bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival impact of homologous recombination deficiency in veterans with cholangiocarcinoma including mutual exclusivity with pathogenic KRAS and TP53.
Authors: Bergstrom Colin P. , Lin Ethan Samuel , Mehlhaff Eric G. , Lesnik Dyan M. , LoConte Noelle K. , Lubner Sam Joseph , Matkowskyj Kristina A. , Patel Monica Arun , Ronnekleiv-Kelly Sean , Uboha Nataliya Volodymyrivna , Wachsmann Megan , Wang David H. , Lin Albert Y. , Kratz Jeremy D.
Published: January 2024

546

Background: Cholangiocarcinoma (CCA) has poor prognosis and limited treatment options. The US Veteran Health Administration’s (VHA) National Precision Oncology Program (NPOP) was established to characterize pathogenic drivers across the integrated VA network. Here, we summarize an important subgroup of CCA with homologous recombination deficiency (HRD) and its impact on overall survival (OS). Methods: Next-generation sequencing (NGS) was performed using FoundationOne CDx Analysis included clinicopathological, molecular alterations including, single nucleotide variants, gene amplification/loss, and gene fusion/rearrangements obtained from centralized data of the VHA’s Corporate Data Warehouse. Homologous recombination deficiency was defined by pathogenic variant mutations (MT) in ARID1A, ATM, ATR, BAP1, BRCA1, BRCA2, CDK12, CHEK2, FANC, NBN, PALB2, and RAD51. Statistical analysis was performed using Chi-squared test for concurrent gene enrichment and log-rank Kaplan-Meier analysis. Results: 483 CCA samples underwent tissue NGS as standard of care. Pathogenic variants in HRD genes included ARID1A (15.5%, n=75), BAP1 (9.5%, n=46), ATM (2.7%, n=13), PALB2 (2.3%, n=11) and BRCA (2.0%, n=10), representing 31.7% (n=153) of the population. HRD mutations were found in similar proportions of localized (31.8%) and metastatic (31.5%) clinical presentations at diagnosis. OS was not significantly different between CCA with HRD mutations (12.3 mo WT vs. 13.8 months with HRD MT, p=64). KRAS MT (n=77, 15.9% of population) did not impact OS (WT 12.3 mo v. MT 13.1 mo) including subgroup analysis stratified by HRD status. There was increased frequency in KRAS MT with HRD WT 18.5% versus HRD MT10.4% (p<0.03). Additionally, there was increased frequency in TP53 MT with HRD WT 54.8% versus HRD MT 28.1% (p<0.00001). TP53 MT (n=224, 46.3% of population) conferred inferior OS (WT 12.3 mo v. MT 13.1 mo) including subgroup analysis stratified by HRD status. Subgroup analysis of TP53 MT had worsened OS with concurrent HRD MT (n=39, 4.1 mo) v. HRD WT (n=158, 9.0 mo; p<0.04). Conclusions: Across a diverse integrated healthcare system of Veterans, mutations associated with HRD were found to be common, however, not prognostic in OS across a diverse patient population of CCA. Further work is needed to clarify exposure to platinum containing chemotherapy. TP53 MT CCA remains a critical unmet need that drives worsened outcomes including here in patients with mutations in HRD. Future analysis should consider mutation signatures of HRD, loss in heterozygosity of HRD, and platinum exposure to further define the subgroups of CCA with mutations in HRD. [Table: see text]
Actionable molecular alterations in veterans with advanced cholangiocarcinoma.
Authors: Lin Ethan Samuel , Mehlhaff Eric G. , Bergstrom Colin P , Lesnik Dyan M. , LoConte Noelle K. , Lubner Sam Joseph , Matkowskyj Kristina A. , Patel Monica Arun , Ronnekleiv-Kelly Sean , Uboha Nataliya Volodymyrivna , Wachsmann Megan , Wang David H. , Lin Albert Y. , Kratz Jeremy D.
Published: January 2024

548

Background: Cholangiocarcinoma (CCA) requires integrated efforts to understand the heterogeneity in available molecular targets. Chemotherapy remains a non-selective standard of care, however defining distinct populations with molecular actionability remains a critical need. The Veteran Health Administration’s (VHA) National Precision Oncology Program (NPOP) was established to characterize comprehensive genomic profiles across the integrated VHA network. Methods: Veterans with CCA underwent next-generation sequencing (NGS) with FoundationOne CDx, which enhanced sensitivity in the reporting of gene fusions. Analysis included dedicated chart review for date of diagnosis and survival utilizing the VHA’s Corporate Data Warehouse. Molecular alterations included mutations(mut), amplifications (amp) and fusion/rearrangements (fus). Log-rank Kaplan-Meier survival analysis was stratified by primary tumor location, and actionable driver alterations defined by VA Clinical Pathways. Results: Veterans diagnosed with CCA (07/2008-04/2023) underwent tissue-based NGS (n=483) including 96 unique VHA sites with male predominant population (96.9%). There was a predominance of localized disease at clinical presentation (55.3%). A summary of common pathogenic variants is provided (see table). Actionable alterations defined as IDH1mut, FGFR2fus, ERBB2amp, BRAFmut (V600E), and MSI-H collectively represented 21.1% of all Veteran CCA. The largest population was intrahepatic CCA (n=327) with actionable alterations including IDH1mut (13.5%), ERBB2amp (4.3%), and FGFR2fus (4.3%). Data suggested improved overall survival (OS) in IDH1mut Intrahepatic CCA including median OS 19.8 months (mo) v. 10.7 mo (p<0.03). ERBB2amp (n=32) was enriched in extrahepatic (8.1%) and gallbladder cancer (17.2%), however did not improve OS including 7.1 mo in ERBB2amp v. 13.2 mo in wildtype (p=0.15). PIK3CAmut CCA (n=35) was found to confer inferior OS across the population with median OS of 7.5 mo v. 13.2 mo in wildtype (p<0.02). Additional pathologic mutations in genes of homologous recombination deficiency (31.7%), PIK3CA (7.2%), and amplifications in MDM2 (5.0%). Conclusions: Across an integrated healthcare system of Veterans, actionable molecular alterations from VA Pathways were seen in 21.1% of the population. Further data is needed to clarify the prognostic versus predictive value of integrated precision-based strategies in clinical practice. The Veteran population includes important molecular subtypes to consider in future prospective trial design. [Table: see text]
Developing a comprehensive cell-free DNA (cfDNA) epigenetic signature (ep-Sig) with diagnostic and prognostic value in hepatocellular carcinoma (HCC).
Authors: Manne Ashish , Jogi Soumya , Jeepalyam Sravan , Esnakula Ashwini K.
Published: January 2024

553

Background: HCC is one of the deadliest tumors with poor outcomes often diagnosed in late stages. Current surveillance strategies (alfa-fetoprotein (AFP) plus ultrasound (USG)) for high-risk population (HRP) have poor sensitivity (SN) and reasonable specificity (SP) of 61% and 92%, respectively. Triple phase computed tomography (CT) imaging has good sensitivity and specificity (≈ 90% for both) but the evidence does not support its use for routine surveillance. All these modalities do not have prognostic (survival) value. We attempted to develop a non-invasive, cfDNA-based tests to improve the diagnostic value of the current standard of care modalities (AFP and USG) and help in predicting the outcomes at diagnosis. We hypothesized that RNA and gene expression in HCC tissues is a surrogate for epigenome (DNA-methylation changes). Methods: We curated a 21-gene cfDNA ep-Sig from the literature with a proven prognostic value. Evidence suggests epigenetic changes in every gene of this panel affect HCC outcomes influencing clinicopathological characteristics (large tumor size, vascular invasion, advanced staging) or early post-operative recurrence, and survival. We compared RNA and gene expression of the genes in the ep-Sig between normal (NT) and HCC tissues using a web-based tool, TNMplot.com that uses the data from the Gene Expression Omnibus of the National Center for Biotechnology Information (NCBI-GEO) or Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories was used create this tool. It uses Mann-Whitney or Kruskal-Wallis tests to compute statistical significance. Results: RNA expression of all the genes from the ep-Sig was significantly higher in HCC than NT (1.133, p=5.84e-15). Gene expression was 19/21 genes was higher in HCC tissues (1.15, p=1.3e-08). The other 2 genes were not detected in the tested samples. Conclusions: Our ep-Sig which has a proven prognostic value and reliable prevalence in HCC patients. This study is the first step in developing clinically useful blood-based test that can revamp the current diagnostic and screening practices when used alongside AFP and USG.
Impact of next-generation sequencing in biliary tract cancer treatment.
Authors: Goyal Priya , Ouf Mahmoud , Agarwal Seema , Kupfer Gary , Mukherji Reetu , Weinberg Benjamin Adam , Noel Marcus Smith , Marshall John , He Aiwu Ruth
Published: January 2024

560

Background: Incorporating molecular profiling in BTC treatment has increased. With this study, we aimed to analyze the impact of molecular profiles on the survival of patients with BTC. Methods: This is the retrospective analysis of patients with biopsy-proven biliary tract cancer at our comprehensive cancer center GI oncology clinic from 2018-2022. Only patients with continued care at Lombardi Comprehensive Cancer Center were included in the study. Results: Of 217 patients screened; 160 patients were included in the final analysis. The mean age of the cohort was 63 years, and the majority were females (55%). In the order of frequency, intrahepatic cholangiocarcinoma (77.5%) was the most common type of cancer followed by extrahepatic cholangiocarcinoma (15.6%), and carcinoma of the Gallbladder (6.9%). Molecular profiling was performed in 49.4% of the patients and actionable mutations for FDA approved treatments or clinical trial enrollment were found in 42 patients (26.3%) of the patients. The spectrum of actionable mutations in decreasing order of frequency was KRAS (n=11), FGFR2 (n=9), IDH-1 (n=8), Her-2neu (n=5), BRCA1/2 (n=5), & PD-L1(n=4). Patients who underwent molecular profiling had significantly better survival (43±5 months vs. 25±4, p 0.013). Notably, patients with actionable mutations had even better survival as compared to the rest of the cohort (52±8 months vs. 26±7 months, p 0.019). Conclusions: BTC exhibits diverse genetic alterations. Patients who underwent molecular profiling as a part of the treatment plan had better survival. Identifying actionable mutations was associated with even better survival.
Preoperative risk factors related to relapse-free survival after R0 resection of gallbladder cancer.
Authors: Lee Sang Hun , Seol Yong Mi , Kim Dong Uk
Published: January 2024

566

Background: Gallbladder (GB) cancer shows high prevalence in South Korea, and tends to be fatal. In surgically fit patients, radical resection aiming R0 margin combined with lymphadenectomy is the mainstay of curative-intent therapy. In spite of R0 resection, however, high recurrence rate is observed in GB cancer, demanding a need to find out risk factors related to recurrence after surgery. Methods: This is a single center, retrospective cohort study conducted on 148 patients with GB cancer who underwent R0 resection between January 1st, 2014 and December 31st, 2019. Several variables were analyzed with statistical tools to identify risk factors related to prognosis. Relapse free survival (RFS), defined as time from treatment of disease to any event, was analyzed with Cox regression analysis. Results: Based on statistical analysis, risk factors related to RFS were age over 65 (hazard ratio [HR] 3.82, 95% confidence interval [CI] 1.71 – 8.56, p= .001), glycated hemoglobin (HbA1c) level more than 6.5% (HR 2.72, 95% CI 1.31 – 5.66, p=0.007), surgical T stage more than T3 (HR 5.60, 95% CI 3.05 – 10.25, p<0.001), surgical N stage more than N1 (HR 4.07, 95% CI 2.25 – 7.36, p<0.001), pathologic differentiation of moderate or poor differentiation (HR 2.80, 95% CI 1.46 – 5.37, p=0.002), reversed albumin-globulin ratio (HR 0.16, 95% CI 0.06 – 0.40, p<0.001), and high gamma glutamyl peptidase (GGT) level (HR 1.00, 95% CI 1.00 – 1.00, p<0.001). Conclusions: Advanced pathologic stage and high inflammatory marker levels, reflecting high tumor burden, were related with poor surgical outcome. Interestingly, high HbA1c level was related to reduced RFS as well. In conclusion, active screening for early detection, reducing inflammatory conditions, and managing diabetes might enhance RFS after R0 resection of GB cancer. [Table: see text]
A novel image-guided laparoscopic liver resection with integrated fluorescent imaging and artificial intelligence: A preliminary study.
Authors: Tashiro Yoshihiko , Aoki Takeshi , Kobayashi Nao , Kumazu Yuta , Tomioka Kodai , Saito Kazuhiko , Yamazaki Tatsuya , Hirai Takahito , Shibata Hideki , Date Hiromi , Watanabe Ryohei , Matsuda Kazuhiro , Kusano Tomokazu , Yamazaki Kimiyasu , Watanabe Makoto
Published: January 2024

568

Background: Technology innovations improve surgical techniques. ICG fluorescence imaging is beneficial for real time navigation tool during surgery and enables accurate surgery. Recently, the prediction of anatomical structures by artificial intelligence (AI) is expected to support surgeons as navigation tool. We developed a visual-support AI system to perform the laparoscopic liver resection (LLR) using ICG fluorescence imaging and AI technology. Methods: Procedure: ICG fluorescence imaging was used for liver mapping and securing surgical margin. AI model development and evaluation: Over 430 images extracted from 13 videos of LLR for hepatocellular carcinoma and colorectal liver metastasis was used to develop and evaluate the AI algorithm at Anaut Inc. The annotation was performed on video frames capturing a LLR performed by 2 surgeons for hepatic vein and Glisson sheath. The performance of AI on unlearned LH videos was evaluated quantitatively using Intersection-Over-Union (IOU) and Dice coefficients, and qualitatively on a five-point scale (from 1 to 5) by 10 hepato-biliary-pancreatic surgeons using 35 randomly extracted still images from the analyzed videos. Results: ICG fluorescence imaging could visualize the demarcation line and clarified the boundaries of the liver transected surface. The hepatic veins and Glisson sheath were appeared in the parenchymal transection plane during segmentectomy and securing surgical margin, and this AI system enabled to recognize and display these vascular structures through color-coding under bleeding and ICG fluorescent imaging without visual discrepancies. The AI model accurately recognized vascular structures of any size (IoU=0.33, Dice=0.44) in real-time (<0.12 s) In the qualitative evaluation by surgeons, the mean sensitivity score was 4.10 ± 0.92 (range 3.61–4.76). Additionally, this AI system also recognized vascular structures during robot-assisted liver resection. Conclusions: This is the first study demonstrating that AI can precisely identify vascular structures during LLR. Novel image-guided LLR using ICG fluorescent imaging and artificial intelligence is expected to provide safer and more accurate LLR, thereby contributing to reduce complications and improve survival rates.
Risk of relapse after surgical resection of localized appendiceal adenocarcinoma.
Authors: Fanaeian Mohammad Mahdi , Yousef Mahmoud M.G. , Yousef Abdelrahman M.G. , Foo Wai Chin , Taggart Melissa , Beaty Karen A. , Scally Christopher , Mansfield Paul F. , Fournier Keith F. , Helmink Beth A , Shen John Paul Y.C.
Published: January 2024

58

Background: Appendiceal adenocarcinoma (AA) encompasses a heterogenous mix of histologic subtypes and frequently presents with peritoneal metastases. Data regarding the risk of relapse after surgical resection in patients with localized AA (stages I–III) is limited. More accurate evaluation of features predictive of relapse is critical to counsel patients, determine follow-up, and guide decisions regarding adjuvant therapy. Methods: The Foundry software platform was used to query the MD Anderson Cancer Center (MDA) Electronic Health Record database to identify and extract clinical information from AA patients presented to MDA from 2004 to 2023. Results: We identified 296 patients with localized AA, split into two cohorts: patients who underwent surgery at MDA (n=133) and patients with surgery at an outside institution later referred to MDA (n=163). The most common histologic subtypes were mucinous (n=124, 41.9%) and goblet (n=121, 40.9%) with less frequent colonic-type (n=42, 14.2%) and signet ring cell (SRC, n=9, 3%). With a median follow-up of 47 months, the relapse rate (RR) for the MDA surgical cohort was only 6% (n=8), with a median time to relapse of 24 months (range=8-74). Evaluating all 296 localized AA patients, histologic subtype was significantly associated with risk of relapse, with goblet AAs having lowest risk (6%, n=7), followed by colonic-type (12%, n=5), mucinous (27%, n=33), and SRC (44%, n=4; overall P< 0.001), with a median time of relapse of 26 months (range=3-96). Patients with a positive LN, higher grade, and/or higher T stage showed a higher RR (Table). Use of adjuvant chemotherapy (AC) was not associated with RR in our cohort, with odds ratio trending towards increased risk of relapse (14.4% vs 19.2%, OR=1.4, 95% CI=0.76-2.6; P=0.27). Restricting to only high-risk patients (poorly differentiated, LN-positive, and/or T4, n=205), similar results were observed with 18.4% (n=17) relapsed without AC vs 19.4% (n=22) relapsed with AC (OR=1.06, 95%CI=0.52-2.15; P=0.85). AC was also not associated with improved RFS (HR=1.2, 95%CI=0.63-2.2, P=0.59). Conclusions: Patients with localized AA who undergo surgical resection have a low risk of relapse, especially those with goblet AA. This retrospective analysis did not identify a benefit from adjuvant chemotherapy. Considering the clear histologic and molecular differences between AA and CRC, these data call into question the current practice of applying CRC data to guide AC decisions in AA. Prospective clinical trials of AC in AA, stratified by histologic subtype, are urgently needed. [Table: see text]
Prognostic factors for overall survival in patients with advanced digestive neuroendocrine carcinoma treated with first-line cisplatin-based chemotherapy: A post-hoc analysis of JCOG1213.
Authors: Hirano Hidekazu , Hirata Kenro , Honma Yoshitaka , Morizane Chigusa , Machida Nozomu , Kato Ken , Okusaka Takuji , Boku Narikazu , Sekine Shigeki , Hiraoka Nobuyoshi , Ogawa Gakuto , Sano Yusuke , Shibuya Yuichi , Takahashi Masanobu , Fujimori Nao , Nomura Motoo , Doki Yuichiro , Ueno Makoto , Yoshikawa Takaki , TAKEUCHI HIROYA
Published: January 2024

594

Background: Advanced digestive neuroendocrine carcinoma (ADNEC) is a rare and aggressive malignancy without evidence of prognostic factors assessed in prospective studies. We aimed to evaluate prognostic factors in patients with ADNEC receiving first-line cisplatin-based chemotherapy. Methods: This is a post-hoc analysis of JCOG1213, which is a phase 3 randomized trial showing equivalent overall survival (OS) for cisplatin plus etoposide versus cisplatin plus irinotecan as first-line chemotherapy for patients with ADNEC. The primary endpoint of JCOG1213 was OS. For this post-hoc analysis of prognostic factors, patients who had ineligible histology based on the central pathological review or who lacked the necessary clinical data for analysis were excluded. A Cox proportional hazard model was used to assess the effect of independent variables on OS. Priori variables selected on previous reports (performance status (PS), Ki-67 index, and serum LDH level), as well as variables that remained at a level of p-value <0.20 by backward stepwise selection, were incorporated in the final model of OS. Results: Among 170 patients enrolled in JCOG1213, a total of 129 patients with ADNEC were included in this analysis. In multivariable analysis, serum LDH level (> upper normal limit vs. normal) was identified as a significant prognostic factor for OS (HR = 1.721, 95% CI: 1.144–2.589, p = 0.009). Other clinicopathological factors were not found to be significant, including PS (1 vs. 0; HR = 0.784, 95% CI: 0.507–1.214, p = 0.276), Ki-67 (≥ 55% vs. < 55%; HR = 1.475, 95% CI: 0.588–3.698, p = 0.407), liver metastasis (present vs. absent; HR = 1.434, 95% CI: 0.968–2.124, p = 0.072), sex (female vs. male; HR = 1.387, 95% CI: 0.937–2.053, p = 0.102), and serum ALP level (> upper normal limit vs. normal; HR = 0.948, 95% CI: 0.639–1.406, p = 0.789). OS of patients with elevated serum LDH levels was shorter than those with normal serum LDH levels (median: 9.5 months vs. 15.6 months, p = 0.0019). No statistically significant differences were observed between the two groups regarding objective response rate (58.8% vs. 54.1%, p = 0.594) and progression-free survival (median: 4.5 months vs. 5.9 months, p = 0.141). A numerically lower proportion of patients with elevated serum LDH levels received second-line chemotherapy than those with normal serum LDH levels (76.5% vs. 88.3%). Conclusions: Serum LDH level may serve as a prognostic factor in the daily practice of patients with ADNEC and as a risk stratification factor in future randomized clinical trials. Clinical trial information: UMIN000014795 .
Advances in the treatment of gastroenteropancreatic poorly differentiated neuroendocrine carcinoma at our hospital.
Authors: Nishina Shinichi , Yokota Mitsuru , Nagahisa Yoshio , Kawata Kenji , Okabe Michio , Masui Toshihiko , Kawamoto Kazuyuki
Published: January 2024

595

Background: Overall survival after first-line chemotherapy for metastatic or recurrent gastroenteropancreatic poorly differentiated neuroendocrine carcinoma (GEP-NEC) is reported to be less than 1 year. Platinum drugs in combination with etoposide or irinotecan have been used as first-line chemotherapy for GEP-NEC patients, but no standard treatment has been established for second-line and subsequent chemotherapy. Recently, however, we have seen patients with a good prognosis after treatment based on comprehensive cancer genomic profiling (CGP). We retrospectively reviewed GEP-NEC patients treated with chemotherapy. Methods: Patient background, treatment regimen, overall survival, and toxicity were evaluated in 20 GEP-NEC patients who started first-line platinum combination chemotherapy at our hospital between October 2016 and September 2022. Results: Median age was 71 (48 to 81) years, 16 were male, and primary sites were esophagus in 2 patients, stomach in 7 patients, small intestine in 2 patients, large intestine in 6 patients, and pancreas in 3 patients. Five patients had an adenocarcinoma component. Stage III, IV, and recurrence were observed in 2, 16, and 2 patients, respectively. Progression-free survival and overall survival after first-line chemotherapy were 4.0 (2.3 to 7.0) and 8.1 (4.7 to 17.0) months, respectively. Grade 3 or higher toxicity was observed in 13 patients. No differences in overall survival were observed in chemotherapy regimen including etoposide or irinotecan and cisplatin or carboplatin. Patients who underwent CGP had significantly longer survival. After second-line chemotherapy, a regimen containing irinotecan, 5-FU, paclitaxel, ramucirumab, and nivolumab was used, and overall survival was 5.2 (1.8 to NA) months. There were 4 of 20 patients who survived for more than 1000 days after first-line chemotherapy. Durable responses were observed in colonic NEC patients harboring the POLE P286R mutation treated with nivolumab and in those harboring the BRAF V600E mutation treated with cetuximab and encorafenib. Conclusions: Overall survival of GEP-NEC patients treated with platinum combination chemotherapy was very poor at only 8 months. However, in some cases, long-term survival has been achieved with molecular targeted therapy based on CGP results.
Potential biomarkers for treatment response in advanced non-pancreatic neuroendocrine tumors.
Authors: Sonti Sahithi , Wang Katy , Attwood Kristopher , Minderman Hans , Maguire Orla , Ryan Courtney , Sharma Nitika , Konda Bhavana , Iyer Renuka V. , Krishnamurthy Anuradha
Published: January 2024

599

Background: Well-differentiated NETs are highly vascular and hence, inhibition of angiogenesis is of interest. VEGF, a key molecule in promoting angiogenesis, has also been shown to promote an immunosuppressive tumor microenvironment. Nintedanib, an oral inhibitor of FGFR1–3, VEGFR1–3 and PDGFRA, has previously been evaluated in a phase II clinical trial in well-differentiated, non-pancreatic NETs, where 83% of the evaluable patients were progression-free at 16 weeks and median PFS was 11 months. In preclinical studies, nintedanib has been shown to increase PD-L1 expression in tumor cells, which then results in improved outcomes with immune checkpoint inhibition. There are multiple indicators of T-cell exhaustion, including PD-L1 and LAG-3. LAG-3+ T-cells have been found to correlate with poor response to treatment in neuroendocrine neoplasms. Given these findings, this study evaluates serum VEGF and LAG-3 expression to determine potential biomarkers of response in patients treated with nintedanib. Methods: 27 sets of paired samples collected at baseline and 8-weeks post treatment with nintedanib, from clinical trial NCT02399215 were used for this study. With IRB approval, we tested for serum VEGFa and serum LAG-3 using Luminex test kits: HCKP1-11K-01 (LAG-3) and HCYTA-60K-01 (VEGFa). We compared the baseline, 8-week, and percentage change in serum VEGF and serum LAG-3 levels with Rd Cd8+ pAkt+ T-cells (activated cytotoxic T-cells) as a marker of immune activation, Rd CD25+ pAkt+ T-cells (regulatory T-cells) as a marker of immune suppression, and PFS. Results: The median VEGF levels at baseline and 8-weeks were 10.50 pg/mL and 11.90 pg/mL respectively. The median LAG-3 level at baseline and 8-weeks were 59000 pg/mL and 62900 pg/mL respectively. Higher VEGFa levels in the post-treatment samples were associated with poorer progression free survival (HR= 1.009, 95% HR CI: [0.999, 1.019], with P= 0.0760). Higher levels of VEGF at baseline were also associated with lower numbers of Rd CD8+ pAkt + cells (Pearson coefficient = -0.42, p-value 0.04) at baseline. Increased baseline CD25+ pAkt+ levels were positively correlated with percent change in serum LAG-3 levels between baseline and post-treatment samples. (Pearson Co-efficient: 0.45; p=value: 0.02). Conclusions: Elevated serum VEGFa levels at 8-weeks post treatment correlated with lower PFS. Serum VEGFa level is a potential indicator of effector T-cell suppression, as evidenced by low number of activated cytotoxic T-cells in patients with higher VEGFa levels at baseline. Higher baseline regulatory T-cells were associated with a greater increase in serum LAG-3 levels, suggesting that serum LAG-3 may be an indicator of an immunosuppressive tumor microenvironment.
Socioeconomic variables in the National Cancer Database: Utilization and impact of income and education in survival models for patients with resected pancreas cancer.
Authors: Luo Qianyun , LaRocca Christopher James , Ankeny Jacob , Jensen Eric Hans , Marmor Schelomo , Brauer David
Published: January 2024

607

Background: The National Cancer Database (NCDB) is commonly used for analyzing survival outcomes in pancreatic cancer and has a robust number of patient-specific socioeconomic variables. Although these aggregated variables are commonly collected, their utility and impact on survival has infrequently been assessed. We aim to assess the distribution of income and education variables on their impact on survival models for patients who underwent resection for pancreatic ductal adenocarcinoma (PDAC). Methods: Patients undergoing definitive surgery for PDAC between 2004-2020 were identified from the NCDB. Variables of interest were income and education according to the patient’s ZIP code of residence. Pearson and Spearman correlation was assessed. Overall survival (OS) was calculated using Kaplan Meier method. The effects of income and education was calculated using Cox proportional Hazard (PH) models. Results: 69,362 patients met inclusion criteria. Median age was 66 (IQR 59-73), with 48.9% female. The correlation coefficient between income and education based on the 2020 American Community Survey data was 0.48 (p<0.01). Median OS from the time of diagnosis was 21 months. The 5-year OS was 19.4 and 22.7 months for groups with lowest and highest education (p<0.01). Group with missing education has a 5-year OS of 22.4 month, comparable to the group with highest education (p=0.82). The 5-year OS based on income quartiles was 18.7 and 22.5 months for the Q1 and Q4 (p<0.01). Group with missing income has a 5-year OS of 22.4 month, similar to the highest income group (p=0.85). When including combinations of income, education and their interaction, the concordance of Cox models was changed by less than 0.002. Conclusions: For patients who underwent definitive surgery for PDAC, the income and education variables are only mildly correlated, and their inclusion do not have significant impact on OS models. Investigators should reconsider the utility of the aggregate NCDB measures, as they many not fully elucidate income and education disparities and impact on survival. [Table: see text]
Demographic and social vulnerability factors associated with late diagnosis of gastrointestinal cancers.
Authors: Khan Muhammad Sohaib , Meier Jennie , Nehrubabu Mithin , Murimwa Gilbert Zvikomborero , Young Sean , Dimartino Lisa , Kazmi Syed Mohammad Ali , Pogacnik Javier Salgado , Wang Sam C. , Yopp Adam C. , Zeh Herbert J. , Polanco Patricio M.
Published: January 2024

610

Background: Almost 30% of gastrointestinal cancers (GI) are diagnosed at an advanced stage. These patients have a poor prognosis with no curative options. Certain demographic and social factors adversely impact health outcomes. However, these have not been well studied in the context of late diagnosis of GI cancers. Methods: Texas and California cancer registries, merged with CDC’s Social Vulnerability Index (SVI) database, were used to identify patients diagnosed with gastric, colorectal, pancreatic and liver cancer from 2004 to 2019. To determine the association of demographic and 16 social vulnerability factors, while accounting for differences in tumor characteristics, univariate and multivariate logistic regression analysis (MVA) was performed for each cancer separately. Results: In total, 589,405 patients were included. Of these 166,910 (28.3%) patients had metastasis at diagnosis. This included 55%, 39%, 21%, and 17% of all pancreatic, gastric, colorectal and liver cancers respectively. On MVA, odds of metastatic cancer at presentation decreased with increasing age (except for pancreatic cancer where odds increased). Across all 4 cancer types, females and Asians had decreased odds while Blacks, uninsured and patients on Medicaid had increased odds of metastatic cancer at diagnosis. Poverty below 150% increased odds of metastatic pancreas, liver, and colorectal cancers at diagnosis. Odds were decreased for households with adults aged over 65 years for pancreas, colorectal and gastric cancers. Conclusions: This study has identified multiple demographic and social factors associated with odds of having metastatic GI cancer at diagnosis. Interventions aimed towards these at-risk populations offer an opportunity for early diagnosis and improved survival.[Table: see text]
Real-world comparison of low- versus high-dose continuous 5FU infusion in patients receiving triplet chemotherapy plus bevacizumab for newly diagnosed metastatic colorectal cancer (mCRC).
Authors: Chapin William Joseph , Hwang Wei-Ting , Mamtani Ronac , O'Hara Mark H.
Published: January 2024

62

Background: Several randomized trials demonstrated an overall survival (OS) benefit to triplet chemotherapy (5-FU, oxaliplatin, and irinotecan) plus bevacizumab compared to doublet chemotherapy plus bevacizumab in patients with newly diagnosed mCRC, though with higher rates of neutropenic fever and diarrhea. These trials used high-dose continuous infusion 5-FU (3,200 mg/m2/48 hours), but national guidelines suggest low-dose continuous infusion 5-FU (2,400mg/m2/48 hours) due to lower tolerance in U.S. patients. We performed a retrospective cohort study in a U.S. population to compare the effectiveness of low- vs high-dose continuous infusion 5FU in patients undergoing triplet chemotherapy plus bevacizumab for newly diagnosed mCRC. Methods: We used the nationwide Flatiron Health electronic health record-derived database, comprising de-identified patient-level structured and unstructured data curated via technology-enabled abstraction from ~280 cancer clinics. Patients with newly diagnosed mCRC who initiated triplet chemotherapy plus bevacizumab between 10/23/14 and 10/31/22 with non-missing height, weight, and dosing data were included. 5FU infusion doses of 2,000 – 2,799 mg/m2 were categorized as low-dose while those >/= 2,800 mg/m2 were categorized as high-dose. OS from first-line treatment initiation was assessed by dosing group using the Kaplan Meier method with log-rank testing. Multivariable analysis with adjustment for pre-specified variables with imbalance (defined by standardized difference < - 0.10 or > 0.10) was performed using multivariable Cox proportional hazards modeling. Missing data were imputed using multiple imputation with chained equations. Results: Among 320 patients included, 244 received low-dose and 76 patients received high-dose continuous infusion 5FU. Imbalance between low- and high-dose groups was observed in the use of 5FU bolus (23% vs 3%), year of metastatic diagnosis 2018 - 2022 (80% vs 55%), mean irinotecan dose (156.4 vs 160.5 mg/m2), left-sided primary (73% vs 64%), MMR deficiency (3% vs 6%) and mean CEA (478 vs 691 µg/L). In univariate analysis, median OS was 33 months (95% CI 26 – 39) in the low-dose group compared to 34 months (95% CI 24 – 48) in the high-dose group (HR 1.16; 95% CI 0.79 – 1.69; p = 0.44). After adjusting for imbalanced covariates, there was no difference in hazard of death between low- and high-dose groups (HR 0.99; 95% CI 0.64 – 1.53; p = 0.97). Conclusions: In this real-world, U.S. population with newly diagnosed mCRC receiving triplet chemotherapy plus bevacizumab, there was no association with survival between low- vs high-dose continuous infusion 5FU. This supports current guidelines recommending low-dose continuous infusion 5FU (2,400mg/m2/48 hours) for patients with mCRC receiving triplet chemotherapy in the U.S.
Nutritional impact and prognostic role of systemic inflammatory response index (SIRI) in advanced pancreatic cancer: PANTHEIA-Spanish Society of Medical Oncology (SEOM) study results.
Authors: Pacheco-Barcia Vilma , Mariño Méndez Axel , Carmona-Bayonas Alberto , Gallego Javier , Fabregat Franco Carles , Adeva Jorge , Cerdà Paula , Cabezon-Gutierrez Luis , Custodio-Cabello Sara , Ghanem Ismael , Hernandez Irene , Lamarca Angela , Laquente Berta , López-Alfonso Ana , Martinez Lago Nieves , Macarulla Teresa , Peiro Inmaculada , Visa Laura , Jimenez-Fonseca Paula , Muñoz Andrés
Published: January 2024

623

Background: Whilethe systemic inflammatory response assessed by SIRI has been recognized as a prognostic factor in advanced pancreatic cancer, understanding its association with patients' nutritional status may provide deeper insights into disease biology and outcomes. Methods: This is an observational, non-interventional and multicenter study (15 Spanish hospitals) promoted by SEOM, including retrospective and prospectively patients with metastatic pancreatic cancer in routine clinical practice. Clinical and nutritional data was recorded, and SIRI was calculated using the formula: (neutrophils x monocytes) / lymphocytes. We considered SIRI score as low (SIRI-L) or high (SIRI-H) using a cutoff of <2.3 or ≥2.3, respectively based in our previous findings. PANDORA-SEOM tool was used for electronic data collection. The main outcome is to correlate SIRI with the nutritional status. Other aims were to correlate the overall survival (OS) and progression-free survival (PFS) with SIRI and weight loss in the 3 months prior to diagnosis using the Kaplan-Meier method and multivariate Cox regression model. Data from the pilot study is presented in this abstract, and more data is expected to be available prior to the Congress. Results: We included 144 patients retrospectively: 65% men, with median age of 66 years (range 45-81). The most common 1st line chemotherapy regimen were gemcitabine + nab/paclitaxel (63.2%), mFOLFIRINOX (20.1%) and FOLFOX (11.8). Prior to diagnosis, 54.2% of patients had weight loss >5 Kilograms (Kg) and 22.9% lost >10 Kg. SIRI-H was significantly associated with weight loss >5Kg compared to SIRI-L, 35.7 vs 24% respectively (p=0.028). Patients with a pretreatment SIRI-H showed shorter OS compared to SIRI-L (median OS 5 vs 12 months, Hazard Ratio (HR) 3.047, 95% Confidence Interval (CI) 2.069-4.488, p<0.001), as well as shorter PFS (median PFS 5 vs 10 months, HR 2.364, 95% CI 1.650-3.387, p<0.001). In the patient subgroup that experienced >5Kg weight loss, SIRI-H was associated with worse OS (median OS 4 vs 12 months). We didn’t find an association between CA19.9 level and SIRI or weight loss. Multivariate analysis identified SIRI as an independent prognostic factor for OS (HR 2.962, 95% CI 1.911-4.591, P<0.001). Conclusions: Our findings underscore the importance of SIRI as a significant predictor of nutritional status and disease aggressiveness in patients with metastatic pancreatic cancer. Prospective data will help us to validate these findings.
Predictive machine learning models for survival outcomes in patients with pancreatic cancer.
Authors: Shen Yang-Chen , Chen Po-See , Lin Cheng-Feng , Liu Ping-Yen , Lin Peng-Chan , Yen Chia-Jui , Shan Yan-Shen
Published: January 2024

625

Background: Identifying prognostic markers is essential for accurately assessing risk levels in pancreatic cancer patients, leading to more personalized treatment approaches. In light of this, our study endeavors to build a survival prediction model for pancreatic cancer patients using various machine learning (ML) techniques, taking into account both clinical and inflammatory factors. Methods: The research included 311 pancreatic cancer patients on a prospective basis. Their data was sourced from the Clinical Data Warehouse of National Cheng Kung University Hospital. For the purpose of predicting 6 and 12-month survival, patients were randomly allocated into training, validation, and test groups in an 8:1:1 ratio. We utilized machine learning techniques and assessed them on the QOCA Aim (Quanta Omni Cloud Care for AI Medical Platform, version 2.0) platform. The model's effectiveness was gauged using the area under the receiver operating characteristic curve (AUC). Results: The cohort exhibited a mean age of 63.5 years with a standard deviation of 11. The median overall survival was documented at 16.8 months (95% confidence interval [CI] = 15.6–18). Analytical evaluation indicated that the optimal model for prognostication of 6-month survival was the balanced bagging classifier, yielding an AUC of 93.7%. Conversely, for the 12-month survival prediction, the k-nearest neighbors (kNN) classifier was superior, demonstrating an AUC of 86.1%. Subsequent variable importance analysis elucidated that salient predictors encompassed C-Reactive protein (CRP), surgical intervention, carbohydrate antigen (CA)19-9, age at diagnosis, and the neutrophil–lymphocyte ratio (NLR). Conclusions: The findings indicated that machine learning can be employed to develop high-efficacy predictive models for survival in pancreatic cancer patients. Such models offer promise for enhanced risk categorization and personalized prognostic assessment in this patient cohort.
Pancreatic cancer and diabetes: The effects of race and genes.
Authors: Shu Michael , Moreland Katie , Olowokure Olugbenga Olanrele , Latif Tahir , Rojan Adam , Wilson Gregory , Patel Sameer H. , Sussman Jeff , Ahmad Syed , Pan Jianmin , Rai Shesh , Sohal Davendra
Published: January 2024

627

Background: Pancreatic cancer and diabetes mellitus (DM) have been shown to be connected, but the genetic associations between the two have not been well characterized. The goal of this study was to identify racial and genomic patterns that relate the timing of DM onset with a pancreatic cancer diagnosis. Methods: Consecutive pancreatic cancer patients treated at the University of Cincinnati Cancer Center with available tumor genomic profiles were studied. Descriptive statistics for 133 genes, patient characteristics, cancer stage, treatment details, and family history were analyzed. Categorical variables were compared using the Pearson Chi-square test for contingency tables (or Fisher’s exact test when the expected frequency within any cell was less than 5 in the contingency table), and the t-test or ANOVA was used for continuous variables. For overall survival, we generated Kaplan-Meier curves by DM diagnosis, and fit univariable Cox Proportional-Hazard models for each interest variable for all patients, and multivariable Cox models, which included only significant variables. Results: Of 147 individuals with pancreatic cancer (median age 67 years, 49% female, 12% Black), 46.3% had a DM diagnosis. Of these, 62% had chronic DM, while 38% were diagnosed within one year of their pancreatic cancer diagnosis. Black individuals were more likely to have DM diagnosed (76.5% vs 41.7%, p = 0.007), and were more likely to have been diagnosed within a year of pancreatic cancer (69.2% vs 30.2%, p = 0.023), compared with White individuals. There were 15 genes found to be upregulated in those with DM and pancreatic cancer, and 11 genes found to be downregulated. RNF43 mutation was more prevalent in pancreatic cancer patients with chronic DM than those without DM (71.4% vs 32.5%, p = 0.048), although absolute number of individuals with the mutation were low. No other genomic association on the timing of DM and pancreatic cancer was found. A SMAD4 mutation was associated with a 121% increased risk of mortality (HR = 2.21, 95% CI 1.16-4.19, p=0.016). Conclusions: In a cohort of pancreatic cancer patients at a single center, Black individuals were more likely to have DM diagnosed closer to pancreatic cancer diagnosis (rather than earlier), compared with other races. No remarkable genomic association was found. This highlights that a diagnosis of diabetes may be related to inequities in healthcare, as opposed to true genomic differences, and needs to be explored in larger datasets.
Real-world overall survival and time to next treatment in patients with metastatic pancreatic ductal adenocarcinoma who received FOLFIRINOX and modified FOLFIRINOX in the first line.
Authors: Dennen Syvart , Boppudi Naga Sai Sriteja , Cockrum Paul , Paluri Ravi Kumar
Published: January 2024

629

Background: FOLFIRINOX (FFX) is a recommended first line (1L) treatment option for patients (pts) with mPDAC but is known for its high toxicity. Efforts to balance pts’ quality of life (QoL) during treatment with treatment effectiveness have led to the use of modified FOLFIRNOX (mFFX) regimens that employ decreased doses of FFX components. Further evidence is needed to assess OS and progression-free survival (PFS) among pts who receive FFX or mFFX treatment in the real world compared to the trial setting. We identified a real-world (RW) sample of pts with mPDAC treated with FFX and mFFX in 1L and assessed their OS, and, as a RW proxy for PFS, TTNT. Methods: This retrospective observational study utilized the Flatiron Metastatic Pancreatic Cancer Enhanced Data Mart. Adult pts diagnosed with mPDAC between January 2014 and May 2022 who initiated treatment with FFX or mFFX in 1L within 90 days of their diagnosis for metastatic disease were included in the study. mFFX was defined as administration of <150mg/m2 of irinotecan or <2,720mg/m2 5-FU total (bolus+infusion) during cycle 1; doses greater than these were considered FFX. TTNT was defined as duration between 1L treatment initiation and the start of second line therapy or death. Kaplan-Meier analyses were used to assess median OS and TTNT from the start of 1L FFX or mFFX treatment and log-rank tests for the statistical significance of differences in OS and TTNT. Results: 2,212 mPDAC pts met the study inclusion criteria, with 507 pts (23%) receiving FFX and 1,705 pts (77%) receiving mFFX in 1L. For FFX vs. mFFX, the median age at 1L initiation was 63yr vs. 65yr, 72% vs. 56% were male, 67% vs. 63% were white, 36% vs. 30% had an ECOG score of 0, 31% vs. 32% had an ECOG score of 1, and 83% vs. 81% received treatment at community oncology centers. For FFX vs. mFFX, median OS was 9.5 (95% CI: 8.9–10.7) vs. 9.0 months (95% CI: 8.4–9.7) (p=.452) and median TTNT was 4.8 (95% CI: 4.5–5.5) vs. 4.8 months (95% CI: 4.5–5.2) (p=.256). Conclusions: In a RW sample of 2,212 pts receiving 1L FFX and mFFX at primarily community oncology practices in the United States from 2014–2022, more than three-quarters received mFFX. Pts experienced similar median OS and TTNT across the two regimens, indicating that full-strength FFX may provide little benefit to OS in exchange for its increased toxicity. In the PRODIGE 4/ACCORD 11 trial of unmodified FFX, conducted earlier (2005–2009) among a group of 342 French pts, median OS was 11.1 months (95% CI: 9.0–13.1) and median PFS was 6.4 months (95% CI: 5.5–7.2). The median RW OS of FFX and mFFX pts in our study was numerically lower than the trial, as was RW TTNT compared with trial PFS. Future research should seek to understand the factors driving differences in RW and clinical trial outcomes as well as to assess the tradeoff between regimen toxicity and survival benefit.
Retrospective analysis of the real-world demographics, clinical characteristics, and treatment patterns in metastatic CRC among patients treated with encorafenib in combination with cetuximab in the United States.
Authors: Parikh Aparna Raj , Vieira Maria Cecilia , Silver Michelle , Rava Andrew , Rau Reina , Li Benjamin
Published: January 2024

63

Background: The presence of BRAF V600E mutations (BRAF-m) occurs in approximately 7% of patients with metastatic CRC (mCRC). Encorafenib (enco) plus cetuximab (cetux) were approved in April 2020 as the first targeted therapy for the treatment of adult patients with BRAF-m mCRC. The purpose of this study is to assess the demographics, clinical characteristics, and treatment patterns in BRAF-m mCRC among patients treated with enco, based on a claims database in the US. Methods: This was a retrospective cohort study in the IQVIA PharMetrics Plus claims database. Adults ≥18 years old with ≥1 claim for enco (first claim for enco on/after 4/1/2020) with concurrent cetux, as approved, or with EGFR panitumumab (pani), ≥2 ICD-9/10 codes for malignancy of the colon or rectum ≥30 days apart in the 1 year before index date, and ≥1 day of pharmacy and medical continuous enrollment during the index date were included. Patients were excluded if they had a record of melanoma or non-small cell lung cancer during the year before index date, were enrolled in a clinical trial any time after the CRC diagnosis date or did not have a treatment regimen starting on or after CRC diagnosis date. Index date was the date of first treatment of enco+EGFR during the identification period (4/1/2020-3/31/2022). Patient demographics and disease characteristics were assessed at baseline, and treatment patterns were evaluated during the pre-index and follow-up periods. Results: 125 patients were included. Median (Q1 [1st quartile], Q3 [3rd quartile]) age at index was 58 (49, 63) years; 52.0% were female; 47.2% residents in the South, 26.4% in the Midwest, 14.4% in the East and 12.0% in the West. In terms of healthcare coverage, 64.0% were under commercial, 27.2% self-insured and 8.8% under Medicare plans. Most patients (60.8%) at the start of enco had metastases in 3 or more sites, predominantly in the liver (76.8%), lymph nodes (50.4%), and lung (43.2%). The 2011 Modified Quan Charlson Comorbidity Index was 0 for 44.8% of the patients, 1-2 for 39.2%, and 3 or more for 16.0%. Mean (SD [standard deviation]) number of pre-index treatment regimens was 0.87 (0.73). Among the enco patients who had a previous treatment computed in claims, FOLFOX +/- bevacizumab (beva) and FOLFIRI + beva were the most common. Among the ones who had a subsequent treatment computed in claims, FOLFIRI +/- beva was the most common. Conclusions: This study provides current RW demographics, disease characteristics and treatment patterns among BRAF mCRC patients treated with enco in the US.