tbuckley/cabot-search huggingface dataset:
Noncanonical RET fusions in Chinese patients with non-small cell lung cancer from DNA-based next-generation sequencing.
Authors: Hao Lin, Yujie Liu, Ruitao Zhou, Yutao Feng, Huiya Cao, Peisu Suo, JIA Guo, Shifu Chen
Journal: Journal of Clinical Oncology (2024)

e20000 Background: The FDA has approved selpercatinib and pralsetinib for the treatment of metastatic RET fusion-positive non-small cell lung cancer in adult patients. Although the overall response rate is high and the response is durable, the outcomes may vary due to different fusion types of the same driver gene. Methods: We retrospectively collected and analyzed 14062 samples (tumour tissue or plasma) from Chinese lung cancer patients who underwent tissue-based or ctDNA-based next-generation sequencing (NGS) assays at HaploX Genomic Sequencing Center from May 18, 2020, to January 11, 2024. All samples with a RET gene fusion were included and classified based on the fusion partner gene and breakpoint position. Results: A total of 157 (1.1%) samples with DNA-based NGS harbored a RET gene fusion. Among the samples with a RET gene fusion, the most common RET fusion partners at the DNA level were KIF5B (73.2%) and CCDC6 (21.0%). We categorized RET fusions into canonical fusions and noncanonical fusions based on fusion partner and breakpoint position, and the proportions of canonical fusions and noncanonical fusions were 88.5% (139/157) and 11.5% (18/157) respectively. Among the samples with a noncanonical RET fusion, 5 samples harbored a RET fusion with an uncommon fusion partner, it remains unclear whether these fusions lead to RET activation. Conclusions: In this retrospective study, we identify different types of RET fusions in Chinese lung cancer patients. The majority are canonical fusions, which can benefit from tyrosine kinase inhibitors in clinical, the rest are noncanonical fusions, and their role in precision therapy needs further verification by RNA-based NGS or other assays. All in all, our research helps guide precision therapy in clinical settings. [Table: see text]
Association of N-adhesin and focal adhesion kinase with frequency of tumor spread through the airspace (STAS) in stage I lung carcinoma and correlation with recurrence.
Authors: Hongbing Liu, Yunchang Meng
Journal: Journal of Clinical Oncology (2024)

e20020 Background: Spread through air spaces (STAS) is one of the many modes of lung cancer dissemination. Aberrant activation of epithelial-mesenchymal transition (EMT) has been associated with enhanced tumor cell migration and invasiveness, a process that is accompanied by a decrease in adhesion molecules that maintain contact between epithelial cells, leading to cell separation and increased cell motility. Our objectives were to investigate the effect of adhesion molecule expression levels on STAS occurrence and postoperative recurrence in patients undergoing radical resection for stage I lung carcinoma. Methods: We examined the association of adhesion molecules with STAS as the primary endpoint and the Disease-Free Survival (DFS) as a secondary endpoint. E-cadherin, P-cadherin, N-cadherin, focal adhesion kinase (FAK), epithelial cell adhesion molecule (EpCAM) neural cell adhesion molecule 1 (NCAM1), vascular cell adhesion molecule 1 (VCAM1), intercellular cell adhesion molecule-1 (ICAM-1) were analyzed by immunohistochemistry in patients undergoing radical resection for stage I lung carcinoma. Associations between those adhesion molecules expression levels and STAS were determined by using the chi-square test and logistic regression model. DFS was analyzed by using the log-rank test and Cox proportional risk model. Results: As of January 1, 2024, 12 of 60 patients undergoing radical resection for stage I lung carcinoma had a disease recurrence. All of 60 patients’ tissue specimens were retrospectively analyzed, and there were no significant differences between patients with STAS-positive(n=30) and STAS-negative(n=30) in baseline clinicopathologic features, except for histological growth patterns, and lymphovascular invasion.Higher incidence of STAS was significantly associated with low expression of E-cadherin (P=0.002), high expression of N-cadherin (P=0.018) and FAK (P=0.027), and males (P=0.026), independent of tumor size, age, and clinical stage. Multivariate analysis showed that STAS (P=0.025), low E-cadherin/high N-cadherin (P=0.038), low E-cadherin/high FAK (P=0.025), and high N-cadherin/FAK (P=0.003) were significantly correlated with a higher risk of recurrence. In addition, females (P=0.034), and high N-cadherin/FAK (P=0.032) were associated with a high risk of recurrence in patients with STAS. Conclusions: Low expression of e-cadherin, high expression of N-cadherin and FAK were independent predictors of higher incidence of STAS. Tumors with low E-cadherin/high N-cadherin, low E-cadherin/high FAK, and high N-cadherin/FAK expression were important predictors of recurrence in patients with stage I lung carcinoma. Additionally, high N-cadherin/FAK expression in tumors provides information about a higher risk of recurrence in STAS-positive stage I lung carcinoma.
Optimization of fusion detection in non-small cell lung cancer by amplicon-based RNA sequencing.
Authors: Qin Feng, Yue Wang, Dongmei Lin, Junling Zhang, Mengli Huang, Ding Zhang, Yating Zheng, Depei Huang, Jing Ma, Lei Xiong
Journal: Journal of Clinical Oncology (2024)

e20042 Background: In non-small cell lung cancer (NSCLC), more and more driver fusions are suitable for targeted therapy. Sequential or parallel DNA and RNA sequencing is an option, but it is costly and requires sufficiently high quality biopsy material. The purpose of this study was to confirm the consistency of fusion genes detected by DNA-based NGS and RNA-based NGS in the same sample, and to validate the performance of FFPE samples for RNA-based NGS. Methods: In this study, we evaluated the benefits of capture-based DNA sequencing and amplicon-based RNA sequencing in identifying gene fusion and exon-skipping events in 98 NSCLC patients. All cases were FFPE samples stored for 1-5 years. In addition, we investigated the limiting performance of RNA-based NGS for RNA initiation. Results: In the cases of positive DNA sequencing fusion samples, the fusion consistency detection rate of RNA sequencing was 95% (38/40). Two cases were not detected by RNA-based NGS, one was a five-year FFPE sample and the other was due to a probe not covered problem. In patients with negative DNA fusion genes, RNA sequencing could detect 12.07% more fusion-positive cases involving ALK (n = 1), ROS (n = 3), MET 14 exon skipping (n = 1), RET (n = 1), and BRAF (n = 1). Moreover, the FFPE samples stored for 3-5 years inevitably degrade the RNA, but could still be used for RNA-based sequencing. Among 66 FFPE samples stored for 3-5 years, the detection rate of fusion consistency between DNA sequencing fusion samples and RNA sequencing was 96.77%(30/31). In patients with negative DNA fusion genes, RNA sequencing was able to detect 14.29% (5/35) more fusion-positive cases. The performance verification of the other 8 samples with different RNA input amounts found that 87.5% (7/8) of the samples could meet the quality control of RNA sequencing and accurately detect fusion mutations as low as 1 ng. Conclusions: Molecular profiling based on mixed DNA and RNA sequencing improves the effectiveness of detection of fusion-driven NSCLC. The method was feasible on small tissue samples as well as FFPE samples stored for 3-5 years, and could greatly reduce the complexity and cost of molecular examination.
Ponatinib (PON) in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) and the T315I mutation (mut): 4-year results from OPTIC.
Authors: Michael Deininger, Jane Apperley, Christopher Kevin Arthur, Charles Chuah, Andreas Hochhaus, Hugues de Lavallade, Jeffrey Howard Lipton, Elza Lomaia, James K. McCloskey, Lori J. Maness, Michael J. Mauro, Beatriz Moiraghi, Carolina Pavlovsky, Gianantonio Rosti, Philippe Rousselot, Maria Undurraga Sutton, Xiaowei Ren, Alexander Vorog, Hagop M. Kantarjian, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2024)

6501 Background: PON, an approved BCR::ABL1 TKI, potently inhibits native BCR::ABL1 and all reported single-resistance muts, including T315I. In the primary analysis of the phase 2 OPTIC study (NCT02467270) at 12 mo, pts with CP-CML and the T315I mut had robust responses to PON. We present 4-year results from the OPTIC trial in pts with the T315I mut. Methods: Pts with CP-CML resistant to ≥2 TKIs or with the BCR::ABL1 T315I mut were randomized 1:1:1 to PON starting doses of 45, 30, or 15 mg QD, with dose reduction to 15 mg upon achievement of ≤1% BCR::ABL1 IS in the 45-mg and 30-mg cohorts. This subgroup analysis evaluated 48-mo ≤1% BCR::ABL1 IS , PFS and OS rates and safety outcomes in pts with the T315I mut. Results: Overall, 283 pts received PON (45 mg/30 mg/15 mg: n=94/95/94); 23.8% had the T315I mut (n=25/21/21). At the data cutoff for the 4-year analysis (May 8, 2023), median follow-up in the 45-, 30-, and 15-mg cohorts was 60.6, 63.5, and 60.7 mo, respectively. The proportion of pts with the T315I mut achieving ≤1% BCR::ABL1 IS by 48 mo was highest in the 45-mg cohort (64%; Table). Median time to response (mo) and estimated median duration of response (mo) were 6.0 and 16.7 in the 45-mg cohort, 3.1 and 12.0 in the 30-mg cohort, and 6.0 and not reached (NR) in the 15-mg cohort. In the 45- and 30-mg cohorts, 15 and 5 pts had dose reduction to 15 mg after achieving ≤1% BCR::ABL1 IS , of which 7 and 2 maintained response; of pts not maintaining response, 6 and 1 regained response after dose re-escalation. Median PFS was NR, 28.4 mo, and 45.6 mo in the 45-, 30-, and 15-mg cohorts, respectively, and median OS was NR in all groups. The 45-mg cohort had the highest 4-year survival rates (OS: T315I 86%; overall 88%; Table). Grade ≥3 TEAE rates in the 45-, 30-, and 15-mg cohorts were 60%, 38%, and 38%, with TEAEs leading to discontinuation in 8%, 14%, and 5%, respectively. Arterial occlusive events (AOEs) occurred in 8%, 14%, and 5% of pts in the 45-, 30-, and 15-mg cohorts; exposure-adjusted AOE rates were 2.4%, 7.3%, and 2.8%, respectively. Conclusions: PON demonstrated robust long-term efficacy and manageable safety in this 4-year update in pts with the T315I mut. A PON starting dose of 45 mg with reduction to 15 mg upon achievement of ≤1% BCR::ABL1 IS provided the optimal benefit:risk ratio. Clinical trial information: NCT02467270 . [Table: see text]
A retrospective comparison of abbreviated course “7+7” vs standard hypomethylating agent plus venetoclax doublets in older/unfit patients with newly diagnosed acute myeloid leukemia.
Authors: Alexandre Bazinet, Courtney Denton Dinardo, Naszrin Arani, Alex Bataller, Caitlin R Rausch, Abhishek Maiti, Mahesh Swaminathan, Naval Guastad Daver, Tapan M. Kadia, Farhad Ravandi-Kashani, Hagop M. Kantarjian, Samy Chraibi, Justine Decroocq, Laurent Pascal, Delphine Lebon, Sarah Bonnet, Nicolas Gauthier, Arnaud Pages, Stéphane De Botton, Christophe Willekens
Journal: Journal of Clinical Oncology (2024)

6507 Background: Hypomethylating agent (HMA) plus venetoclax (VEN) regimens are standard of care in older/chemotherapy ineligible patients with acute myeloid leukemia (AML). While the VEN label recommends continuous 28-day cycles, shortened VEN durations may mitigate cytopenias and improve tolerability. It is unknown how shorter VEN cycles compare to standard HMA+VEN in terms of efficacy/safety. Methods: We performed a retrospective comparison of patients with newly diagnosed (ND) AML treated with azacitidine (AZA) x 7 days plus VEN x 7 days (“7+7” regimen) at 7 French centers (n=82, Willekens, ASH 2022) vs patients treated with standard dose HMA+VEN (s-HMA/VEN) at a US center (n=173), generally consisting of 21-28 days of VEN. We compared composite complete remission rate (CRc, consisting of CR + CRi), overall survival (OS), event-free survival (EFS), and myelosuppression between regimens. Results: Baseline characteristics are shown in the table. The s-HMA-VEN group consisted of 10-day decitabine (DAC) in 59% with the remaining patients receiving 5-day DAC or 7-day AZA. The CRc rate was similar; 72% with “7+7” vs 71% with s-HMA/VEN (p=0.89). The CR rate was 57% with “7+7” vs 55% with s-HMA/VEN (p=0.72). Median cycles to first response was 1 in both groups, however 42% of responders on “7+7” required more than 1 cycle for first response whereas almost all responders on s-HMA-VEN (99%) had a first response after cycle 1. Median cycles to best response was 2 with “7+7” vs 1 with s-HMA-VEN (p=0.02). 4-week mortality was similar (2% with “7+7”, 6% with s-HMA-VEN; p=0.24). 8-week mortality was higher with s-HMA-VEN (17%) compared to “7+7” (6%) (p=0.02). The median OS was 11.2 months (2-year 28%) with “7+7” vs 10.1 months (2-year 33%) with s-HMA/VEN (p=0.93). Outcomes stratified by molecular groups will be updated at the meeting. Fewer patients required platelet transfusions during cycle 1 with “7+7” compared to s-HMA/VEN (62% vs 77%, p=0.01). The cycle 1 rates of neutropenic fever and red cell transfusion requirements were similar. Conclusions: Acknowledging the limitations of a retrospective comparison across multiple centers, we did not observe a signal for a difference in efficacy between "7+7" vs standard VEN-based HMA doublets in ND-AML. The “7+7” regimen was associated with lower platelet transfusion requirements and lower 8-week mortality. [Table: see text]
Multimodal risk stratification of non-metastatic lung adenocarcinoma using AI on histology and immunohistochemistry slides.
Authors: Benjamin Adjadj, Pierre-Antoine Bannier, Andreas Papadakis, Nancy Fournier, Roni Rayes, Reem Marza, Archana Srivastava, Jason S. Agulnik, Jonathan Spicer, Pierre-Olivier Fiset, Hangjun Wang, Kathryn Schutte, Alan Spatz
Journal: Journal of Clinical Oncology (2024)

e20083 Background: While immunohistochemistry (IHC) slides are commonly used to assess the presence of actionable biomarkers, the recent advances in artificial intelligence (AI) focus exclusively on hematoxylin and eosin (H&amp;E) slides. Nonetheless, many IHC slides, potentially rich in prognostic information, remain underexplored for risk stratification and outcome prediction. Our study aims to assess the complementarity of H&amp;E and IHC slides through the development of a multimodal prognostic AI model for lung adenocarcinoma patients. Methods: We collected 1 H&amp;E slide, 8 IHC slides (PD-L1, FOXP3, HELA2, CD3, CD4, CD8, CD163, KI67), and 2 double-stained slides (PDL1-CD163 and CD3-CD163) from 245 resected patients with lung adenocarcinoma at two different hospitals (median OS = 54.0 months [11.3 - 138.0]). Patients underwent various adjuvant treatments (chemotherapy n=92; immunotherapy n=4; other n=36; no treatment n=152). We cross-validated 11 AI models (one model per staining) to predict overall survival in these patients. We used Harell’s C-index and the 70-month cumulative AUC to evaluate the performance of our models. To assess their stratification power, each model’s predictions were split into high-risk and low-risk populations to compute a Hazard Ratio and a log-rank test p-value. Subsequently, a Cox proportional hazards model aggregated the predictions of the 11 models to compute a final risk score. We performed a grid search to find the combination of markers yielding the highest C-index. We calculated the hazard ratios to determine each biomarker's predictive value. Results: The H&amp;E model was the best unimodal model, with a C-index of 0.69 [0.67 - 0.71]. The best-performing multivariate model was obtained by combining the risk scores from univariate models in a Cox regression using H&amp;E, CD8, PD-L1, HELA2, and FOXP3 slides, reaching a C-index of 0.71 [0.69 - 0.73] (Table). We found that the predictions from H&amp;E (HR = 1.39; P = 0.03) and PD-L1 (HR = 1.17; P = 0.04) were significantly associated with survival. Conclusions: By significantly improving patient stratification with non-metastatic lung adenocarcinoma, our multivariate model proves that some IHC markers contain complementary proteomic information to H&amp;E slides. Consequently, this study paves the way for developing more comprehensive risk assessment tools from H&amp;E and IHC stainings. [Table: see text]
Comprehensive genomic and transcriptomic profiling of pulmonary nodules in synchronous multiple primary lung cancer.
Authors: Xingsheng Liu, Yi Zhang, Li Han, Zhenzhen Li
Journal: Journal of Clinical Oncology (2024)

e20022 Background: Synchronous Multiple Primary Lung Cancer (sMPLC) exhibits distinct histopathological characteristics among pulmonary nodules. However, a comprehensive understanding of the somatic mutation landscape and transcriptome heterogeneity is lacking. Therefore, our study aims to meticulously investigate genomic distinctions among multiple pulmonary nodules within individual patients. Methods: We performed targeted sequencing on tumor specimens and conducted bulk RNA transcriptome analysis on 53 multiple nodules originating from 26 lung cancer patients. The multiple nodules from the same patient was determined as major nodule and minor nodule. Additionally, the tumor tissues underwent histopathological evaluation through H&amp;E staining, complemented by a comprehensive series of immunohistochemistry (IHC) analyses to detect protein expression. The detected protein markers encompassed PD-L1, Ki67, and others. Results: For the 53 nodule samples from 26 MPLCs patients, EGFR was the mostly mutated genes, and the TP53 mutation frequency demonstrated notably different between major and minor nodules. Furthermore, pathway enrichment analysis based on the differentially expressed genes (DEGs) between major and minor nodules revealed the significantly active cell cycle and p53 pathways in the major nodules. Additionally, both major and minor nodules demonstrated mostly similar immune microenvironment and PD-L1 protein expression, and a significantly higher expression of Ki67. A noteworthy suppression was observed in the immune microenvironment in nodules, revealed by the expression of macrophage, neutrophils, and NK cells. Furthermore, minor nodules exhibited a modestly elevated expression of macrophages compared to major nodules. Additionally, among the significantly up-regulated cell cycle related genes in the major nodules when compared with minor nodules, CCNE1 mRNA expression demonstrated significant correlation with poor prognosis in the lung cancer. Conclusions: This study validated molecular distinctions between samples from major and minor nodules in patients with sMPLC at both genomic and transcriptomic levels. The major nodules exhibited heightened activity in tumor cell proliferation pathways and demonstrated malignancy-related biological characteristics, which correlated with pathological assessment results.
Impact of JAK2 allele burden on MF outcome in the era of ruxolitinib.
Authors: Julie Braish, Prithviraj Bose, Naveen Pemmaraju, Sherry Pierce, Koji Sasaki, Zeev Estrov, Keyur P. Patel, Hagop M. Kantarjian, Lucia Masarova
Journal: Journal of Clinical Oncology (2024)

6514 Background: Myelodepleted myelofibrosis (MF), characterized bycytopenias, lower JAK2V617F allele burden (JAK2%) and shorter benefit from JAKi ruxolitinib (RUX), has worse survival (OS) compared to myeloproliferative MF. Lower JAK2% and inferior OS is more typical for primary MF (PMF) vs MF from essential thrombocythemia or polycythemia vera (PPV/PET-MF). We sought to investigate the impact of JAK2% (&lt;/≥ 50%), cytopenias and the use of RUX in outcome of PMF/PPV-PET-MF patients from our center. Methods: 601 medical charts of JAK2 mutated patients with MF (known JAK2%) were retrospectively reviewed. We divided patients based on the absence (-) or presence (+) of cytopenias (hemoglobin &lt; 10 g/dL or platelets &lt; 100 x10^9/L) and leukocytosis (WBC ≥ 25 x10^9/L) into: Gr1 = (-)/(-) [absence of both]; Gr2 = (-)/(+) [proliferative]; Gr3 = (+)/(-) [cytopenic]; Gr4 = (+)/(+) [cytopenic and proliferative]) and evaluated OS per JAK2 &lt;/≥ 50% and PMF vs PPV/PET-MF. We assessed the tolerance of RUX ≥3 years. We used descriptive statistics, Kaplan-Meier curve with log-rank test and regression analysis for demographics, estimation of OS and its comparison. OS was censored at the time of stem cell transplantation. Results: Median age of the entire cohort was 75 years (64% males). Patients with JAK2 &lt;50%, more likely PMF, had more anemia and thrombocytopenia, higher blasts, less leukocytosis, and smaller splenomegaly. JAK2 &lt;/≥ 50% did not discriminate OS of the entire group, PMF or PPV/PET-MF (median OS of ~ 45 months for each; only PPV/PET-MF with 64 months). OS of Gr1-4 according to JAK2 &lt;/≥ 50% and PMF/ PPV/PET-MF and combined OS of patients with comparable outcome (A-D) are shown in the table. The final groups with distinct outcomes included: A+B) non-cytopenic PET/PPV-MF and PMF irrespectively of proliferation and JAK2% - with one exception of non-cytopenic, proliferative PMF with JAK2 ≥50% - had median OS of 70 months (range, 54-86); D) cytopenic and proliferative PMF with any JAK2% and PPV/PET-MF with JAK2 &lt; 50% of median OS 19 months (range, 13-25), and C) the rest of the cytopenic patients and non-cytopenic, proliferative PMF with JAK2 ≥50% with a median OS of 36 months (range, 32-42). Among the 3 final groups, similar proportion of patients were exposed to RUX during their follow-up: 36% (A+B), 31% (B) and 28% (C), respectively (p =0.13). The most patients in (A+B) group were able to tolerate RUX for ≥3 years (p =0.036). All patients had improved OS with RUX (data to be presented). Conclusions: Cytopenias and/or proliferation, rather than JAK2 &lt;/≥50%, define the outcome of PMF and PPV/PET-MF patients. [Table: see text]