tbuckley/cabot-search huggingface dataset:
Extracellular (EC) Mucin5AC (MUC5AC) detection after neoadjuvant therapy (NAT) and the risk of recurrence in resected pancreatic ductal adenocarcinoma (R-PDA).
Authors: Ashish Manne, Ashwini K. Esnakula, Ankur Sheel, Amir Sara, Kai He, Jordan M. Cloyd, Anne M. Noonan, John L. Hays, Sameek Roychowdhury, Arjun Mittra, Pannaga G. Malalur, Ning Jin, Shafia Rahman, Susan Tsai, Mary Dillhoff, Wancai Yang, Lianbo Yu
Journal: Journal of Clinical Oncology (2024)

4171 Background: The clinical significance of MUC5AC glycoforms is unclear to date. Our earlier study showed the association of lower mature (MM) and immature (IM) MUC5AC in R-PDA with pathological treatment response and EC detection of MM (EC-MM). Here, we have the significance of EC-MM detection in the tissue of R-PDA post-NAT. Methods: Formalin-fixed paraffin-embedded tissue blocks of R-PDA from January 2010 to June 2021 were obtained from the Ohio State University biorepository. Using monoclonal antibodies for 45M1 (MM) and CLH2 (IM), immunohistochemistry was performed to study the cellular expression of MM and IM, and H-scores were calculated. Also, the presence or absence of EC expression of MM is noted. progression-free survival (PFS) and overall survival (OS) were the primary endpoints. Univariate and multivariate Cox regression models were used to model PFS and OS, and clinical and pathological variables were adjusted in the multivariate models. We performed univariate logistic regression analysis to examine the impact of MUC5AC expression on pathological features in resected specimens. Results: Among 100 R-PDA patients, 43 received NAT and 57 had upfront surgery (UpS)). In NAT-group (36-FOLFIRINOX, 2-FOLFOX, and 5-gemcitabine/nab-paclitaxel), EC-MM detection in the resected specimens was associated with worse PFS on multivariate analysis (MVA) (Hazard Ratio (HR) 0.2, 95 % CI: 0.059-0.766, p = 0.01). In the FOLFIRINOX-treated group, the EC-MM detection had a similar impact (HR 0.2, 95 % CI: 0.052-0.847, p = 0.02) on PFS. Cellular MM and IM expression were significant (p &lt; 0.05) on MVA for OS in both groups, but the HRs were not clinically significant (NAT-group, MM - 0.9 &amp; IM - 1.04, FOLFIRNIOX-group, MM - 0.8 &amp; IM -1.02). Expression levels of cellular MM and IM in FOLFIRINOX group and MM alone in NAT-group significantly (p &lt; 0.05) correlated with incomplete resection (R1/R2 vs R0) and perineural invasion. In the UpS group, MUC5AC glycoforms did not significantly correlate with survival or pathological features. Conclusions: Post NAT EC-MM detection and cellular MUC5AC (MM and IM) expression levels are associated with worse PFS and pathological features. Their role in the treatment of naïve patients is still unclear. MUC5AC can be a clinically useful predictive biomarker. Future research should focus examining its importance in advanced tumors and manipulating it for therapeutic purposes.
Durvalumab and stereotactic ablative body radiotherapy (SABR) in locally advanced (LA) and borderline resectable (BR) pancreatic cancer (PDAC): Long-term outcomes and correlative insights.
Authors: Fergus Keane, Richard Tuli, Catherine A O'Connor, Carly Schwartz, Wungki Park, Anna M. Varghese, Maria Perry, Anupriya Singhal, Santosha Vardhana, Andrew Eugene Hendifar, Zeynep Tarcan, Olca Basturk, Raymond S. McDermott, Marsha Reyngold, Christopher H. Crane, Eileen M. O'Reilly, Joshua David Schoenfeld
Journal: Journal of Clinical Oncology (2024)

4174 Background: Immune checkpoint blockade (ICB) has limited activity in genomically unselected patients (pts) with PDAC. While anti-tumor activity with combination SABR/ICB has been shown, biomarkers of response are poorly defined. We conducted a phase 1/2 study of PD-L1 inhibitor Durvalumab (D) and SABR after induction chemotherapy in LA and BR PDAC (NCT03245541). We report long-term outcomes and correlative biospecimen analyses. Methods: A multi-institutional, single arm phase 1/2 trial was conducted at Cedars-Sinai and Memorial Sloan Kettering. Initial clinical data reported by Tuli et al, ASCO 2023. Pre-treatment tissue assessed for p40 and GATA3 to determine classical vs basal subtype by immunohistochemistry. Tissue interrogated by immunofluorescence for PD-L1 expression and infiltration of immune cell subsets. Multiparametric immunophenotyping of peripheral blood mononuclear cells (PBMCs) by flow cytometry conducted on baseline and on treatment samples. Wilcoxon rank sum test used to determine difference in biomarkers from each timepoint; p-value &lt;0.05 significant. Results: N= 36 enrolled from 08/2017-05/2022; N=31(86%) LA, N=5 (14%) BR. N= 9 (25%) underwent resection; all R0. At median follow up 36.5 months, 6- and 12-month PFS 69%, 36%. Median PFS 8.7m (95% CI 6.1-14), median OS 16m (95% CI 13-26). N=2 (6%) alive without disease progression. Correlative analyses summarized (table). Key findings; Classical/basal subtyping feasible on N=9 (8 classical, 1 basal). Median PD-L1 score not associated with survival. Peri-tumoral, but not intratumoral CD8+ cells associated with PFS &gt;6 months. Flow cytometry feasible for 70 samples from N=35. Frequency of pre-treatment non-naïve CD4 + FoxP3 + T reg associated with PFS &gt;12. CD103 + CD8 + T Cells significantly expanded on treatment only in patients with PFS&gt;12m (p=0.038) and were significantly enriched relative to PFS&lt;12m on treatment. Conclusions: A proportion of pts with LA PDAC achieve durable control with D and SABR after induction chemotherapy. Baseline peri-tumoral CD8 + cells and peripheral CD103 + CD8 T cells and CD4 + T reg in PBMCs at baseline and on treatment may predict for benefit. Further analyses ongoing and validation in larger cohorts is warranted. Clinical trial information: NCT03245541 . [Table: see text]
Comparing toripalimab combined with chemoradiotherapy versus chemoradiotherapy alone for locally advanced esophageal squamous cell carcinoma: A multicenter, open-label, randomized phase II clinical trial.
Authors: Yujin Xu, Qi Cheng, Yu Wang, Weiguo Zhu, Jing Huang, Dexi Du, Zhifeng Tian, Haihua Yang, Chao Zhou, Suna Zhou, Xiaojiang Sun, Yuezhen Wang, Jin Wang, Zhun Wang, Xiao Hu, Ming Chen
Journal: Journal of Clinical Oncology (2024)

4079 Background: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype in Asia, representing approximately 90% of all esophageal cancer cases. Despite definitive chemoradiotherapy (CRT) being the standard treatment for unresectable locally advanced ESCC, the prognosis remains poor. The introduction of PD-1 inhibitors has shown significant improvement in survival outcomes for advanced ESCC. This study aims to evaluate the efficacy and safety of combining induction and consolidation toripalimab (a PD-1 inhibitor) with CRT in patients with locally advanced ESCC (Clinical trial information: NCT04084158). Methods: Patients aged 18-75 years with unresectable, locally advanced ESCC and an ECOG performance status of 0-1 were eligible. Participants were randomly assigned (1:1) to either two cycles of toripalimab (3mg/kg q2ws) followed by concurrent CRT with 50.4Gy+weekly paclitaxel and carboplatin (TC), TC consolidation, and toripalimab (study arm), or standard CRT alone (control arm). The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS) and objective response rate (ORR). Results: Between September 2019 and July 2020, 46 ESCC patients (40 males) were screened for eligibility across four participating centers in China. Forty-four patients were eligible for survival analysis, all with histopathologically confirmed ESCC. Median ages were 64 years (range 49-75) in the study arm and 61 years (range 47-74) in the control arm, with similar clinical AJCC stages. As of the February 1, 2024 cutoff, the median follow-up was 50.6 months. Median PFS was 10.0 months in the study arm and 17.8 months in the control arm (HR: 1.567, 95% CI: 0.755-3.251, p=0.228). Median OS was 23.7 months and 25.9 months, respectively (HR: 1.140, 95% CI: 0.536-2.427, p=0.733). ORR rates were 64% and 86% (p=0.164), respectively. The incidence of grade 3 or worse treatment-related adverse events was similar between groups, with the most common adverse event being lymphopenia. Conclusions: Our findings indicate no significant benefit in adding induction and consolidation immunotherapy to CRT for treating locally advanced ESCC. However, the combination of radiotherapy and immunotherapy warrants further exploration. Ongoing analyses of biomarker correlates of response and survival will provide additional insights. Clinical trial information: NCT04084158 .
Effect of ctDNA whole-exome sequencing in pancreatic adenocarcinoma on prognostic value, actionable alterations, and organ tropisms in metastatic disease.
Authors: Marisol Huerta, Jorge Martín-Arana, Francisco Gimeno-Valiente, Juan Antonio Carbonell-Asins, Blanca García-Micó, Belén Martínez-Castedo, Daniel G. Camblor, Tania Fleitas, Miguel García Bartolomé, Clara Alfaro-Cervello, Marina Garcés-Albir, Dimitri Dorcaratto, Elena Muñoz-Forner, Isabel Mora-Oliver, Valentina Gambardella, Susana Roselló-Keränen, Luis Sabater, Desamparados Roda, Andres Cervantes, Noelia Tarazona
Journal: Journal of Clinical Oncology (2024)

4149 Background: The dismal prognosis associated with pancreatic ductal adenocarcinoma (PDAC) needs a deeper understanding of progression mechanisms and personalized treatment. While the prognostic value of ctDNA has already been established, this study purposes to apply plasma whole-exome sequencing (WES) to identify molecular alterations beyond KRAS. This approach aims to predict survival, uncover progression mechanisms, and identify therapeutic targets. Methods: Eighty metastatic PDAC patients were prospectively recruited and divided into two consecutive cohorts: discovery (n=37) and validation (n=43). Tumor and plasma obtained at diagnosis were analyzed using WES. The variant allele frequency (VAF) of KRASmutations was quantified by ddPCR in plasma at baseline and at response from all patients (n=80). Results: Plasma WES identified at least one pathogenic variant across all individuals, which can be categorized into four pathways: oncogenic mechanisms, DNA repair, microsatellite instability and TGFb pathway alterations. 7 unique druggable mutations were detected in tissue and 11 in plasma. Other targetable mutations ( CDK12, NF1, BRCA2, and TSC2), were prevalent in plasma but absent in tissue. Patients with survival less than 11 months showed enrichment in cellular organization pathways and exclusive targetable CDK12 mutations. Longer survival cases exhibited exclusive mutations in DNA regulation and repair genes. Patients with liver metastasis displayed unique mutations not just in KRAS but also in the adaptive immune response pathway genes. Baseline plasma KRAS mutations detected by ddPCR was associated with worse progression-free survival. (HR=2.315, CI 95%= 1.027-5.217, p = 0.038; and HR= 3.022, CI 95% = 1.299 - 7.030, p= 0.007 in the discovery and validation cohort, respectively). A significant risk of progression (p = 0.006) was observed if KRAS VAF at response assessment did not decrease, at least, 84.75% in both cohorts. Conclusions: ctDNA WES unveils molecular signatures of rapid progression, potential actionable alterations, and liver metastasis-specific mutations in the adaptive immune response pathway. KRAS detection at baseline and its evolution during treatment emerge as prognostic biomarkers. [Table: see text]
Adjuvant mFOLFIRINOX (mFFX) for resected pancreatic cancer (PC): Long term clinical and genomic outcomes.
Authors: Fergus Keane, Drew Moss, Catherine A O'Connor, Maria Perry, Joanne F. Chou, Fionnuala Crowley, Parima Saxena, Amelia Chan, Wungki Park, Anna M. Varghese, Kenneth H. Yu, Marinela Capanu, T. Peter Kingham, Michael Ian D'Angelica, Vinod P. Balachandran, William R. Jarnagin, Alice C Wei, Kevin Soares, Fiyinfolu Balogun, Eileen M. O'Reilly
Journal: Journal of Clinical Oncology (2024)

4170 Background: Adjuvant chemotherapy with mFFX is the standard for pts with ECOG 0-1 (1) after pancreatectomy for resectable PC. Herein, we report long-term survival data on an expanded cohort and present comprehensive genomic analyses. Methods: Pts with resected PC who received &gt;1 dose of adjuvant mFFX identified from institutional databases. Primary endpoints: Recurrence Free Survival (mRFS) and Overall Survival (mOS) calculated from start of treatment until recurrence or death. Key secondary endpoints: clinical factors, genomic descriptors ( KRAS status, whole genome doubling (WGD), and homologous recombination deficiency (HRD)) associated with outcome. Kaplan-Meier method used to estimate RFS and OS. Univariate Cox proportional hazards model correlated clinico-genomic characteristics with RFS and OS. Results: N=147 identified between 01/2015-01/2022. Median age: 67 years; N= 22 (15%) &gt; 75 years. Several prognostically unfavorable groups; N=52 (36%) stage III disease/ N2 nodal status; N=115 (78%) lymphovascular invasion (LVI); N=133 (90%) perineural invasion (PNI). Median time from surgery to start mFFX: 1.78m (IQR; 1.45, 2.12). Median CA 19-9 at start mFFX: 21 (range 0-1,124). N=124 (84%) pts completed 12 doses mFFX (+/- 12 doses oxaliplatin). N=98 pts (67%) stopped oxaliplatin early for neuropathy. With the median follow up 35.1m (range 5.1, 73.0), mRFS 27m (95% CI 20, 39) and OS not reached (NR). For &gt;75 cohort, mRFS 12m (95% CI 9.6, NR) and mOS 30m (95% CI 19, NR). mFFX started &lt;8 weeks from resection associated with improved RFS (HR 0.62; 95% CI 0.41, 0.96; p= 0.033) and OS (HR 0.53; 95% CI 0.3, 0.94; p= 0.030). T3 tumors associated with worse RFS (HR 2.82, 95% CI 1.28, 6.20; p=0.010) and OS (HR 5.10, 95% CI 1.45, 18; p=0.011). Genomic variables summarized (Table). KRASmutation (+), WGD (+), and higher KRAS CNV trended to shorter RFS and OS; statistical significance limited by small subgroups. HRD status did not confer differences in OS. Conclusions: Adjuvant mFFX is an effective therapy and results in long-term OS outcome in resected PC in a non-trial setting, including for pts &gt;75 years. Early initiation of adjuvant mFFX may optimize outcome. Trends observed for improved outcome in select genomic subsets, which require large-scale validation. 1. Conroy, JAMA Onc, 2022. [Table: see text]
Primary prophylaxis with pegylated-granulocyte colony-stimulating factor for patients with unresectable pancreatic cancer treated with modified-FOLFIRINOX: A randomized phase II trial.
Authors: Choong-kun Lee, Il-Hwan Kim, Chang Gon Kim, Hye Jin Choi
Journal: Journal of Clinical Oncology (2024)

4145 Background: Pancreatic cancer patients treated with FOLFIRINOX often suffer from severe neutropenia leading to dose reductions and sometimes fatal outcomes. However, there is no high-level evidence for primary prophylaxis of peg-GCSF for those patients. We report the result of a multi-institutional, open-label, randomized phase II trial of the peg-GCSF for unresectable pancreatic cancer patients treated with first-line modified-FOLFIRINOX. Methods: Treatment-naïve patients with histologically confirmed locally advanced or metastatic pancreatic cancer from two Korean cancer centers were enrolled. Patients received oxaliplatin 85mg/m 2 D1 + leucovorin 400mg/m 2 D1 + irinotecan 150mg/m 2 D1 + 5-FU 2,400mg/m2 46h continuous infusion, every other week. After 1:1 randomization, peg-GCSF (pegteograstim 6 mg, GC Biopharma Corp.) was administered on day 4 for initial 8 cycles for primary prophylaxis group, where no G-CSF was given for control group. Crossover to administer peg-GCSF was permitted if patients in control group developed grade 3-4 neutropenia during initial 8 cycles. Co-primary endpoints were grade 3-4 neutropenia or febrile neutropenia during initial 8 cycles of mFOLFIRINOX. Secondary endpoints included relative dose intensity (RDI), patient reported quality of life, bone pain, and survival. Results: Between Feb 2022 and Jan 2024, 38 patients were randomized to peg-GCSF primary prophylaxis group and 39 patients were randomized to control group. Peg-GCSF group patients had significantly less grade 3-4 neutropenia during initial 8 cycles of mFOLFIRINOX, compared to the control (1/38, 2.6% vs 15/39, 38.5%, P=0.0001). None of peg-GCSF group patients experienced febrile neutropenia, where 5 patients (12.8%) experienced febrile neutropenia in control group. Cumulative RDIs of mFOLFIRINOX until progression or 8th cycles were similar between two groups with 93%. Although this trial was not powered for survival comparison, median PFS (9.0 vs 7.3 months) was numerically longer for peg-GCSF group compared to control. OS was not reached for both arms, but hazard ratio was 0.48 for peg-GCSF group. Conclusions: Primary prophylaxis with peg-GCSF significantly reduced grade 3-4 neutropenia and febrile neutropenia in patients with locally advanced or metastatic pancreatic cancer treated with mFOLFIRINOX events. Considering the study design of permitting the crossover, cumulative RDI was similar. Further follow-up of survival and quality of life results will be presented. Clinical trial information: KCT0006536 .
Conversion surgery for tislelizumab combined chemotherapy for T4a/N3 esophageal squamous cell carcinoma (ESCC): A prospective, single-arm, phase II study.
Authors: Chen Zhang, Xiaobin Shang, Jie Yue, Chuangui Chen, Xiaofeng Duan, Zhao Ma, Zuoyu Chen, Shangren Wang, Gang Zhao, Liang Liu, Weihong Zhang, Runmei Li, Yanjuan Xiong, Fan Yang, Jianyu Xiao, Fuliang Cao, Feng Guo, Dejun Zhou, Xiubao Ren, Hongjing Jiang
Journal: Journal of Clinical Oncology (2024)

4069 Background: T4a/N3 ESCC is treated with neoadjuvant concurrent chemoradiotherapy plus surgery or radical chemoradiotherapy according to NCCN guidelines. This study aimed to evaluate the safety and efficacy of conversion therapy of Tislelizumab combined with chemotherapy in patients with T4a/N3 ESCC. Methods: This is a prospective, single-arm, single-center clinical trial. A total of 40 patients with newly diagnosed ESCC (cT4a/N3) received 2-4 cycles of paclitaxel (135 mg/m 2 ) on day 1, and cisplatin (80 mg/m 2 ) on day 1, Tislelizumab (200 mg) on day 2, every 3 weeks. After an efficacy evaluation, the patients will undergo radical esophagectomy resection within 4-6 weeks after conversion therapy. The primary endpoints are the safety and the R0 resection rate. The secondary endpoints include the objective response rate (ORR), a postoperative pathological complete response (pCR), major pathological response (MPR), overall survival (OS), disease-free survival (DFS). Exploratory endpoint is to examine immune biomarker of the efficacy of conversion therapy for ESCC. Results: 40 patients were enrolled, the ORR was 95%(38/40), and 60% (24/40) patients who completed conversion treatment underwent esophagectomy. R0 resection rate was 100% (24/24) with no reoperations or perioperative deaths. 70% (28/40) patients experienced at least one treatment-related adverse event (TRAE) and 12.5% (5/40) patients reported grade 3 and above TRAEs. For these surgical patients, the MPR and pCR rates were 33% (8/24) and 20.8% (5/24) respectively. Flow cytometry showed that the percentage of CD3 + CD4 + CD8 - T cells was significantly increased in peripheral blood after conversion therapy (p-value 0.02). Conclusions: Tislelizumab combined with chemotherapy, followed by radical esophagectomy resection has promising efficacy and good safety for T4a/N3 ESCC. Clinical trial information: NCT05449483 .
The function of KRAS4B isoform in pancreatic cancer.
Authors: Kexin Wang, Laura Beltran Sangüesa, Daniela Kalla, Theresa Pauli, Angelika Schnieke, Tatiana Flisikowska, Krzysztof Flisikowski
Journal: Journal of Clinical Oncology (2024)

4147 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a significant challenge in the field of oncology, demanding the creation of models that faithfully replicate the human condition to aid in early diagnosis and the discovery of effective treatments. To address this need, we have developed the genetically engineered pig PDAC model. The model closely recapitulates the pathophysiological aspects of the human disease, including disease progression, histopathological subtypes of tumors, and the occurrence of metastasis. Alternative splicing variants have been proven to be novel targets in PDAC. KRAS undergoes mutations in PDAC more often than any other oncogene. The distinction between the two KRAS isoforms arises from the alternative splicing of exon 4 within the KRAS locus, resulting in the expression of major KRAS4A and minor KRAS4B splice isoforms, with KRAS4B is understudied, and functions in cancer are unknown. Based on this strong rationale, we initiated a study to functionally validate the role of the KRAS4B isoform in PDAC. Methods: qPCR was carried out to determine the expression level of KRAS4A and KRAS 4B in PDAC tumors and cell lines as well as in different tissues. To investigate the function of KRAS4B, we generated two pancreatic cancer cell lines harboring the genetic signature of Pdx Cre /Kras G12D /p53 R167H mutation (KPC) or Pdx Cre /Kras G12D mutation (KC). Using CRISPR/Cas9 technology to knockout KRAS4B isoform. Additionally, we designed a vector for investigating the overexpression of KRAS4B. Results: At the molecular level, we revealed a differential expression of KRAS isoforms 4A and 4B in PDAC tumors and cell lines. Notably, the KRAS4B isoform was exclusively expressed in the advanced stages of PDAC. At the cellular level, we successfully disrupted the KRAS4B isoform in both cell lines. The overexpression vector of KRAS4B has been successfully constructed for further analysis. Subsequent functional assays will encompass analyses of mRNA and protein expression levels, along with assessments of key cellular behaviors, including proliferation, invasion, migration, and morphological alterations. Moreover, we will discern changes in tumor subtypes by examining the distinct expression patterns of epithelial and mesenchymal markers. Conclusions: Therefore, we engineered KRAS4B knockout and overexpression vectors to investigate its role in PDAC, utilizing our cell lines derived from our genetically engineered pig model. This approach offers a robust platform that enhances the bridge between translational and preclinical research in studying PDAC.