bluuebunny/crossref_metadata_2025 huggingface dataset:
A multi-institutional, single-arm, phase II trial of neoadjuvant modified-FOLFIRINOX for resectable pancreatic ductal adenocarcinoma.
Authors: Lee Choong-kun , Hwang Ho Kyoung , Jeung Hei-Cheul , Chon Hongjae , Park Hyung Soon , Kim Min Hwan , Kim Sung Hyun , Park Mi-Suk , Kang Chang Moo , Choi Hye Jin
Published: January 2023

715

Background: Various peri-operative treatments have been tested to increase the survival of localized PDAC. Even with superior survival among various disease extent of PDAC, resectable PDAC still shows poor outcomes with surgery followed by adjuvant chemotherapy. We report the result of a multi-institutional phase II trial of modified-FOLFIRINOX as neoadjuvant treatment for resectable PDAC. Methods: Treatment naïve pts with histologically confirmed resectable PDAC were enrolled. Resectability was confirmed by both CT and MRI according to NCCN resectability criteria (no arterial tumor contact to celiac axis, SMA or CHA; no tumor contact with SMV or PV or ≤180° contact without vein contour irregularity) in multidisciplinary team meeting. Patients received oxaliplatin 85mg/m2 D1 + leucovorin 400mg/m2 D1 + irinotecan 150mg/m2 D1 + 5-FU 2,000mg/m2 46h continuous infusion, every other week for 6 cycles (12 weeks). Response assessments were performed every 6 weeks using the RECIST criteria version 1.1. Baseline MRI, PET-CT scan, and pre-surgery MRI after 6 cycles were mandatory. The primary endpoint was R0 resection rate. Secondary endpoints included survivals, ORR, safety, resection rate, and correlative biomarker exploration. (NCT05066802). Results: Total of 27 pts were enrolled between May 2020 and Feb 2022. Among total 27 pts, 24 pts underwent curative aim surgery after neoadjuvant treatment (resection rate 88.9%), and 23 pts showed R0 resection (23/27=85.2%), meeting the primary endpoint. Among 27 pts, 19 pts (70.4%) completed the neoadjuvant treatment per protocol. The reasons for neoadjuvant treatment discontinuation included progression of the disease (n=3, 11.1%) and pts withdrawal (n=5, 18.5%). Among 19 patients who underwent surgery per protocol, only one patient was R1 resected (R0 resection rate=94.7%). As of Sep 1, 2022 (median follow-up duration = 15.2 months) 6 pts recurred after surgery (6/19=31.6%). Median recur-free survival was 18.7 months (95%CI 13.6-NR) and median OS was not reached (95%CI 17.6-NR) for the per protocol treated pts. Treatment-related AE (≥G3) occurred in 10 pts (37.0%) including 7 (25.9%) with neutropenia G3-4. Conclusions: Three months of neoadjuvant mFOLFIRINOX was feasible and tolerable for resectable PDAC. Larger randomized trial is needed to validate the impact of neoadjuvant chemotherapy for resectable pancreatic cancer and to find subgroup of pts who would get benefit most from the neoadjuvant treatment. Post hoc genomic analyses with paired pre-neoadjuvant treatment and surgical tissues are ongoing. Clinical trial information: NCT05066802 .
Prediction of early treatment failure of second-line nal-iri/5-FU/FA in patients with advanced pancreatic adenocarcinoma (AIO-PAK-0216).
Authors: Karthaus Meinolf , Ansorge Nikolaus , Barmashenko Gleb , Burkart Christof , Decker Thomas , Ettrich Thomas Jens , Gerhardt Anke , Hoefling Sabine , Jacobasch Lutz , Koenigsmann Michael , Räth Sebastian , Schulte Markos , Schulte Nadine , Schwarzer Andreas , Siegler Gabriele Margareta , Waldschmidt Dirk , Lutz Manfred P.
Published: January 2023

721

Background: Second-line Nal-Iri/5-Fluorouracil/Folinic Acid (Nal-Iri/5-FU/LV) increases overall survival of unselected patients (pts) with metastatic pancreatic ductal adenocarcinoma (PDAC) after gemcitabine-based therapy. It is unknown, which pts will likely benefit or could probably profit more from alternative approaches. Methods: In this prospective trial, 156 pts with locally advanced or metastatic PDAC were included for treatment with biweekly Nal-Iri/5-FU/LV (70 mg/m², 2.4 g/m², 400 mg/m²) after failure of 1st line chemotherapy with Gemcitabine/nab-Paclitaxel, with comprehensive evaluation of prior treatment characteristics, potential predictive factors, and quality of life. Primary end point is the correlation of time to treatment failure (TTF) of 1st and 2nd line therapy. Moreover, translational research was done to measure and evaluate biomarkers in blood and tumor tissue. Here, we explore patient characteristics in two subgroups with short or long treatment duration, with the aim to evaluate potential predictive factors for further analysis. Results: 139 (90%) of the 156 pts included between 03/2018 and 07/2021 in 40 German sites received medication. End of treatment is documented for 128 pts, with 5 still on treatment as of 05/2022 Mean (±SD) treatment duration was 15.5 weeks or 7.7±7.1 cycles (median 7 weeks; 5 cycles). 37 (25%) pts received ≥ 10 cycles. The median was used to separate two subgroups of short and long treatment duration (STD, ≤ 5 cycles, n=66 (52%) vs. LTD, > 5 cycles, n=62, (48%)). Reasons for treatment discontinuation clearly differed between the two subgroups: death in 9% vs. 3%, toxicity in 9% vs. 2%, unrelated medical condition in 12% vs. 2%, and progressive disease in 46% vs. 73%, respectively. Investigator´s decision was a reason for discontinuation in 6% vs. 5%. Pts with STD had a lower performance status (ECOG 1 or 2 in 74% vs. 52%, ECOG 0 in 20% vs. 44% in STD vs. LTD group), lower albumin levels (below normal in 36% vs. 24.2%) and were more likely to suffer from liver metastases (overall 82% vs. 66%). There were no relevant differences with regard to age, sex and tumor burden (number of metastases or CA19-9 levels). Conclusions: Early treatment discontinuation was primarily associated with patient-related factors such as low performance status, low albumin levels and comorbidities, characteristics which could be used to spare patients from treatment with an unfavorable risk-to-benefit ratio. In contrast, surrogate markers for tumor burden did not correlate with treatment success. Clinical trial information: NCT03468335 .
Using tumor growth rate to inform treatment efficacy in pancreatic adenocarcinoma: From the metastatic to the neoadjuvant setting.
Authors: LaRose Meredith , Yeh Celine , Zhou Mengxi , Sigel Keith Magnus , Jameson Gayle S. , White Ruth Aroon , Safyan Rachael A , Saenger Yvonne M. , Hecht Elizabeth , Chabot John A. , Schreibman Stephen M. , Fojo Antonio Tito , Manji Gulam Abbas , Von Hoff Daniel D. , Bates Susan Elaine
Published: January 2023

726

Background: The development of new treatments in oncology is a long, costly, and, too often, unsuccessful process. Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials are needed. Methods: We used a mathematical model of tumor growth kinetics fit to serial radiographic tumor measurements or CA19-9 values to estimate rates of exponential tumor growth [g] and decay [d] during treatment for pancreatic ductal adenocarcinoma (PDAC). Results: We retrospectively collected and analyzed data from 2691 patients with stage III-IV PDAC who were enrolled in five clinical trials or were included in two large real-world data sets from Columbia University Irving Medical Center and Veterans Administration Medical Centers. Using log-rank comparison of Kaplan-Meier plots by quartile of g, we found that in patients with metastatic PDAC g correlates highly with overall (OS) and progression-free survival (PFS) (p<0.001), with slower g associated with improved survival in this population. Pairwise comparisons showed significantly slower median g in the experimental arm versus control arm in the pivotal trials analyzed (p<0.001). At the individual patient level, g was significantly faster for liver metastases as compared to primary pancreatic tumors and g consistently increased towards the end of therapy (often a threefold increase) suggesting development of chemoresistance. In addition to utility in the metastatic setting, a pilot analysis of data from a prospective study of patients treated with gemcitabine + docetaxel + capecitabine (GTX) in the neoadjuvant setting suggests that the emergence of a detectable g during neoadjuvant therapy may portend worse OS following surgery though sample size was small (n=45, median OS with detectable g 13.6 m v 33.1 without detectable g, p =0.35). Conclusions: We applied a tumor growth model to the data of over 2500 patients with PDAC and showed that g is inversely associated with survival in this population. Given the strong association between g and survival, g could be useful in clinical trials as an informative endpoint to expedite the assessment of novel therapies for the treatment of PDAC. Furthermore, g offers valuable patient-level data, including trends in resistance and variations in growth rate by metastatic disease site We plan to evaluate whether the emergence of g during neoadjuvant therapy should be considered a prompt to change treatment regimens.
Intra-arterial gemcitabine vs IV gemcitabine PK substudy in patients with locally advanced pancreatic cancer.
Authors: Zureikat Amer H. , Pishvaian Michael J. , Meredith Kenneth , Hatoum Hassan , Zervos Emmanuel E. , Nazemzadeh Reza , Novelli Paula M. , Tsobanoudis Alex , Agah Ramtin
Published: January 2023

728

Background: Localized dual-balloon-mediated, intra-arterial delivery of Gemcitabine (IAG) directly into tumors/tissue can lead to higher local drug potency1. Furthermore, IAG may lead to decreased systemic drug concentration and associated side effects. In patients with Locally Advanced Pancreatic Cancer (LAPC), this approach is currently being tested in a contemporary Phase III clinical trial, TIGeR-PaC. Herein we report the results of a 10-patient PK analysis sub-study within TIGeR-PaC. Methods: We analyzed a total of 10 subjects from 5 sites who received intra-arterial gemcitabine with the RenovoCath dual balloon catheter at 1000mg/m2 over 20 minutes. The target treatment artery was either the celiac axis (n=5) or the superior mesenteric artery (n=5). Samples were drawn at T = -5, 10, 15, 20, 30, 40, 60, and 90 minutes from the onset of infusion. At each timepoint, we collected 2mL of blood in heparinized tubing containing 25 mcg/mL of tetrahydrouridine. The blood samples were then centrifuged collect, freeze, and ship the plasma to a reference lab to perform a gemcitabine assay. The PK parameters for a single dose was estimated for Cmax, AUC, clearance, and distribution volume based on the terminal phase. These values are compared to historical data for intravenous gemcitabine (IVG) infusion at 1000mg/m2 over 30 minutes2. Results: At this time, data has been analyzed for 4 of 8 collected samples. We expect to complete collection and analysis of all 10 samples by November of 2022. We show results available so far; historical values for IVG are given as a reference point. The results suggest that IAG is associated with decreased systemic exposure of gemcitabine compared to IVG. Conclusions: Localized dual-balloon-mediated, intra-arterial delivery of gemcitabine can lead to decreased systemic levels of gemcitabine. This approach increased local potency and may be beneficial in decreasing gemcitabine-related systemic side effects. 1. Farsad K, et al. 04:21 PM Abstract No. 392 . J Vasc Intervent Radiol 2019;30(3):S172. doi:10.1016/j.jvir.2018.12.467. 2. Chow ECY, Zirkelbach JF. Clinical Pharmacology and Biopharmaceutics Review(s) {209604Orig1s000}. FDA: Center for Drug Evaluation and Research. Clinical trial information: NCT03257033 . [Table: see text]
Interim analysis results of gut microbiota in patients with unresectable cholangiopancreatic cancer: SCRUM-Japan MONSTAR-SCREEN.
Authors: Tezuka Shun , Sakai Shunsuke , Yamashita Riu , Horasawa Satoshi , Fujisawa Takao , Sawada Kentaro , Yoshikawa Ayumu , Nakamura Yoshiaki , Umemoto Kumiko , Shibata Nobuhiro , Ohtsubo Koushiro , Itoh Shinji , Todaka Akiko , Sudo Kentaro , Furukawa Masayuki , Ikeda Masafumi , Morizane Chigusa , Ueno Makoto , Yoshino Takayuki
Published: January 2023

733

Background: MONSTAR-SCREEN prospectively assessed the gut microbiota of 2000 patients (pts) with advanced solid cancer at 31 Japanese institutions. Here, we report the interim analysis results of the correlation between gut microbiota and the efficacy of first-line chemotherapy in pts with unresectable pancreatic cancer (PC) and bile tract cancer (BTC). Methods: We analyzed unresectable 205 PC and 83 BTC pts with clinical data as data cut-off on April 30, 2021, and 16S ribosome analysis results of stool samples. Among PC pts, 133 and 40 were treated with GnP (gemcitabine (GEM) plus nab-paclitaxel) and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), respectively. Among BTC pts, 32 and 33 were treated with GC (GEM plus cisplatin) and GCS (GEM, cisplatin, plus S-1), respectively. Pts with an above-median overall survival (OS) were defined as long-term survivors (LTS), and those with below-median OS and OS events were defined as short-term survivors (STS). We compared the alpha diversity index (ADI) of LTS and STS, and identified potential microbial biomarkers of LTS, STS, responders, and non-responders to first-line chemotherapy according to RECIST version 1.1, by linear discriminant analysis effect size (LEfSe). In each cohort, the top three microbiota with linear discriminant analysis scores of ≥ 3.0 were considered significant. Results: The median OS of PC and BTC pts was 13.5 and 15.9 months, respectively. In PC pts, no significant difference was noted in the ADI between LTS (n=20) and STS (n=40). In BTC pts, the ADI of LTS (n=10) was significantly higher than that of STS (n=20) in the Shannon index. LEfSe analysis in PC pts revealed that Burkholderiales and Sutterellaceae were predominant in LTS, while Lactobacillaceae was, in STS. In PC pts, Brachyspiraceae and Erysipelotrichales were predominant in responders (n=67), while Enterococcaceae and Lactobacillaceae were, in non-responders (n=137). In BTC pts, Peptostreptococcaceae, Fusobacteriaceae, and Clostridiaceae in LTS; Cardiobacteriaceae, Prevotellaceae, and Actinobacteriota in responders (n=24); and Bacilli in non-responders (n=59) were overrepresented. Conclusions: This interim analysis identified potential biomarkers of the gut microbiota that may contribute to the prognosis and efficacy of chemotherapy in pts with unresectable PC and BTC. The results of this analysis will be validated in the primary analysis.
The divergent role of the GM-CSF/GM-CSFR signaling pathway in cholangiocarcinoma and pancreatic ductal adenocarcinoma.
Authors: Dave Yatee A. , Burchard Paul R. , Ruffolo Luis I. , Ullman Nicholas A. , Georger Mary , Jewell Rachel , Belt Brian A. , Linehan David
Published: January 2023

736

Background: The granulocyte-macrophage colony-stimulating factor ligand and receptor (GM-CSF/GM-CSFR) pathway plays a multifaceted role in the setting of cancer, exerting an anti-tumorigenic or pro-tumorigenic effect depending on GM-CSF expression. In previous work, we and others have shown increased GM-CSF expression to correlate with poor prognosis in patients with cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC). We also demonstrated how GM-CSF neutralization leads to reduced tumor size in murine CCA models, in part due to inhibition of alternative macrophage polarization. Here, we explore the impact of blocking GM-CSFR signaling in CCA and PDAC, two immunologically cold tumors with poor prognoses. Methods: Immunohistochemistry (IHC) and digital quantification of staining was performed on tissue from a human PDAC and CCA databank. Murine F4/80+ bone marrow-derived macrophages were cultured in tumor-conditioned media (TCM) derived from PDAC (KP2) or CCA (URCCA4.3) cell lines, with and without anti-GM-CSFR antibody. Quantitative real time PCR (qRT-PCR) analysis was performed for gene expression. URCCA4.3 and a luciferase-labeled PDAC (KCKO) cell line were orthotopically implanted into Bc/BIL3 knockout (KO) mice which lack GM-CSFR and C57BL/6 mice. Mice implanted with URCCA4.3 were enrolled into vehicle or gemcitabine treatment groups. Mice implanted with KCKO were untreated. Tumor growth was monitored by ultrasonography or bioluminescence imaging. Results: Digital analysis of IHC staining for GM-CSFR in human PDAC tumors revealed low expression to be associated with improved overall survival (OS) and greater number of days to recurrence, while high levels were associated with worse OS and fewer days to recurrence (p<0.01). In addition, human CCA specimens had greater GM-CSFR expression compared to normal uninvolved liver (p<0.01). qRT-PCR analysis of RNA from bone marrow-derived macrophages exposed to either CCA or PDAC TCM demonstrated lower expression of genes associated with alternative macrophage polarization ( Arg1, Cd274, Pdcd1lg2) and chronic inflammation ( Ccl2, Ccl17, Irf4) (all p<0.01) in response to GM-CSFR blockade. GM-CSFR KO mice implanted with URCCA4.3 demonstrated no differences in tumor growth with or without chemotherapy, compared to wild-type controls. Similarly, KO mice implanted with an immunogenic PDAC cell line (KCKO) had no differences in tumor size compared to wild-type controls. Conclusions: GM-CSFR expression is prognostic in the setting of PDAC and elevated in human CCA compared to normal liver. In vitro, GM-CSFR blockade downregulated pro-tumor genes associated with immunosuppression and inflammation. However, complete disruption of GM-CSFR signaling reversed the efficacy generated with GM-CSF ligand neutralization, suggesting some signaling is required for inducing anti-tumor immune responses.
Clinical and molecular presentation of KRAS G12D-mutated pancreatic ductal adenocarcinoma in real-world settings.
Authors: Sturgill Emma G. , Kolli Sahiti , Feustel Kavanya , Luckett Daniel , Jones Carissa , Holt Marilyn Elaine , Hyde Annastasia , Jones Suzanne Fields , Perez Cesar Augusto , Wang Judy S. , Divers Stephen G. , Pelster Meredith , Henry Jason Timothy , Spigel David R. , Burris III Howard A. , McKenzie Andrew Jacob
Published: January 2023

738

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating diagnosis with an overall 5-year survival rate of ~10%. Therapies targeting KRAS G12D, a prevalent molecular driver of PDAC, represent an active area of investigation with many agents currently in clinical development. This study characterizes the real-world clinico-genomic landscape of patients with KRAS G12D-mutated PDAC to inform ongoing therapeutic development and clinical trial design. Methods: We conducted a retrospective, records-based analysis of 2,805 patients with PDAC from across 299 community-based oncology clinics. All patients had broad-panel next generation sequencing (NGS) from commercial vendors performed as standard of care. Patients were stratified into KRASWT (26%), KRASG12D (31%), and KRASnon-G12D (43%) cohorts according to NGS results and assessed for co-mutations, overall survival, and time to chemotherapy failure. Results: The KRASG12D and KRASnon-G12D cohorts exhibited similar mutational landscapes with frequent alterations in TP53, CDKN2A, and SMAD4 ( > 20% frequency occurrence) and infrequent actionable co-mutations (i.e. ATM, MTAP, BRCA1/2, PIK3CA, and MYC; < 5% frequency occurrence). KRASG12D exhibited significantly decreased overall survival compared to KRASWT (m (95% CI); 32.4 months (27.6-37.6 months) [ KRASWT], 20.1 months (17.0-22.7 months) [ KRASG12D], 21.7 months (20.0-25.0 months) [ KRASnon-G12D]; Cox model p-value < 0.001) as well as significantly shortened time to chemotherapy failure compared to both KRASnon-G12D and KRASWT (m (95% CI); 10.8 months (9.6-11.6 months) [ KRASWT], 7.8 months (7.3-8.7 months) [ KRASG12D], 9.8 months (8.8-11.1 months) [ KRASnon-G12D]; Cox model p-value < 0.01). Within the KRASG12D cohort, no co-mutations were significantly associated with overall survival. Conclusions: This study demonstrates the acute need for KRAS G12D-targeted agents in the clinic, as patients with KRAS G12D-driven PDAC experience particularly poor patient outcomes and lack alternative molecular targets.
Depth of response in patients with locally advanced pancreatic cancer treated with modified FOLFIRINOX or gemcitabine plus nab-paclitaxel combination therapy: An exploratory subgroup analysis of JCOG1407.
Authors: Shibuki Taro , Ikeda Masafumi , Ozaka Masato , Kobayashi Satoshi , Ohba Akihiro , Todaka Akiko , Uemura Kohei , Sano Yusuke , Horie Yoshiki , Kumamoto Yusuke , Shioji Kazuhiko , Kanai Masashi , Nishina Tomohiro , Okabayashi Takehiro , Fujimori Nao , Katanuma Akio , Takayama Yukiko , Tsumura Hidetaka , Furuse Junji , Ueno Makoto
Published: January 2023

746

Background: Depth of response (DpR; max% reduction from baseline in sum of target lesion diameters), has been reported to be associated with improved prognosis in several malignancies. However, there have been few reports regarding DpR in patients with locally advanced pancreatic cancer (LAPC). Thus, we investigated the association between DpR and overall survival (OS), and whether there were any differences in treatment efficacy on DpR between modified FOLFIRINOX (mFFX) versus gemcitabine plus nab-paclitaxel (GnP) as 1st-line chemotherapy for LAPC, using the results from JCOG1407 which was a randomized phase II trial comparing these regimens. Methods: Of the 126 patients enrolled in JCOG1407, patients were eligible except for the followings; patients who never had an imaging study or had only non-target lesions. The association between DpR and OS was investigated by dividing DpR into 3 groups at the tertile point (T1, T2 and T3 from largest to smallest), and whether DpR contributes to OS was examined by multivariable analysis. The differences in treatment efficacy between both regimens were investigated byevaluating DpR, time to DpR, and duration of response (DoR). Results: A total of 109 patients were eligible for this study (n = 53/56 in mFFX/GnP). The number of patients in T1, T2, and T3 were 37, 36, and 36, respectively. The median OS of T1, T2, and T3 were 29.3 (95% CI, 21.0-NE), 20.6 (95% CI, 15.8-24.5), and 19.0 months (95% CI, 12.7-22.4), respectively ( P= 0.0237). Multivariable analysis identified DpR as an independent prognostic factor for OS (HR 1.883, 95% CI 1.030-3.442, P= 0.040 for T2 vs. T1, and HR 2.523, 95% CI 1.342-4.744, P= 0.004 for T3 vs. T1). The median DpR in GnP was better than that in mFFX (28.9 vs. 22.7%; P= 0.041). The median DoR in mFFX tended to be longer compared to that in GnP (8.2 vs. 5.3 months; P= 0.132). No differences in mean time to DpR were observed between the two regimens. Conclusions: In LAPC patients receiving 1st-line chemotherapy, larger DpR contributed to OS. Although OS and PFS between mFFX and GnP were similar, the treatment efficacy on DpR and DoR might be different between the two regimens. Clinical trial information: UMIN000023143 .
The role of Smad4/TGFB signaling in tumorigenesis of pancreatic ductal adenocarcinoma (PDAC).
Authors: Yoo Hannah , Means Anna
Published: January 2023

748

Background: Pancreatic cancer ranks 4th among cancers as a cause of death in the United States and 85- 90% of pancreatic cancer are pancreatic ductal adenocarcinoma (PDAC). Previous studies have demonstrated 2 major types of precursors to PDAC including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN); the mechanisms by which IPMNs give rise to PDAC are incompletely defined. We hypothesize that SMAD4 signaling is specifically involved in IPMN pathway with PanINs and IPMN having partially overlapping signaling pathways and molecular markers. Methods: We performed immunohistochemistry staining on different precursor lesions of mouse pancreatic tissue (PanIN precursor: Ptf1aCre LSL-KrasG12D; IPMN precursor: Ptf1aCreERT LSL- KrasG12D Smad4fl/fl treated with tamoxifen) using markers of different IPMN subtypes and signaling pathways known to be involved in PDAC including, MUC1, MUC2, MUC5AC, SMAD4, ERK1/2, SOX9, and YAP. We treated IPMN cells lines derived from Ptf1aCreERTM LSL-KrasG12D GnasR201C mice with TGF-β, BMP-2, or vehicle control and quantified RNA expression of Smad7, Serpine1, Id2, and normalized to Pmm1 expression. We performed a western blot to detect the protein expression of phospho-SMAD1, phospho-SMAD2, SMAD1, and SMAD2. Results: Both PanIN and IPMN mouse models exhibited strong expression of MUC5AC and MUC1, reflecting the pancreatobiliary subtype. The tumor cells in both models expressed phosphorylated substrates of protein kinase A, phosphorylated ERK1/2, and SOX9. Regional differences were noted for SOX9 signaling with IPMN demonstrating a greater expression around the outer edges of the lesion, compared to the center. PanIN model demonstrated a more prominent nuclear YAP staining. Treatment of BMP2 and TGF-β in pancreatic IPMN cells from Ptf1aCreERTM LSL-KrasG12D GnasR201C cell line significantly increased RNA levels of Serpine1 (2.4 and 199.6, respectively; n = 4; p < 0.05) and Smad7 (2.9 and 6.3, respectively; n = 4; p < 0.05). BMP2 treatment significantly increased RNA levels of Id2 (1.9; n = 4; p < 0.05) while TGF-β significantly decreased Id2 level (0.3; n = 4; p < 0.05). Phosphorylated-SMAD2 was detected only with TGF-β treatment while phosphorylated-SMAD1 was detected with vehicle, TGF-β, and BMP2 treatment with the highest level with BMP2 treatment. Conclusions: Knocking out Smad4, concurrent with activating KrasG12D mutation, induces a specific IPMN progression model that shares similar molecular markers as the PanIN progression model, shown in Kras mutation alone. SMAD4 signaling remains intact in IPMN lesions that arise from activating the KrasG12D GnasR201C mutation, possibly suggesting that Smad4 mutation induces the IPMN-PDAC progression model that differs from Gas-cAMP-PAK-YAP1 cascade found in GNAS signaling.
Clinical performance of a multimodal screening blood test for advanced adenomas and CRC in an average-risk cohort of 1,038 participants.
Authors: Friedland Shai , Watson Drew , Rex Douglas K. , Nimgaonkar Ashish , Zhang Zhen , Atkins Alex , Hsieh Ben , Lai Jr-Ming , Su Stephen , Wu Jen-chia , Shao Hung-Jen , Tesoriero Jessica , Hannah Lindsey , McGowan John , Gupta Samir , Sninsky John J. , Mei Rui
Published: January 2023

75

Background: The National Polyp Study and 2021 USPSTF CRC-update highlight that the detection and removal of precancerous advanced adenomas (AA) prevents colorectal cancer (CRC), decreases mortality, and leads to higher cost savings than early cancer detection. Performance of a multimodal blood-based test for the detection of CRC and AA that integrates sensitive and accurate detection of circulating gastrointestinal epithelial cells and somatic oncologic variants as well as SEER data of the impact of sex and age is described. Methods: The prospective study included average-risk, asymptomatic screening subjects from 18 geographically dispersed US colonoscopy centers with blood drawn before colonoscopy. Monte Carlo cross-validation (MCCV) methods were used to evaluate the robustness of test performance through 2000 iterations of independent training and validation using bootstrap resampling with stratification to balance patient histopathology, age, and gender. Results include point estimates, confidence intervals, and distributions of sensitivity and specificity to detect AA and CRC. Results: The study cohort (53.2% female; mean age 56.7 yrs.) consisted of 1,038 subjects (White 65.1%; Black 8.5%; Hispanic 24.8%; Asian 1.7%); of which 954 (92%) were asymptomatic, average-risk screening subjects without age enrichment (including 11 CRC and 93 AA) and 84 (8%) were enriched case-control (65 CRC and 19 AA) subjects. The algorithm derives a test score from 0 (low risk) to 100 (high risk) as a quantitative measure of AA and CRC risk. A pre-defined cut point of 47.2 yields a test specificity > 90%, and 92.1% and 54.5% sensitivity for the detection of CRC and AA, respectively. Estimated sensitivities and selected Clopper-Pearson (Exact) 95% confidence intervals based on validation results from MCCV are presented. A split analysis shows for the 954 intended-use, asymptomatic, average-risk screening subjects, the sensitivity for CRC and AA are 100% and 55.9%. Conclusions: A multi-site, prospective, average-risk CRC screening study using a multimodal assay had high sensitivity and specificity for AA and CRC. The quantitative correlation of test scores with disease pathology indicates that the modes of the assay interrogate the primary underlying pathophysiology of disease. The results demonstrate the potential of this novel test to meet the clinically unmet need for a noninvasive strategy for CRC screening and prevention that detects CRC and AA. Clinical trial information: NCT05127096 . [Table: see text]
The Endoscopic Ultrasound Molecular Analysis of Pancreatic Cancer (EUMEPC) study.
Authors: Lundy Joanne , Gao Hugh , Wilson Trevor , McKay Owen , Perry Andrew , Marshall Vikki M , Croagh Daniel
Published: January 2023

751

Background: Pancreatic cancer carries a dismal prognosis and limited treatment options. Attempts to implement precision therapies have proved difficult to date, in part due to challenges obtaining high quality genetic material from pancreatic biopsies. Endoscopic ultrasound (EUS) is a common diagnostic procedure, but limited data is available on the clinical utility of these biopsies for comprehensive molecular profiling (CMP) to inform therapeutic choices. Methods: This study aimed to enrol up to 150 patients undergoing EUS biopsies for pancreatic cancer, in order to complete targeted DNA/RNA sequencing on 100. The primary outcome was to characterise the proportion of patients able to undergo CMP on their diagnostic EUS biopsies, with fresh-frozen biopsies preferred but FFPE specimens accepted if there was no alternative. Secondary endpoints included the proportion of patients with clinically relevant molecular findings as determined by Molecular Tumour Board (MTB) discussion, proportion of patients initiating targeted therapies, and quantitative/qualitative analysis on molecular material derived from fresh-frozen versus FFPE EUS biopsies. Results: 109 patients have been enrolled since May 2020, and molecular profiling has been completed for 102 patients. 2 patients (1.8%) were excluded due to having no available biopsies, and 5 biopsies (4.7%) were unable to be sequenced due to inadequate quality metrics. Common oncogenes were detected at roughly expected frequencies, with mutations in KRAS occurring in 91 (89.2%), TP53 in 67 (65.7%), SMAD4 in 11 (10.8%) and CDKN2A in 7 (6.8%). Median tumour mutation burden (TMB) in this cohort was low at 3.1Mut/Mb although 7 patients (6.9%) had a high TMB (defined as >10Mut/Mb), of which 3 (2.9%) had markedly hypermutated tumours (>200Mut/Mb). All processed samples were microsatellite stable. Therapeutically relevant mutations were detected in 21 (20.6%) including RNF43 in 7 patients (6.9%), KRAS G12C and BRCA in 3 patients each (2.9%), in addition to BRAF V600E in 2 (1.9%), and CHEK2 and BARD1 mutations in 1 each (0.9%). High TMB was observed in 7 patients (6.9%). To date, 5 patients (4.9%) have commenced on targeted therapies, with one patient notably experiencing a complete response to targeted therapy which has now been sustained for >12 months. Conclusions: This real-world study confirms the utility of endoscopic biopsies as a valuable and reliable source of genetic material for clinically relevant molecular tumour profiling. Secondary analyses are underway to further characterise treatment and survival implications in this cohort.
Clinical benefit of granulocyte-colony stimulating factor (GCSF) use during chemoimmunotherapy treatment for metastatic pancreatic adenocarcinoma (mPDAC).
Authors: Lyman Jaclyn P. , Cabanski Christopher R , Maddock Stephen , Wolff Robert A. , Wainberg Zev A. , Ko Andrew H. , Rahma Osama E. , Fisher George A. , Gabriel Peter Edward , Doucette Abigail , Zheng-Lin Binbin , Maloy Molly A. , Dugan Ute , Fairchild Justin P. , Spasic Marko , O'Donnell-Tormey Jill , Vonderheide Robert H. , O'Hara Mark H. , O'Reilly Eileen Mary
Published: January 2023

757

Background: GCSF is used for primary/secondary prophylaxis of chemotherapy(chemo)-associated neutropenia in patients (pts) with mPDAC. GCSF may also increase the populations of healthy, naïve immune cells in an otherwise immunologically dysregulated and cold environment, potentially augmenting therapy outcome with immunomodulatory (IO) agents. Here, we describe the impact of GCSF administration on OS, PFS, and time on treatment (TOT) in the setting of mPDAC for (1) a trial in which pts were administered chemo-IO combinations and (2) a synthetic control arm using retrospective real-world data from pts who received standard-of-care (SOC) chemo (PASCAL). Methods: PRINCE is a ph1b/2 study evaluating gemcitabine (gem) and nab-paclitaxel (NP) ± sotigalimab (sotiga; CD40 agonist) ± nivolumab (nivo; anti-PD1) for pts with mPDAC (NCT0324250), where prophylactic GCSF use was prohibited. PASCAL pts received SOC gem/NP and primary/secondary GCSF use was allowed. In this retrospective analysis, GCSF use was defined as receiving at least 1 dose of GCSF anytime during treatment. OS, PFS, and TOT and associated HRs and CIs were calculated using Kaplan-Meier and Cox methods. PFS data not available for PASCAL. Results: 32/123 (26%) and 16/68 (24%) pts received GCSF in PRINCE and PASCAL, with 84% and 88% of pts receiving at least 1 dose within the first 3 cycles, respectively. In PRINCE, GCSF use was associated with significant improvements in OS (HR [95% CI]: 0.62 [0.40-0.97]), PFS (0.71 [0.47-1.08]), and TOT (0.67 [0.45-1.01]). These improvements were most notable in the sotiga-containing arms (table). In the absence of IO treatment, however, no statistical significance was observed in PASCAL (HR [95% CI]: OS = 0.81 [0.44-1.51]; TOT = 0.90 [0.51-1.58]). Additional work is ongoing to understand the association of GCSF usage with known prognostic factors. Conclusions: These analyses suggest that GCSF use may enhance the clinical benefits of chemo-IO in mPDAC. These potential benefits of GCSF usage warrant further evaluation in other chemo-IO trials as well as prospective evaluation in pre-clinical and clinical settings. Clinical trial information: NCT03214250 . [Table: see text]
Next-generation whole blood transcriptome-based assay for advanced adenoma detection.
Authors: Ehrensberger Sahar Hosseinian , Wosika Victoria , Hadadi Noushin , Fonseca Costa Sara , Durandau Eric , Monnier-Benoit Sylvain , Ciarloni Laura , Scherer Stefan J. , Tejpar Sabine
Published: January 2023

77

Background: Colorectal Cancer (CRC) is the second leading cause of cancer mortality worldwide although highly curable if detected early. An accurate liquid biopsy test for early cancer and precancerous lesion, detection is key to promote prevention and reduce mortality. We previously developed a liquid biopsy test based on immune cells response to the tumor, commercialised under the name of Colox, with best-in-class clinical performances for AA detection (52% sensitivity and 92% specificity) (Ciarloni L et al, Clin Cancer Res, 2016). An improved second generation of the test, leveraging transcriptome profiling and advanced machine learning tools, is under development and first results are presented. Methods: Prospective peripheral whole-blood (PAXgene) samples from subjects diagnosed with CRC, advanced adenoma (AA), non-advanced adenoma, other types of cancer as well as controls without colorectal neoplasia (CON) were divided into discovery and validation sets. Transcriptome profiles were generated by RNA-seq and gene expression signatures identified leveraging Novigenix’s proprietary LITOseek platform, which integrates several advanced Machine Learning (ML) methods into a ranking systems. Biological functional analysis was performed by over-representation (ORA), gene set enrichment (GSEA) and gene network analyses (STRINGdb). Results: Significant changes in the whole blood transcriptome profile of AA compared to CON were identified. Functional analysis highlighted upregulation of fatty acid derivative biosynthesis, interferon signaling, tryptophan catabolism to kynurenine, and downregulation of DNA repair in AA blood samples compared to CON. A novel gene classifier was generated, showing for AA detection 71% sensitivity, 94% specificity and an AUC of 74% by cross-validation on the discovery set. Validation of the gene classifier in an independent set is currently ongoing and will be presented at the congress. Conclusions: Capturing immune-related information using whole blood trascriptome profiling and applying cutting-edge machine learning technologies demonstrated to be valuable for identifying gene signatures for advanced adenoma detection. This differentiated solution has demonstrated best-in-class potential to significantly improve patient outcomes by detecting precancerous lesions with a simple non-invasive blood test.
Social vulnerability and survival in GI cancers.
Authors: Murimwa Gilbert Zvikomborero , Meier Jennie , Nehrubabu Mithin , Yopp Adam C. , Zeh Herbert J. , Polanco Patricio M.
Published: January 2023

787

Background: Social vulnerability is a federal metric used to assess a community’s resilience in facing external stressors from disease or disaster. The social vulnerability index (SVI) includes 15 social factors obtained at the census tract level within counties and ranks them along 4 themes – socioeconomic status, household composition and disability, minority status & language, and housing/transportation. Social vulnerability has never been explored at the census tract level in any malignancy and the Texas cancer registry provides granular detail at both the patient and census block group level not available in national datasets. We sought to characterize the relationship between social vulnerability and survival in gastrointestinal cancers, as well as its potential to identify themes for focused interventions to mitigate disparities. Methods: We retrospectively reviewed 196,651 patients with colorectal (CRC), gastric (GC), pancreatic (PDAC), and hepatocellular cancer (HCC) from the Texas Cancer Registry from 2004-2019. We analyzed patient demographics, social vulnerability (SVI), individual poverty index (PI), and clinicopathologic factors to understand their impact on survival at 2 years. Unadjusted and covariable-adjusted cox proportional hazards were used for survival analysis. Values were considered significant at p<0.05. Results: Of 196,651 patients, 119,667 (61%) were CRC, 31,636 (16%) PDAC, 18,249 (9%) GC, and 27,099 (14%) HCC. The majority of HCC were localized (51.4%) while most CRC was regional (38%) and PDAC (55%) and GC (40%) were metastatic at diagnosis (median 65 years). In our cohort, 60% of patients received surgery and 34% received chemotherapy while half of those with pancreatic/hepatic malignancies received no therapy. Percentiles for SVI themes were consistently near the national average except for GC which was in the 80th percentile for the minority/language theme. At 2 years, individual poverty at 5-9%, 10-19%, and >20% of the federal poverty line (HR 1.06, 95%CI 1.03 - 1.09; HR 1.09, 95%CI 1.06 - 1.12; HR 1.13, 95%CI 1.10 - 1.17) was associated with increased risk of death. Medicaid as primary insurance, (HR 1.41, 95%CI 1.36 - 1.47), SVI socioeconomic status (HR 1.18, 95%CI 1.13 - 1.24), and household composition themes (HR 1.06, 95%CI 1.02 - 1.10) also associated with increased likelihood of death at 2 years. Notably, the minority theme was associated with improved survival (HR 0.85, 95%CI 0.82 - 0.89). Conclusions: Across four GI cancers, social vulnerability and poverty independently predicted survival at 2 years. Among SVI themes, socioeconomic status was the strongest predictor of worse survival, and the minority theme was associated with improved survival, potentially reflecting the Hispanic paradox. These findings suggest that the SVI may be used as a tool for identifying where resources can be targeted at a local level to mediate the survival disparity for vulnerable populations with GI malignancies.
The inequity in emergency room utilization prior to colorectal cancer diagnosis and the opportunity to improve access to colorectal cancer screening.
Authors: Barzi Afsaneh , Zhang Juanjuan , Liu Lihua , Kim Sue
Published: January 2023

79

Background: The opportunity for early detection of colorectal cancer via screening is not fully realized. Previous efforts to maximize use of screening had targeted patients and primary care providers. Other wildly used healthcare settings may be suitable targets for intervention. We explored emergency room (ER) utilization in patients with colorectal cancer prior to their diagnosis using the linkage between California Cancer Registry (CCR) and OSHPD (Office of Statewide Health Planning and Development). Methods: Patients with diagnosis of colorectal cancer 2010-2015 were identified in the CCR and their records were linked with OSHPD (2009 – 2016) to assess ER utilization. This study aimed to evaluate the patterns of ER utilization (all and nay reason for ER visit) prior to the diagnosis of colorectal cancer. Results: A total of 66,451 colorectal cancer patients were identified, of which 57,876 (87%) were linked with OSHPD data. Among the linked population, 41% (23,890) had at least one ER visit prior to their diagnosis of colon cancer. Of the 23,890 with ER visit, 14% had 3 or more ER visits. The median number of days from first ER visit to diagnosis was 539 days (range: 2551 – 1). A total of 14,372 patients (25%) had an ER visit within one year of their colorectal cancer diagnosis. The median age of patients who had ER visits was younger than those who didn’t have an ER visit, 66 vs. 68 years. There was no difference in the number of ER visits between patients 50 and younger and those older than 50 years. There was no significant difference in the stage at presentation between those with prior ER visit and those without. Patients in high socioeconomic status were less likely to have an ER visit prior to colorectal cancer diagnosis (44%) compared to those with low SES status (36%). Patients with private insurance had a significantly lower likelihood of ER visits compared to those with federal and state funded insurance. Conclusions: A significant percentage of patients with colorectal cancer had ER visit prior to their diagnosis, many within one year of their diagnosis. Inequity in access to care, measured via poor SES and insurance type, was associated with higher chance of ER visit among colorectal cancer patients. Emergency room may be a targetable opportunity to remind and coordinate screening for colorectal cancer.
Identification of risk factors for gastrointestinal irAEs associated with immune checkpoint inhibitors.
Authors: Morikawa Ryo , Nitta Kentaro , Yasuda Shuntaro , Noji Rika , Kano Yoshihito , Sato Shingo , Ikeda Sadakatsu , Nagata Masashi , Mori Takehiko , Suenaga Mitsukuni
Published: January 2023

791

Background: Immune checkpoint inhibitors (ICIs) are widely used in tumor-agnostic therapy showing remarkable survival benefit in various cancer types. Gastrointestinal (GI) toxicities are common immune-related adverse events (irAEs) with limited reports for risk factors. In this study, we investigated potential risk factors for GI-irAEs in patients receiving immunotherapy. Methods: We retrospectively reviewed medical records of cancer patients treated with ICIs between January 2020 and December 2021 at Tokyo Medical and Dental University hospital, and analyzed the relationship between GI-irAEs and patients’ clinicopathological characteristics, treatment duration or the number of treatment cycles. Results: Among 474 patients, 136 were eligible for analysis. Patient characteristics were as follows: the median age, 68 years (range, 32-92); male/female, 104 (76.5%)/32 (23.5%); and cancer types were mainly GI in 36 (26.5%), head and neck in 33 (24.3%), urinary tract in 35 (25.7%), and others in 32 (23.5%). Details of ICIs were nivolumab in 47 (34.6%), pembrolizumab in 61 (44.9%), atezolizumab in 17 (12.5%), and nivolumab + ipilimumab in 11 (8.1%). GI-irAEs was observed in 29 patients (21.3%), and more frequent in female than male (OR: 3.07, 95% CI: 1.31-7.68, P=0.0146). The median number of treatment cycles to the onset of GI-irAEs from ICIs initiation was 4 (range, 1-70). Female had a shorter event-free survival than male (HR: 2.12, 95% CI: 0.914-4.9, P=0.041). There was no significant difference in gender for the number of treatment cycles to the onset of GI-irAEs from ICIs initiation. Of 17 patients (12.5%) with grade 2≤ GI-irAEs, female had trend toward higher incidence (OR: 2.63, 95% CI: 0.99-7.22, P = 0.122). The outcomes after the GI-irAEs onset were as follows: treatment continuation in 9 patients (52.9%), treatment discontinuation followed by observation in 1 (5.9%) and administration of corticosteroids in 7 patients (41.2%). Of 7 patients receiving corticosteroids, 2 resumed chemotherapy with other drugs, 2 resumed chemotherapy with same drugs, and 3 discontinued chemotherapy. Conclusions: Our results suggest that female is a potential risk factor for GI-irAEs during ICI treatment regardless of cancer types.
Efficacy and tolerability of immune checkpoint inhibitors in elderly patients with MSI/dMMR gastrointestinal cancers and impact of toxicities on efficacy: The immunoMSI cohort.
Authors: Mailly-Giacchetti Leah , Colle Raphael , Lopez-Trabada Ataz Daniel , Duval Alex , Andre Thierry , Cohen Romain
Published: January 2023

795

Background: Immune checkpoint inhibitors (ICI) are the new standard of care for some MSI/dMMR advanced tumors in first-line setting or after progression under conventional chemotherapy. Frequency of MSI/dMMR increasing with age, the tolerability and efficacy of ICIs in elderly patients, appears as a crucial clinical issue. We aimed to evaluate the tolerability and efficacy of ICIs in ≥ 75 years patients with metastatic MSI/dMMR gastro-intestinal (GI) cancer. Methods: All pts with MSI/dMMR metastatic GI cancer treated by anti-PD1 ± anti-CTLA4 without concomitant chemotherapy at Saint-Antoine hospital and included in our prospective, monocenter cohort, were analyzed. Pts were divided into the elderly (≥75 years) and non-elderly (<75 years) groups. The incidence and evolution of grade ≥ 3 immune-related adverse events (irAE) and grade ≥ 2 endocrine adverse events were evaluated. Secondary objectives were progression-free survival (PFS) and overall survival (OS) regarding age and the occurrence of irAEs. Results: Two hundred and one patients were included: 24 pts≥75 years (75 to 90 years) and 177 pts< 75 years (22 to 74 years). 171 (79%) had mCRC. In the entire population, the incidence of irAEs was 40.5% with anti-PD1 plus anti-CTLA4 and 23% with anti-PD1 monotherapy (p= 0.011). Combination of anti-PD1 and anti-CTLA4 were administered to 29% of the elderly group and 40% of the non-elderly group. There was no statistical difference in the incidence of irAEs between the two populations (37.5% in the elderly group vs 29% in the non-elderly group; p=0.48) neither in their type (12% vs 7% of hepatic cytolysis, 13% vs 16% of endocrine irAEs) or management (17% vs 19% corticosteroid therapy, 21% and 16% of ICI discontinuation). No significant difference was observed between elderly/non elderly for PFS (HR 0.91, 95%CI 0.40-2.06; p=0.83) and OS (HR 1.6, 95%CI 0.65-3.96; p= 0.21). Pts experiencing irAEs had superior survival outcomes than those without irAEs (PFS HR 2.93, 95%CI 1.69-5.09; p=0.02 and OS HR 2.05, 95%CI 1.13-3.74; p=0.045) in the whole cohort (n=201). Conclusions: Tolerability and efficacy of ICIs for pts with MSI/dMMR GI cancers are similar for elderly compare as for non-elderly pts. Pts experiencing irAEs had superior survival outcomes. Further prospective studies with systematic geriatric assessment are required to evaluate the tolerability of ICIs especially for frail elderly pts.