tbuckley/cabot-search huggingface dataset:
Effect of novel polygenetic variant of HUNT lung cancer model on lung cancer risk assessment over clinical model among light smokers (average &lt;9 pack-years).
Authors: Olav Toai Duc Nguyen, Yannis Fotopoulos, Therese Haugdahl Nøst, Maria Markaki, Vincenzo Lagani, Ioannis Tsamardinos, Oluf Dimitri D. Røe
Journal: Journal of Clinical Oncology (2024)

e20066 Background: As lung cancer incidence and mortality increase, methods of early diagnosis are needed to increase survival. The validated HUNT Lung Cancer Model (HUNT LCM) predicts individual 6-year risk of lung cancer in ever smokers with an AUC of 0.87 based on eight clinical variables: sex, age, BMI, pack-years, smoking intensity number of cigarettes per day, quit time, daily cough, and daily indoors smoke exposure. We aimed to explore whether the performance of the HUNT model can be improved by adding genetic information, and in what group of ever smokers these differences in performance emerges. Methods: Based on the eight clinical variables of the HUNT LCM and 22 single nucleotide polymorphisms (SNPs) previously identified in the literature as highly associated with lung cancer risk, the novel lung cancer risk prediction model HUNT Lung-SNP was developed. Clinical and genetical data of ever-smokers from the HUNT2 population study (n = 30746, median follow-up 15.26 years) where 160 individuals were diagnosed with lung cancer within six years were used for the model fitting. External validation was performed in another population-based cohort, the Tromsø Study (n = 2663) where 39 were diagnosed with lung cancer within 6 years. Results: The integrated discrimination improvement index (IDI) between the HUNT Lung-SNP and the HUNT LCM shows that the HUNT Lung-SNP significantly improve the LC risk stratification within six years with an IDI of 0.019 (95% CI 0.015-0.025), p &lt; 0·001 and of 0.013 (95% CI 0.008-0.018), p &lt; 0·001 in the HUNT2 and Tromsø cohorts, respectively. Of the cases, 21/160 (13%) and 10/39 (25%) in the HUNT and Tromsø cohort respectively, were low risk by the HUNT LCM but high risk by the HUNT Lung-SNP model. The main difference in characteristics among cases predicted by the HUNT Lung-SNP model, but missed by the HUNT LCM, was the average number of pack-years: 8.22 vs. 29.8 (p &lt; 0.001) in HUNT2 and 7.7 vs. 33.7 (p &lt; 0.001) in Tromsø cohort. Conclusions: A genetic approach combined with clinical variables of the HUNT LCM can improve the lung cancer risk prediction significantly by increasing the sensitivity among light smokers. Thus, we identified a high-risk population in two independent cohorts that would not be eligible for screening by clinical cutoffs nor with a clinical risk prediction model. This novel HUNT Lung-SNP needs further validation in other populations to evaluate its clinical utility.
Comparative genomic analysis of circulating tumor cells and primary tissues in early-stage lung cancer: Unveiling signatures of metastatic potential.
Authors: Jinsu Lee, Hyejin Sung, Jeemin Park, Soojeong Ji, WooJung Kim, Sojin Jung, Sukki Cho
Journal: Journal of Clinical Oncology (2024)

e20021 Background: Recent studies substantiate the circulating tumor cells (CTCs) as biological markers for the cancer progression and metastasis. Nevertheless, isolating CTCs is challenging due to their relatively low abundance in the bloodstream. The innovative CTC detection and characterization method, iDXGate TO by BeyondDx, has overcome these challenges, facilitating the seamless identification of genomic alterations, deepening understanding of the functions of CTCs in cancer progression. Methods: In this study, a total of 50 patients diagnosed with early-stage lung cancer, without a history of anticancer therapy at Seoul National University Bundang Hospital from August 2023 to December 2023 participated to compare the genomic alterations between primary cancer tissue and CTCs. Resected tumor tissues and whole blood were collected during surgery, and DNA was freshly extracted and transferred. iDXGate TO, designed specifically for early-stage lung cancer, employs EpCAM, EGFR, and HER2 Biomarkers for targeted capture of circulating tumor cells (CTCs). Targeted sequencing was performed on the genomic DNA extracted from both cancer tissues and CTCs of each patient. Out of the CTC samples, 16 were excluded due to insufficient DNA. Results: Detailed analysis involved sequencing data from 34 CTC samples and 50 tissue samples. CTCs exhibited 100% (34/34) likely pathogenic alterations, compared to 42.00% (21/50) in tissues. Predominant genomic alterations in CTCs included MSH6 (100.0%), FANCE (91.2%), CDK12 (85.3%), HNF1A (85.3%), AXIN2 (82.4%), and FLCN (79.4%). Tissues were frequently associated with EGFR (40.0%), TP53 (34.0%), FAT1 (18.0%), LRP1B (16.0%), NOTCH3 (16.0%), and KMT2D (16.0%). Alterations in MSH6, FANCE, and CDK12 underscore the critical role of DNA repair mechanisms in CTCs, contributing to genomic instability. Alterations in HNF1A suggest implications in metabolic regulation, influencing the tumor microenvironment. Alterations in AXIN2 and FLCN hint at involvement in Wnt signaling and cellular growth regulation, potentially contributing to tumorigenesis. Conclusions: The iDXGate TO selectively identifies tumor-specific circulating tumor cells (CTCs) and explores a new realm of liquid biopsy through molecular and phenotypic integrated analysis. Detection of altered genes in CTCs highlights the molecular heterogeneity. Further exploration of these genetic alterations could offer valuable insights into the underlying mechanisms propelling cancer progression. Additionally, CTCs could serve as pivotal biomarkers for real-time monitoring of tumor evolution, potentially guiding the development of targeted therapies tailored to the specific genomic landscape of CTCs.
Outcomes of blast-phase MPN and <i>JAK2</i>, <i>MPL</i>, and <i>CALR</i>mutated de novo AML: A propensity score-adjusted cohort study.
Authors: Daniel Paul Nurse, Emily Craig Zabor, Daniel Cancilla, Kawther Abdallah, Bridget Adcock, Heya Batah, Hadil Zureigat, Asad Rauf, Gautam Anand Shrivastava, Joy Nakitandwe, Mark Chen, Ismail Elbaz Younes, Austin Ingraham, Akriti Gupta Jain, Sophia Balderman, Abhay Singh, Anjali S. Advani, Hetty E Carraway, Aaron Thomas Gerds, Moaath Khader Mustafa Ali
Journal: Journal of Clinical Oncology (2024)

6526 Background: Progression to blast phase (BP) occurs in about 10% of patients with BCR-ABL-negative myeloproliferative neoplasms (MPN) and is associated with an extremely poor prognosis with no defined standard of care. The VIALE-A trial, which showed that venetoclax (VEN) improves overall survival (OS) in patients with acute myeloid leukemia (AML) when combined with azacitidine, excluded patients with MPN-BP. Rarely, patients develop de novo AML with a genetic profile like an MPN, harboring JAK2, MPL, or CALR mutations. However, there are a lack of data on the outcomes of these patients. Methods: We conducted a single-center retrospective cohort study to compare composite complete response (CCR), OS and event-free survival (EFS) of patients with MPN-BP or de novo AML with underlying JAK2, MPL, or CALR mutations (AML-D-MPN). CCR was defined as complete response (CR) or CR with incomplete count recovery. Propensity score (PS) modeling was used to adjust for baseline characteristics at AML diagnosis: age, sex, race, comorbidities, ECOG status, cytogenetics, and underlying mutations. Results: Of 750 patients treated from 2015 to 2023, 61 had MPN-BP and 12 had AML-D-MPN. The table describes baseline characteristics. The median time for MPN to BP transformation was 8 years (IQR: 2.8-13.6). With a median follow-up of 8.2 months (mo) (95CI: 1.6-59.6), the median OS for MPN-BP was 4.8 mo (95CI: 2.7-8) and for AML-D-MPN was 6.1 mo (95CI: 1.6-NC). In the MPN-BP, 40 received therapy, which included: intensive regimen [7+3 (n=13); CPX-351 (n=1)], hypomethylating agents (HMA) (n=11), HMA+VEN (n=11) and others (n=4). All AML-D-MPN received therapy, which included 7+3 (n=4), HMA (n=1), HMA+VEN (n=2), and others (n=5). In the whole treated population (n=52), the unadjusted CCR was 60% in intensive regimen, 20% in HMA, 20% in HMA+VEN and 0% in others (p=0.3). The PS-adjusted median (m) OS in mo (95%CI) was: 2.6 (1.4-NC) in intensive regimen, 6.2 (1.2-NC) in HMA, 15 (10-15) in HMA+VEN and 1.7 (0.46-NC) in others (p=0.1). The adjusted m-EFS in the same treatment groups was 1.5 (0.43-NC), 6.2 (1.2-NC), 15 (4.3-15) and 0.92 (0.46-NC) (p=0.16), respectively. In MPN-BP group, the adjusted m-EFS in mo (95%CI) was: 0.62 (0.43-NC) in the intensive regimen, 6.2 (1.2-NC) in HMA, 15 (4.2-15) in HMA+VEN and 0.92 (0.92-NC) in others (p=0.25). Conclusions: Patients with MPN-BP and AML-D-MPN have poor survival with similar responses to therapy. These patients have variable outcomes with different treatments; however, there is a trend toward improved survival with the use of HMA+VEN. [Table: see text]
Accurate identification of lung cancer in the early phase by serum exosomal miR-1271-5p.
Authors: Jinmin Zhang, Lian Wang, Haijun Zhang
Journal: Journal of Clinical Oncology (2024)

e20029 Background: Exosomal miRNAs are associated with the proliferation, migration, and invasion of lung cancer cells. We aim to investigate the clinical significance of serum exosomal miR-1271-5p in early-stage lung cancer (ESLC) mainly characterized by pulmonary nodules to push forward the prevention and treatment of lung cancer. Methods: The serum exosome (sEVs) miR-1271-5p was obtained from a total of 134 subjects from the patients with ESLC and the benign nodule (BLN) and healthy controls, and the expression level of miR-1271-5p were detected by RT-qPCR. Through analysis the clinical feature and CT (Computed Tomography) imaging finding of the subjects confirmed by pathology, independent risk factors for ESLC were obtained according to univariate and multivariate logistic regression analysis. R software was incorporated to build a mathematical prediction model of nomogram, and the clinical significance of sEVs-miR-1271-5p in the prediction and diagnosis of ESLC was verified by ROC curve. Results: The relative expression of sEVs-miR-1271-5p was lower in the patients with ESLC than the patients with BLN and healthy controls. The AUC value of the ESLC predicted by sEVs-miR-1271-5p was 0.9845 (95%CI: 0.9649-1.000, P &lt; 0.0001). The results of multi-factor logistic regression analysis showed that gender (OR = 0.213, p = 0.046), nodule diameter (OR = 0.794, p = 0.031), lobulation (OR = 0.013, p &lt; 0.0001), and sEVs-miR-1271-5p (OR = 0.014, p = 0.037) were independent risk factors for ESLC. Based on these independent risk factors, a prediction model for ESLC was established, with an AUC value of 0.8810 (95% CI: 0.8076-0.9553, P &lt; 0.0001), the sensitivity, specificity, positive and negative predictive value and accuracy of the model were 85%, 80.43%, 79.07%, 86.05% and 82.56% respectively. Conclusions: Serum exosomal miR-1271-5p may break through the early diagnosis of lung cancer and provide important therapeutic targets.
Predicting pathological response to neoadjuvant immunotherapy plus chemotherapy in resectable non-small cell lung cancer through liquid biopsy.
Authors: Siyu Lei, Haiyan Xu, Yaning Yang, Linyan Tian, Yan Wang
Journal: Journal of Clinical Oncology (2024)

e20073 Background: Neoadjuvant immunotherapy (ICI) plus chemotherapy (CT) provides a significant benefit compared to CT alone in resectable non-small cell lung cancer (NSCLC). However, further research is needed to identify the populations benefitting from this combined strategy. Methods: Patients (pts) diagnosed with stage II-III resectable NSCLC who opted for neoadjuvant ICI plus CT were enrolled. Plasma samples were collected before treatment initiation (T1) and before surgery (T2). A next-generation sequencing (NGS) platform spanning 769 cancer-related genes was utilized to detect circulating tumor DNA (ctDNA). The ctDNA concentration was presented as haploid genome equivalents (hGE) per mL of plasma. Additionally, low-pass whole-methylome sequencing was employed to explore three features of cell-free DNA, including methylated fragment ratio (MFR), fragment size index (FSI), and chromosomal aneuploidy of featured fragments (CAFF). Clinical and pathological data was obtained from medical records. Results: Out of 24 pts enrolled, 18 pts were evaluable on both platforms. The major pathological response (MPR) rate was 70.8% (17/24), and the pathological complete response (pCR) rate was 37.5% (9/24). Squamous cell carcinoma (SCC) showed a higher MPR rate than adenocarcinoma (P = 0.014). Pts with clinical T stage 2 showed a trend toward a higher MPR rate than those with T stage 3/4 (P = 0.069). No single molecular biomarker was found to be independently associated with MPR or pCR at T1. A linear discriminant model was constructed based on clinical T stage, MFR, and hGE at T1, which predicted both MPR and pCR with an accuracy of 83.3% (n = 18). In pts with SCC (n = 15), the accuracy of this model in predicting MPR and pCR was 80.0% and 86.7%, respectively. Moreover, the CAFF score at T2 was significantly higher in non-MPR pts than in MPR pts (P = 0.003). The dynamic change of CAFF score [calculation: (T2-T1) / T1] was also significantly related to MPR (P = 0.006). Conclusions: Baseline cfDNA features and clinical parameters effectively predicted pathological response of neoadjuvant ICI plus CT in resectable NSCLC, which could potentially serve as a tool for identifying patients that would benefit most from the combined approach.
Prussian Blue‐Derived Nanocomposite Synergized with Calcium Overload for Three‐Mode ROS Outbreak Generation to Enhance Oncotherapy
Authors: Wenting Xu, Hongmei Zhou, Bangli Hu, Xinqiang Liang, Yanping Tang, Shufang Ning, He Ding, Piaoping Yang, Chen Wang
Journal: Advanced Healthcare Materials (2024)

Abstract Calcium overload can lead to tumor cell death. However, because of the powerful calcium channel excretory system within tumor cells, simplistic calcium overloads do not allow for an effective antitumor therapy. Hence, the nanoparticles are created with polyethylene glycol (PEG) donor‐modified calcium phosphate (CaP)‐coated, manganese‐doped hollow mesopores Prussian blue (MMPB) encapsulating glucose oxidase (GOx), called GOx@MMPB@CaP‐PEG (GMCP). GMCP with a three‐mode enhancement of intratumor reactive oxygen species (ROS) levels is designed to increase the efficiency of the intracellular calcium overload in tumor cells to enhance its anticancer efficacy. The released exogenous Ca 2+ and the production of cytotoxic ROS resulting from the perfect circulation of the three‐mode ROS outbreak generation that Fenton/Fenton‐like reaction and consumption of glutathione from Fe 2+ /Fe 3+ and Mn 2+ /Mn 3+ circle, and amelioration of hypoxia from MMPB‐guided and GOx‐mediated starvation therapy. Photothermal efficacy‐induced heat generation owing to MMPB accelerates the above reactions. Furthermore, abundant ROS contribute to damage to mitochondria, and the calcium channels of efflux Ca 2+ are inhibited, resulting in a calcium overload. Calcium overload further increases ROS levels and promotes apoptosis of tumor cells to achieve excellent therapy.
Cutaneous adverse event profile of epidermal growth factor receptor tyrosine kinase inhibitors in patients with non-small cell lung cancer: A meta-analysis of phase 3 randomized controlled trials.
Authors: Susu Zhou, Parissa Alerasool, Noriko Kishi, Nicholas Cole Rohs
Journal: Journal of Clinical Oncology (2024)

e20049 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the frontline treatment of choice for patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, EGFR-TKIs are associated with unique and dramatic dermatologic side effects that negatively impact patients’ quality of life, potentially resulting in poor adherence, including dose reductions or premature treatment cessation. Thus, it is crucial for the oncologists to be familiar with the array of dermatologic manifestations caused by these drugs for effective patient management. Methods: We performed a systematic search of PubMed, Embase, Web of Science, and Cochrane library for phase 3 randomized controlled trials (RCTs) comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with NSCLC. We calculated the odds ratio (OR) of all- and high-grade 10 dermatologic adverse events (dAEs). We conducted a meta-analysis using a random-effects model to compare the risk of dAEs in patients receiving EGFR-TKIs versus placebo/chemotherapy. Subgroup analysis based on control arm (placebo or chemotherapy) and individual EGFR-TKIs (afatinib, dacomitinib, erlotinib, gefitinib of osimertinib) were conducted. Results: 35 RCTs comprising 16,151 patients were included. In addition to all- and high-grade rash (all-grade: 12.21, 95% CI: 9.00-16.56; high-grade: OR 7.83, 95% CI: 5.11-12.00), EGFR-TKIs were associated with a significantly increased risk of all-grade acne (OR 12.24, 95% CI: 3.11-48.2), dermatitis acneiform (OR 8.46, 95% CI: 4.03-17.8), dry skin (OR 6.15, 95% CI: 4.02-9.40), palmar-plantar erythrodysesthesia syndrome (OR 11.14, 95% CI:3.00-41.4), paronychia (OR 31.97, 95% CI: 17.9-57.1), pruritus (OR 2.86, 95% CI: 2.17-3.77), skin exfoliation (OR 7.62, 95% CI: 2.55-22.8), and skin fissures (OR 11.59, 95% CI:4.86-27.6). The increased risk of EGFR-TKI-related dAEs was more prominent when compared with chemotherapy than placebo. In subgroup analyses of individual EGFR-TKIs, the risk of high-grade rash was significantly increased in patients treated with erlotinib or gefitinib but not in those treated with other EGFR-TKIs. Conclusions: This is the most comprehensive meta-analysis summarizing currently available evidence on cutaneous toxicity profile of EGFR-TKIs. These findings provide physicians with a better understanding for prompt recognition and management of these dAEs, to avoid unnecessary dose modifications and/or termination, and to prevent impairments in patients' quality of life.
Evaluating progression-free survival of EGFR exon 20ins in patients with advanced non-small lung cancer receiving EGFR inhibitors: A real-world data study.
Authors: Suad Kabbaha, Sarah Carder Dempsey, Kristian Thorlund
Journal: Journal of Clinical Oncology (2024)

e20092 Background: EGFR mutations with exon 20 insertions (Exon20ins) have emerged as a distinct subset with significant clinical implications. Their prevalence is approximately 10%. Patients with Exon20ins have fewer available treatment options compared to common EGFR mutations. We therefore aimed to evaluate progression-free survival (PFS) in advanced and recurrent non-small cell lung cancer (NSCLC) patients harboring Exon20ins and treated with EGFR inhibitors. Methods: We searched the OpenCase database for stage III-IV advanced and recurrent NSCLC patients harboring (Exon20ins) mutation and limited to patients having received at least commercially available EGFR inhibitors (including off-label use). We extracted time to progression or longest duration of follow-up for all patients as well as key baseline characteristics. We calculated median PFS (IQR) across all patients. Subgroup analysis compared the sub-populations contingent on each having data from n&gt;9 patients: line of therapy (1st, 2nd and 3rd+, Sex, Age (&lt;65 years vs older), and smoking status (never vs former/current). Results: The number of patients harboring Exon20ins mutation was n=93. Filtering to patients who had received EGFR inhibitors yielded a sample size of n=36 patients. Fourteen patients had data on 2 or 3 lines of treatments, thus yielding n=53 PFS data points. The median age was 56.5 years (IQR: 39.7-68) with 63.8% females, and 69.4% never-smokers (11% missing values). PFS was available for 21, 12, and 13 patients on 1st, 2nd and 3rd+ line of therapy, respectively. EGFR inhibitors were Afatinib (13), Osimertinib (12), Furmonertinib (6), Anlotinib(6), Crizotinib (3), Poziotinib(2), Almonertinib(2), Apatinib (2), Other (8). The overall median PFS was 9.0 months (IQR: 5.0 to 10.3, min-max: 1 to 38). The median PFS was similar for 1st, 2nd and 3rd+ lines of treatment at 8.13, 8.0 and 9.5 months, respectively. The median PFS for females was 9 months (IQR: 3.8 to 12, n=36) versus 6.2 months (5 to 10, n=17). Lastly, the median PFS for patients younger than 65 years was 9 months (IQR: 5.3 to 12, n=39) versus 5.6 (IQR: 2,5 to 9.4, n=15) for older patients. Subgroup comparison for smoking status was not possible due to low number of former/current smokers. Conclusions: Our exploratory analysis suggested improved PFS among female, and younger patients. No differences were observed by treatment line or treatment.
Trajectories of patient-reported outcomes after prolonged stays for hematopoietic cell transplant.
Authors: Lucy Gao, Zachariah Michael DeFilipp, Yi-Bin Albert Chen, Stephanie Lee, Thomas William LeBlanc, Hermioni L. Amonoo, Areej El-Jawahri, Richard Newcomb
Journal: Journal of Clinical Oncology (2024)

6553 Background: Patients hospitalized for hematopoietic cell transplantation (HCT) may have prolonged length of stay (PLOS). The longitudinal effect of PLOS in this population on quality of life (QOL) and psychological distress is unknown. Methods: We conducted secondary analyses of data from three prospective studies of patients undergoing HCT (2011-2022) at three academic centers. We defined PLOS as ≥30 days for allogeneic and ≥21 days for autologous HCT from date of admission. We collected patient-reported outcomes (PROs) for QOL, anxiety, depression, and posttraumatic stress disorder (PTSD) symptoms at baseline, 2 weeks, 3 and 6 months post-HCT. We used multivariate logistic regression to assess the effect of change in PROs from baseline to week 2 on PLOS adjusting for age, transplant type, donor, and diagnosis. We then fit linear mixed effects models to characterize the trajectory of PROs by PLOS over time. Results: 593 patients (mean age 56 years) were included, the majority of whom were male (57%), white (82%), and underwent allogeneic HCT (52%). The most common diagnosis was acute leukemia (28%). Patients with PLOS (26%) were younger (57 [range 18-78 yrs], 53 [19-75 yrs], p = 0.002), had acute leukemia (26%, 34%, p = 0.001), received myeloablative conditioning (21%, 41%, p &lt; 0.001), and underwent allogeneic HCT (50%, 60%, p &lt; 0.001). At baseline, patients with PLOS had lower QOL (108, 102, p = 0.001) and more depression symptoms (4.4, 5.3, p = 0.02). There was no difference in baseline anxiety or PTSD symptoms. An increase in depression symptoms from baseline to week 2 was associated with greater odds of PLOS (adjusted OR = 1.08, p = 0.04). The table depicts longitudinal differences in PROs by PLOS. Compared to those without PLOS, patients with PLOS reported lower QOL (time*PLOS interaction, ∆ = -6.6, SE = 2.1, p = 0.001) and greater increase in depression symptoms (time*PLOS interaction, ∆ = 1.9, SE = 0.6, p &lt; 0.001) at week 2. Lower QOL in those with PLOS persisted through 6 months (Table). PLOS was associated with more re-admissions (0.8, 1.1, p = 0.02) and mortality (9%, 19%, p = 0.001) within 1 year of HCT. No difference was seen in rate of relapse and severe acute or chronic graft- versus-host disease. Conclusions: Patients with PLOS experienced worse QOL and increased psychological distress. Increase in depression symptoms from admission to week 2 may be an early indicator of PLOS and supports mental health screening during the index HCT hospitalization. Patients with PLOS may benefit from enhanced supportive care during and after HCT.[Table: see text]