bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment patterns and survival outcomes of older patients with advanced pancreatic cancer (APC): A Canadian real-world evidence study.
Authors: Batra Atul , Ramjeesingh Ravi , Meyers Brandon M. , Vickers Michael M. , Goodwin Rachel Anne , Armstrong Dawn Elizabeth , Cheung Winson Y. , Kim Christina ,   on behalf of Cancer Health Outcomes Research Database (CHORD) Consortium
Published: January 2021

385 Background: We aimed to compare chemotherapy regimens used and overall survival (OS) among geriatric patients (≥ 75 years) with APC as compared to old (65-74 years) and young (< 65 years) patients with APC. Methods: In this retrospective population-based analysis, we identified patients with APC (defined as inoperable/metastatic disease) from 5 large provinces in Canada who were diagnosed from 2011 to 2016. Kaplan-Meier curves were plotted to derive OS and multivariable Cox regression models were constructed to determine the associations of different age groups on OS. Results: We included 636 patients diagnosed with APC of whom 258 (40.6%), 247 (38.8%) and 131 (20.6%) were young, old and geriatric. Approximately half (45.7%) of all patients were women. Eastern Cooperative Oncology Group performance status (ECOG PS) was known in 508 patients at diagnosis among whom 62.2% were 0-1 and 37.8% were 2+. ECOG PS was more likely to be 2+ in the geriatric group (46.8% vs 41.1% vs 31.3%; P = 0.017). Most patients (95.8%) had metastatic disease while the remaining patients had inoperable locally advanced disease. Within the study cohort, 38.7% received chemotherapy. Treatment rates differed based on age: 41.9% in young patients, 40.9% in old patients and 28.2% in geriatric patients (P = 0.02). Choice of first-line chemotherapy varied and included FOLFIRINOX (F) in 99 (40.2%), gemcitabine and nab-paclitaxel (GN) in 91 (37.0%) and gemcitabine (G) in 56 (22.8%). F, GN and G were administered in 27.0%, 32.4% and 40.5% of geriatric patients, 40.6%, 32.7% and 26.7% of old patients, and 44.4%, 42.6% and 13.0% of young patients, respectively (P = 0.007). After adjusting for baseline factors, both geriatric (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.42-1.17; P = 0.175) and old patients were as likely to receive chemotherapy (OR, 1.04; 95% CI, 0.70-1.56; P = 0.815) as their young counterparts. The median OS was 7.1 (6.3-8.4), 6.7 (5.5-8.9) and 5.3 (4.3-6.8) months in young, old and geriatric patients, respectively. After adjusting for baseline variables, both geriatric (hazard ratio [HR], 1.25; 95% CI, 0.96-1.62; P = 0.101) and old patients (HR, 1.16; 95% CI, 0.94-1.42; P = 0.171) experienced similar OS as young patients. ECOG PS 2+ at presentation was associated with worse OS as was treatment with G. Conclusions: Overall treatment rates for APC are low in the real world. The poor OS in geriatric patients with APC is driven by poor PS and use of less intensive chemotherapy. Age alone should not be considered a contraindication for more intensive chemotherapy since treatment benefit is observed across all age groups. [Table: see text]
Reference values for EORTC QLQ-C30, for metastatic pancreatic cancer (mPC): Enhancing the interpretation of HRQoL scores in the POLO trial.
Authors: Kindler Hedy L. , Amin Suvina , Joo Seongjung , Patel Nikunj , Yoo Hyun Kyoo , Johnson Colin , Byrnes Hilary , Costa-Cabral Sara , Nolte Sandra 
Published: January 2021

393 Background: Metastatic pancreatic cancer (mPC) and its treatments significantly impact patients’ (pts) health-related quality of life (HRQoL). POLO, a randomized, double-blind, placebo-controlled phase 3 trial evaluated the efficacy of olaparib as maintenance therapy in mPC pts who had not progressed during ≥16 weeks of first-line platinum-based chemo. HRQoL was assessed in POLO using EORTC QLQ-C30. To enhance the interpretation of HRQoL scores in POLO, we derived EORTC QLQ-C30 reference (ref) values for mPC from the literature, as these had not been previously established. Methods: A systematic literature review was conducted to identify existing baseline values in published data. EORTC QLQ-C30 ref values were calculated by deriving mean scores based on studies meeting all inclusion criteria. EORTC QLQ-C30 mean values were calculated for POLO using pooled baseline data from both study arms (olaparib; placebo). Results: Out of 186 studies identified, 4 met all inclusion criteria. Depending on respective EORTC QLQ-C30 subscale, the final sample sizes ranged from n=466 to n=639. Compared to the newly derived EORTC QLQ-C30 ref values based on the literature, POLO pts reported markedly better HRQoL scores at baseline across most subscales, with eight subscales showing differences of >15 points (table). Conclusions: This is the first study to systematically derive EORTC QLQ-C30 ref values for mPC. We found that mPC pts enrolled in POLO had better HRQoL scores compared with those reported in the literature and often close to or better than general population norm data, possibly due to positive effects of prior platinum-based first-line treatment, resolution of chemotherapy-related symptoms, response shift, or a combination. These newly derived ref values enhance the interpretation of patients’ HRQoL trajectory within a maintenance treatment setting. [Table: see text]
Comparative efficacy of commonly used first-line chemotherapy regimens in advanced pancreatic cancer: A network meta-analysis.
Authors: Haddad Philip A. , Gallagher Kevin Michael , Hammoud Dalia 
Published: January 2021

403 Background: Pancreatic adenocarcinoma is one of the deadliest cancers, ranking fourth in mortality and accounting for up to 7% of all cancer related deaths in the United States. For many years, Gemcitabine and its combinations have been the standard first-line treatments for patients with unresectable locally advanced or metastatic pancreatic cancer (aPC). Recently, FOLFIRINOX was shown to be associated with a survival advantage as well. These chemotherapy combinations have not been compared to each other. We conducted this network meta-analysis to evaluate the relative efficacy of the commonly used chemotherapy regimens in patients with aPC. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of aPC; treatment with Gemcitabine (GEM) combined with Capecitabine (CAPE), Erlotinib (ERLO), or nab-Paclitaxel (NABPAC) and treatments with FOLFIRINOX; and randomized studies reporting survival and response rates. A frequentists network meta-analysis was conducted using netmeta package and random-effects model. Results: Six studies comprising a total of 2,717 participants were included. FOLFIRINOX demonstrated a significantly better relative risk (RR) of progression and death (P&D) followed by GEM+NABPAC, GEM+ERLO, GEM+CAPE, and GEM in a decreasing order. When compared to GEM-based combination as a group, FOLFIRINOX maintained its superior RR for P&D. Moreover, FOLFIRINOX and GEM+NABPAC had significantly better response rates than GEM+CAPE and GEM+ERLO. Inconsistency analysis did not reveal any significant differences between direct and indirect estimates. Conclusions: This network meta-analysis is the first to compare and rank commonly used treatment regimens in aPC. It indicates that FOLFIRINOX combination seems to be superior to GEM-based combinations with respect to P&D as well as response rates. Nevertheless, among GEM-based combinations, GEM+NABPAC seems to have the best profile given its lower RR for P&D and higher response rates.
Efficacy and preclinical safety of ARB202, a potential first-in-class anti-CDH17/CD3 bispecific T-cell engager, for treatment of pancreatic and colorectal cancers.
Authors: Wong Dennis A , Luk Moon Ching , Wong Tony K , Staunton Donald E , Harlan John M 
Published: January 2021

405 Background: Globally, gastrointestinal (GI) cancers, which account for around 28% of all cancers, has increased constantly at a CAGR of 2% (2014-2019), while the treatment options remain limited and often ineffective. This is largely due to late diagnosis and lack of new tumor associated antigens for most of the GI malignancies. Cadherin-17, CDH17 (aka CA17), is being evaluated as a potential therapeutic target and molecular marker for GI cancers, of which aberrant expression of CDH17 was reported in 50-90% in tumor samples (including stomach, pancreas, liver/bile duct and colon) by multiple groups. The present study aims to develop a humanized CDH17-CD3 bispecific T-cell engager antibody, ARB202, to treat advanced pancreatic and metastatic colon cancers. Methods: The ARB202 bispecific was generated from anti-CDH17 monoclonal ARB102 as previously described (Lum Y et al, Mol. Pharm. 2020) by linking a CD3-binding scFv in the format of IgG4-scFv. Biophysical properties, efficacy and safety were evaluated. Efficacy was addressed in cytotoxicity assays, IL2-release assays and subcutaneous xenograft models using multiple GI tumor target lines. Preclinical safety profiles include Tissue cross-reactivity assays and GLP repeat-dose toxicity studies in NHP. Results: The ARB202 bispecific antibody was efficiently produced (yield ~1 g/L) and remained stable for at least 3 months under accelerated stress tests. Binding affinity (Kd [M]) of ARB202 to CDH17 and CD3 was at 10-10 and 10-9 respectively, with cellular affinities of 10-9 and 10-8. In vitro cytotoxicity assays demonstrate that ARB202-mediated tumor cell killing is CDH17-dependent and requires immune synapse formation with effector T cells. By contrast, normal cells and CDH17-negative cancer cells are resistant. Pancreatic AsPC1 xenograft model revealed an ARB202 (co-inoculated with human PBMC) dose-dependent inhibition of tumor growth. Human IL-2 release in mice blood samples was consistent with functional CDH17 and CD3 engagement. ARB202 PK profile in rodents and NHP was found to be excellent relative to other bispecifics and GLP toxicity studies showed no significant findings nor adverse effects. Conclusions: ARB202 bispecific antibody promises to be a first-in-class biologic, which may tackle approximately 50% of GI cancers that which have been reported CDH17 positive. First-in-human clinical study with advanced GI cancers is scheduled to start in Q1 2021.
Evaluating the clinical utility of universal screening to identify Lynch syndrome in stage III/III colorectal cancer patients: A prospective observational study in Japan.
Authors: Yamamoto Yasuaki , Tsukada Yuichiro , Kuwata Takeshi , Kojima Motohiro , Hiraoka Yumie , Taniguchi Hiroya , Bando Hideaki , Yoshioka Takahiro , Sasaki Takeshi , Nishizawa Yuji , Ikeda Koji , Akagi Kiwamu , Yoshino Takayuki , Ito Masaaki 
Published: January 2021

41 Background: Universal screening for Lynch syndrome (LS) by identifying deficient DNA mismatch repair (MMR) in the tumor tissue of all new colorectal cancer (CRC) patients is widely accepted. The population prevalence of LS is approximately 3% in Western countries, whereas it is approximately 0.7% in Japan. In addition, the number of relatives diagnosed per proband is 3.6 in Western countries, whereas there are even fewer diagnoses per proband in Japan. To address the issue of LS remaining largely underdiagnosed in Japan, we prospectively evaluated the clinical utility of universal screening of LS in CRC patients. Methods: From March 2016 to August 2019, all consecutive new cases of stage II/III CRC underwent immunohistochemistry (IHC) screening for MMR using MLH1, MSH2, MSH6, and PMS2 antibodies. The patients negative for both MLH1 and PMS2 (MLH1-/PMS2-) were subjected to reflex testing for BRAF V600E mutation. Patients with both MLH1-/PMS2- and BRAF negative (cohort A, n = 14) and those with other IHC patterns (cohort B, n = 13) were referred for genetic counseling (GC) and genetic testing (GT). Furthermore, relatives of probands with confirmed LS were referred for GC/GT if they were willing. Results: Overall, 591 pts were enrolled in this study. Patient background were as follows: > 70 y/o, 35%; right-sided/left-sided colon/rectum, 24%/24%/53%; and cStage II/III, 65%/35%. Of 591 patients, 40 (6.8%) had MMR deficiency. Of 27 patients with MLH1-/PMS2-, 24 underwent BRAF reflex testing; only 10 of these patients tested positive for mutation. Of 27 patients recommended for GC, 25 were referred for GC and 22 for GT, which revealed 12 LS cases (2%, mutation genes:MLH1/PMS2/MSH2; 4/2/6). The frequency of LS diagnosis with respect to patient background was as follows: > 70/≤70 y, 1.0/2.6%; right-sided/left-sided colon/rectum, 5.8/0/1.3%; and cStage II/III, 2.6/1.0%. Interestingly, only 3 (25%) of 12 patients who underwent GC/GT in cohort A had LS compared with 9 (90%) of 10 patients in cohort B ( p= 0.004). Moreover, among 11 relatives of 5 families who were willing to undergo GC/GT, six (55%) had LS, of whom two were first-degree relatives (33%), one was a second-degree relative (50%), and three were third-degree relatives (100%). Conclusions: This study showed that universal screening of LS in CRC patients is significantly useful in Japan. Furthermore, implementing a reflex testing strategy demonstrated high adherence to guidelines and the appropriateness of our referrals for GC/GT.
Early outcomes of irreversible electroporation after stereotactic body radiation therapy for the treatment of locally advanced pancreatic adenocarcinoma (LAPC): A matched pair analysis.
Authors: Boyer Emanuel , Palm Russell , Frakes Jessica M. , Hoffe Sarah E. , Malafa Mokenge Peter 
Published: January 2021

410 Background: Outcomes remain poor for those diagnosed with unresectable pancreatic cancer. SBRT and IRE have independently demonstrated high rates of local control and minimal toxicity for patients with locally advanced pancreatic cancer (LAPC). Data is limited regarding safety and efficacy in the sequential use of both therapies. Materials and Methods: A single institution retrospective matched cohort analysis was performed for patients with non-metastatic pancreatic cancer treated with induction chemotherapy and SBRT followed by IRE, compared with patients of the same cohort who did not receive IRE. Patients were paired based on age, tumor stage, GTV D95, CA19-9 prior to SBRT, and chemotherapy type to mitigate selection bias in surgical candidates. Overall survival (OS), progression free survival (PFS), freedom from local failure (FFLF) and freedom from distant failure (FFDF) were the primary outcomes compared via Kaplan-Meier survival analysis with log-rank methods. Results: From July, 2014 to February, 2020 17 patients received SBRT followed by IRE. These patients were matched with 17 patients who received SBRT from January, 2012 to March, 2019. Most patients received neoadjuvant FOLFIRINOX (82.4%) and were AJCC 8 stage III (79.4%). Median age of the overall cohort was 65.5 years and 50% were male. Median dose delivered to 95% of gross tumor volume was 32.61 Gy, and median pre SBRT CA19-9 value was 70.5 U/mL. There were no statistically significant differences in matched characteristics between the two cohorts. Among the SBRT+IRE, the median time between IRE and SBRT was 66 days (range:49-467 days). The median OS, PFS, FFLF, and FFDF for IRE+SBRT vs. SBRT alone from SBRT was 10.8 vs 15.1 months, 9.6 vs. 15.3 months, 15.7 vs. 15.3 months, 15.9 vs. 14.4 months respectively (all P > .10). 11 patients in the entire cohort experienced toxicity as a result of their radiation therapy (35%), with one G3 GIB and one patient experiencing G3 abdominal pain. Among the 17 patients who underwent IRE, nine patients experienced toxicity (53%). Most of these events were G3, with two G4 intestinal bleeds. There was zero mortality in the 90 day period post operatively. Conclusions: In a retrospective cohort,non-selective delivery ofIRE afterSBRT demonstrated no oncological benefit for patients with unresectable pancreatic adenocarcinoma compared to only SBRT. Compared to historical experiences of IRE alone, there was no increase in overall toxicity with the combination of SBRT and IRE. The optimal timing, sequencing, and indications for IRE and SBRT in LAPC remain unknown and are best assessed prospectively. [Table: see text]
Prognostic value of KRAS and PI3K pathway mutations for advanced pancreatic ductal adenocarcinoma (PDAC) patients (pts).
Authors: Diehl Adam , Hannan Lindsay Marie , Chiorean Elena Gabriela 
Published: January 2021

424 Background: KRAS mutation (MUT) variants (var) have been associated with differential clinical outcomes in advanced PDAC pts (Hendifar, 2020). Recent data from PDAC cell lines suggests that, unlike KRAS G12D/V, the KRAS G12R var is unable to interact with p110α PI3Kα and relies on KRAS-independent p110γ PI3K activity to support macropinocytosis, a nutrient uptake process necessary for tumor growth (Hobbs, 2020). Methods: We retrospectively reviewed advanced PDAC pts who received at least first-line (1L) systemic therapy and underwent next generation sequencing (NGS) at University of Washington between 2013 and 2020. We analyzed, using Fisher’s exact test, whether KRAS var were associated with PI3K pathway mutations (PI3K MUT). Using multivariate (Cox proportional hazards) analysis, we compared overall survival (OS) and progression-free survival (PFS) from start of 1L therapy for pts whose tumors harbored any KRAS var with and without stratification by PI3K MUT status. Results: 127 pts had NGS (96% tissue, 4% ctDNA). Median OS (mOS) and PFS were 16.8 months (mos) and 8.6 mos, respectively. 111 PDAC were KRAS MUT (87%): 43 (39%) G12D, 35 (32%) G12V, 23 (21%) G12R, 1 (0.9%) G12C, 6 (5%) Q61. 15 PDAC (12%) had 16 PI3K MUT, including 7 PIK3CA, 3 AKT2, 3 RICTOR, 1 PTEN, 1 PIK3C2B, and 1 PIK3R1. PI3K MUT occurred in 26% of tumors with KRAS G12R vs 8% in other KRAS var (p=0.0265). In multivariate analysis controlling for age, performance status, stage at diagnosis, type of 1L chemotherapy, TP53 MUT and GATA6 amplification status, pts with KRAS G12R var PDAC vs other variants had longer mOS (20.4 vs 14.5 mos, HR 0.67 (95% CI 0.47 – 0.93), p=0.0215) and mPFS on 1L therapy (12.2 vs 6.8mos, HR 0.60 (95% CI 0.40 – 0.85), p=0.0040). In pts with KRAS G12R var PDAC, concurrent PI3K MUT vs PI3K WT associated with shorter mOS (19.4 vs 24.2mos, HR 2.79 (95% CI 0.97 – 10.6), p=0.0570). In pts with non-G12R KRAS var tumors, PI3K MUT vs WT did not confer shorter OS (mOS 17.6 vs 14.5 mos, HR 1.20 (95% CI 0.72 – 2.0), p=0.55). Conclusions: KRAS G12R PDAC have a higher incidence of PI3K MUT than other KRAS var. KRAS G12R status may confer improved prognosis vs other KRAS variants, albeit this benefit is offset by the presence of concurrent PI3K MUT.
Genomic biomarker discovery of first-line gemcitabine/nabpaclitaxel treatment in Chinese advanced pancreatic carcinoma patients.
Authors: Du Juan , Pan Qiuyue , Sha Huizi , Zou Zhengyun , Kong Weiwei , Qiu Xin , Lu Changchang , Zhang Xin , Liu Baorui 
Published: January 2021

436 Background: Pancreatic carcinoma is one of the most lethal malignancies worldwide and is characterized by extremely poor prognosis. Gemcitabine plus Nab-paclitaxel (GNp) has been recommended by international guidelines for first-line treatment of locally advanced or metastatic pancreatic carcinoma. However, exploration into molecular biomarkers of GNp treatment is still limited. This study aims to observe and evaluate the efficacy and safety of first-line GNp treatment of pancreatic carcinoma, and to explore potential predictive and prognostic biomarkers to screen advantageous population. Methods: From December 20, 2018 to July 6, 2020, patients with metastatic pancreatic carcinoma, who received first-line GNp treatment, were enrolled. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse events (AE). Patients were collected formalin fixed paraffin embedded (FFPE) samples and sequenced by a next-generation sequencing (NGS)-based 450 gene panel carried out by OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: In this study, tissue samples from 101 patients were assessed by NGS, including 58 (57.4%) primary tissues and 43 (42.6%) metastasis tissues. So far, 72 patients were available for efficacy analysis, the ORR and DCR were 38.2% and 77.9%, respectively, and were similar between patients sampled from primary lesions and metastasis lesions. The PFS and OS were 176 days and 308 days, respectively. The most frequently mutated genes were KRAS (91.9%), TP53 (76.8%), CDKN2A (32.3%) and SMAD4 (26.3%). Germline pathogenic BRCA2 mutations were detected in 3 (3.0%) patients, while somatic mutations of BRCA2 were found in 2 (2.0%) patients. For KRAS, missense mutations resulted in single amino acid substitutions primarily at G12 (88.1%), and lower frequencies at Q61 (4.0%) and V14 (1.0%). At G12, five different amino acid substitutions have been identified, with G12D (37.6%) the predominant mutation, G12V (32.7%), G12R (11.9%), G12C (3.0%) and G12A (1.0%). The ORR to AG treatment was significantly higher in TP53-alteration (-alt, 47.1%) than in TP53-wild-type (-WT, 11.1%) subgroups (p=0.01). Median OS times in CDKN2B-alt and CDKN2B-WT patients were 180 days and 323 days (p=0.029), respectively. Conclusions: Current evidence indicates that GNp is a valuable option for the first-line treatment of metastatic pancreatic cancer. TP53 may serve as a novel response-predictive gene for GNp treatment in pancreatic carcinoma. Overall survival was significantly prolonged in CDKN2B-WT patients compared with CDKN2B-alt patients. This study provided insights in identifying patients who might potentially benefit from GNp therapy. Clinical trial information: NCT03768687.