RAS
Q61

RAS
mutant

Mutational Frequency
KRAS
85.7%
0.8%
6.3%
91.8%

NRAS
0.1%
Below threshold
0.1%
0.2%

Incidence
KRAS
51,300
600
3,700
55,600

NRAS
100
Below threshold
100
200
Updated trends in incidence and mortality of pancreatic cancer. an analysis of the Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Ntukidem Olanipekun Lanny , Ogedegbe Oboseh John , Bai Sakshi
Published: January 2025

786

Background:
Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. The prognosis for pancreatic cancer remains poor despite advances in cancer therapy. In this study, we provide updated trends in pancreatic cancer incidence and mortality using the SEER database, with a subset analysis of age and gender.
Methods:
Using the SEER Stat software, we gathered data from the Surveillance, Epidemiology, and End Results (SEER) database (2000–2021). We employed Jointpoint regression to analyze the secular trend of incidence and incidence-based mortality (IBM), which we classified and arranged according to age and sex.
Results:
235,116 cases met the inclusion criteria for our study. These included diagnosed cases of pancreatic cancer from 2000 to 2001. The total age-adjusted incidence rate was 12.5 per 100,000. 118,791 (50.5%) were males and 116,325 (49.5%) were female. While the annual percentage change (APC) from 2000-2019 was 0.92 (p < 0.05), signifying an annual cumulative increase, APC from 2019-2021 was -0.085, signifying an annual cumulative decrease. For males, the APC was 0.94 (p < 0.05) from 2000 to 2018 and -0.55 from 2018-2021, and for females, the APC was -0.89 (p < 0.05) from 2019-2021. The pancreatic cancer IBM APC from 2000-2022 was 22.60 (p < 0.05) and 0.54 (p < 0.05) from 2002-2021. For males, IBM APC was 21.10 (p < 0.05) from 2000-2002 and 0.58 from 2002-2021. For females, IBM APC was 25.15 from 2000-2002 and 0.42 from 2002-2021. We also studied pancreatic cancer IBM based on age. For 30-49 years, APC from 2000-2002 was 34.65 (p < 0.05), and -0.64 (p < 0.05) from 2002-2021. For 50-69 years, APC from 2000-2002 was 28.05 (p < 0.05) and 0.3 from 2002-2021. For 70+ years, APC from 2000-2002 was 21.28 (p < 0.05) and 0.73 from 2002-2021.
Conclusions:
There was a statistically significant rise in incidence and incidence-based mortality across the board, underscoring the need for improved diagnostic and therapeutic modalities of management of pancreatic cancer.
The impact of prediabetes on cerebrovascular risk among patients with gastrointestinal malignancies.
Authors: Uttam Chandani Kanishka , Agrawal Siddharth Pravin , Raval Maharshi , Sait Mohamed Ayaan , Kondapally Apoorva , Nadeem Ahmed , Sharma Tanuj , Ijaz Ambreen , Siddiq Sajid , Chintakuntlawar Ashish V. , Mittal Kriti
Published: January 2025

817

Background:
Cancer screening ingastrointestinal (GI) malignancies has translated into an improvement in overall survival due to detection at an earlier stage. The majority of survivors (up to 67%) are over the age of 65. The impact of metabolic profiles on cerebrovascular events amongst this population of cancer survivors is unclear.
Methods:
Data from the NIS database from 2016 to 2020 were reviewed for patients with seven GI malignancies. Analysis was performed based on the presence or absence of prediabetes using ICD-10 codes. Baseline characteristics, comorbidities, and cerebrovascular outcomes were studied in these 2 cohorts.
Results:
1,532,250 hospitalizations of patients with seven GI malignancies, namely colorectal cancer (CRC), pancreatic cancer, hepatocellular carcinoma (HCC), gastric cancer, small intestinal cancer, cholangiocarcinoma, and esophageal cancer, were evaluated and divided into two subgroups: prediabetics (15,610) and non-prediabetics (1,516,640). Prediabetics with GI malignancies as compared to non-prediabetics with GI malignancies were noted to be older (67.7 years vs. 65.64 years), with higher total hospitalization charges (USD 87,267 vs. USD 80,173), greater rates of elective admissions (34.92% vs. 25.89%) but a lower length of stay (6.018 days vs. 6.53 days). Prediabetic patients with GI malignancies were noted to have a higher prevalence of obesity (18.64% vs. 7.69%), dyslipidemia (52.99% vs. 26.16%), and hypertension (49.59% vs. 39.37%). Prediabetics with CRC, as compared to non-prediabetics, had higher adjusted odds ratios (aORs) of occlusion/stenosis of precerebral or cerebral arteries not leading to cerebral infarction, and cerebral infarction, with aORs of 2.03 (95% CI 1.24-3.30, p 0.004), and 1.63 (95% CI 1.01-2.63, p 0.045) respectively. Additionally, prediabetics with pancreatic cancer had a higher aOR of cerebral infarction as compared to non-prediabetics, with aOR of 2.42 (95% CI 1.70-3.44, p<0.001).
Conclusions:
Prediabetic patients with CRC had higher aORs of cerebral infarction and occlusion/stenosis of precerebral arteries not leading up to cerebral infarction, and prediabetics with pancreatic cancer had twice the risk of cerebral infarction as compared to non-prediabetics. This study highlights the impact of prediabetes, a modifiable risk factor, on cerebrovascular outcomes in patients with GI malignancies.
Low-dose aspirin to reduce recurrence rate in colorectal cancer patients with PI3K pathway alterations: 3-year results from a randomized placebo-controlled trial.
Authors: Martling Anna , Lindberg Johan , Hed Myrberg Ida , Nilbert Mef , Mayrhofer Markus , Gronberg Henrik , Glimelius Bengt ,   ALASCCA Trial Study Group
Published: January 2025

LBA125

Background:
Colorectal cancer (CRC) affects 1.9 million individuals globally each year. Among patients with stage II-III CRC, 20-40% develop metastatic disease. Aspirin lowers the incidence of adenomas and CRC in high-risk patients. In addition, observational studies suggest that post-diagnosis aspirin treatment improves disease-free survival (DFS) in unselected populations. Furthermore, retrospective findings indicate that somatic PIK3CA mutations predict treatment response, but requires validation in randomized trials.
Methods:
The ALASCCA trial was a randomized, double-blind, multicenter, placebo-controlled trial with two parallel arms, across 33 hospitals in Sweden, Denmark, Finland, and Norway. Patients with stage I-III rectal cancer or stage II-III colon cancer exhibiting somatic alterations in the PI3K signaling pathway were included. Patients were randomized to receive either 160 mg of aspirin daily or placebo, initiated within three months post-surgery and continued for three years. To detect a hazard ratio (HR) of 0.36 for the primary outcome of time to recurrence (TTR) assessed at 3 years, with 80% power and a two-sided alpha of 0.05, 150 patients with PIK3CA mutations in exon 9 and/or 20 (“Group A”) were required per arm. An additional 300 patients with other somatic PI3K pathway driver alterations (PIK3CA outside exon 9/20, PIK3R1, or PTEN; "Group B") were required for secondary analyses. A stratified Cox proportional hazards model was fitted for the primary efficacy analysis.
Results:
A total of 3508 patients were screened for somatic alterations in the PI3K pathway. Of the 2980 patients with conclusive genomic analyses, 1103 patients (37%) had an alteration in the PI3K pathway: 515 patients (17.3%) in Group A and 588 patients (19.7%) in Group B. In total, 626 patients were randomized. After three years of follow-up, the HRs for TTR comparing aspirin to placebo were 0.49 (95% CI; 0.24-0.98; p=0.044) in Group A and 0.42 (95% CI; 0.21-0.83; p=0.013) in Group B. For DFS, the HRs were 0.61 (95% CI; 0.34-1.08; p=0.091) in Group A, and 0.51 (95% CI; 0.29-0.88; p=0.017) in Group B. Three patients experienced aspirin-related severe adverse events (one GI-bleeding, one hematoma, one allergic reaction).
Conclusions:
Primary endpoint was met. Adjuvant treatment with 160 mg aspirin daily for three years reduced recurrence rate in CRC patients with somatic alterations in the PI3K signaling pathway. These findings could lead to immediate changes in clinical praxis for about a third of CRC patients.
Clinical trial information: NCT02647099
.
A phase 2, multicenter, open-label study of AlloStim in-situ cancer vaccine immunotherapy as 3L therapy in MSS/pMMR metastatic colorectal cancer.
Authors: Har-Noy Michael , Lausoontornsiri Wirote
Published: January 2025

TPS317

Background:
Neoantigen therapeutic cancer vaccines have had limited clinical benefit in metastatic tumor settings. Tumor immunoediting selects tumor clones over time that are non-immunogenic. In addition, the metastatic tumor microenvironment (TME) becomes profoundly immunosuppressive. Microsatellite stable (MSS) and mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) tumors do not accumulate mutations, resulting in low mutational burden (TMB) and a lack of neoantigen targets. Consequently, therapeutic vaccine approaches for mCRC have had difficulty in demonstrating clinical effectiveness. Novel approaches that boost the immune response in low TMB tumors may benefit mCRC patients. AlloStim is an allogeneic, non-genetically manipulated, living Th1-like cell immunotherapy. The Th1-like cells are ex-vivo differentiated and expanded from healthy blood donors and activated prior to infusion. These cells are designed to be rejected upon intradermal (ID) injection. Repeated ID injections elicit high titers of allo-specific Th1 memory cells in circulation. In allo-primed patients, intravenous (IV) infusion of AlloStim causes a rejection response that releases cytokines, such as IL-12, which non-specifically activate circulating memory T cells and NK cells. Activated host memory T-cells and NK cells extravasate and traffic to metastatic tumor sites. This creates the conditions for “in-situ vaccination”. Activated NK cells cause disruption of the cell membrane and release of chaperoned neoantigens into the tumor microenvironment, a process known as immunological cell death (ICD). The release of neoantigens into the microenvironment in the context of inflammation mediated by infiltrating Th1 memory cells creates conditions for
in-situ
vaccination.
In situ
vaccination represents an alternative immunotherapy approach in which a therapeutic cancer vaccine is generated
in vivo
without the need to previously identify and isolate tumor neoantigens.
Methods:
To investigate this novel in-situ vaccine mechanism, a phase 2, multicenter, single-arm clinical trial in 3L MSS/pMMR mCRC subjects that have been previously treated with oxaliplatin-containing and irinotecan-containing chemotherapy regimens, anti-EGFR (RAS wt and left-sided) and anti-VEGF was initiated. Patients were administered weekly AlloStim in three 28-day cycles consisting of 4 ID injections and a combination ID and IV infusion on the final week in each cycle to create self-amplifying waves of allo-specific and tumor-specific host immune cells in circulation which traffic to tumors upon IV infusion. The primary end-point is overall survival. 21 evaluable patients have been enrolled and are currently being followed for maturity of the survival data.
Clinical trial information: NCT04444622
.
BXQ-350, a novel sphingolipid metabolism modulator, in combination with mFOLFOX7 and bevacizumab in newly diagnosed metastatic colorectal cancer (mCRC) patients: A phase 1b/2 randomized study.
Authors: Flora Daniel Blake , Patel Reema Anil , Lee Fa-Chyi , Tapolsky Gilles , Takigiku Ray , Beach Jim , Gazda Michael , Arshad Tariq
Published: January 2025

TPS320

Background:
Ceramides and sphingosine-1-phosphate (S1P) are key bioactive signaling molecules. Ceramides are proapoptotic and mitigate chemoresistance. Conversely, S1P promotes cancer cell proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Several studies in colorectal cancer patients have shown high levels of ceramides are associated with improved survival, while high S1P levels are associated with a poor prognosis. Hence, modulation of sphingolipid metabolism could be a promising therapeutic approach. BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P and increases C18 ceramide. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in cancer patients with advanced solid malignancies (NCT02859857). BXQ-350 was safe and well-tolerated (no DLT, no MTD). Also, 13 patients (~17.8% of evaluable patients) had a clinical benefit up to cycle 6 and beyond (PR, SD). Among patients with PFS > 6 months, there were 4 recurrent CRC patients: 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 7 years suggesting potential long-term benefit. Furthermore, there were signs that BXQ-350 may alleviate symptoms of CIPN as 4 out of 10 patients with chronic CIPN at time of enrollment experienced an improvement of their symptoms.
Methods:
BXQ-350 is being investigated in a Phase 1b/2 study in combination with mFOLFOX7 and Bevacizumab in newly diagnosed mCRC patients (NCT05322590) to assess the efficacy and safety of BXQ-350. Design of the Phase 1b (open label study): 1) A safety dose escalation part to establish the RP2D: patients will initially receive 1.8 mg/kg BXQ-350 in combination with mFOLFOX7 and Bevacizumab. If safe (no MTD), dose of BXQ-350 will be increased to 2.4 mg/kg and 9 additional patients will be entered at this dose level. If safe, then this dose will be the RP2D and 21 additional patients will be enrolled, completing a 30 patient expansion cohort 2) Efficacy will then be evaluated for all patients entered at the RP2D. Primary objectives of the Phase 1b are to assess safety, identify RP2D, and assess preliminary efficacy of BXQ-350 in this combination. A secondary objective is to determine if BXQ-350 decreases CIPN. Enrollment in the expansion cohort of 30 patients is nearly complete, with 26 patients enrolled as of September 2024.
Clinical trial information: NCT05322590
.
Phase 1/2 study of FOG-001, a first-in-class direct β-catenin:TCF inhibitor, in patients with colorectal cancer, hepatocellular carcinoma, and other locally advanced or metastatic solid tumors.
Authors: Papadopoulos Kyriakos P. , Cecchini Michael , Khushman Moh'd M. , Pelster Meredith , Rodon Ahnert Jordi , Kummar Shivaani , Yaeger Rona , Sharma Sunil , Wells Amber L. , Garofalo Amanda , Akella Lalith V , Yu Ziyang , Iyer Varsha , Nguyen Marie Huong , Orford Keith W. , Klempner Samuel J.
Published: January 2025

TPS322

Background:
Wnt/B-catenin pathway activation, which is frequently present in most colorectal cancers and a variety of other solid tumors, is associated with poor prognosis and resistance to immunotherapy. FOG-001 is a Helicon peptide that competitively inhibits the interaction between β-catenin and the T-cell factor (TCF) family of transcription factors. Experiments in patient-derived-xenograft (PDX) models of colorectal cancer (CRC) and hepatocellular carcinoma (HCC) have demonstrated that FOG-001 can inhibit tumor growth and promote tumor regression when administered as monotherapy or in combination with immune checkpoint inhibitors or standard of care therapies, including bevacizumab and 5-FU.
Methods:
This first-in-human, Phase 1/2, multicenter, open-label, dose escalation (Part 1) and dose-expansion (Part 2) study evaluates the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor effects of FOG-001 as monotherapy and in combination with other anti-cancer therapies. Eligible patients must have received at least one prior systemic anti-cancer therapy and either progressed on, not responded to, or be unfit for available therapies. In Part 1, FOG-001 is administered intravenously, either weekly or every other week, at escalating dose levels evaluated sequentially in a standard 3+3 design as monotherapy in patients with: (1a) microsatellite stable (MSS) CRC or any solid tumor with a documented Wnt/b-catenin pathway activating mutation (WPAM) and (1c) HCC with WPAM. Part 1b will evaluate PD effects in cohorts of approximately six patients with MSS CRC. Upon selection of the preliminary recommended Phase 2 dose from Part 1a for weekly dosing, combination dose escalation (1d) evaluates the safety/tolerability, PK and anti-tumor effects of FOG-001 in CRC patients combined with FOLFOX+bevacizumab, anti-PD-1/PD-L1 (also includes other solid tumors with known WPAM), or trifluridine/tipiracil+bevacizumab. Part 2 dose expansion evaluates FOG-001 monotherapy in MSS CRC, HCC, and other solid tumors with documented WPAM. Combination dose expansion evaluates the combinations initially evaluated in Part 1d. Primary endpoints are safety/tolerability and preliminary anti-tumor effects (objective response rate). Secondary endpoints are PK, PD, and other anti-tumor responses (e.g., best objective response, duration of response, and progression free survival). Enrollment in Parts 1 and 2 is ongoing in the USA.
Clinical trial information: NCT05919264
.
Phase 2 trial of defactinib in combination with avutometinib in patients with advanced diffuse-type gastric cancer.
Authors: Moy Ryan H. , Wu Lawrence Wen , Cho Hope , Wang Shikun , Sta Ana Sarah , Strickland Matthew , Sender Naomi , Klempner Samuel J.
Published: January 2025

TPS505

Background:
Diffuse-type gastric cancer (DGC) accounts for approximately one third of gastric cancer diagnoses. DGC is characterized by poor differentiation, discohesive growth, frequent peritoneal spread, chemoresistance, and inferior survival compared to intestinal-type gastric cancer. Moreover, DGC is commonly genomically stable and often lacks clinically actionable targets such as
ERBB2
amplification. Alterations enriched in DGC including loss-of-function
CDH1
mutations and gain-of-function
RHOA
mutations can facilitate increased focal adhesion kinase (FAK) signaling that drives tumor proliferation, invasiveness, and metastasis. Recent preclinical studies demonstrated that the FAK inhibitor defactinib can inhibitor DGC growth
in vitro
and
in vivo
. FAK inhibitor monotherapy leads to compensatory mitogen-activated protein kinase (MAPK) pathway upregulation, which can be overcome with combined FAK and MEK inhibition. In preclinical DGC xenograft models, defactinib plus the RAF/MEK clamp avutometinib led to deep tumor regressions, suggesting synergistic activity of the combination. The goal of this study is to investigate the efficacy and tolerability of avutometinib plus defactinib in patients with advanced DGC refractory to standard therapy.
Methods:
This investigator-initiated, multicenter phase 2 trial will enroll 27 patients with metastatic/unresectable gastric or gastroesophageal junction carcinoma classified as diffuse, poorly cohesive, signet ring cell, or mixed type with progression on at least one line of therapy including platinum/fluorouracil chemotherapy. Patients with known pathogenic
CDH1
and/or
RHOA
alterations regardless of histology are also eligible. Patients must have ECOG PS 0/1 and can have either measurable or evaluable non-measurable disease per RECIST 1.1 criteria. Avutometinib is given 3.2 mg orally twice weekly and defactinib is given 200 mg orally twice a day, both for 3 weeks on/1 week off for each 28-day cycle. The primary endpoint is 6-month PFS rate, with secondary endpoints including ORR, OS, DOR, and tolerability. Exploratory studies will interrogate FAK/MAPK pathway activation, ctDNA dynamics, and the impact of the combination of avutometinib/defactinib on the tumor microenvironment from pre- and on-treatment biopsies. The trial was opened for enrollment in August 2024.
Clinical trial information: NCT06487221
.
Beamion BCGC-1: A phase Ib/II trial of the HER2-selective tyrosine kinase inhibitor (TKI) zongertinib (BI 1810631) + trastuzumab deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1) for patients with metastatic breast cancer (mBC) and metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma (mGEAC).
Authors: Nakayama Izuma , Berz David , Aykut Yazgili Sila , Erzen Damijan , Shitara Kohei
Published: January 2025

TPS509

Background:
Approximately 15% of mGEAC tumors overexpress HER2. Currently, the HER2-targeted antibody-drug conjugate (ADC), T-DXd, is approved in mGEAC as a second-line or later-line treatment option following the failure of prior trastuzumab-containing therapy. Zongertinib (BI 1810631) is a novel, orally administered HER2-selective TKI that spares EGFR. In a Phase I trial (NCT04886804), zongertinib showed encouraging tolerability and efficacy in patients with HER2 aberration-positive advanced solid tumors, including mGEAC. Beamion BCGC-1 (NCT06324357) is a Phase Ib/II dose escalation/optimization trial investigating zongertinib plus T-DXd or T-DM1 in patients with HER2+ mGEAC or mBC. Here we focus on the mGEAC cohorts, in which patients will receive zongertinib in combination with T-DXd.
Methods:
Across the whole trial, approximately 240 patients will be enrolled from approximately 48 sites in 6 countries. In the mGEAC cohorts, approximately 80 patients with histologically/cytologically confirmed locally advanced/metastatic, unresectable, HER2-positive, pre-treated mGEAC will be enrolled. All patients must have investigator-assessed progression and documented HER2-positive disease (overexpressed and/or amplified; confirmed by immunohistochemistry and
in situ
hybridization). In Phase Ib, approximately 20 patients will receive escalating doses of zongertinib plus a fixed approved dose of T-DXd (6.4 mg/kg, once every 21 days). Dose escalation will be guided by a Bayesian Logistic Regression Model, with overdose control. In Phase Ib, the primary endpoint is the occurrence of dose-limiting toxicities (DLTs) during the maximum tolerated dose evaluation period (first 21-day cycle); secondary endpoints include objective response (RECIST v1.1), DLTs during the on-treatment period and pharmacokinetics. In Phase II, up to 60 patients with mGEAC will be randomized 1:1 to receive one of two zongertinib dose levels (dose levels informed by Phase Ib), plus a fixed approved dose of T-DXd. In Phase II, the primary endpoint is objective response; secondary endpoints include progression-free survival, disease control, treatment-emergent adverse events leading to dose reduction, pharmacokinetics and patient-reported outcomes. Patients will remain on treatment until disease progression, undue toxicity or any other protocol-defined stopping criterion. Enrollment is ongoing.
Clinical trial information: NCT06324357
.