tbuckley/cabot-search huggingface dataset:
Pan-cancer microsatellite instability testing using a multiplex assay including long mononucleotide repeats.
Authors: Dustin A. Deming, Jeff Bacher, Irina Vyazunova, Dawn Albrecht, Madeleine Buratti, Laura Ruelle, Cheri Pasch, Santina Snow, Kristina Matkowskyj, Ryan Sappenfield, Richard Halberg
Journal: Journal of Clinical Oncology (2025)

290 Background: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) testing is a critical component of molecular testing for gastrointestinal cancers, among others. These analyses are important for the identification of patients with lynch syndrome and eligibility for treatment with immunotherapy. The current standard of care testing can identify most cases, however improved identification of MSI-H status is needed for non-colorectal cancers and for cancers with alterations outside MLH1/PMS2. A recent analysis indicated the potential for improved MSI-H detection with a multiplex assay including long mononucleotide repeats (LMR). Methods: Patients were selected based on MSI status, MMR gene variants, or the presence of a high tumor mutation burden and consented for participation as part of an IRB-approved protocol (UW15068). Formalin-fixed tissue slides were annotated by a pathologist for tumor and normal tissue. Slides were scraped and DNA isolated. The LMR MSI Analysis System (Promega, Madison, WI) and the OncoMate MSI Dx Analysis System (Promega) were performed on cancer DNA and normal tissue DNA when available per the manufacturer’s protocols. Instability of microsatellites and the MSI score were reported and correlated with clinical MMR immunohistochemistry (IHC) and commercial next-generation sequencing (NGS). Results: A total of 96 cancer samples were tested across 94 patients with over 20 different cancer types, including lung, colon, rectal, gynecologic, and esophagogastric cancers. Tumors from 20 patients were known to have microsatellite instability based on clinical NGS testing. 27 cases were found to be MSI-H based on the OncoMate assay. All of these cases were also MSI-H per the LMR assay and an additional 3 cases were found to be MSI-H using only the LMR assay. Of these 3 cases all were microsatellite stable by NGS. This number includes 1 colorectal and 2 esophagogastric cancer cases. One of the cases was found to have loss of MSH6 by IHC with an MSH6 mutation (MSH6 L1061fs). One of the cases was MMR intact by IHC, though did have a MSH6 exon 7 splice acceptor alteration that failed NGS calling quality control. The last case did not have MMR IHC performed, no detected MMR gene alterations, and a tumor mutation burden of 6.3 mutations per megabase. Conclusions: In this limited dataset, the utility of various methods for determination of MSI, dMMR, and TMB including PCR, IHC, and NGS were demonstrated using a patient cohort spanning solid tumor types. Promising results were observed with the LMR MSI Analysis System. These findings need to be further validated in a larger dataset and correlated with the response to immunotherapeutics.
Clinical characteristics and treatment outcomes for metastatic early-onset small bowel adenocarcinoma treated with first-line chemotherapy.
Authors: Shotaro Yamaguchi, Hidekazu Hirano, Momoko Sano, Toshiharu Hirose, Natsuko Tsuda Okita, Hirokazu Shoji, Atsuo Takashima, Ken Kato
Journal: Journal of Clinical Oncology (2025)

796 Background: Small bowel adenocarcinoma (SBA) is an aggressive rare cancer with its incidence on the rise. Although early-onset SBA (EO-SBA: diagnosed at &lt; 50 years old) accounts for approximately 10% of all SBA, characteristics and survival outcomes of advanced EO-SBA remains under-evaluated. This study aims to evaluate clinical features and treatment outcomes of patients with advanced EO-SBA receiving first-line chemotherapy. Methods: We retrospectively analyzed the clinical data of patients who received fluoropyrimidine plus oxaliplatin as first-line treatment for recurrent or metastatic SBA at our hospital between January 2012 and July 2024 Patients were divided into two groups: those who were diagnosed at age of &lt; 50 years old (EO-SBA) and those who were diagnosed at age of ≥50 years old (late-onset SBA, LO-SBA). Clinicopathological characteristics and treatment outcomes (objective response rate [ORR], progression-free survival [PFS], overall survival [OS], and adverse events [AEs]) were compared between two groups. Survival outcomes were estimated using the Kaplan–Meier method and compared by the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were calculated by univariable and multivariable Cox regression analyses. Results: A total of 69 patients (EO-SBA 18, LO-SBA 51) were included in this study. Compared to the LO-SBA group, the EO-SBA group were more likely to have non-duodenum tumor (89% vs. 49%, p = 0.002), lesser number of metastatic sites (≤2, 100% vs.78%, p = 0.007), and prior resection of primary tumor (83% vs 49%, p = 0.008). The EO-SBA group had longer PFS compared to the LO-SBA group (median PFS: HR = 0.32 [95% CI 0.12 - 0.85] p = 0.022). The EO-SBA group had a trend of longer OS compared to the LO-SBA group (median OS: HR = 0.39 [95%CI 0.15 - 1.01] p = 0.053). Age group was not identified as an independent prognostic factor for OS (HR = 0.63 [95% CI: 0.21 - 1.85], p = 0.40) and PFS (HR = 0.47 [95% CI: 0.16 - 1.37], p = 0.17) by multivariable analyses adjusted for previously reported prognostic factors (performance status, liver metastasis, primary site, histological classification, prior resection of primary tumor, and carcinoembryonic antigen [CEA] elevation). Among patients with measurable lesions (EO-SBA 9, LO-SBA 41), the EO-SBA group showed a numerically higher ORR compared with the LO-SBA group (63% vs 29%, p = 0.07). There were no significant differences of AE frequencies between two groups except for anemia (grade 3/4. EO-SBA 0% vs LO-SBA 22%, p &lt; 0.001). Conclusions: Our study indicates the difference of clinical characteristics between two age groups in patients with advanced SBA. EO-SBA was not identified as independent prognostic factor for OS and PFS in patients treated with first-line chemotherapy.
The TAB-EOAO study: Trends in use and benefit of adjuvant chemotherapy between early onset and average onset locally advanced colon cancer.
Authors: Carolina Bernabe, Dennis Orkoulas Razis, Jee-Young Moon, Chenxin Zhang, Jihoon John Choi, Bahar Laderian, Fernand Bteich, Chaoyuan Kuang, Yvonne M. Saenger, Andreas Kaubisch, Jesus Del Santo Anampa
Journal: Journal of Clinical Oncology (2025)

105 Background: Despite the declining incidence rates (IR) in average onset colon cancer (AO-CC), IR for early onset colon cancer (EO-CC), defined as patients (pts) younger than 50-years-old at diagnosis, has been increasing. Treatment for high risk locally advanced colon cancer (CC) is surgical resection followed by adjuvant chemotherapy (AC). Data indicates a more permissive chemotherapy use in EO-CC. There is limited data about treatment and survival trends in EO-CC. Thus, we aimed to assess the use and benefit of AC between in EO vs AO CC in locally advanced disease. Methods: CC diagnosed between 2000-2020 were identified in the Surveillance, Epidemiology, and End Results Program (SEER) Database. Eligible pts were adults (≥18), Stage II or III at diagnosis. Stage II disease was further stratified as low risk (pT1-3) and high risk (pT4). Logistic regression methods were used to assess Odds Ratio (OR) of AC between EO-CC and AO-CC; Cox models were used to compare overall survival (OS) and Cancer-specific survival (CSS) between both groups during 2000-2010 and 2011-2020. Results: Our study included 136,676 pts (AO-CC= 121,606; EO-CC =15,070). The median age for EO-CC was 44 years versus 71 years for AO-CC population. The use of AC increased over time for both the EO-CC (63% vs 66%) and AO-CC (33% vs 40%). Moreover, pts with AO-CC received less AC than EO-CC in the entire study time (see table). In pts with AO-CC, AC improved CSS (HR=0.69 for 2000-2010, HR=0.50 2011-2020). However, among those with EO-CC, AC improved CSS in 2011-2020 (HR=0.76) but did not improve CSS in 2000-2010 (HR=1.02). Conclusions: Over the past 20 years EO-CC has been managed aggressively, especially for stage II low risk patients where current guidelines do not support the use of AC. In this real world data set we show that for EO-CC AC did not improve CSS in the decade 2000- 2010 but did improve CSS in the 2011- 2020 period. Further analysis may clarify stage specific benefits of AC. There clearly remains a need for better risk stratification, including the use of ctDNA, to identify the subpopulations of EO-CC patients that will best benefit from AC. Multivariable logistic regression model of chemotherapy by timeframe with interaction term: Age* stage. 2000-2010 2011-2020 AO-CC vs EO-CC OR 95% CI OR 95% CI Stage II low risk 0.23 (0.21, 0.26) 0.28 (0.24, 0.32) Stage II high risk 0.28 (0.22, 0.36) 0.28 (0.21, 0.36) Stage III 0.36 (0.32, 0.4) 0.30 (0.26, 0.34)
Predictive methylation signature for gemcitabine sensitivity in pancreatic ductal adenocarcinoma: A pathway to personalized treatment.
Authors: Deepak Sherpally, Sravan Jeepalyam, Harshitha Puram, Ashish Manne
Journal: Journal of Clinical Oncology (2025)

768 Background: Gemcitabine (Gem) is a key drug used in chemotherapy regimens for treating pancreatic ductal adenocarcinoma (PDA). Identifying a biomarker to predict patient response to Gem could be crucial in personalizing treatment selection between Gemcitabine and fluorouracil (5-FU)-based therapies, thereby improving patient outcomes. We hypothesize that DNA methylation changes in genes linked to Gem resistance may serve as surrogates for the expression of corresponding proteins, thereby predicting treatment outcomes in patients with PDA receiving this therapy. Methods: We curated a 93-gene panel through a literature review spanning from January 1970 to April 2024. The proteins encoded by these genes have demonstrated either preclinical evidence (from cell line or mouse models) or clinical evidence (from tissue-based studies) of affecting the response to Gem in PDA. We evaluated the prognostic significance of methylation at specific CpG (cytosine-phosphate-guanine) sites within these genes using data from The Cancer Genome Atlas (TCGA) database, focusing on patients who had received Gem (106 /184 patients). We utilized elastic net multivariate analysis to analyze survival and created Kaplan-Meier plots based on our gene panel to estimate overall survival (OS). We compared RNA and gene expression levels for the clinically significant gene signatures between normal (NT) and PDA tissues using TNMplot.com, a web-based tool developed from data in the Gene Expression Omnibus of the National Center for Biotechnology Information (NCBI-GEO), TCGA, Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories. This tool employs Mann-Whitney or Kruskal-Wallis tests to determine statistical significance. Results: We identified an 8-CpG site methylation signature across eight genes, distinguishing a high-risk subgroup within the Gem-treated cohort in the TCGA database. Patients exhibiting methylation at specific CpG sites in this signature experienced significantly worse OS, with median survival times of 20.35 months compared to 49.38 months (p=0.0068). Additionally, the RNA expression (fold change: 2.11, p=2.12e-55) and gene expression (fold change: 1.42, p=3.14e-18) of these genes were markedly higher in PDA tissues compared to normal tissues. Notably, the candidate genes in our signature do not overlap with those used to classify PDA into classical versus basal subtypes. In an ongoing study, we are also investigating methylation changes of these candidate genes in the blood (cell-free DNA) of PDA patients. Conclusions: We present a signature that can predict Gem sensitivity or resistance in patients with PDA. This signature serves as a critical first step toward personalizing treatment strategies.
Effect of dose adjustments on overall survival (OS) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX: A post hoc analysis of NAPOLI 3.
Authors: Anjan J Patel, Ashley Ann Laursen, Paul Cockrum, Yutong Liu, Andy Surinach, Whitney Rhodes, Li Zhang, Jia Li, Fiona Maxwell, Zev A. Wainberg, Eileen M. O'Reilly
Journal: Journal of Clinical Oncology (2025)

716 Background: NALIRIFOX is approved by the US Food &amp; Drug Administration and European Medicines Agency for the first-line treatment of adults (no upper age limit) with mPDAC. Approval was based on the results of NAPOLI 3 (NCT04083235), in which NALIRIFOX demonstrated significant improvements in OS (primary outcome) and progression-free survival compared with nab-paclitaxel plus gemcitabine. In this exploratory post-hoc analysis of NAPOLI 3, we examined the impact of NALIRIFOX dose adjustments on OS in patients treated in North America. Methods: Patients (N = 770) with confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m 2 + oxaliplatin 60 mg/m 2 + leucovorin 400 mg/m 2 + 5-fluorouracil 2400 mg/m 2 (NALIRIFOX) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 on days 1, 8 and 15 of a 28-day cycle. In this analysis, liposomal irinotecan dose reductions, delays, and exposure were examined descriptively in patients who received NALIRIFOX at centers in North America. OS was evaluated using Kaplan–Meier methods; no statistical tests were performed. Results: Overall, 120 patients were randomized to receive NALIRIFOX at centers in North America (intention-to-treat [ITT] population) and 112 received treatment (safety population). Dose adjustments (dose reductions and dose delays) occurred in a higher proportion of patients presenting with longer OS. Patients with the longest duration of liposomal irinotecan exposure and highest cumulative dose had the longest OS. Conclusions: This finding suggests that tolerability-guided dose modification of liposomal irinotecan does not adversely affect efficacy outcomes and suggests a path forward to further optimize the OS of patients with mPDAC receiving NALIRIFOX. Clinical trial information: NCT04083235 .
Distribution of lymph node metastasis and prognosis in duodenal bulb tumors: A multicenter retrospective study.
Authors: Kazuhiko Hisaoka, Satoru Matsuda, Hirofumi Kawakubo, Masashi Takeuchi, Takeyuki Wada, Shigeki Sekine, Takeshi Takamoto, Mai Tsutsui, Masahiro Yura, Hiroki Ishida, Yoshihiro Ono, Satoshi Kamiya, Etsuro Bando, Souya Nunobe, Takahiro Kinoshita, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2025)

797 Background: Duodenal tumors, especially duodenal bulb tumors, is a relatively rare malignancy of the gastrointestinal tract. The optimal surgical procedure for primary duodenal tumors has not been established because of its low incidence. The purpose of this study was to examine the distribution of lymph node (LN) metastasis in duodenal bulb tumors. Specifically, in T1a and T1b tumors, we aimed to evaluate the feasibility of distal gastrectomy with duodenal bulb resection combined with lymphadenectomy of regional gastric LNs. Methods: Data from patients who underwent surgery for either adenocarcinoma or neuroendocrine tumor located in the duodenal bulb between 2000 and 2020 were retrospectively analyzed from five high-volume centers in Japan. Patient background, clinicopathological factors, type of surgery, distribution of LN metastasis, and long-term outcomes were evaluated. Results: Of the 128 patients evaluated, LN metastasis was observed in 36%. The frequency of LN metastasis in T1b was 18%. Metastatic LNs were identified in #3, #5, #6, #8a, #8p, #12a, and #13 in T1b. The distribution of LN metastasis in T1b was similar between adenocarcinoma and neuroendocrine tumors. The 3 years overall survival rate in T1a, T1b, and T2–4 was 100%, 93%, and 64%, respectively. ln T1b, while there were three patients with a recurrence, two cases were observed in distant organs without regional LNs, and one patient who underwent pancreaticoduodenectomy had metastasis in the gastric regional LNs. Conclusions: Based on the distribution of LN metastasis with pT1, distal gastrectomy with duodenal bulb resection and regional LN dissection is considered a curative treatment. Conversely, pancreaticoduodenectomy is recommended in tumors with T2 or deeper.
Impact of HER2-positivity on prognosis and targeted therapeutic outcomes in advanced biliary tract cancer.
Authors: Choong-kun Lee, Dong Hyun Seo, Daniel Aaron Fox, Jaime Haro-Silerio, Taek Chung, Chang Gon Kim, Deepak Bhamidipati, Funda Meric-Bernstam, Shubham Pant, Milind M. Javle, Sunyoung S. Lee
Journal: Journal of Clinical Oncology (2025)

629 Background: HER2 overexpression and amplification have been identified as a promising druggable target in biliary tract cancer (BTC). This study aims to characterize the clinical and molecular outcomes associated with HER2 positivity in BTC and evaluate the prognostic implications of HER2-targeted therapies. Methods: A retrospective study was conducted involving patients with advanced BTC diagnosed at Yonsei Cancer Center (YCC) and the University of Texas MD Anderson Cancer Center (MDACC) between 2009 and 2023. Patients were classified as HER2-positive either by immunohistochemistry (IHC 3+ or 2+/ISH+) or by next-generation sequencing (NGS, ERBB2 amplification). Overall survival (OS) and palliative first-line progression-free survival (PFS) were analyzed using Kaplan-Meier and Cox regression methods. Results: A total of 389 advanced BTC patients were initially screened (310 from YCC; 79 from MDACC). Among the 310 BTC patients from YCC with available HER2 IHC results, 78 (25.2%) were HER2-positive and 232 (74.8%) were HER2-negative. HER2 positivity was significantly more common in gallbladder cancer (55.1%) compared to its prevalence in intrahepatic or extrahepatic cholangiocarcinoma (22.8%, p&lt;0.001). Of the 201 patients with available NGS data, 186 (92.5%) were ERBB2 non-amplified; among these, 27 (14.9%) were HER2-positive by IHC. For survival analysis, 310 patients were eligible: 239 from YCC (both HER2-positive and negative) and 71 from MDACC (all HER2-positive). Kaplan-Meier survival analysis indicated a trend towards shorter OS in HER2-positive patients compared to HER2-negative patients (median OS, 13.7 vs. 17.1 months, p=0.084, HR=1.246, 95% CI=0.97–1.60) regardless of exposure to HER2-targeted therapy, while first-line PFS on chemotherapy only was significantly shorter in the HER2-positive group (5.1 vs. 7.4 months, p&lt;0.001, HR=1.906, 95% CI=1.46-2.48). Among HER2-positive patients, 56.8% received HER2-targeted therapy in the second line setting. HER2-positive patients who did not receive HER2-targeted therapy had a significantly poorer prognosis compared to HER2-negative patients (median OS 8.1 vs. 17.1 months, HR=2.46, 95% CI=1.73-3.48), whereas those receiving HER2-targeted therapy had comparable OS to HER2-negative patients (median OS 18.2 vs. 17.1 months, HR=0.95, 95% CI=0.71-1.27). Multivariable analysis identified a history of surgical treatment, radiation therapy, HER2 positivity, and HER2-targeted therapy as independent prognostic factors for OS. Conclusions: HER2 positivity is associated with a poorer prognosis in advanced BTC. However, HER2-targeted therapies improve outcomes, suggesting their potential inclusion in standard care for HER2-positive subgroups. Discrepancies between IHC and NGS in HER2 assessment emphasize the need for optimized testing guidelines in BTC.
Impact of inpatient palliative care on end-of-life care among patients with early-onset colorectal cancer.
Authors: Suriya Baskar, Bohae R Lee, Rajiv Midha, Udhayvir Singh Grewal
Journal: Journal of Clinical Oncology (2025)

305 Background: Palliative care has proven benefits in elderly patients with advanced cancer; however, the objective benefits of palliative care in younger patients with cancer remain under-studied. We sought to examine the impact of inpatient palliative care consultation on end-of-life (EOL) care among hospitalized patients with early-onset colorectal cancer (EO-CRC). Methods: This study analyzed all admissions in the National Inpatient Sample (NIS) between 2016 and 2020 for patients younger than 50 years old with a diagnosis of CRC and death during the admission. Patients with CRC were identified utilizing ICD-10 codes C18.x, C19.x, and C20.x. Patient cohorts were made based on if they received inpatient palliative care consultation (ICD-10 code Z515). We assessed these encounters for patient demographics, Charlson comorbidity index (CCI), utilization of mechanical ventilation, vasopressors or blood transfusion, and presence of a Do Not Resuscitate (DNR) order. Results: Among 4,060 patients with EOCRC, 2,425 (59.7%) received inpatient palliative care consultation. There was no significant difference in age or length of stay between groups. The cohort of patients who received palliative care consultation had more female patients (44.3% vs 39.8%, p=0.004) and had higher comorbidity burden measured by the CCI (8.6 vs 8.3, p&lt;.001). Patients receiving inpatient palliative care consultation at EOL were significantly more likely to have a DNR order (83.3% vs 44.6%, p&lt;.001) in place and less likely to receive aggressive interventions, including mechanical ventilation (20.4% vs 43.4%, p&lt;.001), blood transfusion (14.8% vs 22.6%, p&lt;.001), vasopressor use (6.2% vs 8.6%, p=.004), and surgical intervention (3.0% vs 7.3%, p&lt;.001). There was no difference in chemotherapy use between cohorts (2.8% vs 2.9%, p=0.8). Admissions including palliative care consultation were also associated with significantly lower average hospital charges ($99,387 vs $131,993, p&lt;.001). Conclusions: Inpatient palliative care consultation at EOL among patients with EOCRC was associated with lesser use of aggressive interventions and higher rates of DNR code status. We also noted significantly lower costs of hospitalization among patients receiving inpatient palliative care consultation at EOL. These results underscore the importance of integration of inpatient palliative care consultation among patients with EOCRC at EOL. No PalliativeN=1635 PalliativeN=2425 p-value Age (in years) 41.9 ± 6.1 42.1 ± 6.5 .28 CCI 8.3 ± 2.6 8.6 ± 2.3 &lt;.001 Total Charges 131993 ± 206404 99387 ± 151864 &lt;.001 DNR 730 (44.6%) 2020 (83.3%) &lt;.001 Blood transfusion 370 (22.6%) 360 (14.8%) &lt;.001 Mechanical ventilation 710 (43.4%) 495 (20.4%) &lt;.001 Vasopressor 140 (8.6%) 150 (6.2%) .004 Chemotherapy 45 (2.8%) 70 (2.9%) .800 Surgery 125 (7.3%) 75 (3.0%) &lt;.001