tbuckley/cabot-search huggingface dataset:
Pulsed low dose rate radiation to mitigate tumor-permissive responses in pancreatic cancer-associated fibroblasts: Introducing the HOST-factor.
Authors: Edna Cukierman, Janusz Franco-Barraza, Tiffany Luong, Kristopher Raghavan, Jessica Karen Wong, Debora Barbosa Vendramini Costa, Ralph Francescone, Jaye C. Gardiner, Sanjay S. Reddy, Elizabeth A. Handorf, Joshua E. Meyer
Journal: Journal of Clinical Oncology (2024)

682 Background: Pancreatic ductal adenocarcinoma (PDAC) features a distinctive tumor microenvironment comprising cancer-associated fibroblasts (CAFs) and their self-produced extracellular matrix (ECM), forming functional CAF units (CAF u). The current total neoadjuvant therapy (TNT), involving conventional chemoradiotherapy (CRT), yields suboptimal responses while promoting a tumor-permissive CAF u state. To address this, we explored pulsed low dose rate radiation (PLDR)-based TNT, as an alternative to CRT, to treat three-dimensional in vivo-like human PDAC CAF u cultures. We assessed gemcitabine combined with PLDR versus CRT using theHOST Factor, a “harmonized output of stroma traits” factor, comprising several established CAF u functional indicators, which inform on the functional status of the PDAC microenvironment. Methods: The unique CAF u functional values used corresponded to: i) ECM anisotropy; ii) persistent cell-ECM signaling; iii) sustained cytokine-induced activation; iv) cytoskeletal bundling; and v) systemic features of fibroblastic activation. The validity of the resultant HOST factor was assessed using the unit’s ECM ability to elicit fibroblastic activation, indicated by a high αSMA/F-actin ratio value. Results: Ex-vivo CRT led to a HOST factor that was 2-fold greater than chemotherapy alone (p=0.6), which was functionally gauged as a tumor-permissive CAF u. In contrast, PLDR averted CRT-induced tumor-permissive response and established a 6-fold lower HOST factor, suggestive of a “normalized” CAF u, when compared to the HOST factor value established when using conventional TNT (P=0.0016 vs. CRT, and P= 0.0086 vs. gemcitabine alone). The multi-parameter HOST factor validity was confirmed as CRT treated CAF u’s ECM activated human pancreatic fibroblasts (αSMA/F-actin = 70% ± 29) while PLDR-treated CAF u's ECM failed to do so (αSMA/F-actin = 32% ± 26), reaching a 30% mean rank difference (P &lt;0.0001). Conclusions: PLDR mitigates conventional CRT-based TNT-induced tumor-permissive responses, restoring the fibroblastic units' tumor-suppressive function. These results lend support to a phase 1 trial designed to evaluate whether radiation with PLDR-based TNT, constitutes a safe and more effective treatment for PDAC patients. The novel HOST factor is being used to appraise specimens from NCT04452357.
Molecular profiling of hepatoid adenocarcinoma and adenocarcinoma with enteroblastic differentiation.
Authors: Yosuke Matsumoto, Keiichi Hatakeyama, Masanori Terashima, Wataru Soneda, Yusuke Koseki, Furukawa Kenichiro, Keiichi Fujiya, Yutaka Tanizawa, Shimoda Tadakazu, Takashi Sugino, Etsuro Bando
Journal: Journal of Clinical Oncology (2024)

394 Background: Hepatoid adenocarcinoma (HAD) and adenocarcinoma with enteroblastic differentiation (ACED) are rare types of gastric cancer that produce alpha-fetoprotein (AFP) and morphologically resemble liver or fetal gut cells. The molecular characteristics of these tumors are poorly understood. We aimed to investigate the molecular profile of HAD and ACED in the comparison with common type of gastric cancer. Methods: We analyzed tissue and blood samples from 496 patients who underwent gastrectomy for gastric cancer and participated in the Project HOPE (High-tech Omics-based Patient Evaluation) in our hospital, from 2014 to 2019. We excluded patients with other special types of gastric cancer, remnant gastric cancer and preoperative chemotherapy. We analyzed gene mutation, copy number, and gene expression between 10 HAD/ACED and 486 common types of gastric cancers. Results: The mutated genes with high frequency (&gt; 20%) in HAD/ACED were TP53 (100%) CSMD3 (30%), LRP1B, FAT3, TG, APOB, CREBBP, PASK, DROSHA and STK40 (20%). The tumor mutation burden (TMB) of all the cases were less than 10. TMB of HAD/ACED was equivalent to that of common type of gastric cancer with microsatellite stable type. The copy number of 20q13.2 encoding SALL4 was significantly gained in HAD/ACED ( p = 0.03). Furthermore, 17 genes were highly expressed in these tumors, and many of these genes were associated with hepatocytes and fetal organs, including LIN28B, IGF2BP1, and HMGA2, which are related to TP53 mutation. Conclusions: Our molecular profiling revealed similarities between HAD/ACED and hepatocytes/fetal organs and high expression of LIN28B, IGF2BP1 and HMGA2, which are associated with TP53 inactivation. These results suggest that these genes may define morphological features of HAD/ACED.
Kinetics of CA19-9 decline in a randomized phase III study of irinotecan liposome injection, oxaliplatin, 5-fluorouracial/leucovorin (NALIRIFOX) or nab-paclitaxel plus gemcitabine (GEM+NABP) in patients who have not previously received chemotherapy for metastatic adenocarcinoma of the pancreas (NAPOLI 3).
Authors: Sreenivasa R Chandana, Zev A. Wainberg, Davide Melisi, Teresa Macarulla, Roberto A. Pazo Cid, Christelle De La Fouchardiere, Andrew Peter Dean, Igor Kiss, Woo Jin Lee, Thorsten Goetze, Eric Van Cutsem, Andrew Scott Paulson, Tanios S. Bekaii-Saab, Shubham Pant, Richard Hubner, Zhimin Xiao, Jia Li, Fawzi Benzaghou, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2024)

687 Background: The NAPOLI 3 study (NCT04083235, N = 770) reported that NALIRIFOX improved overall survival (OS) vs Gem+NabP with manageable toxicity in 1L treatment of metastatic pancreatic adenocarcinoma. We explored changes in CA19-9 levels and their potential associations with efficacy as an important tumor marker in pancreatic adenocarcinoma. Methods: In NAPOLI 3, CA19-9 was evaluated at baseline and every 8 weeks until patients discontinued study treatment. The detection limit of CA19-9 was 8000 kU/L in this study. The Cox proportional hazards regression and logistic regression were employed to investigate the relationship between CA19-9 decrease and OS, progression-free survival (PFS), and overall response rate (ORR). Results: Patients with evaluable CA19-9 (levels =&lt; 8000) at baseline and additional measurements at weeks 8 and 16 were included in the analysis (NALIRIFOX, n = 179; Gem+NabP, n = 194). The median baseline CA19-9 level was 378.0 and 409.7 kU/L for the NALIRIFOX and Gem+NabP arms, respectively. Overall, patients with (vs without) any CA 19-9 decrease by week 16 had a higher ORR (59.9% vs 35.2%; p = 0.002), a longer median PFS (9.2 vs 6.2 months; p &lt; 0.001) and a longer median OS (14.2 vs 8.7 months; p = 0.005), respectively in a pooled analysis of the treatments. In the NALIRIFOX arm, patients with any CA19-9 decrease by week 16 had a higher confirmed ORR of 65.1% compared with those without at 42.4% ( p &lt; 0.001), a median PFS of 9.5 vs 7.1 months ( p &lt; 0.001) and a median OS of 15.4 versus 8.4 months ( p = 0.004), respectively. In the Gem+NabP arm, patients with CA19-9 decrease by week 16 had a higher ORR of 55.5% compared with those without at 23.8% ( p = 0.012), a median PFS of 7.6 versus 5.8 months ( p &lt; 0.001) and a median OS of 13.7 versus 11.9 months ( p = 0.235), respectively. Conclusions: CA19-9 decrease by week 16 has the potential to be an early prognostic factor for OS, PFS and ORR. The results should be interpreted with caution as a considerable percentage of patients were excluded due to non-evaluable CA19-9 that exceeded the lab detection limit of 8000 kU/L. Clinical trial information: NCT04083235 .
Prognostic impact of ectopic fat deposition within psoas muscle in patients undergoing systemic chemotherapy for stage IV gastric cancer.
Authors: Takako Ikegami, Toshifumi Yamaguchi, Hiroki Yukami, Toru Kadono, Dai Okemoto, Shin Kameishi, Masahiro Goto, Hiroki Nishikawa
Journal: Journal of Clinical Oncology (2024)

285 Background: Sarcopenia is a progressive condition characterized by loss of skeletal muscle mass, muscle strength, and physical function, and is identified as an important prognostic factor in malignant tumors. The patients of gastrointestinal (GI) malignancies are often poor nutrition, weight loss, and loss of skeletal muscle mass due to pathophysiology such as the dysfunction of nutritional absorption and GI obstruction. The prevalence of sarcopenia is high in GI malignancies, especially in advanced gastric cancer (GC), which is reported to be 30%. Recently, in assessing sarcopenia, muscle quality as well as skeletal muscle mass has been considered important and some studies suggest that intramuscular adipose tissue is useful in assessing muscle quality. In this study, we focused on the fat ratio within psoas muscle (FRPM) and sought to clarify the impact of FRPM on overall survival (OS) in GC patients undergoing systemic chemotherapy. Methods: We retrospectively analyzed the patients with histologically confirmed stage IV GC receiving at least one systemic chemotherapy between February 2017 and March 2021 in our hospital. We measured PMI (Psoas Muscle Index: bilateral muscle mass (cm 2 )/height squared(m 2 )) and FRPM both at the lumber three level on the CT images before chemotherapy. PMI and FRPM values were classified into two groups, High and Low, according to whether they were higher or lower than the median, and differences in OS were analyzed for each group. Results: The analysis included 79patients (median age: 69 years, 59 males). The median FRPM was 1.67%. The FRPM-high group and the FRPM-low group were 40/39patients, respectively. The median PMI in male and female patients was 4.35 cm 2 /m 2 and 2.88 cm 2 /m 2 . Thirty male patients and ten female patients were defined as the PMI-high group, and the remaining 39 patients were in the PMI-low group. The 1, 2 and 3year cumulative OS rate in patients with FRPM-high and FRPM-low was 67.3%, 14.3% and 7.6% in the FRPM-high group and 74.8%, 40.5% and 32.4% in the FRPM-low group ( P = 0.0341). The 1, 2 and 3year cumulative OS rate in patients with PMI-high and PMI-low was 86.7%, 40.4% and 30.0% in the PMI-high group and 55.8%, 12.8% and 6.4% in the PMI-low group ( P &lt; 0.0001). In the multivariate analysis of factors associated with OS, PMI ( P = 0.0047) and FRPM ( P = 0.0019) were independent predictors for the OS. Conclusions: High-FRPM may be associated with declined physical activity, suggesting that skeletal muscle function may be an important prognostic factor in patients with GC receiving systemic chemotherapy.
A phase 1b/2 trial of pepinemab and avelumab as second line therapy for patients with metastatic pancreatic adenocarcinoma.
Authors: Bailey Hilty, Luis I. Ruffolo, Brian A. Belt, Matthew Byrne, Yatee A. Dave, Paul R. Burchard, Terrence Lee Fisher, Elizabeth E. Evans, Crystal L. Mallow, Megan Boise, Maurice Zauderer, Daniel Mulkerin, Jen Jen Yeh, David Linehan
Journal: Journal of Clinical Oncology (2024)

TPS712 Background: Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related mortality with poor prognosis despite maximal therapy and is unresponsive to immune checkpoint blockade (ICB). This failure of response is hypothesized to be driven in part by the characteristic immunosuppressive tumor microenvironment. In PDAC, Semaphorin 4D (SEMA4D) expression is prognostic in patients who have undergone surgical resection and correlates with tumor infiltration of activated CD8+ T-cells. Additionally, preclinical models suggest that antibody-mediated SEMA4D blockade promotes tumoral infiltration and activation of CD8+ T-cells and sensitizes PDAC to ICB, with improved overall survival with standard of care chemotherapy and ICB in combination with pepinemab (humanized anti-SEMA4D). Thus, we hypothesized that pepinemab may improve clinical outcomes in PDAC by sensitizing tumors to ICB. Methods: We designed a phase Ib/II single-arm clinical trial to evaluate the safety, tolerability, and efficacy of humanized anti-SEMA4D (pepinemab) with anti-PD-L1 (avelumab) in patients with chemotherapy-refractory PDAC. Patients must have failed first-line 5-fluorouracil or gemcitabine-based combination chemotherapy. The study follows a dose de-escalation schema starting at a dose combination of 20mg/kg pepinemab and 800mg avelumab every two weeks. Patient accrual for phase 1b utilizes the Bayesian Optimal Interval Design (BOIN) targeting a dose-limiting toxicity rate of 30% or less. After 16 subjects receive a given combination dose, a Simon’s two stage assessment of futility will be undertaken with expansion to phase 2 if 2 or more subjects demonstrate response. The trial is designed to evaluate a total cohort of 40 subjects and powered to detect a response rate of 23% or greater, with alpha set at 0.1% and 80% power. Treatment response is assessed via RECIST 1.1 criteria with surveillance CT prior to enrollment and after completion of two cycles (8 weeks). Baseline and on-treatment tumor biopsies (after completion of one cycle, 4 weeks) are performed to analyze changes in immune, stromal, and genomic profiles to elucidate mechanisms of treatment response and failure. Patient reported outcomes are incorporated (FACT-Hep and FAACT subdomains) to assess disease-specific symptoms. To date, 7 patients have been enrolled (Clinical Trial NCT05102721). Clinical trial information: NCT05102721 .
Abemaciclib in patients (pts) with esophageal cancer (EC) with <i>CDKN2A</i> loss or mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Tareq Al Baghdadi, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Kathleen J Yost, Vi Kien Chiu, Herbert Leon Duvivier, Meredith McKean, Jens Rueter, Mark A. Taylor, Gina N. Grantham, Abby Gregory, Dominique C. Hinshaw, Susan Halabi, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2024)

308 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with EC with CDKN2A loss or mut treated with abemaciclib are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 200 mg (four 50 mg tablets) of abemaciclib twice daily for a total daily dose of 400 mg until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete or partial (PR) response per RECIST v. 1.1, or stable disease of at least 16 weeks (wks) duration (SD16+). Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled; otherwise, the cohort is closed. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. DOR is defined as time from pt’s first documented OR to progressive disease. Results: 10 pts with EC (8 adenocarcinoma, 2 squamous) and CDKN2A loss (n=5) or CDKN2A mut (n=5) were enrolled from Dec 2019 to June 2022. 6 pts had HER2 negative EC, 1 pt had HER2 low EC, 1 pt had HER2 positive EC, and 2 pts were not tested for HER2. All pts were evaluable for efficacy and toxicity. Table summarizes pt demographics and outcomes. 1 pt with CDKN2A loss had a 27-wk PR for a DC rate of 10% (1-sided 90% CI, 1% to 100%) and OR rate of 10% (95% CI, &lt;1% to 45%). The null DC rate was not rejected (p=0.80). Median PFS was 8 wks (95% CI, 2 to 13) and median OS was 17 wks (95% CI, 9 to 35). The pt with PR had HER2 negative adenocarcinoma, ECOG PS of 1 and 2 prior lines of therapy. 4 pts had 12 serious adverse events at least possibly related to tx, including anemia, atrial fibrillation, increased creatinine, dehydration, dyspnea, generalized muscle weakness, heart failure, lung infection, pericardial effusion and thrombocytopenia. 4 pts had a drug-related grade 3 AEs including anemia, increased bilirubin and thrombocytopenia. Conclusions: Abemaciclib monotherapy did not demonstrate sufficient clinical activity in pts with advanced EC with CDKN2A loss or mut for continued evaluation in this pt population. Other tx should be considered for these pts, including tx offered in clinical trials. Clinical trial information: NCT02693535 . [Table: see text]
A phase 1b study of the OxPhos inhibitor ME-344 in combination with bevacizumab in refractory metastatic colorectal cancer.
Authors: Patrick M Boland, Heinz-Josef Lenz, Mike Cusnir, Vaia Florou, Michael J. Pishvaian, Deirdre J. Cohen, Kristen Keon Ciombor, Arthur Winer, Jessie Yanxiang Guo, Sandra Algaze, Sandra E Wiley, Richard Ghalie, Howard S. Hochster
Journal: Journal of Clinical Oncology (2024)

TPS222 Background: ME-344 is a synthetic small molecule that inhibits oxidative phosphorylation, resulting in energy starvation and cell death via caspase-dependent and -independent mechanisms. The activity of mitochondrial inhibitors is enhanced when mitochondrial respiration is upregulated, a situation achieved in solid tumors by inducing vascular normalization and hypoxia correction with antiangiogenics. In a CT26 colon carcinoma syngeneic murine model, ME-344 in combination with regorafenib showed significantly reduced tumor growth compared to regorafenib alone (Navarro et al. Cell Reports. 2016;15:2705). A randomized phase 0/1 window of opportunity study in HER2-negative breast cancer showed significant decrease in the proliferation marker Ki67 in patients administered ME-344 plus bevacizumab vs. bevacizumab alone (Quintela-Fandino et al, Clin Cancer Res. 2020;26:35). The current study evaluates the safety and efficacy of ME-344 in combination with bevacizumab in refractory metastatic colorectal cancer, a clinical setting where continued antiangiogenic inhibition has established benefit. Prior phase 1-1b studies of ME-344 as a single agent and in combination have established the RP2D at 10 mg/kg when administered intravenously weekly. Methods: This is an open-label phase 1b study in patients ≥18 years old with metastatic colorectal cancer after failure of standard therapies, including fluoropyrimidine-, irinotecan-, and oxaliplatin-based regimens, anti-EGFR if RAS wild-type, PD/L-1-blocking antibody if MSI-H/dMMR, and BRAF-targeted therapy if BRAF V600E mutated. Other key eligibility criteria include measurable disease, ECOG performance status 0-1, adequate bone marrow, liver and renal function, no uncontrolled brain metastatic disease, no peripheral neuropathy grade ≥2, no uncontrolled hypertension or diabetes, and no increased hemorrhagic risk. Enrollment will proceed in 2 cohorts of 20 patients each. Cohort 1 will be administered ME-344 at 10 mg/kg on days 1, 8, and 15 of a 28-day cycle and bevacizumab 5 mg/kg on days 1 and 15. Cohort 2 will be administered ME-344 at 10 mg/kg and bevacizumab 5 mg/kg both on days 1 and 15 of a 28-day cycle. Treatment will continue until disease progression or intolerance. Tumor assessment is performed every 8 weeks for 6 months and then every 3 months using RECIST-1 criteria. The primary endpoint is 16-week PFS. Secondary endpoints are PFS, response rate, and safety. Correlative analysis will evaluate treatment-related metabolic response. The study is actively enrolling, funded by MEI Pharma, and registered under NCT02100007. Clinical trial information: NCT02100007 .
Gastrointestinal cancer trends in the Hispanic population: A SEER database population study (2000-2019).
Authors: Sharon Hechter, Ivan Nikiforov, David B. Greenberg
Journal: Journal of Clinical Oncology (2024)

725 Background: Cancer continues to be the leading cause of death in the Hispanic population. Gastrointestinal cancer surveillance data in Hispanic individuals has only recently become available in the last 3 decades. Differences in incidence rates among Hispanics and Non-Hispanic Whites (NHWs) need further elucidation. In this study, we analyzed trends in Hispanics and NHW populations across multiple gastrointestinal cancers. Methods: Gastrointestinal cancers (liver, colon and rectum, pancreas, esophagus, gallbladder, stomach, small intestine, anus, anal canal and anorectum) diagnosed between 2000-2019 were identified in the Surveillance, Epidemiology, and End Results Program (SEER) Database. We calculated incidence rates, confidence intervals and incidence rate ratios. Rates are per 100,000 and age adjusted to the 2000 US standard population. Rate ratios are the rounded rates in Hispanic individuals divided by the rounded rates in NHWs. Results: There was a higher incidence of liver, gallbladder, and stomach cancers among Hispanics when compared to NHWs between the years 2000-2019. Liver cancer incidence rate is (11.5 per 100,000) in Hispanics compared with (6.3 per 100, 000) in NHWs with an incidence rate ratio of 1.8. Gallbladder cancer incidence rate is (2.2 per 100,000) in Hispanics compared with (0.9 per 100,000) in NHWs with an incidence rate ratio of 2.4. Stomach cancer is (10.9 per 100,000) in Hispanics compared with (5.7 per 100,000) in NHWs with an incidence rate ratio of 1.9. The lowest incidence rate ratio was seen for anus, anal canal and anorectum cancers in Hispanics compared to NHWs. The incidence rate is (1.2 per 100,000) in Hispanics compared with (2.1 per 100,000) in NHWs with an incidence rate ratio of 0.6. Remaining cancers had incidence rate ratios less than 1.0 and were more likely to occur in NHWs. Conclusions: This study illustrates differing incidence rates of multiple gastrointestinal cancers among Hispanics compared to NHWs. Liver, gallbladder and stomach cancer incidence rates in Hispanics is double that of NHWs. Interestingly, the remaining gastrointestinal cancers had higher incidence rates among NHWs. Further research is warranted to understand the differences in cancer risk within the Hispanic population as well as healthcare access, language barriers and cultural differences that may play a role.[Table: see text]