tbuckley/cabot-search huggingface dataset:
In-training and private physicians' knowledge, attitudes, practices and perceived barriers on the utilization of low dose chest CT scan as lung cancer screening for high-risk patients in a tertiary hospital: Single center experience.
Authors: Jesilyn Palec, Ivy Dimayuga de Dios
Journal: Journal of Clinical Oncology (2024)

150 Background: Lung cancer is the leading cause of cancer-related deaths worldwide. Aside from smoking cessation efforts and guidelines from all proficient panels, utilizing Low dose CT scan (LDCT) of the chest as lung cancer screening (LCS) has been poorly adopted. Methods: This was conducted after institutional review board approval. The respondents were handed hard copy or electronic consent forms and survey questionnaire depending on the platform of their choice. Results: Majority of the respondents were in-training female physicians with median age of 31 years old who specialized in Internal Medicine practicing between 1-5 years who catered to more than 10 patients per week in outpatient clinics. Nearly half of the respondents answered that the recommended frequency for lung cancer screening (LCS) for high-risk individuals is done bi-annually. Majority agreed that lung cancer screening is effective in decreasing lung cancer mortality and morbidity. Most respondents have initiated discussion about the risks and benefits of low dose chest CT scan (LDCT) as lung cancer screening among eligible high-risk patients. However, most of the respondents disagreed that lung cancer screening is cost effective. The top three perceived barriers on the utilization of Low dose chest CT scan as lung cancer screening reported in descending order revealed that it is not cost-effective, some forgets to screen patients and lung cancer screening has the potential to cause mental anguish or anxiety to patients. Conclusions: This study recommends conducting further studies exploring the socio-economic burden and impact assessment of lung cancer in the Philippines to enable translation of more meaningful strategies for local and national lung cancer screening access, health policies and financing. Promoting continuous lung cancer screening forums, lectures and information dissemination of annual LDCT of the chest among high risk patients will encourage and strengthen interdepartmental and multidisciplinary referral and collaboration in increasing earlier detection of lung cancer and decreasing related morbidity and mortality.
Molecular tumor board: Real-world experience in a tertiary cancer centre in Singapore.
Authors: Su Fen Ang, Daniel Shao-Weng Tan
Journal: Journal of Clinical Oncology (2024)

107 Background: Genomic profiling is increasingly employed to support diagnosis and treatment of cancer. Our Molecular tumor boards (MTBs) serves as a collaborative platform for a multi-disciplinary team of oncologists, pathologists, scientists, bioinformaticians, genetic counsellors and research coordinators to discuss and match patients to the most relevant therapies and/or clinical trials. We report here the evaluation of our MTBs for year 2023 with the aim of identifying challenges and opportunities for successful implementation of precision oncology. Methods: Regular monthly MTBs were conducted to discuss molecular profiles from predominantly advanced-stage patients enrolled to the IMPACT study (Individualized Molecular Profiling for Allocation to Clinical Trials NCT02806388). Next-generation sequencing was performed either in-house using Oncomine or commercial FoundationOne panels. Additional tests such as whole transcriptome sequencing (WTS), immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) were also performed where indicated. MTB recommendations were documented for follow-up and analysis. Results: A total of 102 out of 611 profiled patients were discussed in MTBs in 2023, with an average of 8.6 patients per month. Top 3 cancer types were gastrointestinal (32%), breast (18%) and lung (18%). 65/102 (63.7%) cases had MTB recommendations, of which 21 (20.6%) had multiple recommendations. Overall uptake rate for recommendations was 23.8% (29/122). Conclusions: MTB plays an important role in identifying therapeutic opportunities by factoring in patient variables, available data and physician experience while at the same time provides an avenue for further investigation to gather cumulative evidence. Frequent reasons encountered for not adopting the recommendations include: (1) insufficient sample to proceed with further investigations, (2) limited access to off-label treatments, and (3) additional considerations to participate in clinical trials. To fully realize the value of MTB, we will focus on (1) defining the molecular tests for efficient profiling, (2) crafting a route for special access to treatments and (3) increasing awareness and understanding of clinical trials. [Table: see text]
i-Biomarker CaDx: A circulating miRNA-based multi-cancer detection test with generative and explainable AI for colorectal cancer.
Authors: Alexandru Floares, Larisa Sarghie, Adrian Vasile Zety, Lampros Androutsos, Rafael Oliveira, George Calin, Carmen Floares, Florin Manolache
Journal: Journal of Clinical Oncology (2024)

64 Background: Colorectal cancer (CRC), the second most deadly cancer, underscores the critical need for early detection to significantly improve treatment outcomes and survival rates. Colonoscopy, flexible sigmoidoscopy, and the fecal immunochemical tests (FIT), often fail to capture early disease, significantly decreasing the survival chance. Circulating miRNA is a promising non-invasive biomarker for various cancers, including CRC. The i-Biomarker CaDx (patent pending) is an innovative multi-cancer early detection and diagnosis platform, covering 32 cancer types with an impressive accuracy rate of 99-100%. This study focuses on the effectiveness of i-Biomarker CaDx for CRC, employing significant data collection and leveraging insights from Generative AI (GenAI) and Explainable Artificial Intelligence (XAI). Methods: We collected various available datasets (e.g. GSE106817, etc.) encompassing 305 colorectal cancer patients and a matching number of healthy controls. Microarray was employed to profile circulating miRNAs. We used various classification paradigms, e.g., decision trees, neural networks, etc. Hyperparameter optimization was conducted, and the best-performing classifiers were amalgamated in the final model, weighted by their respective efficacies. We assessed i-Biomarker CaDx's performance through cross-validation and independent test sets. The XAI provided detailed insights into miRNA variations associated with personalized diagnostic. GenAI integrated the test into the screening and early detection best practice workflows and performs Functional Analysis. Results: i-Biomarker CaDx shows exceptional diagnostic accuracy of 99-100%, surpassing conventional colorectal cancer diagnostic methods like colonoscopy, flexible sigmoidoscopy, and FIT. It can also be used for personalized treatment response monitoring. I-Biomarker effectively deciphers intricate miRNA relationships relevant to colorectal cancer using XAI. Thus, our analyses shed light on miRNA patterns and their associations with colorectal cancer, enhancing the understanding of the underlying molecular complexities of the disease. It goes further by explaining the personalized cellular and molecular mechanisms involved, and it will be integrated into the corresponding medical workflows. Conclusions: Our AI-powered multi-cancer early diagnostic platform demonstrates outstanding performance in detecting CRC, surpassing traditional diagnostic methods like colonoscopy, flexible sigmoidoscopy, and FIT. XAI allows for in-depth exploration of miRNA alterations and their impact on CRC, enriching our interpretations at both the population and individual levels. These findings underscore the substantial potential of i-Biomarker CaDx as a transformative, non-invasive diagnostic tool for CRC.
An exploratory investigator-initiated trial via intrathecal or intracerebroventricular delivery of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.
Authors: Xiaoyun Shang, Xuetao Li, Xuewen Zhang, Yulun Huang
Journal: Journal of Clinical Oncology (2024)

23 Background: The MT027, developed by T-Maximum, is a B7-H3 (CD276)-directed genetically modified allogeneic T cell, targeting CD276-overexpressed tumor cells. Here, we reported a first-in-human, single-center, open-label investigator-initiated trial (IIT) via intrathecal or Intracerebroventricular delivery targeting recurrent high-grade glioma (ChiCTR2100047968). Methods: As of March 7, 2024, a total of 50 adult patients with recurrent high-grade glioma, B7H3+ expression, and KPS ≥40 were enrolled and administered at least one dose of MT027 (FAS), of whom, 32 received at least 3 doses (PPS1), 15 subjects with ≥3 doses and at least 1 efficacy visit (PPS2). 4 dose levels of 1.0, 1.5, 2.0, 2.5×10 7 cells per injection were administered once every 4 weeks. Results: The overall results demonstrated the favorable tolerability, safety, PK/PD characteristics, and preliminary efficacy. In FAS, the most common AE were fever and headache, without any CRS, ICANS, GvHD, or drug-related death. There were 4 cases (8%) of grade 3 AE or greater and 3 cases (6%) of SAEs. The copies of CAR in all groups reached 10000-100000 copy/ug, and persisted for &gt; 60 days after a single dose. After multiple doses, the MT027 CAR-T cell numbers maintained at a high level (median 8850 copies /μg (range: 200-385900)) and for a long time. The levels of IL6, TNF-α and IFN-γ in CSF increased significantly and maintained for a long time. The mOS was 13.54 m (95% CI: 7.45; 19.63) and 20.73 m (95% CI: 16.12; 25.34) in PPS1 and PPS2, respectively. The 12-month OS rate was 53.30% (95%CI: 37.5%-75.7%) and 84.60% (95%CI: 67.1%-100%) in PPS1 and PPS2, respectively (historical data: 14%). The objective response rate (ORR) was 33% and the disease control rate (DCR) was 80% in PPS2. Conclusions: In patients with relapsed high-grade glioma, the intrathecal or ICV administration of MT027 cell therapy was found to be safe and well-tolerated. The toxicity of grade 3 or above was 1/5 of similar products. The pharmacokinetics and pharmacodynamics of single-dose and multiple-dose treatments were stable. MT027 exhibited longer persistence in the body of the patients, and the cell numbers and cytokine responses induced in vivo were 1-2 orders of magnitude higher than those of similar products. MT027 cell therapy demonstrated the excellent efficacy in treating relapsed high-grade glioma, with significantly prolonged overall survival and higher objective response rate compared to the historical data and similar product data. Currently, we are preparing for the IND filing in US (expected in 2024) with the recurrent glioblastoma as the first indication. Clinical trial information: ChiCTR2100047968 .
Investigation of the effect of macrophage and epithelial cell interaction in the progression of different subtypes of breast cancer.
Authors: Banani Majumdar, Barnali Dolui, Anupam Basu
Journal: Journal of Clinical Oncology (2024)

10 Background: In the realm of tumor progression, the immunosuppressive role of macrophages has been well-established. However, a significant lacuna persists concerning the mechanisms through which epithelial cells regulate macrophages. Furthermore, the precise manner in which macrophages modulate breast cancer cells remains unclear. Hence, the primary objective of the current investigation is to delve into the influence of macrophages on the progression of distinct subtypes of breast cancer. Methods: Human monocyte cell-derived macrophages (M0) were cultivated in the presence of conditioned media (CM) from various subtypes of breast cancer cells. Conversely, human luminal breast cancer cell line T47D, and basal cell line MDA MB 231 were cultured in the presence of CM from macrophages. Results: When macrophages were incubated with CM of T47D, they exhibited a spindle-shaped morphology with pseudopodia. Conversely, exposure to CM of MDA MB 231 induced macrophages to adopt a foamy, round shape with numerous filopodia. Flow cytometry analysis revealed that T47D-CM promoted a higher proportion of CD80+ cells, while MDA MB 231-CM led to an increase in both CD206+ and CD80+ cells. Moreover, both T47D and MDA MB 231-CM escalated the production of various cytokines including IL-1β, IL-2, IL-4, IL-5, IL-7, IL-12(p70), IL-13, IL-17, G-CSF, IFN-γ, and MIP-1β. Intriguingly, MDA MB 231-CM induced a significant increase in IL-6, GM-CSF, and TNF-α. Subsequent cultivation of cancer cells in the presence of macrophage-CM resulted in a marked proliferation of MDA MB 231 cells, while T47D cell proliferation decreased significantly. Correspondingly, there was a notable increase in apoptosis among T47D cells. Scratch wound healing assays revealed heightened migration of MDA MB 231 cells following treatment with macrophage-CM, whereas there was negligible alteration in T47D cell migration. Proteomic analysis unveiled dysregulation of 247 and 596 proteins in MDA MB 231 and T47D cells, respectively. Particularly noteworthy were three proteins—MDHM, H1.5, and LEG8—abundant in MDA MB 231 cells, yet scarce in T47D cells. These proteins have been implicated in promoting tumor growth across various cancer types. Conclusions: This study first time elucidates subtype specific role of macrophage in breast tumour. In triple-negative breast cancer, infiltrating macrophages induce an immunosuppressive effect, altering cytokine expression and fostering the expression of tumor-promoting factors in epithelial cells, thereby facilitating cellular proliferation and metastasis. Conversely, in luminal breast cancer, infiltrating macrophages exhibit a predominantly pro-inflammatory profile, resulting in minimal tumor-promoting effects. Key Words: Breast Cancer, Macrophage polarization, Conditioned Media, Cytokines, Proteomics. Acknowledgements, DBT – Govt of India, NIBMG, Kalyani.
A phase 2, open-label, single-arm study evaluating the combination of pembrolizumab (pembro), lenvatinib, and chemotherapy in patients (pts) with metastatic non-small cell lung cancer (NSCLC) harbouring a targetable mutation who experienced disease progression on standard tyrosine kinase inhibitors (TKIs).
Authors: Hoi Wai Chan, Chris Chun Long Tse, Yu-Chung Li, Roland Ching-Yu Leung, Jeffrey Sum Lung Wong, Gin Wai Kwok, Hoi Lam Li, Wing Yan Josephine Tsang, Cho Wing Li, Jenny WY Lo, Vikki Tang, Rina Hui, Thomas Yau, James CM Ho, Joanne W Chiu
Journal: Journal of Clinical Oncology (2024)

198 Background: Pts with metastatic NSCLC harbouring a targetable mutation who progressed on standard TKIs often receive chemotherapy as the next line of treatment. We report efficacy and safety of a novel combination of pembro, lenvatinib and chemotherapy for these pts. Methods: This was a phase 2, open-label, single-centre, single-arm study enrolling pts with metastatic NSCLC with sensitizing EGFR, ALK or ROS1 mutation who progressed on standard TKIs. Eligible pts had measurable disease, no untreated brain metastasis and ECOG PS ≤1. Pts received pembro 200 mg, pemetrexed 500 mg/m 2 and carboplatin AUC 5 every 3 weeks for 4 cycles plus lenvatinib 8 mg QD. The maintenance regimen without carboplatin was continued as tolerated for up to 2 years. The primary endpoint was objective response rate (ORR) by independent radiology review (IRR) as per RECIST 1.1. The secondary endpoints were PFS, overall survival (OS) and safety. Results: At the data cutoff date (2 nd February 2024), 24 pts were screened and 19 were enrolled: median age 64 years (range 29–77); 10 (53%) female. Four pts were excluded at screening due to untreated brain metastasis. All enrolled pts were evaluated for safety while 15 pts were evaluable for response. All pts had adenocarcinoma with targetable mutation: EGFR mutation in 18 (95%) pts and ALK fusion in 1 (5%) pt. The median follow-up time was 11.3 months. Treatment was ongoing in 8 pts on the date of analysis, while 6 pts permanently discontinued due to disease progression and 1 pt permanently discontinued due to a treatment-related adverse event (TRAE). The ORR was 40% (6/15, 95% CI 19.8%–64.3%). All responses were partial responses. The median PFS was 11.9 months (range 3.5–20.3). The OS was not reached. TRAEs of any grade (Gr) occurred in 74% (14/19) of the pts. Most of the TRAEs were Gr 1–2, which occurred in 63% (12/19) of the pts. The most common TRAEs were hypothyroidism (31.6%), nausea (26.3%), neutropenia (26.3%), thrombocytopenia (26.3%), anorexia (21.1%), hypertension (15.8%), anaemia (10.5%), pruritus (10.5%) and rash (10.5%). G1 diarrhoea was reported in 1 pt (5.3%) and G1 adrenal insufficiency in 1 pt (5.3%). Gr 3 TRAEs were neutropenia in 2 pts, anaemia in 1 pt and thrombocytopenia in 1 pt. The only Gr 4 TRAE was thrombocytopenia. No treatment related death was observed. Conclusions: The combination of pembro, lenvatinib and chemotherapy demonstrated a favourable ORR and safety in treating metastatic NSCLC pts with a targetable mutation who progressed on standard TKIs. Clinical trial information: NCT04989322 .
A randomized, multicenter, phase II trial of camrelizumab (Cam) with and without metastasis-directed therapy (MDT) in recurrent/metastatic nasopharyngeal carcinoma (R/M-NPC).
Authors: Xin Zhang, Jin Yan, Qianqian Lei, Lu Zhang, Jieying Yang, Sze Huey Tan, Melvin L.K. Chua, Ying Wang, Jiangdong Sui
Journal: Journal of Clinical Oncology (2024)

141 Background: To investigate the on- and off-target treatment responses of MDT when added to camrelizumab – an anti-programmed cell death 1 antibody in patients with R/M-NPC. Methods: We conducted an open-label, randomized, controlled, multicenter, phase II trial in 3 centers from China (NCT04830267). Patients with R/M NPC, without prior exposure to immune checkpoint inhibitors, who presented with ≥2 lesions, and at least 1 measurable lesion were screened and randomized 1:1 to either Cam (200 mg IV 2-weekly) alone or Cam plus MDT (Cam+MDT). Patients randomized to the MDT group must have 1 lesion that is amendable to MDT using stereotactic body radiotherapy (SBRT) prescribed to 27Gy in 3 fractions every other day between the first and second dose of Cam. Primary endpoint was off-target objective response rate (ORR) by RECIST v1.1. Secondary endpoints included on-target ORR, disease control rate (DCR), progression-free (PFS), overall survival (OS), and safety. Results: Between March 1, 2021, and August 16, 2023, 39 patients with R/M NPC were randomly assigned to receive either Cam alone (n=20) or Cam+MDT (n=19). 17/39 (44%) patients had oligometastatic disease (≤3 lesions); 18/39 (46%) had liver metastasis. Median duration of Cam was 4.1 mo (95%CI: 2.4-10.9) and 4.7 mo (95% CI: 2.3-11.0) in both treatment groups, respectively. Sites of MDT included lungs (8/19, 42%), followed by liver (4/19, 21%), bones (4/19, 21%), and lymph nodes (3/19, 16%); median SBRT target volume was 5.8 cc (IQR: 2.7-13.5). Off-target ORR did not differ between the treatment groups (26% vs 30%, P=0.51), although DCR was 74% in the Cam+MDT group compared with 60% in the Cam only group ( P=0.37, Table). After a median follow up of 25.8 mo, median PFS was 9.3 mo (95% CI:6.2-NR) in the Cam+MDT group and 8.8 mo (95% CI: 3.3-NR) in the Cam group (P=0.75), and median OS was not reached in the Cam+MDT gorup (95% CI: 20-NR) and 13.7 mo (95% CI: 11-NR) in the Cam group. Interestingly, exploratory analyses suggest a longer OS with Cam+MDT for patients with &gt;3 metastatic lesions ( HR 0.228 [95% CI: 0.067-0.769]), and no liver involvement ( HR 0.287 [95% CI: 0.068-1.208]). G3 and above adverse events were comparable between the treatment groups (14.3% vs 12.5%). Conclusions: We did not observe a difference for off-target ORR with the addition of MDT to Cam in patients with R/M-NPC, although DCR was higher with combinatorial treatment due to a higher proportion of stable disease. Interestingly, OS was prolonged with Cam+MDT in a subset of patients with &gt;3 lesions and no liver involvement. Clinical trial information: NCT04830267 . [Table: see text]
Characterization of estrogen receptor mutant breast cancer in 3D cell culture.
Authors: Olivia Mayer, Jordan Wright, Caroline Rinderle, Bruce Bunnell
Journal: Journal of Clinical Oncology (2024)

14 Background: Breast cancer is a leading cancer in women worldwide. Many primary breast cancers are estrogen receptor positive (ER+) and responsive to anti-estrogenic therapies. These tumors can mutate estrogen receptors to survive, allowing the tumors to become more triple-negative-like and therefore more dangerous. Triple-negative breast cancer (TNBC) has been particularly challenging to treat due to its lack of estrogen (ER), progesterone (PR), and human epidermal growth factor (HER2) receptors. Due to the lack of treatment options, TNBC has a poor prognosis and contributes to a significant percentage of breast cancer mortalities. These ER mutants act more like TNBC, resulting in worse clinical outcomes. Current research on these ER mutants has been conducted using two-dimensional (2D), monolayer cell culture, which does not translate effectively in animal models, and ultimately, humans. Three-dimensional (3D) cell culture, which allows for the formation of spheroids, mimics actual tumors and provides results more consistent with tumor treatment in vitro. Due to the lack of research on these ER mutants in 3D culture, they must be characterized to determine baseline gene expression and behavior. After characterization, identifying changes resulting from drug treatment will be possible. Methods: Parental, ER+ MCF7-Luc cells, and daughter D538G and Y537S mutants were seeded at a density of 3000 cells/well in a low-attachment, round-bottomed 96-well plate. 48 hours and 7 days post-seeding, newly-formed spheroids were imaged. Using ImageJ analysis software, diameter, area, perimeter, circularity, aspect ratio, roundness, and solidity were determined. After 7 days in culture, spheres were collected for RNA extraction. Next, cDNA was synthesized, and qRT-PCR was performed to assess gene expression differences. Results: The wild-type ER+ spheres have smaller diameters, spherocity values closer to one, and are more compact. They express different levels of EMT markers from the controls, indicating alterations to signaling pathways. These 3D cultures vary in expression from the 2D cultures of the same cell lines. Conclusions: MCF-7 ER+ breast cancer cells aggregate more readily than ER+ mutants. The ER must be involved in signaling that promotes aggregation, as reduced ER signaling decreases the ability for spheroid formation. This phenomenon and the differences in gene expression may explain why mutants tend to behave in a more triple-negative manner. Cells cultured in 3D express some genes to different extents, confirming the importance of 3D culture for identifying future therapies – cells behave differently in different culturing contexts, 3D being more consistent with tumor behavior. Therefore, characterizing ER+ mutants prior to drug treatment studies is crucial to understanding how compounds affect cancer cells, as well as for identifying differences in various ER+ mutants for better treatment outcomes.