bluuebunny/crossref_metadata_2025 huggingface dataset:
A prospective phase II study of biweekly S-1, leucovorin and gemcitabine in elderly patients with locally advanced or metastatic pancreatic adenocarcinoma.
Authors: Bai Li-Yuan , Li Chung-Pin , Shan Yan-Shen , Chuang Shih-Chang , Chen Jen-Shi , Chiang Nai-Jung , Chen Yen-Yang , Tsou Hsiao-Hui , Chuang Mei-Hsing , Chiu Chang-Fang , Liu Tsang-Wu , Chen Li-Tzong
Published: January 2022

550

Background: A chemotherapeutic regimen for elderly patients with advanced pancreatic cancer is necessary because of the considerable toxicities associated with current standard regimens. A modified combination of gemcitabine, S-1, and leucovorin (GSL) was used as a first-line treatment for elderly patients with newly diagnosed locally advanced or metastatic pancreatic adenocarcinoma in a prospective, phase II, multicenter clinical trial (NCT03559348). Methods: Patients more than 70 years of age with ECOG performance status score 0-2 were treated with GSL. GSL was administered every 2 weeks, intravenous gemcitabine 800 mg/m2 at a fixed-dose rate of 10 mg/m2/min on day 1 and oral S-1 (80-120 mg/day) plus leucovorin 30 mg twice daily on days 1-7, until disease progression, withdrawal, or intolerable toxicities. The primary endpoint was progression-free survival (PFS). Results: Overall, 49 patients were enrolled into the trial between 10 July, 2018 and 25 March, 2020, with a median follow-up of 12.5 months. The data cut-off point was on 15 June, 2021. The median patient age at diagnosis was 76 years (range, 70–87 years), and thirty-two (65.3%) patients had metastatic lesions before GSL treatment. Patient frailty was evidenced by the Vulnerable Elders Survey (VES)-13 score (median 5, range 0-13) and Geriatric 8 (G8) score (median 10.5, range 3-15) at baseline. Among the 44 evaluable patients, 13 demonstrated a partial response (29.5%) and 24 presented with stable disease (54.5%). The median PFS was 6.6, 6.6, and 6.3 months, and OS was 12.5, 12.7, and 11.6 months for total population, patients with locally advanced disease, and patients with metastatic lesions, respectively. Patients had improved emotional function and global health status score during GSL treatment. The most frequent grade 3 or higher treatment-related toxicities included anemia (20.4%), decreased neutrophils (18.4%), decreased white blood cells (16.3%), and oral mucositis (12.2%). Conclusions: The GSL regimen results in impressive efficacy with tolerable toxicity in this group of frail patients. In addition, quality of life can be maintained during the treatment. GSL could be a treatment of choice for elderly patients with locally advanced or metastatic pancreatic cancer. Clinical trial information: NCT03559348.
Salvage ablative radiation therapy for loco-regionally recurrent pancreatic ductal adenocarcinoma following surgical resection.
Authors: Ng Victor , Zinovoy Melissa , Hajj Carla , Romesser Paul Bernard , Wu Abraham Jing-Ching , Cuaron John J , Jarnagin William R. , O'Reilly Eileen Mary , Crane Christopher H. , Reyngold Marsha
Published: January 2022

552

Background: Dose escalated radiation therapy for localized pancreatic ductal adenocarcinoma (PDAC) is associated with improved outcomes (Reyngold, JAMA Onc, 2021). Overall survival (OS) and loco-regional failure (LRF) rates with ablative radiation therapy (A-RT) in unresectable PDAC approach those of surgery. Herein, we report outcomes of A-RT as loco-regional salvage after resection. Methods: A prospective database (2016 onward) has been maintained of all patients receiving A-RT at for PDAC. A-RT is defined as a biologically effective dose (BED) ≥96 Gy (α/β = 10). We analyzed consecutive patients from June 2016 through January 2021 who received A-RT for isolated loco-regional recurrences after resection. Survival was calculated using the Kaplan-Meier method. Results: Sixty-nine patients (40 men, 29 women) with median age of 67 received A-RT for loco-regionally recurrent PDAC. At diagnosis of recurrence, median disease-free interval from time of initial resection was 15.6 months (range 6.2–82.7) and median CA 19-9 was 65 U/mL (range < 1–1087). Twenty-one patients (30%) received neoadjuvant chemotherapy prior to surgery: pancreaticoduodenectomy (57 patients, 83%) or distal pancreatectomy (12 patients, 17%). There was a negative resection margin in 55 patients (80%). Most had T1/T2 (61 patients, 88%) and node-positive disease (44 patients, 64%). Radiation fractionation ranged from 5-25 fractions (median 25) to a total dose of 50-75 Gy (median 75). Median follow up was 16.2 months from RT. Median OS was 26.5 months from diagnosis of recurrence and 20.7 months from time of salvage A-RT. Twelve- and 24-month OS were 78.5% (95% CI 66.3–86.7) and 40.3% (25.8–54.3), respectively. In-field local failure was 8.5% (0.3–36.0) at 12 months and 27.5% (5.2–57.0) at 24 months. Respective disease-free survival at 12 and 24 months were 32.9% (21.7–44.1) and 12.3% (5.7–21.6). Grade 3 or greater gastrointestinal bleeding (GIB) occurred in 7 patients (10%), including one grade 4 event while on anticoagulation and one grade 5 event in a patient with portal hypertension. Conclusions: A-RT achieves favorable OS and LRF outcomes in patients with PDAC and an isolated loco-regional recurrence after surgical resection.
Randomized phase 2 study of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy in patients with refractory metastatic pancreatic cancer (CHECKPAC).
Authors: Chen Inna Markovna , Johansen Julia S. , Theile Susann , Hjaltelin Jessica X. , Novitski Sif I. , Brunak Søren , Hasselby Jane P. , Willemoe Gro L. , Lorentzen Torben , Madsen Kasper , Jensen Benny V. , Wilken Eva E. , Geertsen Poul F. , Behrens Claus , Nolsoe Christian , Hermann Kirstine L. , Svane Inge Marie , Nielsen Dorte
Published: January 2022

554

Background: Pancreatic ductal adenocarcinoma remains one of the most lethal diseases. Investigating novel treatment strategies for patients with metastatic pancreatic cancer (mPC) is crucial. The purpose of this phase II trial study was to evaluate the clinical benefit of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy (SBRT) in patients with mPC. Methods: Between November 2016 and December 2019, patients with refractory mPC were randomly assigned 1:1 to SBRT of 15 Gy with nivolumab or nivolumab/ipilimumab stratified by performance status. Primary endpoint was clinical benefit rate (CBR) defined as proportion of patients with complete or partial response (PR) or stable disease, according to RECIST 1.1. Simon’s 2-stage phase II optimal design was used independently for both arms with CBR determining expansion to second stage. Secondary endpoints included safety, overall response rate, duration of response (DOR), progression free survival and overall survival (OS). Exploratory analyses included biomarkers related to immune response. Results: Eighty-four patients (41 SBRT/nivolumab and 43 SBRT/nivolumab/ipilimumab) received at least one dose of study treatment. CBR was 17.1% (95% CI, 8.0 to 30.6) for SBRT/nivolumab and 37.2% (95% CI, 24.0 to 52.1) for SBRT/nivolumab/ipilimumab. PR was observed in one patient in SBRT/nivolumab and lasted for 4.6 months. Six patients in SBRT/nivolumab/ipilimumab obtained a PR with a median DOR of 5.4 months (95% CI, 4.2 - not reached). All responders had mismatch repair proficient tumors. Grade 3 or higher treatment-related adverse events occurred in 10 (24.4%) patients in SBRT/nivolumab and in 13 (30.2%) patients in SBRT/nivolumab/ipilimumab. PD-L1 expression by tumor proportion score or combined positivity score of ≥1% was not associated with clinical benefit. On-treatment decrease in serum interleukin (IL)-6, IL-8 and CRP levels was associated with better OS. Conclusions: Clinical meaningful antitumor activity and a manageable safety profile were demonstrated after SBRT/nivolumab/ipilimumab in patients with refractory mPC. Clinical trial information: NCT02866383.
Machine learning for tracking planned versus delivered dose in pancreas SBRT.
Authors: Janopaul-Naylor James , Liu Yingzi , Lei Yang , Brackin Riley , Wang Tonghe , Yang Xiaofeng , Patel Pretesh R.
Published: January 2022

561

Background: Cone-beam CT (CBCT) used for daily image guidance in pancreatic stereotactic body radiotherapy (SBRT) is fraught with imaging artifacts leading to poor visualization of target and avoidance structures. Machine learning methods can be used to generate synthetic CT (sCT) images from CBCT to eliminate imaging artifacts. We sought to compare planned versus delivered radiation dose to luminal GI organs at risk (OARs) during pancreas SBRT using sCT. Methods: Previously treated patients from a single institution were eligible if treated with 5 fractions of pancreas SBRT using daily CBCT and inspiration breath hold. CBCT-based sCT was generated for each treatment fraction using our previously reported cycleGAN technique. Physicians manually contoured GI OARs (stomach, duodenum, and bowel [remaining small bowel and large bowel]) on sCTs. Rigid online registration from treatment was used to re-calculate the delivered dose on each sCT. Fractional delivered dose to OARs was compared to planned dose and dose constraints with descriptive statistics. Max dose to 1cc or 20cc of an OAR was defined as D1cc and D20cc respectively. Results: 7 patients and 35 cumulative SBRT CBCT datasets were included. The median SBRT cumulative dose was 8 Gy x 5 fractions (40 Gy total). Each GI OAR was constrained per fraction to D1cc < 7 Gy (cumulative D1cc < 35 Gy) and D20cc < 4 Gy (cumulative D20cc < 20 Gy) during SBRT planning. Table shows the estimated OAR delivered doses on each sCT compared to planned doses and dose constraints. Each patient had at least 1 fraction that exceeded a planned GI OAR dose; 2 patients had delivered dose to 1cc of duodenum exceeding constraint for all 5 fractions. After a median follow-up of 9 months (range 5-34), there were 2 CTCAE Grade 1 and no Grade 2+ GI toxicity events possibly or likely related to SBRT. Conclusions: Physician contouring and dose calculation using CBCT-based sCT was feasible. Estimated delivered doses of pancreas SBRT generally exceed planned doses. Further study of sCT in pancreas SBRT is warranted for improved localization, dose calculation, and adaptive radiotherapy.[Table: see text]
Neoadjuvant gemcitabine, docetaxel, and capecitabine results in comparable surgical outcomes to modified FOLFIRINOX in patients with pancreatic ductal adenocarcinoma who also receive radiation: A single institution experience.
Authors: Wong Winston , Jamison Jacob K.R. , May Michael S. , Michel Alissa , Lee Tristan , Manrique David , Raufi Alexander , Pan Samuel M , Safyan Rachael A , Horowitz David Paul , Schrope Beth , Kluger Michael , Kachnic Lisa A. , Hu Jianhua , Bates Susan Elaine , Chabot John A. , Manji Gulam Abbas
Published: January 2022

565

Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a minority of patients (pts) eligible for curative resection. Currently, systemic treatment options for down-staging pts with borderline resectable or locally advanced PDAC is extrapolated from the metastatic setting and modified FOLFIRINOX (FFX) +/- radiation (RT) is the most widely used regimen. Herein, we report the outcomes of combination gemcitabine, docetaxel, and capecitabine (GTX) +RT as compared to FFX +RT in the neoadjuvant (NA) setting via a single institution retrospective cohort review. Methods: We retrospectively reviewed the outcomes of pts with PDAC who underwent surgical resection at Columbia University Irving Medical Center (CUIMC) between 2011-2020. We evaluated demographics, treatment, clinical, surgical, and pathological outcomes. Statistical analysis includes Kaplan-Meier analysis and paired t-tests. Results: We reviewed 717 pts who underwent surgical resection at CUIMC of which 227 pts were confirmed to have received NA chemotherapy. Of those 227 patients, 133 pts also received RT. In total, 39 pts received GTX+RT and 42 pts received FFX+RT. Median age at diagnosis of pts who received NA GTX+RT or FFX+RT was 65 and 63 years, respectively. All pts were AJCC stage III at diagnosis and ECOG 0 or 1. There was a significantly greater percentage of pts who achieved R0 resection after GTX+RT as compared to FFX+RT, 35 (89.7%) vs 29 (69.0%), respectively (p=0.022). Significantly more pts achieved N0 lymph node status after GTX+RT as compared to FFX+RT, 29 (74.4%) vs 22 (52.4%), respectively (p=0.041). No statistically significant difference was detected in recurrence-free survival (RFS) or median overall survival (mOS) in pts who received GTX+RT and achieved R0 resection as compared to FFX+RT. See Table for summary. Conclusions: GTX appears to be a viable and active NA regimen in Stage III PDAC. In our small cohort study, more patients who received GTX+RT achieved R0 resection and N0 status as compared to FFX+RT. No difference in survival was detected but this may be due to inadequate power or choice of subsequent therapies. Larger prospective studies evaluating GTX+RT as an alternative treatment in the NA setting are warranted.[Table: see text]
“Super massive” intrahepatic cholangiocarcinoma: Potential role of radiation therapy.
Authors: Abi Jaoude Joseph , De Brian , Nieves Jiménez Humberto R , Upadhyay Rituraj , Taniguchi Cullen M. , Koay Eugene Jon , Ludmir Ethan B.
Published: January 2022

567

Background: Intrahepatic cholangiocarcinoma (ICC) is a cancer of the bile ducts within the liver. Most patients have unresectable disease and die of tumor-related liver failure (TRLF); prior data suggest that radiation therapy (RT) may play an important role in decreasing TRLF and improving survival. However, for patients with exceptionally large liver tumors, the role of RT is uncertain. Here, we present our experience using hypofractionated RT for so-called “super-massive” ICC (gross tumor volume > 800cc). Methods: We retrospectively collected data from ICC patients treated at the University of Texas MD Anderson Cancer Center. We included inoperable patients (both M0 and M1) who were treated with RT, identified those with a gross tumor volume of 800cc or more (median: 1,300cc IQR: 900-1,900). We analyzed overall survival (OS), local and distant recurrence, tumor-related liver failure (TRLF), and treatment toxicity. Results: A total of 12 patients were included. The median age was 60 (IQR: 55-67). The average maximal tumor diameter was 14.1cm (IQR: 12.6-15.8). All but 1 patient received pre-RT systemic therapy. Eight patients (67%) were treated with IMRT, and 4 patients (33%) with proton RT. RT was delivered to a median of 67.5Gy (IQR: 60-73.1) over 15 fractions. At a median follow up of 17.4 months, 5 patients were still alive (2-year OS: 41.7%). Median OS, local recurrence, and distant metastasis from RT were 20.0, 20, and 11.3 months, respectively. Two patients (16.7%) died from TRLF. No grade 2 or higher toxicities were noted. No radiation-induced liver toxicity was present. Conclusions: Hypofractionated RT was safe and showed promising clinical outcomes for patients with “super massive” inoperable ICC, compared to historical data. Future studies are still needed to better assess the role of RT in this patient population.
Prognostic factors associated with survival in patients with pancreatic cancer treated on early phase immune-checkpoint inhibitor clinical trials.
Authors: Surana Rishi , Rogers Jane E. , Nogueras-Gonzalez Graciela M. , Hong David S. , Yap Timothy A. , Rodon Ahnert Jordi , Naing Aung , Wolff Robert A. , Smaglo Brandon George , Meric-Bernstam Funda , Subbiah Vivek , Pant Shubham
Published: January 2022

577

Background: Immune-checkpoint inhibitors (ICI) have altered the treatment landscape of various solid tumors, but clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) continue to remain dismal. Data are needed to determine prognostic factors of survival to ICI-therapies in pancreatic cancer to better inform future recruitment in immunotherapy-based early clinical trials. Methods: This is a single center, retrospective analysis of patients with PDAC treated with ICI-based therapy as part of phase I trials at MD Anderson Cancer Center. Patients enrolled in a phase I study and treated between 2014 to 2021 were included in the analysis. Descriptive analysis included patient characteristics, progression free survival (PFS) and overall survival (OS). Cox proportional hazards were used to assess associations between patient or tumor characteristics and survival endpoints. Results: One hundred and twenty-two patients were included in this study and received a median of two prior lines of therapy (IQR 1-3). The most commonly utilized ICI were PD-L1 inhibitors (56%) and PD-1 inhibitors (34%). Most patients (96%) received ICI in combination with another investigational agent and 9% of patients received ICI in combination with chemotherapy. The median duration of treatment was 1.38 months (IQR 0.69-2.56). The median PFS was 1.81 months (95% CI 1.78-2.04) and the median OS was 4.83 months (95% CI 4.08-5.92). Univariate analysis showed improved PFS in patients with an albumin of ≥3.5 (1.94 vs 1.32 months, HR 0.29, 95% CI 0.14-0.60, p = 0.001) and Hgb ≥10.5 (1.87 vs 1.81 months, HR 0.63, 95% CI 0.4-0.98, p = 0.039); a longer OS was demonstrated in patients who had lung only metastases (7.92 vs. 4.18 months, HR 0.4, 95% CI 0.21-0.76, p = 0.006), albumin ≥3.5 (5.52 vs. 1.68 months, HR 0.4, 95% CI 0.2-0.8, p = 0.010), and a Hgb ≥10.5 (5.29 vs 4.11 months, HR 0.59, 95% CI 0.38-0.93, p = 0.022). Patients with an ANC/ALC ratio of ≥5 had a shorter OS compared to patients with an ANC/ALC ratio of < 5 (3.98 vs 6.54 months, HR 1.78, 95% CI 1.17-2.69, p = 0.007). Multivariate analysis showed that an albumin ≥3.5 predicted improved PFS (HR 0.41, 95% CI 0.19-0.90, p = 0.026) and an ANC/ALC ratio of ≥5 predicted shorter OS (HR 2.59, 95% CI 1.59-4.19, p < 0.001). Conclusions: Results of this large, single center retrospective study demonstrate that most patients with PDAC treated with ICI based therapies as a part of early phase clinical trials experience disease progression shortly after initiation of therapy and have a limited overall survival. Pretreatment albumin ≥3.5 predicted improved PFS and ANC/ALC ratio ≥5 predicted shorter OS.
Phase 2 study of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, with gemcitabine/nab-paclitaxel (GnP) in first-line advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Mahalingam Devalingam , Carneiro Benedito A. , Safran Howard , Powell Steven Francis , Coveler Andrew L. , Davis Elizabeth J. , Cervantes Andres , Sahai Vaibhav , Steeghs Neeltje , Huerta Marisol , Berlin Jordan , Mulcahy Mary Frances , Giles Francis J. , Cavalcante Ludimila , Saeed Anwaar
Published: January 2022

578

Background: GSK-3β overexpression is associated with worse prognosis and chemotherapy resistance in PDAC. GSK-3β inhibition reverses chemotherapy-resistance by inhibiting chemotherapy-induced, ATR-mediated, DNA damage response. 9-ING-41 has significant anti-tumor activity through apoptosis induction, anti-fibrotic activity and NK/T-cell effector stimulation. We hypothesized that 9-ING-41 in combination with GnP chemotherapy would lead to anti-tumor activity, with improved tumor responses in patients with advanced PDAC in the first line setting. Methods: Primary endpoint is disease control rate (DCR). DCR = confirmed complete response (CR), partial response (PR), or stable disease (SD) ≥ 16 weeks (wks). Secondary endpoints are safety and ORR (overall response rates). Eligibility: Advanced PDAC, ECOG PS 0-2, no prior therapy in the metastatic setting and no systemic therapy in prior 6 months. Pts received 9-ING-41 15mg/kg IV twice-weekly with G 1,000 mg/m2 and nP 125 mg/m2 on days 1,8,15 of a 28-day cycle. Simon 2-Stage Design for DCR of 65% and null hypothesis of 50% (historical control), 80% power and 2 sided-significance level of.05. Up to 23 fully evaluable pts planned for stage 1 and if ≥ 12 evaluable patients achieve a DCR 37 additional pts will be enrolled on a second stage or a randomized study commenced. Results: As of Sept 27, 2021, 42 pts enrolled. Median age: 67. 24 females, 18 males. 38 pts with metastatic and 4 with locally advanced disease. Prior adjuvant therapy: 4 pts each FOLFIRINOX and gemcitabine-based. No 9-ING-41-attributable SAEs to date. 9-ING-41 attributed AEs: visual disturbance: 24 (75%) G1/2, 1 (3%) G3; infusion reactions 9 (28%) G1/2. Chemotherapy-related AEs: anemia 13 (40%) G1/2, 1 (3%) G3; neutropenia 2 (6%) G1/2, 13 (40%) G3/4; thrombocytopenia 9 (28%) G1/2, 2 (6%) G3/4; diarrhea 8 (25%) G1/2, 4 (13%) G3; fatigue 9 (28%) G1/2, 3 (9%) G3; nausea/vomiting 24 (75%) G1/2, 1 (3%) G3; constipation 9 (28%) G1/2; febrile neutropenia 5 (16%) G3/4. In 21 pts currently evaluable for response, DCR was 62% and ORR 43%. There were 2 confirmed CRs, 6 confirmed and 1 unconfirmed PRs, 4 SD and 8 disease progressions were observed. Amongst responder’s median duration of response has not yet been reached. Conclusions: 9-ING-41 plus GnP demonstrated encouraging clinical activity but chemotherapy-related AEs were significant. Based on efficacy data to date, including confirmed CRs, we have commenced a randomized phase 2 study, evaluating 9-ING-41 plus GnP vs Gn P alone. Enrollment to the randomized study is now open (NCT03678883). Clinical trial information: NCT03678883.
Prognosis and correlation with Ca19.9 of circulating tumor cells (CTCs) in locally advanced and metastatic pancreatic cancer.
Authors: Muñoz Martín Andrés J. , Ortega Morán Laura , Gutiérrez Alonso Natalia , Megias Diego , Lopez-Alfonso Ana , del Monte Millán Maria , Bernat Rebeca , Martín Lozano Rocío , Jiménez Rodríguez Roberto , Gonzalez Caraballo Irene , Villarejo López Lucía , Massarrah Tatiana , Torres Pérez-Solero Gabriela , Calvo Ferrándiz Aitana , Blanco-Codesido Montserrat , Garcia-Alfonso Pilar , Martin Miguel
Published: January 2022

586

Background: In recent years CTCs have been extensively studied in different neoplasms. However, in PC CTCs are still emerging as a potential prognostic tool and the significance in different stages of the disease and the correlation with tumor markers are poorly understood. Methods: We conducted an observational, prospective, cohort study in two Spanish centers. Isolation was carried out with Isoflux technology (Fluxion Biosciences, Inc. San Francisco, CA, USA), that is combining cell separation by immunomagnetic particles (positive selection) with a microfluidic system. Before isolation, it was performed a first cell enrichment step using the density gradient cell separation technique (Ficoll). Four different markers were used, including two mesenchymal markers, EpCAM and EGFR (EMT Enrichment Kit:EpCAM/EGFR/Mesenchymal). The count of CTCs was done in a confocal microscope using the iMSRC (intelligent Matrix Screen Remote Control). A high throughput system was performed over the entire area, using a 20x objective, increasing to a 60x objective. Primary endpoint was the prognostic significance of CTCs, correlating the number of CTCs at diagnosis with overall survival. Secondary endpoints: Correlation between number of CTCs with Ca19.9/CEA values, and the difference in the median value of CTCs in metastatic compared to locally advanced disease. CTCs were analyzed at day 0 (CTC-0), just before first chemotherapy cycle was administered. Results: Thirty-four patients were analyzed. Clinical characteristics: Table 1. Median follow up 12.0 months. Median value of CTC-0 was 347 (range 104 - 3273) for metastatic and 436 (81 - 1082) for locally advanced patients (p = 0.942). Correlation coefficient for Ca 19.9 0.006 (p = 0.97); CEA correlation coefficient 0.191 (p = 0.303). For a cutoff of 500 CTCs, we found an AUC of 0.8 for mortality. Kaplan-Meier analysis showed an estimated median overall survival for patients with ≥500 CTCs of 8.6 months (95% confident interval [95% CI] 5.3 – 12) vs not reached for patients with < 500 CTCs (p = 0.007). HR for mortality 3.3 (95% CI 1.3 – 8.4; p = 0.011) for patients with ≥ 500 CTCs. Conclusions: Our data suggest 500 CTCs might be a potential cutoff for prognostic assessment. The absence of differences of CTC-0 between metastatic and locally advanced patients supports the idea of a systemic disease irrespective of the presence of metastases at diagnosis. CTC-0 seems not to correlate with tumor markers at diagnosis.[Table: see text]
Efficacy of MDX-124, a novel anti-annexin-A1 antibody, in preclinical models of pancreatic cancer.
Authors: Dempsey Fiona C. , Al-Ali Hussein , Crichton Scott J. , Fabian Charlene , Roberts Emily , Pepper Chris , Schmid Michael C. , Parris Christopher N.
Published: January 2022

590

Background: Pancreatic cancer is a highly fatal disease with poor survival and response to both chemotherapy and immunotherapy. Novel approaches to treat this disease are urgently required. Annexin-A1 (ANXA1) is secreted in response to several physiological stimuli where it activates formyl peptide receptors (FPR1/2) triggering multiple oncogenic processes. High ANXA1 expression in pancreatic cancer patients is associated with poor overall survival, and influences cancer progression, drug sensitivity, migration and invasion. MDX-124 is a novel humanized antibody targeting ANXA1 and we have previously presented data demonstrating its significant antiproliferative activity. Here we present further data showing the efficacy of MDX-124 in several preclinical models of pancreatic cancer. Methods: In-vitro models utilized MIA PaCa-2, PANC-1 or BxPC-3 human pancreatic cancer cell lines. Cell cycle progression was evaluated by measuring changes in DNA content via flow cytometry. Pancreatic cancer cell viability following incubation with MDX-124 (0-10 µM) and 5FU (IC50) was assessed via MTT assay. A transwell migration assay was used to evaluate the effect of MDX-124 (0-50 µM) on pancreatic cancer cell migration. In-vivo efficacy was evaluated using an orthotopic mouse model of metastatic pancreatic cancer (FC1242luc/zsGreen; KPC-derived cell line) with bioluminescent imaging used to quantify the incidence and burden of lung metastases. Results: When compared to untreated MIA PaCa-2 pancreatic cancer cells, MDX-124 treatment decreased the proportion of cells in S-phase by 29% and G2 phase by 9.1%, with a concomitant increase in G1 of 38.1%. This occurred in a dose-dependent manner and is consistent with an MDX-124 mediated increase in cell cycle arrest. MDX-124 significantly reduced the viability of MIA PaCa-2 and PANC-1 cell lines versus an IgG control in a dose-dependent manner. Additionally in these two cell lines, combination of MDX-124 with 5FU (IC50) had a significant synergistic impact reducing cancer cell viability by 99.8% and 91.2% respectively. Furthermore, MDX-124 significantly reduced the migratory ability of MIA PaCa-2 and BxPC-3 pancreatic cancer cells. In the orthotopic model of metastatic pancreatic cancer, the murine analog of MDX-124 (MDX-001), markedly reduced both the incidence and size of lung metastases. Conclusions: MDX-124 demonstrated significant anti-tumor efficacy in several preclinical models of pancreatic cancer as a single agent, with increased potency observed when used in combination with 5FU. Medannex will initiate a First-In-Human study in Q4 2021 to evaluate MDX-124 in solid malignancies, including pancreatic cancer.
Secretory leukocyte proteinase inhibitor: A key player in the dialogue between the tumor and its microenvironment in pancreatic cancer patients.
Authors: Chuluyan Eduardo , Ambrosi Nella , Fraunhoffer Nicolas , Caro Fiorella , Remolins Carla , Reiteri Macarena , Guerrieri Diego , Soubeyran Philippe , Gayet Odile , Roques Julie , Nelson Dusetti J. , Incardona Claudio A. , Iovanna Juan
Published: January 2022

592

Background: Secretory leukocyte proteinase inhibitor (SLPI) is a non-glycosylated pleiotropic protein with anti-protease, microbicidal, healing, anti-inflammatory and immunomodulatory activity. Previous studies have shown that SLPI is associated with pancreatic tumor progression by promoting cancer cell survival and proliferation. However, SLPI can also act on the tumor microenvironment to affect the local immune response. In the present work we evaluate the role of SLPI in patients with pancreatic cancer and its activity as a tumor escape factor from the immune response. Methods: Serum levels of SLPI was measured in pancreatic cancer patients by sandwich ELISA. RNA-seq was performed on 76 patient-derived xenografts (PDX) and we computed independent component analysis focusing the study on the component that best correlated with SLPI gene. Secretome analysis was performed on 38 different cell lines cells culture derived from PDX. Human monocytes were isolated and differentiated into immature dendritic cells in the presence or absence of SLPI or in the presence of a pancreatic tumor cell line that did or did not express SLPI. Results: The frequency distribution of serum SLPI values showed patients with low and high SLPI value (cut-off value 61.5 ng/ml). Most patients with high serum SLPI concentration had unresectable tumors. There was an indirect association between serum SLPI levels and the time of disease recurrence. The transcriptome analysis showed that expression of SLPI is associated with immune and cancer functional clusters. The analysis of the secretome showed that SLPI was present in all cell lines from PDX. The heat map of the secretome exhibited that SLPI was directly associated with factors described in tumor microenvironment and related with tumor immune evasion mechanisms, such as CSF1, SECTM1, LGALS3, IL1RN, CD59, CD55, CD46, Fas, PVR, PVRL2. Remarkably, the closest group associated with SLPI was CSF1. The latter contributes to the depressed function of antigen-presenting cells, as a result of skewed differentiation of monocytes towards macrophage-like cells rather than dendritic cells. Furthermore, in vitro experiments demonstrated that SLPI or SLPI-producing pancreatic tumor cell lines impaired the differentiation of human monocytes towards dendritic cells and their immunostimulatory capacity. Conclusions: These results suggest that SLPI may contribute to the immunosuppressive microenvironment of pancreatic cancer by acting as a tumor immune evasion factor. Clinically, this SLPI activity could be reflected in the association of the serum SLPI value with disease recurrence or progression.
Comparative molecular profiling of pancreatic ductal adenocarcinoma (PDAC) of the head (H) versus body/tail (B/T) and the tumor immune microenvironment (TIME).
Authors: Abdelrahim Maen , Kasi Anup , Baca Yasmine , Xiu Joanne , Walker Phillip , Korn Wolfgang Michael , Lou Emil , Shields Anthony Frank , Weinberg Benjamin Adam
Published: January 2022

598

Background: PDAC of the H and B/T differ in embryonic origin, cell composition, blood supply, lymphatic and venous drainage, and innervation. H tumors tend cause symptoms earlier and to present at earlier stages compared to B/T cancers. The impact of PDAC tumor location on patient presentation and survival has been shown in large national data-based analyses, although with conflicting results. We aimed to compare the molecular and tumor immune microenvironment (TIME) profiles of PDAC of the H vs. B/T. Methods: A total of 3499 PDAC samples were analyzed via next-generation sequencing (NGS) of RNA (whole transcriptome, NovaSeq), DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and immunohistochemistry (IHC, Caris Life Sciences, Phoenix, AZ). RNA deconvolution was performed using QuantiSeq (Finotello 2019, Genome Medicine) to quantify the immune cell infiltration. Pathway gene enrichment analyses were done using Gene Set Enrichment Analysis (GSEA, Subramaniam 2015, PNAS). Significance was determined as p values adjusted for multiple correction (q) of < 0.05. Results: Anatomic subsites of PDAC tumors were grouped by primary tumor sites into H (N = 2058) or B/T (N = 1384). There were significantly more metastatic tumors profiled from H vs. B/T (57% vs. 44%, p < 0.001). KRAS mutations (93.8% vs. 90.2%), genomic loss of heterozygosity (12.7% vs. 9.1%), and several copy number alterations ( FGF3, FGF4, FGF19, CCND1, ZNF703, FLT4, MUTYH, TNFRS14) trended higher in B/T when compared to H (p < 0.05 but q > 0.05). GNAS mutations (2.2% vs. 0.7%) trended higher in H vs. B/T (p < 0.05). No significant difference in immuno-oncology (IO) markers (TMB, PD-L1, MSI-H) were observed, but expression analysis of IO-related genes showed significantly higher expression of CTLA4 and PDCD1 in H (q < 0.05, fold change 1.2 and 1.3) and IDO1 and PDCD1LG2 expression trended higher in B/T (p < 0.05, fold change 0.95). When comparing median cell abundance values as part of TIME analysis, H had increased immune infiltration of B cells (0.045 vs. 0.043), M2 macrophages (0.035 vs. 0.032), neutrophils (0.056 vs. 0.052), NK cells (0.027 vs. 0.026), CD8+ T cells (% > 0: 48.2% vs. 43.2%), while B/T had increased infiltration of M1 macrophages (0.035 vs. 0.032) (all q < 0.05). GSEA showed enrichment of CTLA4 (normalized enrichment score (NES) 1.6, false discovery rate (FDR) 0.19) and primary immunodeficiency pathway enrichment (NES 1.7, FDR 0.11) in H. Conclusions: To our knowledge, this is one of the largest cohort of PDAC tumors subjected to broad molecular profiling. Differences in IO-related gene expression and TIME cell distribution suggest that response to IO therapies may differ in PDAC arising from H vs B/T. Subtle differences in the genomic profliles of H vs. B/T tumors were also observed.
Real-world timelines of BRCA1/2-related molecular testing in pancreatic cancer.
Authors: Li Weiyan , Amin Suvina , Joo Seongjung , Adeboyeje Gboyega , DeArbeloa Patricia , Petricoin Emanuel , Blais Edik Matthew , Pishvaian Michael J.
Published: January 2022

601

Background: BRCA1/2 mutations are present in ̃6-8% of patients with pancreatic adenocarcinoma. Olaparib is a recently approved PARP inhibitor (PARPi) in the US and Europe for germline BRCA1/2-mutated metastatic PaC in the 1st line maintenance setting following response to at least 16 weeks of a platinum-containing regimen. However, the availability of BRCA1/2 testing results at the time of 1st line and subsequent treatment decisions in the advanced stage has not been established in real-world settings. Methods: Longitudinal clinical/molecular data collected between 1/2012-12/2020 were retrospectively analyzed in 75 PaC pts with germline or somatic BRCA1/2 mutations (BRCA1/2m) who enrolled in Perthera’s US real-world observational registry. Tumor NGS testing results were generated by commercial labs for all patients. Germline status was assessed by a molecular tumor board when testing results are available. BRCA1/2m discovery timing (days since advanced presentation), molecular testing turnaround time (days from physician order to result), and platinum utilization were abstracted from physician records. Associations between BRCA1/2m discovery timing and platinum utilization were evaluated using Fisher’s exact test. Results: At the time of advanced PaC diagnosis, BRCA1/2m status was known in a minority of patients (29% (22 of 75). In the remaining 71% (53 of 75) patients, the median time to report BRCA1/2m status was 76 days (IQR=56-558) following advanced diagnosis. The median tumor NGS testing turnaround time was 35 days after physician order (IQR=24-54). Platinum use in any setting was documented in 85% (64 of 75) of patients and the majority of these patients (62%, 40 of 64) initiated a platinum-based regimen before BRCA1/2m status was first reported. Platinum agents were initiated before 2nd line in 75% (48 of 64) patients, and this was associated with BRCA1/2m identification before advanced diagnosis (p=0.03). Conclusions: BRCA1/2 testing results may not always be available when 1st line regimens are chosen which can impact ideal treatment sequencing in PaC patients. These real-world analyses underscore the importance of upfront BRCA1/2 testing in PaC patients.
The impact of germline and somatic mutations in the homologous recombination repair pathway in pancreatic cancer patients who undergo perioperative chemotherapy.
Authors: Jonsdottir Gudbjorg , Masson Asgeir Thor , Jacobus Laura S. , Churchman Michelle L. , Edge Stephen B. , Noonan Anne M. , Cavnar Michael J. , Ulahannan Susanna Varkey , Sahin Ibrahim Halil Halil , Chan Carlos Hou Fai
Published: January 2022

602

Background: Limited data is available regarding the effects of germline and somatic mutations in the homologous recombination repair (HRR) pathway in patients with resectable pancreatic cancer and exactly which mutations can be targeted with platinum-based chemotherapy. We aimed to assess the impact of HRR pathway mutations in a large cohort of pancreatic patients who underwent curative intent surgical resection. Methods: Patients with resectable pancreatic cancer who underwent perioperative chemotherapy, diagnosed from 1999-2020 from the participating members of the Oncology Research Information Exchange Network (ORIEN) were included in the study. Patients with germline and somatic whole exome sequencing data were analyzed for known pathogenic and likely pathogenic variants according to ClinVar in the following HRR pathway genes: BRCA1, BRCA2, PALB2, BRIP1, BRAD1, ATM, RAD51C, RAD51, RAD50, CHECK2, FANCC, FANCA, MRE11 and XRCC2. The Kaplan Meier method was used to compare median overall survival (OS) between patients with adenocarcinoma, with and without HRR pathway mutations. Multivariate cox proportional hazard model was used to calculate HR and 95% CI adjusting for age at diagnosis, sex and pathologic stage. Results: During the study period, the ORIEN cohort included 417 patients with resectable pancreatic cancer and whole exome sequencing. Of these 313 (75%) patients had adenocarcinoma and 104 (25%) neuroendocrine tumor. A total of 19 patients (5%) had an HRR pathway mutation - 15 (5%) in the adenocarcinoma group and 4 (4%) in the neuroendocrine group. In the adenocarcinoma group, 97 (31%) patients underwent platinum-based perioperative chemotherapy. Median OS was 2.8 years (IQR 2.5-3.3) in the adenocarcinoma group without HRR pathway mutation and 3.8 years (IQR 3.4-NA) in the group with HRR pathway mutation (HR 0.6: 95% CI 0.3-1.4, p = 0.76). Conclusions: There was a trend towards improved survival in patients with adenocarcinoma receiving perioperative platinum-based chemotherapy with HRR pathway mutations compared to those without a mutation. This finding supports previous data in the literature regarding the prognostic role of HRR pathway alterations in pancreatic cancer. Larger prospective studies are needed to assess the predictive role of these mutations in the perioperative setting in response to platinum-based chemotherapy.
The impact of CA 19-9 on survival in patients with clinical stage I pancreatic cancer.
Authors: Melucci Alexa D. , Chacon Alexander C , Burchard Paul R. , Ullman Nicholas A. , Tsagkalidis Vasleios , Casabianca Anthony S. , Reitz Alexandra , Swift David A. , Goyal Subir , Switchenko Jeffrey M. , Carpizo Darren R. , Shah Mihir Maheshkumar
Published: January 2022

606

Background: Standard of care for early-stage resectable pancreatic cancer (PC) includes a combination of surgical resection and chemotherapy. Frequently, CA 19-9 is used as a biomarker to monitor treatment effect and has prognostic significance. We evaluated the impact of CA 19-9 on overall survival (OS) in patients with clinical stage I PC (cT1N0 and cT2N0) utilizing the National Cancer Database (NCDB). Methods: The NCDB was queried between 2010 and 2014 to identify patients with clinical stage I PC. Patients who had missing or undocumented CA 19-9 value at diagnosis were excluded. Demographic and clinical characteristics were analyzed. Patients were stratified into two cohorts based on the CA 19-9 value at diagnosis – CA 19-9 < 98 U/mL and CA 19-9 > 98 U/mL. Univariable and multivariable analyses were performed, and variables associated with OS were identified. Kaplan-Meier survival curves were computed to compare the OS between the two cohorts. Results: A total of 12,480 patients met our inclusion criteria. A majority of patients were female (51.9%), white (84.4%), with a median age of 70 years. Nearly, half the patients received care in an academic/research program (49.5%). A majority of patients had tumors located in the head of the pancreas (71.9%), and received single-agent (35.1%) or multiagent (22.9%) chemotherapy. Over half the patients (6505 patients, 52.1%) had a CA 19-9 value > 98 U/mL. A CA 19-9 value > 98 U/mL in patients predicted a significantly shorter median OS of 12.1 months compared to 19.4 months in patients with a CA 19-9 < 98 U/mL, p<0.0001 (Table). The 5-year OS rate was 9.9% in patients with a CA 19-9 value of > 98 U/mL compared to a 5-year OS rate of 18.1% for patients with a CA 19-9 value < 98 U/mL. On multivariable analysis, CA 19-9 > 98 compared to CA 19-9 < 98 (HR 1.53, p<0.001) and black race compared to white race (HR 1.10, p<0.001) was associated with worse survival, whereas tumor location in the body and tail compared to the head (HR 0.82, p<0.001), single-agent (HR 0.55, p<0.001) and multiagent (HR 0.55, p<0.001) chemotherapy compared to no chemotherapy, independently predicted improved OS. Conclusions: This is the first National Cancer Database study to demonstrate the prognostic value of CA 19-9 in patients with clinical stage I pancreatic cancer, with a value < 98 U/mL predicting improved survival. Clinical stage I pancreatic cancer patients appear to derive a significant benefit from chemotherapy, including single and multiagent chemotherapy, irrespective of the CA 19-9 value.[Table: see text]
High-plex proteomic prognostic marker discovery for patients with pancreatic cancer adenocarcinoma using digital spatial profiling.
Authors: Jamieson Nigel Balfour , Legrini Assya , Leslie Holly , Dreyer Stephan , Biankin Andrew V , Chang David Kuang-Fu
Published: January 2022

611

Background: The long-term outcomes following surgical resection for Pancreatic Ductal Adenocarcinoma (PDAC) remain poor, with only 20% of patients surviving 5 years after pancreatectomy. With its immune-privileged nature, starting from the early pre-neoplastic state, it appears to escape easily from the antitumor immune response. Despite rationale for targeting immune pathways in PDAC, there has been little benefit observed at this point. The aim of the current study was to interrogate immune landscape of PDAC utilising the Nanostring GeoMx Digital Spatial Profiler (DSP), a state-of-the art analysis platform enabling Hi-plex proteomic characterisation whilst maintaining tumor microenvironment (TME) topographical features. Methods: We assessed Formalin Fixed Paraffin Embedded (FFPE) tumor samples from 28 treatment-naive PDAC cases represented in a multi-regional tissue microarray (TMA) for which extensive IHC, molecular, genomic characterisation and clinicopathological follow-up data is available. Following multiplex IHC staining for DAPI, panCK, aSMA and CD3 to guide region selection, we employed the GeoMx DSP system (NanoString) to select regions within multiple TMA cores. We quantified 60 immune markers simultaneously in multiple tissue compartments defined by immunofluorescence co-localization including (tumor [panCK+ve], immune stroma (PanCK-ve]. Data analysis was performed by a combination of DSP analysis suite and custom R pipeline. Results: The spatially informed variable assessment by DSP was validated by both regression and variable prognostication compared with IHC for stromal CD3, CD8 CD68 in near serial TMA PDAC sections. Unsupervised analysis of DSP proteome data in the panCK-negative regions identified an immune poor group associated with shorter Overall Survival (OS) (13.0 versus 31.1months, P = 0.005). When transcriptomic subtype was considered, the checkpoint inhibitor B7-H3 was significantly upregulated in the squamous subtype tumours versus the classical group (Log2: 1.63, P = 0.001). Patients with high B7-H3 expression, using a median expression cut-off, were associated with shorter OS on multivariate analysis (Hazard Ratio: 4.16, P = 0.01) including lymph node and resection margin status, a finding that was validated in an external cohort at the transcriptome level. Conclusions: This pilot scale discovery study shows the potential of the Nanostring DSP technology in the identification of spatially-informed biomarkers with prognostic relevance in biopsy sized samples from treatment-naive PDAC. We identified a number of relevant candidate immune predictors in spatial context that are currently undergoing validation in larger independent cohorts and the neoadjuvant setting. Future studies will apply this technology to pre- and post-treatment biopsy samples.
Association of pancreatic adenocarcinoma location (head/body/tail) with DDR mutation status and response to platinum-based therapy.
Authors: Micaily Ida , Blais Edik Matthew , Cohen Steven J , Cannaday Shawnna , Krampitz Geoffrey , Wadlow Raymond Couric , Shroff Rachna T. , McRee Autumn Jackson , Chuy Jennifer W. , Zheng Lei , Hendifar Andrew Eugene , Matrisian Lynn McCormick , Gregory Gary Lee , Thach Dzung , Brody Jonathan Robert , Petricoin Emanuel , Pishvaian Michael J. , Lavu Harish , Yeo Charles , Basu Mallick Atrayee
Published: January 2022

612

Background: Pancreatic adenocarcinoma is an aggressive disease with poor clinical prognosis that can originate from either the head (H) or body/tail (BT). Potential prognostic implications for H versus BT tumors have been reported; however, the molecular underpinnings associated with these differences in survival have not fully been explored. Using a large-scale real-world cohort of H and BT tumors with NGS results available from commercial labs, we retrospectively aim to identify potential differences between H and BT tumors in their response to standard therapies to help understand whether the treatment prioritization for pancreatic adenocarcinoma should take into account anatomical sidedness, as is recognized today with left-sided versus right-sided colorectal cancers. Methods: We analyzed outcomes across 1540 pts with NGS results from Perthera’s Real-World Evidence database who were diagnosed with PDAC originating from the H or BT. Progression-free survival (PFS) was evaluated from initiation of 1st line for advanced disease until discontinuation due to disease progression. Hazard ratios and p-values were computed via Cox regression when comparing PFS between 1st line FOLFIRINOX and gemcitabine/nab-paclitaxel. Differences in frequencies of genomic alterations between proximal and distal were analyzed by Fisher’s exact test. Results: Mutations in BRCA1/ BRCA2/ PALB2 were enriched (unadjusted p-value=0.017) in BT tumors (8.6% of 619) relative to H tumors (5.4% of 921). An expanded set of DDR pathway alterations (e.g. ATM, FANCA, CHEK2, BAP1, BRIP1, etc) were also enriched (unadjusted p-value=0.003) in BT tumors (21.4% of 619) relative to H tumors (15.6% of 921). In BT tumors, mPFS on 1st line FOLFIRINOX was longer (Table) than 1st line gemcitabine/nab-paclitaxel (p=0.0078) but this difference was not observed in H tumors (p=0.34). Overall survival data in these patients and an independent institutional cohort which motivated these analyses will also be discussed. Conclusions: DDR pathway alterations are known predictors of increased benefit from platinums and these real-world insights preliminarily suggest that DDR mutations are more common in BT vs. H. Prospective studies may be warranted to confirm the hypothesis-generating findings that platinum-based regimens should be prioritized in patients with BT tumors while underscoring the importance of routine NGS testing in both BT and H tumors given the prevalence of DDR pathway alterations on both sides of the pancreas.[Table: see text]