tbuckley/cabot-search huggingface dataset:
Prevalence of NTRK gene fusions in solid tumors in northeastern Mexico.
Authors: Christopher Cerda-Contreras, Victor Oyervides, Oscar Vidal-Gutiérrez, Maria Fernanda Noriega, Mario Lozano Aguilar
Journal: Journal of Clinical Oncology (2024)

e15145 Background: Gene fusions (GF) are among the intricate hallmarks of cancer that lead to abnormal cell proliferation and survival. Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are frequent in rare solid tumors but less frequent in common ones. Scarce literature has evaluated the prevalence of this aberration estimated to be from 0.5 to 1% globally. For these particular type of tumors, multikinase inhibitors is an option aside from chemotherapy with good responses. Objective: To determine the prevalence of NTRK gene fusions in a Mexican population. Methods: Sociodemographic, clinical, and histopathological data were collected in a single center from databases of Pathology and Oncology Departments of Hospital Universitario Dr. José E. González in Northeastern Mexico. Patients of all ages with solid tumors were included if tested positive for Pan-TRK by immunohistochemistry (IHC). Confirmation for gene fusion was made using Next Generation Sequencing (NGS) technology in formalin-fixed paraffin-embedded tissue. Results: A total of 156 patients from 2021 to 2023 were included for analysis. 67 (42.9%) did test positive for IHC. Of these, 52.2% were male and 20.8% were pediatric. Adult and pediatric median age of 57 and 13 years, respectively. Most frequent tumors locations were central nervous system &amp; extremities. Gene fusion anomaly was confirmed in 6 patients. Among these, 83.3% were male and 16.7% pediatric population. Only NTRK1 and NTRK3 were found in gene fusions. Four translocations were prevalent TPM3:NTRK1 and ETV6:NTRK3 with 2 cases (33.3%), respectively. Followed by LMNA:NTRK1 and EML4:NTRK3 each with one patient. For location, arranged in descending order, head and neck (33.3%), extremities (33.3%), central nervous system and occult primary tumors both 16.6%. The only non-adult tumor reported was infantile fibrosarcoma. Prevalence was estimated to be 3.8% in our population. Conclusions: Understanding the molecular biology of tumor cells enables the development of targeted treatments other than chemotherapy. In our population, NTRK gene fusions were a little more prevalent (~4%) than global estimation. Unfortunately, in Mexico there's a lack of access to multikinase inhibitors. Further studies with large samples are required in Mexico and all over the world to afford access to these tumor-agnostic therapies.
A blood-based screening test for colorectal cancer (CRC) using methylation sequencing.
Authors: Urvashi Bahadur, Swaraj Basu, Nihesh Rathod, Divya Vishwanath, Prakash Hiremath, Preetha RT, Aditi Chatterjee, Arunima Ghosh, Sameer Phalke, Subuhi Yete, Ankita Khan, Sweta Sanguri, Mohammed Rahman, Sewanti Limaye, Charles Cantor, Vamsi Veeramachaneni, Ramesh Hariharan
Journal: Journal of Clinical Oncology (2024)

e15089 Background: Diagnosis of CRC is biased towards later stages in India (3.8% Stage I, 16.7% Stage II, 50.7% Stage III, 28.8% Stage IV), and five-year survival at &lt; 40% is one of the lowest in the world. A blood-based non-invasive screening test for CRC using cell-free DNA (cfDNA) methylation sequencing is developed here from the blood of 212 controls and 67 treatment naive CRC patients from 21 sites across India and processed in Strand’s reference lab in Bangalore. Methods: Steps involved cfDNA extraction, NEB Enzymatic Methyl-Seq library preparation, Twist Human Methylome hybridisation capture, 2x150bp sequencing on NovaSeq 6000/X. Methylation + fragmentomic features were calculated for each target region. Samples were split randomly into a leave-in set of 170 controls + 53 cancers (I: 8, II 16, III: 23, IV: 6) and a leave-out set of 42 controls + 14 cancers, (I: 5, II: 4, III: 2, IV: 3) with 20 rounds of 4-fold cross-validation done on the leave-in set (random splits). Feature selection per fold was performed using the KS test without access to ¼ of the leave-in set and to the entire leave-out set. Gradient boosted trees with monotonic constraints reflecting the expected association of the scores with cancer were used to build “explainable” models. Test robustness was assessed using differentially methylated regions (DMRs) from other studies, and by assessing predictability using sample metadata alone. Results: At a 91% specificity level, the ensemble model had a median sensitivity of 62.5% for Stage I (95%CI 38%-86%), 87% for Stage II (95% CI 75%-95%), 87% for Stage III (95% CI 75%-95%) and 83.4% for Stage IV (95% CI 84%-100%) in cross-validation, and 60% for Stage I (95%CI 60%-80%), 100% for Stage II (95% CI 80%-100%), 100% for Stage III (95% CI 100%-100%) and 100% for Stage IV (95% CI 100%-100%) on the leave-out set. At a ~98% specificity level, the model had a median sensitivity of 37.5% for Stage I (95%CI 37%-50%), 69% for Stage II (95% CI 56%-75%), 69% for Stage III (95% CI 60%-84%) and 67% for Stage IV (95% CI 50%-84%) in cross-validation, and 40% for Stage I (95%CI 20%-60%), 75% for Stage II (95% CI 75%-100%), 100% for Stage III (95% CI 100%-100%) and 100% for Stage IV (95% CI 66%-100%) with a slight decrease in specificity to 95.2% on the leave-out set. Using DMRs derived from TCGA data and other publications, yielded a comparable (to our models) cross-validation area under the curve (AUC: 0.93-0.95). Cross-validation performance using only the sample metadata in table 1 and without access to the data was significantly poorer (AUC 0.75-0.81). Conclusions: cfDNA-based methylation profiles are consistent across studies and ethnicities, leading to robust and “explainable” CRC screening predictions. [Table: see text]
Initial clinical experience with the first-in-class anti-metastasis therapeutic TTX-MC138.
Authors: Zdravka Medarova, Neil Robertson, Subrata Ghosh, Susan Duggan, Andreas Varkaris
Journal: Journal of Clinical Oncology (2024)

e15072 Background: TransCode is focused on developing nucleic acid-based cancer therapies. Through scientific discovery efforts, miRNA-10b was identified as a master regulator of the viability of metastatic tumor cells. This knowledge allowed development of a therapeutic strategy based on miR-10b inhibition. miR-10b was targeted using antagomirs delivered to metastatic sites by an iron oxide nanocarrier, termed TTX-MC138. Results demonstrated that TTX-MC138 could cause complete and persistent regressions of metastases in cancer models. Methods: TransCode has an active eIND and is conducting a Phase 0 clinical study with radiolabeled TTX-MC138 in patients with advanced metastatic cancer of multiple tissue origins. TTX-MC138 was radiolabeled with Cu64 through a NODAGA chelator. IND enabling studies were conducted in rats and non-human primates to support FDA activation (eIND163800) for the Phase 0 clinical study. In the trial, a single intravenous microdose of Cu-64 labeled TTX-MC138 is administered, which allows for direct visualization of drug tissue distribution in cancer patients via PET-MR imaging. Results: Non-clinical studies were conducted to support the TTX-MC138 clinical development program. In rats, when TTX-MC138 was infused intravenously at a dose of 27 mg/kg, results displayed a blood half-life of 16.7±9.35 hrs. At 24-h, concentrations were highest in the liver and spleen. In non-human primates injected with Cu64-labeled TTX-MC138 at a dose of 100 microg, the organs with the highest uptake were the liver, heart, lung and spleen. The mean whole blood half-life was 12.2 ± 2.3 h (mean ± standard deviation). RadioHPLC analysis of plasma samples showed that the drug is very stable with respect to metabolism. A study in rats involved a single injection with 0, 0.5 or 1 mg/kg followed by a 2-day or 14-day observational period. The drug was well-tolerated at levels up to 1 mg/kg, which was considered to be the no-observed-adverse-effect-level (NOAEL). Preliminary results from the Phase 0 clinical study showed that the first patient tolerated the dosing with no reported adverse reactions, the drug remained stable in circulation, and circulated with a long half-life of 20 hours. Lesion to blood ratios of radioactivity in the region of the metastatic lesions was consistent with accumulation of TTX-MC138. Enrollment, data monitoring, and analysis is ongoing. Conclusions: The results of the non-clinical studies and Phase 0 clinical study have the potential to address the question of delivery to the target tissue. The process leading to the implementation of TTX-MC138 in the clinic is critically dependent on the innate tropism of the TTX delivery platform to tumors and represents a first step towards developing effective nucleic-acid based therapeutics against cancer. Clinical trial information: NCT05908773 .
Dual analysis of IL-8 in non-small cell lung cancer: A clinical perspective on protein and RNA evaluation via imaging mass cytometry.
Authors: Corinne Ramos, Amandine Gerstenberg, Melodie Boute, Marie Lapage
Journal: Journal of Clinical Oncology (2024)

e15068 Background: The cytokine Interleukin-8 (IL-8) plays a pivotal role in the tumorigenesis and progression of non-small cell lung cancer (NSCLC), influencing both the tumor microenvironment and immune escape mechanisms. Given its significance, accurately assessing IL-8 levels at the protein and RNA levels could provide valuable insights into its prognostic value and inform therapeutic targeting strategies. This study utilizes imaging mass cytometry (IMC) to conduct a comprehensive evaluation of IL-8 expression in NSCLC, integrating both protein presence and gene expression analysis within the spatial context of the tumor microenvironment. Methods: Our approach leverages the capabilities of IMC to simultaneously detect protein and RNA levels of IL-8 in NSCLC tissue samples. For protein analysis, antibodies tagged with heavy metal isotopes specifically target IL-8, allowing for precise quantification and spatial localization within the tumor. Concurrently, RNA detection is achieved through hybridization probes designed for IL-8 mRNA, enabling the direct observation of gene expression patterns. This method provides a unique opportunity to correlate IL-8's protein abundance with its mRNA expression, offering insights into the regulatory mechanisms at play and their impact on the tumor's behavior and patient outcomes. Results: Preliminary data demonstrate a marked heterogeneity in IL-8 distribution at both the protein and RNA levels, with distinct patterns emerging that relate to tumor aggressiveness and immune infiltration. High IL-8 expression, identified through our integrated IMC approach, correlates with poor prognosis and reduced response to standard therapies, underscoring its potential as a biomarker for NSCLC management. Furthermore, the spatial analysis afforded by IMC highlights the microenvironmental niches where IL-8-mediated interactions could drive tumor progression and immune evasion. Conclusions: By employing IMC for the dual analysis of IL-8 protein and RNA in NSCLC, our study provides a comprehensive view of this cytokine's role in lung cancer pathology. The ability to visualize and quantify IL-8 expression within the spatial context of the tumor microenvironment opens new avenues for understanding its biological impact and for developing targeted therapies. Our findings advocate for the inclusion of IL-8 in the biomarker panel for NSCLC, with potential implications for patient stratification and personalized treatment planning. Future research will focus on expanding these observations to a larger cohort and exploring the therapeutic modulation of IL-8 as a strategy for improving NSCLC outcomes.
Unraveling the role of ubiquitin C-terminal hydrolase L1 in high grade serous ovarian cancer pathogenesis.
Authors: Corinne Jansen, Julia McAdams, Morgan Woodman, Payton De La Cruz, Kathryn Grive, Nicole James
Journal: Journal of Clinical Oncology (2024)

e15078 Background: High grade serous ovarian cancer (HGSOC) is the most lethal of all gynecologic malignancies, due to the fact that the majority of patients are diagnosed at an advanced stage and eventually develop chemoresistant disease 12-18 months following completion of frontline therapy. Therefore, novel targeted therapies are urgently needed to combat chemoresistance and improve patient clinical outcomes. Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that plays a vital role in protein homeostasis and is highly overexpressed in HGSOC. It was previously uncovered that targeting UCHL1 with small molecule inhibition reduced cell viability in a chemoresistant ovarian cancer cell line. Methods: Comparative-label free proteomic analysis was used to uncover significant changes in HGSOC cell line OVCAR8WT following treatment with UCHL1 small molecule inhibitor, LDN-5744 or corresponding DMSO control. Significant pathway changes were determined by KEGG analysis. Matched chemosensitive and resistant HGSOC cells PEA1 and PEA2 were treated in combination with LDN-5744 and carboplatin, with cell viability was determined by an MTS assay. Furthermore, western blot analysis was employed to compare common cell growth pathway changes as a result of UCHL1 inhibition in HGSOC cells. Results: Proteomic analysis revealed a significant (p&lt;0.05) upregulation in methyl phosphate capping enzyme (MEPCE) (4.9-fold), asparagine synthetase (ASNS) (2.5-fold), Phosphoserine aminotransferase 1 (PSAT1) (1.7-fold), and downregulation in centrosomal protein 55 (CEP55) (-7.2-fold), These identified proteomic changes were confirmed by western blot. KEGG pathways analysis using all significantly (p&lt;0.05) differentially expressed proteins showcased significant (p&lt;0.05) enrichment in amino acid biosynthesis, and metabolism, and chemical carcinogenesis-reactive oxygen species. Chemoresistant PEA2 cells treated in combination with LDN-5744 and carboplatin demonstrated a 59% reduction in cell viability, significantly (p&lt;0.001) lower than the 13% and 22%, that was observed from UCHL1 and carboplatin treatment alone, respectively. Conversely, PEA1, the chemosensitive counterpart to PEA2 demonstrated a significant (p&lt;0.001) 37% increase in cell viability upon combinatorial treatment compared with carboplatin alone, indicating that UCHL1 inhibition rescues the cells from chemotherapy induced cell death. Finally, LDN-5744 treatment in PEA2 led to a reduction in levels of phospho-(p-)AKT, p-STAT3, and p-ERK, while conversely in PEA1 cells levels of these proteins were increase or unchanged. Conclusions: Our findings demonstrate that targeting UCHL1 results in prominent metabolic changes in HGSOC cells and that the efficacy of UCHL1 inhibition is heavily dependent upon platinum status. Overall, this study highlights UCHL1’s novel therapeutic role in the recurrent HGSOC.
Surufatinib plus PD-1/L1 inhibitors as maintenance therapy following first line (1L) platinum-based chemotherapy combined with PD-1/L1 inhibitors in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC).
Authors: Yi Hu, Jianhua Chen, Dongqing Lv, Jinliang Wang, Junxun Ma, Tienan Yi, Shikai Wu, Xiangdong Zhou, Xingxing Zhang, Dongmei Chen, Songhua Fan, Michael Shi, Weiguo Su
Journal: Journal of Clinical Oncology (2024)

e15109 Background: Pts with ES-SCLC have a poor prognosis. PD-1/L1 inhibitors combined with chemotherapy as 1L treatment has been demonstrated to improve the survival. Yet, pts are prone to progression after chemo-immunotherapy followed by anti-PD-1/L1 monotherapy. A multicenter, single-arm phase II study was conducted to evaluate the efficacy and safety of surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) combined with PD-1/L1 inhibitors in pts with ES-SCLC as 1L maintenance therapy. Methods: Key inclusion criteria were cytologically or pathologically confirmed ES-SCLC, ECOG PS 0-1, no disease progression after 4-6 cycles platinum-based chemotherapy combined with PD-1/L1 inhibitors. Enrolled pts received surufatinib (250mg, po, QD) plus PD-1/L1 inhibitors (same as that in prior 1L therapy: Durvalumab, Sintilimab, Toripalimab or Serplulimab) until disease progression or intolerable toxicity. The primary endpoint is progression free survival (PFS) per RECIST 1.1 by investigator. Results: From Sept 2022 to July 2023, 21 pts were enrolled. The median age was 62 years. 90.5% were male, 85.7% were former and current smokers and 52.4% had ECOG PS of 0, 11 pts completed 6 cycles of platinum-based chemotherapy combined with PD-1/L1 inhibitors, and 12 pts received durvalumab in 1L therapy. As of 20 Nov, 2023, the median follow-up duration was 9.2 months. Objective response rate (ORR) was 14.3% and DCR (disease control rate) was 71.4%. The mPFS of 1L maintenance therapy was 4.0 months (95%CI: 2.0-5.6). The mPFS from 1L treatment to disease progression was 8.7 months. mOS was not reached, with 3 mo- , 6 mo- and 9 mo- OS rate was 100%, 94.4% and 75.6%, respectively. 21 (100%) pts experienced treatment-emergent adverse events (TEAEs), and 8 (38.1%) pts experienced grade ≥3 TEAEs, most commonly with platelet count decreased, neutrophil count decreased and pneumonia. There was no treatment-related death. Conclusions: Surufatinib combined with PD-1/L1 inhibitors showed encouraging efficacy and tolerable safety profile as 1L maintenance therapy. Further OS follow-up is warranted. Clinical trial information: NCT05509699 .
FU/FA maintenance therapy with or without panitumumab (pmab) in <i>RAS</i> wild-type metastatic colorectal cancer (mCRC) (PanaMa, AIO KRK 0212): Updated efficacy analyses.
Authors: Dominik Paul Modest, Meinolf Karthaus, Stefan Fruehauf, Ullrich Graeven, Lothar Müller, Alexander Koenig, Ludwig Fischer von Weikersthal, Karel Caca, Eray Goekkurt, Siegfried Haas, Annika Kurreck, Swantje Held, Armin Jarosch, David Horst, Anke C. Reinacher-Schick, Stefan Kasper, Volker Heinemann, Sebastian Stintzing, Tanja Trarbach, Arndt Stahler
Journal: Journal of Clinical Oncology (2024)

3506 Background: The randomized open-label phase II PanaMa trial compared FU/FA with or without pmab maintenance after mFOLFOX6+pmab induction for RAS wild-type mCRC. Updated efficacy results of the Full Analysis Set are presented. Methods: Median progression-free survival (PFS), overall survival (OS), PFS of re-induction (PFS re-ind.), time to failure of strategy (TFS), and objective response rates (ORR) were compared by log-rank test / Cox regression and Fisher’s exact test. Results: PFS was significantly (8.8 vs. 5.8 months, HR=0.73 (95%CI 0.56 – 0.94), P=0.015) and OS numerically longer (29.9 vs. 24.7 months, HR=0.85 (95%CI 0.64 – 1.12), P=0.24). PFS re-ind. was significantly shorter after pmab maintenance (4.1 vs. 7.4 months, HR=1.93 (95%CI 1.33 – 2.82), P&lt;0.001). TFS was comparable (17.1 vs. 15.7 months, HR=0.98 (95%CI 0.68 – 1.42), P=0.92). Molecular subgroups are displayed in Table 1. ORR of FU/FA+pmab was comparable to FU/FA during induction (74.4% vs. 76.4%, P=0.77), higher during maintenance (40.8% vs. 29.3%, P=0.06), but lower at re-induction (8.0% vs. 35.9%, P&lt;0.001). Conclusions: PFS remained improved by the addition of pmab to FU/FA maintenance therapy, while OS was not significantly longer. Re-induction of pmab+mFOLFOX6 did not provide benefit following pmab maintenance regarding PFS. Clinical trial information: NCT01991873 . [Table: see text]
To explain the unexplainable in MONARCH 3 overall survival: the restricted mean survival time. Letter to the Editor regarding ‘Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2− advanced breast cancer: Final overall survival results of MONARCH 3’ by M. P. Goetz et al.
Authors: A. Orlandi, L. Mastrantoni, E. Bria, G. Tortora
Journal: Annals of Oncology (2024)
Reporting an Indian multicentric community oncology practice’s observation on patterns of homologous recombinant deficiency across various solid cancers evaluated through tumor-DNA-based NGS.
Authors: Chirantan Bose, Udip Maheshwari, Dr Disha Morzaria, Ashish Joshi, Vashishth Maniar, Kunal Naishadh Jobanputra, Akash Pawar, Kshitij Chandrakant Joshi, Pritam Kalaskar, Mangesh Mekha, Krushna Chaudhari, Taha Sethjiwala, Devendra Pal, Smit Sheth, Pravin Khandare
Journal: Journal of Clinical Oncology (2024)

e15066 Background: Homologous recombinant deficiency(HRD) is being evaluated across various solid organ malignancies to assess not just the underlying biological behavior of the cancer but also for potential response to PARP inhibitors. HRD status is assessed by measuring mutations in genes involved in the HRR (Homologous Recombinant Repair) pathway along with other genomic aberrations across the tumor genome like Loss of Heterozygosity (LOH), Telomeric Allelic Instability (TAI) and Large Scale Transitions (LST).We compare here overall HRD scores and their sensitivity and specificity to HRR v/s HRR + LOH, TAI, and LST in an attempt to study the prevalence and pattern of HRD scoring and response to PARPi. Methods: The retrospective data of cancer patients who have undertaken the aforementioned test were evaluated to analyze the patterns of HRD. Responses of a limited subset of patients who received PARP inhibitors were also assessed. Results: A total of 101 patients were evaluated from a community oncology practice over the last 1 year who underwent HRD testing of which 58.4% were female and 41.5% were male. 27.7% of patients were therapy-naive of which 67.8% were stage IV, 28.5% were stage III, and 3.5% were stage I/II while 72.2% were pre-treated and mostly ( &gt; 90%) of advanced stage. The most common cancer types that were tested were Gynaecological cancers (20.7%), followed by Pancreatobiliary (18.8%), Lung (13.8%), Genitourinary (13.8%), and other solid cancers (32.4%). Limited-HRD testing based on small panel HRR genes was performed on 9.9% (10/101) while Comprehensive-HRD (including HRR genes, LOH, TAI, and LST) was performed on 90% (91/101). The sensitivity and specificity of Limited-HRD were 43.75% (with 95% CI 26.36% to 62.34%) and 69.46% (with 95% CI 56.13% to 80.81%) showing an accuracy of 60.44% (with 95% CI 49.64% to 70.54%). Comprehensive-HRD analysis showed a sensitivity of 78.12% (60.03% to 90.72%) and specificity of 67.80% (54.36% to 79.38%) with increased accuracy of 71.43% (with 95% CI 49.64% to 7.54%) as compared to Limited-HRD. PARPi were used in 8.9% (9/101) of patients for organ types- Ovary (44.4%), Prostate (33.3%), Stomach (11.1%), and Lung (11.1%) with a clinical benefit rate of 66.6%. It is also reported that in 3% of cases, BRCA1 mutation was detected however, the comprehensive-HRD score was found low. Conclusions: Predictive sensitivity and accuracy improved with Comprehensive-HRD analysis, thereby reflecting the power of LOH, TAI, and LST in the true identification of both positive and negative cases thus expanding the usage of PARPi in deserving patients.