tbuckley/cabot-search huggingface dataset:
CLDN18/CLDN18.2 IHC assay comparison (SP455, 43-14A, EPR19202) and co-prevalence expression with other biomarkers in gastric carcinoma.
Authors: Miranda E Clements, Sophie E Willis, Martin Korade, Lorenzo Ortiz, Stephanie Zalesak-Kravec, Cam Lombard, Chris Richardson, Andrew Chambers, Yeoun Jin Kim, Tsu-Shuen Tsao, Mark Robida, Jan Zaucha, Deborah Berry, Gemma N Jones, Allison Barrett, Nick Durham, Marlon Rebelatto, Maria Broggi, Kenneth S. Thress, Nicolas Giraldo
Journal: Journal of Clinical Oncology (2024)

4089 Background: Despite recent advances in treatment, gastric cancer (GC) remains the fourth leading cause of cancer-related mortality worldwide. Claudin 18.2 (CLDN18.2) has emerged as a promising therapeutic target as its expression is mostly restricted to the gastric epithelium and persists in a significant fraction of GC and other upper gastrointestinal tumors (e.g. pancreatic ductal adenocarcinoma). The goal of this study was to compare the analytical performance of multiple CLDN18/CLDN18.2 IHC assays and understand the prevalence of CLDN18.2 with other GC-relevant biomarkers (PD-L1, HER2) and the tumor immune microenvironment. Methods: Cell lines (n=11) and primary resection specimens from patients with GC (n=91) were studied. To compare the analytical performance of three CLDN18/CLDN18.2 IHC assays, FFPE samples were stained with pan-CLDN18 (43-14A) and CLDN18.2-specific (SP455 and EPR19202) clones. Staining results were validated using orthogonal methods i.e., flow cytometry and mass spectrometry. The relationship of CLDN18.2 expression with PD-L1 (SP263) and HER2 (HercepTest) as well as T cell contexture (CD3/CD8/PanCK; CD3/PD-L1/Ki67) were explored by IHC and chromogenic multiplex IHC. Association of these markers with clinicopathological features was also investigated. Results: Comparison of the three CLDN18/CLDN18.2 IHC assays showed similar analytical performance across cell lines and GC samples. Using orthogonal methods, we determined that the limit of detection and linear range was comparable amongst assays. In GC, samples classified as CLDN18/CLDN18.2 positive at a cutoff of 75% with 2-3+ intensity included 22% (SP455), 22% (43-14A), and 15% (EPR19202) of samples. Classification at other CLDN18/CLDN18.2 cutoffs were also explored and will be presented. Only one case (1%) showed significantly discrepant staining patterns between pan-CLDN18 and CLDN18.2-specific assays (H score 235 vs. 105, respectively). CLDN18.2 positivity did not correlate with HER2 expression, PD-L1 expression, T cell densities (cells/mm2), or any of the tested clinicopathological characteristics i.e., tumor grade, histologic subtype, or TNM stage. Conclusions: We demonstrated a concordant analytical performance between the tested CLDN18/CLDN18.2 IHC assays in GC. Their implementation in the clinical setting might help identify patient candidates that could benefit from treatment with CLDN18.2 targeted therapies. Additional research is needed to confirm similar analytical performance between the three IHC assays in other indications.
The use of micronuclei DNA from erythrocytes for the detection of early-stage gastrointestinal cancers.
Authors: Haobo Sun, Xingyun Yao, Yuehua Han, Yurong Jiao, Xiangxing Kong, Chengcheng Liu, Qingqu Guo, Fei Meng, Honghao Liang, Xiuqin Fan, Jun Li, Kefeng Ding, Xiaofei Gao
Journal: Journal of Clinical Oncology (2024)

4085 Background: Gastrointestinal (GI) cancers account for over a third of cancer deaths. However, their early detection remains a challenge. Micronuclei (MN) are extranuclear bodies containing damaged chromosome segments indicative of genomic instability. Increased MN frequency in hematopoietic cells is observed in patients with solid tumors. We have developed a method (WO2021/228246 A1) for purifying and characterizing micronuclei DNA (MN-DNA) in erythrocytes from peripheral blood. By comparing MN-DNA from healthy donors (HDs) and GI cancer patients, we identified significant changes in read densities at specific genomic locations in patients, which were termed as tumor-associated MN-DNA (taMN-DNA) signatures. Here, we evaluated the potential of these signatures for early-stage GI cancer detection, including colorectal (CC), gastric (GC) and esophageal (EC) cancers. Methods: Peripheral blood (1-2 ml) was collected from healthy donors (HD) and cancer patients MN-DNA isolation and purification from erythrocytes. Participants were randomly divided into training, validation and independent test cohorts in a 7:2:1 ratio, maintaining similar cancer types, CC/GC/EC/HD ratio, gender and age distribution. Distinct MN-DNA features between cancer patients and HDs were identified using sequencing data. Logistic regression algorithms were applied using these features for cancer detection. Results: The study enrolled 1753 participants, including 987 HDs, 420 CC, 282 GC and 64 EC cases. Of these, over half were diagnosed with early-stage diseases; TNM stage 0-I accounted for 40.57%, stage II for 23.32%, stage III for 29.25% and stage IV for 6.87%. The cancer detection model with MN-DNA features yielded an overall accuracy of 87.43%, with a sensitivity of 83.66% and specificity of 90.36%. For individual caner types, sensitivity was 85.37% for CC, 79.31% for GC and 92.31% for EC. For early-stage (stage 0-II) CC, GC and EC, the model demonstrated sensitivities of 95.12%, 86.05% and 100.00%, respectively, at 90.36% specificity. Conclusions: Unlike cell-free DNA, MN-DNA are chromosomal fragments in the cytoplasm. The abundance of erythrocytes in peripheral blood provides an easily accessible source for MN-DNA enrichment. This pilot study illustrates the potential of MN-DNA as a tool for early GI cancer detection, contributing to large-scale efforts towards developing an effective GI cancer screening test.
Neoadjuvant chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine for locally advanced esophageal squamous cell carcinoma: A prospective phase II trial.
Authors: Wen Zhang, Yong Li, Liyan Xue, Dong Qu, Zhichao Jiang, Shugeng Gao, Aiping Zhou
Journal: Journal of Clinical Oncology (2024)

4087 Background: Surgery-based combination therapy is the current primary treatment for nonmetastatic esophageal squamous cell carcinoma (ESCC). An increasing number of results indicate that neoadjuvant chemotherapy alone might be a choice for perioperative treatment. Previously, a retrospective study we conducted showed that neoadjuvant chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine (referred to as the APCC regimen) for locally advanced ESCC had achieved promising results. To further confirm the efficacy of this regimen, we conducted this prospective phase II clinical study. Methods: Patients (pts) with locally advanced ESCC (cT2N+M0, cT3-4aNanyM0) received preoperative chemotherapy with the APCC regimen (albumin-bound paclitaxel 125 mg/m 2 iv, day 1/8, cisplatin 60 mg/m 2 iv day 1, and capecitabine 1750 mg/m 2 po bid day 1-14, repeated every 21 days for 4 cycles). The primary endpoint was pathological complete response (pCR), and the secondary endpoints were major pathological response (MPR), the R0 resection rate, disease free survival (DFS), overall survival (OS), and safety. Results: A total of 82 pts were enrolled and all received 4 cycles of preoperative APCC regimen. Of the 80 (97.6%) pts who underwent surgery, the R0 resection rate was 100%, pCR was observed in 23 (28.7%) pts and 50 (62.5%) pts had an MPR. Postoperative pathology revealed that 42 (52.5%) pts had stage I (ypT0-2N0M0). The most common grade 3/4 adverse events of chemotherapy included neutropenia (25%), leukopenia (14.5%), nausea (7.5%) and peripheral neurotoxicity (5.5%). No neoadjuvant chemotherapy related, or perioperative death occurred. As of December 1, 2023, with a median follow-up time of 36.8 months, 16(19.5%) patients had recurrent disease, among which 8 (8.5%) pts had local recurrence, 10 (12.2%) pts had distant metastasis. The 3-year DFS rate was 79.4%. As of the last follow-up, eight pts died, and the 3-year survival rate was 88.8%. Conclusions: The results meet our initial aim that preoperative chemotherapy with albumin-bound paclitaxel, cisplatin and capecitabine is highly active and resulted in a considerable pCR and MPR rate with promising 3-year survival rate in pts with locally advanced ESCC, while well-tolerated. This triplet regimen could be another effective neoadjuvant treatment strategy for locally advanced ESCC. Clinical trial information: NCT04390958 .
PD-1 inhibitor (sintilimab) and lenvatinib plus TACE-HAIC as conversion therapy for initially unresectable HCC: A single-arm, phase 2 clinical trial (PLATIC).
Authors: Yunfei Yuan, Jiliang Qiu, Zhenkun Huang, Wei He, Yichuan Yuan, Chenwei Wang, Binkui Li
Journal: Journal of Clinical Oncology (2024)

4123 Background: The current standard treatment for initially unresectable hepatocellular carcinoma (uHCC) is transarterial chemoembolization (TACE) or systemic treatments, but these approaches led to poor conversion resection rate. We aimed to investigate the clinical activity and safety of downstage conversion therapy with Sintilimab, a PD-1 inhibitor, Lenvatinib and TACE- HAIC (hepatic arterial infusion chemotherapy) in uHCC patients (PLATIC trial). Methods: This single-arm, Simon two-stage, phase 2 study was done at Sun Yat-sen University Cancer Center, Guangzhou, China. Patients received TACE-HAIC, followed by 200mg Sintilimab, Lenvatinib (8mg for BW &lt; 60kg, 12mg for BW ≥ 60kg). The primary endpoint was the conversion to resection rate. Safety was analyzed in all patients who received at least one dose of treatment. This trial is closed to enrolment and is registered with ClinicalTrials.gov (NCT04814043). Results: Between May 19, 2021, and August 20, 2023, 57 patients were enrolled, and all were included in the efficacy and safety analysis set. The conversion to resection rate was 77.2% (44/57, 95% CI, 64.2 to 87.3) after a median 3 cycles of conversion therapy. Overall response rate was 77.2% per mRECIST and 42.1% per RECIST 1.1 criteria. The median duration of response (mDoR) was 11.5 months (95% CI, 9.8 to NA), and the median progression-free survival (mPFS) was 14.3 months (95% CI, 11.7 to 21.9). Treatment-related adverse events (TRAEs) of grade 3/4 were reported in 37 (64.9%) patients, with the most frequent being increased gamma-glutamyl transferase (36.8%), followed by abdominal pain (19.3%). Among 44 successful conversion patients, 29.5% (13/44) patients obtained a pathological complete response, with a mPFS of 15.3 months (95% CI, 11.9 to NA) and 12-month PFS rate of 59.4% (95% CI, 45.4 to 77.9). Conclusions: Sintilimab plus Lenvatinib and TACE-HAIC provided promising rate of conversion to resection in patients with initially unresectable HCC, with an acceptable TRAEs. Clinical trial information: NCT04814043 . [Table: see text]
A prospective phase 2 single-arm study to evaluate the efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy in patients with locally advanced esophageal squamous cell carcinoma (Keypoint-1).
Authors: Peiran Xu, Polan Su, Weiwei Wang, Jia He, Luo Zhao, Weixun Zhou, Robert Merritt, Li Li, Kai He
Journal: Journal of Clinical Oncology (2024)

4088 Background: Esophageal squamous cell carcinoma (ESCC) is the most prevalent esophageal cancer type worldwide with poor prognosis and limited treatment options. Combination immunotherapy and chemotherapy improved the outcomes in patients (pts) with metastatic esophageal cancer. However, the benefit of neoadjuvant immuno-chemotherapy in pts with locally advanced ESCC is unknown. We evaluated the efficacy and safety of neoadjuvant treatment with pembrolizumab plus chemotherapy in pts with locally advanced ESCC. Methods: Eligible pts who were aged 18-80 years with untreated, locally advanced ESCC were enrolled in this single-arm, phase 2 trial at Peking Union Medical College Hospital (China) from July 2020 to April 2022. Pts received neoadjuvant treatment with docetaxel 75 mg/m 2 , carboplatin area under the curve (AUC) 4-5 (or cisplatin 75 mg/m 2 ), and pembrolizumab 200 mg via IV every 3 weeks. Within 4-8 weeks of completion of neoadjuvant treatment, pts underwent surgery. The primary endpoint was pathological complete response (pCR) rate. The secondary endpoints were treatment-related adverse events and R0 resection rate. The study is registered at ClinicalTrials.gov (NCT05302011). Results: Thirty pts were enrolled (Table). As of December 1, 2023, median follow-up time was 27.9 months. Twenty-eight pts received 4 cycles and 2 received 3 cycles of the neoadjuvant treatment. Six pts did not proceed with surgery because of disease progression (3/6) and personal choice (3/6). Twenty-four pts (24/30, 80%) underwent minimally invasive esophagectomy (MIE). The R0 resection rate was 100%. Perioperative complications were manageable, including anastomotic leakage (2/24, 8.3%) and nerve injury (1/24, 4.2%). Of these 24 pts, 7 (29.2%) achieved pCR and 5 (20.8%) were CAP1 (near complete response, College of American Pathologists protocol). The median disease-free survival (DFS) was 30.6 months. Median overall survival data is not yet available. Grade 3/4 treatment-related adverse events include leukopenia (10, 33.3%), alopecia (3, 10.0%), and pneumonitis (1, 3.3%). One patient died of Stevens-Johnson syndrome. We are conducting molecular and immunological correlative studies to explore potential biomarkers related to the treatment. Conclusions: Neoadjuvant treatment with combination pembrolizumab and chemotherapy demonstrated encouraging anti-tumor activities, good surgical outcomes and a manageable safety profile in pts with locally advanced ESCC, supporting further evaluation in a prospective randomized phase 3 trial. Clinical trial information: NCT05302011 . [Table: see text]
A phase 2 study of BOLD-100 in combination with FOLFOX chemotherapy in patients with pretreated advanced biliary tract cancer: Efficacy and safety analysis (BOLD-100-001).
Authors: Grainne M. O'Kane, Do-Youn Oh, Jennifer Spratlin, Sun Young Rha, Elena Elimova, Petr Kavan, Rachel Anne Goodwin, Yongjun Cha, Seung Tae Kim, E. Russell McAllister, Michelle Jones, Malcolm Snow, Yasmin Lemmerick, Gonzalo Spera, Jim Pankovich
Journal: Journal of Clinical Oncology (2024)

4115 Background: BOLD-100 is a first-in-class ruthenium-based anticancer agent in Phase 2 clinical development for the treatment of advanced gastrointestinal (GI) cancers in combination with FOLFOX. BOLD-100 demonstrated synergy in established preclinical models in combination with various anticancer therapies. Methods: In this prospective Phase 2 study, patients with pretreated advanced biliary tract cancers (BTC) received BOLD-100 (625 mg/m2) in combination with FOLFOX on day 1 of each 14-day cycle until progressive disease or unacceptable toxicity. The primary objective was to evaluate the efficacy of BOLD-100 in three clinical endpoints (PFS, OS, and ORR). Disease Control Rate (DCR) was also determined. Bayesian modelling was used to continually reassess these endpoints, the posterior probability of superiority to an historical landmark for each endpoint. Results: As of 31 Dec 2023, 22 pts with advanced metastatic BTC (5 gall bladder, 5 intrahepatic, 8 distal, 1 perihilar, and 3 unk) were enrolled and treated in the study. At enrollment, pts had a median age of 61 years [range 33, 81] and had a median of 10.9 months from diagnosis of metastatic disease. All patients were ECOG ≤ 1. Patients had a median of 2 prior systemic therapies [range 1, 5] with 13 receiving 2 or more prior regimens. 21/22 BTC patients received prior GEM/CIS, 8 pts had prior 5-FU treatment and 6 prior IO. On study, pts received a median of 4 cycles BOLD-100 + FOLFOX [range 1, 41]. Median PFS was 6.0 [95% credible interval (CI) 3.8, 10] months, median OS 7.3 [CI 4.5, 13] months, ORR 6% [1,23] and DCR 83% [62, 95] in the 18 evaluable patients. Six patients had reductions in their target lesions with 1 partial response. Study treatment was well tolerated. For the 22 treated patients, 21 reported 1 or more treatment-related adverse events (AEs), most commonly neutrophil count decreased (n=10, 46%), nausea (n=8, 36%), fatigue (n=7, 32%), peripheral sensory neuropathy (n=6, 27%), and pyrexia (n=6, 27%). Nine patients (41%) reported G3/4 neutrophil count decreased. Conclusions: BOLD-100 combined with FOLFOX is an active and well-tolerated treatment regimen in Stage IV BTC. There were no new safety signals detected. The mPFS, mOS, ORR and DCR data in this advanced BTC cancer population indicate a treatment combination worthy of further study for this difficult to treat cancer. Clinical trial information: NCT04421820 .
Post-progression therapies and outcomes for patients with advanced, BRCA-related pancreatic cancer after receipt of PARP inhibitors: A national retrospective cohort study.
Authors: Baqir Jafry, Syed Mohammad Ali Kazmi, Salwan Al Mutar, Kim Anna Reiss, Timothy J Brown
Journal: Journal of Clinical Oncology (2024)

4156 Background: Maintenance therapy with poly-ADP ribose polymerase (PARP) inhibitors (PARPi) can delay progression of advanced platinum-sensitive pancreatic cancer in patients with mutations in BRCA1, BRCA2or PALB2. However, there are limited data to guide treatment decisions and outcomes following progression with PARPi. Thus, we sought to compare outcomes of post-progression platinum and non-platinum therapies for patients with pancreatic cancer after receipt of PARPi using a nationwide cohort. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. During the study period, the de-identified longitudinal patient-level data originated from approximately 280 cancer clinics. Patients were eligible for inclusion if they received maintenance olaparib for advanced pancreatic cancer and subsequently received post-progression chemotherapy. Post-progression chemotherapy was characterized as platinum (P) or non-platinum (NP). Demographics, tumor stage, and lab values were compared using the Chi-squared test or Mann Whitney U test. Overall survival (OS) and time to treatment discontinuation (TTD) were evaluated using the Kaplan Meier method with an index date of initiation of post-progression therapy. Given the limited anticipated sample size, no formal comparisons were made between treatment groups. Cox proportional hazards models were constructed to identify associations between baseline clinical factors and outcomes. Results: Of 11,179 patients were included in the database, 26 met inclusion criteria for this analysis after progressing on olaparib and subsequently receiving post-progression chemotherapy. Most patients were white (81%) and non-Hispanic (77%). Twelve (46%) received post-progression P, while 14 (54%) received post progression NP. No significant differences were noted in baseline characteristics between groups. Among patients on P, the most common regimens were gemcitabine and cisplatin (50% n=6), FOLFIRINOX (17%, n=2), and FOLFOX (17%, n=2). Of those on NP, the most common regimens were gemcitabine and nab-paclitaxel (50%, n=7) and FOLFIRI (29%, n=4). The median OS for post progression therapies was 4.8 months for P and 4.1 months for NP group. The median TTD for these post progression therapies was 0.9 months for P and 1.5 months for NP. No baseline clinical factors were associated with time-to-event in Cox regression analyses. Conclusions: In this analysis, patients who progressed on olaparib rapidly progressed on post-progression P and NP and had limited survival. Further work will be needed to identify mechanisms of resistance to PARPi and to optimize post-progression treatments. This work adds to a growing body of literature supporting an individualized approach to post-progression therapy decisions for these patients.
Predicting real-world overall survival for post-operative pancreatic ductal adenocarcinoma: An ASCO CancerLinQ Discovery analysis.
Authors: Kaleem Sohail Ahmed, Sheriff M Issaka, Clayton Thomas Marcinak, Syed Nabeel Zafar
Journal: Journal of Clinical Oncology (2024)

4169 Background: Pancreatic ductal adenocarcinoma (PDAC) is the second leading cause of cancer-related deaths in the US. There is a need to improve risk-stratification of patients to facilitate treatment decisions. Novel datasets such as the American Society of Clinical Oncology (ASCO)’s CancerLinQ Discovery (CLQD) combined with machine learning (ML) methods provide an opportunity to generate new insights from “real-world data” (RWD) to study patient outcomes. The objective of this study was to develop an ML model using RWD to predict 1-year survival (1YS) for patients undergoing pancreatectomy for PDAC. Methods: Using the CLQD database, we identified patients diagnosed with PDAC who had undergone surgical resection between July 1998 and May 2021. Patients with complete data on procedure and tumor characteristics were included. Patients lost to follow-up within 12 months of surgery were excluded. We trained a multivariable Logistic Regression (LR) for baseline comparison. Gradient Boosting Classifier (GBC) and Random Forest (RF) models were then trained on demographic and clinico-pathologic data, with and without pre-operative laboratory (lab) data. GBC-1 and RF-1 were trained only on demographic and clinico-pathologic data (n=1440). GBC-2 and RF-2 were trained on a subset of patients who had non-missing lab data (n=669). We performed a one-way ANOVA to compare the area-under-the-curve (AUC) scores for each GBC and RF model to the corresponding LR. Results: Of the 1440 patients analyzed, 44.7% were male, 53.6% were White, and the mean age was 69.7 ± 10.9 years. Majority had a T3-stage tumor (53.7%) and 70.3% received either neoadjuvant, adjuvant, delayed and/or recurrent chemotherapy. Unadjusted median OS was 16.5 months [95% CI: 15.1-17.6], and 1YS was 60.8% [95% CI: 58.2-63.3]. GBC and RF models were able to outperform the baseline LRs (Table 1). RF-2 and LR-2 performed the best (AUC: 0.83 each) with lab data, followed by RF-1 (AUC: 0.81) without lab data. Factors that were most predictive of survival were: receipt of chemotherapy, tumor size, pre-operative BMI, age, and pre-operative neutrophil count, serum cholesterol, and serum CA-19-9 levels. Conclusions: In this study, we show that ML models using clinicopathologic, demographic, and laboratory data provide more accurate prediction of 1 year survival than prior strategies. Such models can be used to identify patients at high risk for poor outcomes following pancreatectomy and alternative treatments may be offered. [Table: see text]