tbuckley/cabot-search huggingface dataset:
Evaluating the correlation between expression levels of carboxyl terminal modulator protein (CTMP) and the efficacy of trastuzumab in Syrian patients with HER2+ metastatic breast cancer.
Authors: Mania Makhoul, Maher Saifo, Farez Ahmad, Jumana Alsaleh
Journal: Journal of Clinical Oncology (2024)

e13008 Background: Approximately 15-20% of women diagnosed with breast cancer (BC) have HER2+ disease. Trastuzumab, the first Food and Drug Administration- approved targeted therapy for BC, serves as a turning point in the personalized therapy of HER2+ metastatic breast cancer (MBC). However, not all (HER2+MBC) patients respond to trastuzumab treatment. The attendant mechanism of trastuzumab resistance remains unclear and there are currently no conclusive biomarkers for patient response to trastuzumab. Recent studies have submitted assorted likely mechanisms leading to the resistance, including Carboxyl-terminal modulator protein (CTMP). CTMP was shown to bind to the carboxy terminus of Akt and regulate its activity. The goal of this study is to identify the role of CTMP in trastuzumab resistance in Syrian patients with (HER2+MBC). Methods: Patients received trastuzumab plus chemotherapy (either docetaxel or vinorelbine) as an adjuvant treatment until the time of disease progression. Ninety-six patients were assessable for efficacy, progressive disease (PD) and clinical benefit rate (CBR) were achieved in (32.3%) and (67.7%) respectively of the study population. Immunohistochemistry (IHC) staining was performed to examine CTMP expression in formalin-fixed paraffin-embedded (FFPE) archival tissue blocks. Results: Based on IHC scoring, 38 Cases (39.6%) had low CTMP staining, and 58 cases (60.4%) had high CTMP staining. Notably, CTMP overexpression was significantly correlated with histological grade and tumor recurrence. Moreover, the data showed that CTMP staining index is significantly higher in (PD group) than in (CBR group) (P=0.039). Intriguingly, survival analysis indicated that MBC patients with high CTMP expression had lower recurrence-free survival than those with low CTMP expression as determined by Kaplan-Meier method (p=0.048). Conclusions: Our findings confirm that (HER2+MBC) patients with high CTMP expression level tended to be refractory to trastuzumab treatment.
Systemic messenger RNA replacement therapy is effective in a novel clinically relevant model of acute intermittent porphyria developed in non-human primates
Authors: Karol M Córdoba, Daniel Jericó, Lei Jiang, María Collantes, Manuel Alegre, Leyre García-Ruiz, Oscar Manzanilla, Ana Sampedro, Jose M Herranz, Iñigo Insausti, Antonio Martinez de la Cuesta, Francesco Urigo, Patricia Alcaide, María Morán, Miguel A Martín, José Luis Lanciego, Thibaud Lefebvre, Laurent Gouya, Gemma Quincoces, Carmen Unzu, Sandra Hervas-Stubbs, Juan M Falcón-Pérez, Estíbaliz Alegre, Azucena Aldaz, María A Fernández-Seara, Iván Peñuelas, Pedro Berraondo, Paolo G V Martini, Matias A Avila, Antonio Fontanellas
Journal: Gut (2024)

Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks closely associated with hepatic overproduction of potentially neurotoxic heme precursors.
Antigen-independent activation is critical for the durable antitumor effect of GUCY2C-targeted CAR-T cells
Authors: Changsong Qi, Dongqun Liu, Chang Liu, Xiaofei Wei, Mingyang Ma, Xinan Lu, Min Tao, Cheng Zhang, Xicheng Wang, Ting He, Jian Li, Fei Dai, Yanping Ding, Lin Shen
Journal: Journal for ImmunoTherapy of Cancer (2024)

Chimeric antigen receptor (CAR)-T cells face many obstacles in solid tumor therapy, including heterogeneous antigen expression and inefficient T cell persistence. Guanylyl cyclase C (GUCY2C) has been identified as a suitable tumor antigen for targeted therapy due to its intestinal-restricted expression pattern in normal tissues and steady overexpression in gastrointestinal tumors, especially colorectal cancer. An antigen-sensitive and long-lasting CAR-T cell targeting GUCY2C was investigated in this study.
Association of methotrexate polyglutamates concentration with methotrexate efficacy and safety in patients with rheumatoid arthritis treated with predefined dose: results from the MIRACLE trial
Authors: Hiroya Tamai, Kei Ikeda, Toshiaki Miyamoto, Hiroaki Taguchi, Chang-Fu Kuo, Kichul Shin, Shintaro Hirata, Yutaka Okano, Shinji Sato, Hidekata Yasuoka, Masataka Kuwana, Tomonori Ishii, Hideto Kameda, Toshihisa Kojima, Yurie Nishi, Masahiko Mori, Hideaki Miyagishi, Genta Toshima, Yasunori Sato, Wen-Chan Tsai, Tsutomu Takeuchi, Yuko Kaneko
Journal: Annals of the Rheumatic Diseases (2024)

The usefulness of methotrexate-polyglutamates (MTX-PGs) concentration for management of rheumatoid arthritis has been debated. We aimed to clarify the association of MTX-PGs concentration with efficacy and safety in MTX-naïve patients initiating MTX in a prospective interventional clinical trial. The MIRACLE trial enrolled 300 MTX-naïve patients. Oral MTX was initiated and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission according to the Simplified Disease Activity Index at week 24 were randomised to either the continued dose or reduced dose group and were started on subcutaneous adalimumab. We measured the concentrations of MTX-PGs in erythrocytes using liquid chromatography-tandem mass spectrometry and analysed the association of these concentrations with efficacy and safety. The mean concentration of total MTX-PGs increased with an increasing dose of MTX and continued to elevate for another 12 weeks after the dose was fixed. At week 24, the total MTX-PGs concentration was 110.5 (SD 43.8) nmol/L with MTX dose of 12.6 (3.0) mg/week (0.23 (0.07) mg/kg/week). During MTX monotherapy, the higher MTX-PGs concentration was an independent factor for lower disease activity; however, this association disappeared after adalimumab initiation in patients with continued MTX dose. Hepatotoxicity was related to the higher MTX-PGs concentration regardless of adalimumab use. The total MTX-PGs concentration was significantly elevated by lower estimated glomerular filtration rate, serum albumin and body mass index. The MIRACLE trial demonstrated that higher total MTX-PGs concentration in erythrocytes is related to the higher efficacy and lower safety of MTX. NCT03505008.
Peripheral blood immunophenotypic diversity in patients with rheumatoid arthritis and its impact on therapeutic responsiveness
Authors: Satoshi Kubo, Yusuke Miyazaki, Takahiro Nishino, Yuya Fujita, Michihiro Kono, Tsugumi Kawashima, Kazuyoshi Ishigaki, Katsuhide Kusaka, Hiroaki Tanaka, Masanobu Ueno, Yurie Satoh-Kanda, Yoshino Inoue, Yasuyuki Todoroki, Ippei Miyagawa, Kentaro Hanami, Shingo Nakayamada, Yoshiya Tanaka
Journal: Annals of the Rheumatic Diseases (2024)

Considering the diverse aetiologies and immunodysregulatory statuses observed in each patient with rheumatoid arthritis (RA), stratification based on peripheral blood immunophenotyping holds the potential to enhance therapeutic responses to molecular targeted therapies, biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Immunophenotype analysis was conducted on a cohort of over 500 b/tsDMARDs-naïve patients using flow cytometry. Patients with RA were stratified based on their immunophenotypes, and the treatment response to each targeted therapy was evaluated. Validation was performed using an additional cohort of 183 b/tsDMARDs-naïve patients with RA. Patients with RA were stratified into five clusters, two of which exhibited distinct RA phenotypes compared with controls, characterised by significant increases in CD4+ effector memory T cells re-expressing CD45RA. Notably, the effectiveness of different b/tsDMARDs varied across clusters. The group using promising b/tsDMARDs was labelled as 'expected' whereas the 'non-expected' group comprised those using others. The expected group outperformed the non-expected group with higher 26-week remission rates (39.9% vs 24.6%, p=0.0004) and low disease activity achievement (80.8% vs 60.2%, p<0.0001). Trajectory analysis showed the non-expected group's 26-week disease activity was influenced by Clinical Disease Activity Index at baseline unlike the expected group. Additionally, different molecular targeted therapies influenced the proportions of each immune cell subset variably. To validate, immunophenotyping was performed on a validation cohort. When 183 cases were grouped based on their b/tsDMARDs usage into expected/non-expected groups, the expected group had a higher remission rate (p=0.0021), further confirming the observed trend. Our findings offer valuable insights into the diversity of RA and potential therapeutic strategies grounded in the molecular underpinnings.
Oncology Combination Drug Development Strategies for Project Optimus
Authors: Timothy A. Yap, Julie Bullock, Susan Chong, Megan K. Doyle, Azher Hussain, Jackie Kline, Amandine Manon, Karthik Venkatakrishnan, Vijay V. Upreti
Journal: Clinical Cancer Research (2024)

The Project Optimus initiative from the FDA introduced a new dose optimization and selection paradigm in oncology drug development. The FDA has outlined approaches to dose optimization for single agents, but multiple oncology drugs are being developed for use in combination with other therapies. Dose optimization in the context of combination drug development is complex and requires a case-by-case approach. It necessitates commitment to the totality of available evidence, leveraging all relevant data on mechanism of action, nonclinical and clinical pharmacology, safety, and principles of model-informed drug development. In this article, we outline key considerations for sponsors and investigators pursuing dose optimization with combinatorial regimens. We illustrate important strategies for dose optimization in the combination setting using a range of hypothetical case examples that represent typical drug development scenarios. Close discussions and collaboration with regulators regarding the optimal approaches to these scenarios will continue to be critical.
Combined high-resolution H3K27ac epigenomic and single-cell transcriptional profiling as a signature predictive of response to neoadjuvant immune checkpoint inhibitors (ICI) in urothelial cancer (UC).
Authors: Joaquim Bellmunt, Margot Hully, Ilana B. Epstein, Sonsoles Liria, Yingtian Xie, Miguel Muñoz, Paula Garoz, Nuria Fernandez, Oscar Buisán, Toni K. CHOUEIRI, Cecilia Cabrera, Henry Long, Paloma Cejas
Journal: Journal of Clinical Oncology (2024)

4595 Background: Multiple molecular predictors have been associated with response to ICI in metastatic UC (mUC), including clonal TMB, APOBEC mutagenesis and multiple RNA signatures. Tumor-intrinsic and tumor-extrinsic (microenvironmental) properties can drive resistance to PD-1/PD-L1 inhibitors, although the factors that determine resistance specifically in MIBC remains incompletely characterized. Epigenomic analysis combined with single cell (sc) technology can reveal mechanisms of response involving both cancer cells and the microenvironment. Methods: We identified two MIBC patients’ cohorts from Dana-Farber Cancer Institute (DFCI) and from Hospital Trias i Pujol in Spain treated with neoadjuvant therapy with ICI with tissue available pre- and post- treatment. Molecular profiling was performed with H3K27ac in Formalin-Fixed Paraffin-Embedded (FFPE) blocks and scRNAseq from Fresh Frozen (FF) and FFPE tissues. For the analysis, we performed peak calling, unsupervised analysis (using our internal pipeline), comparison of enhancers with a published datasets (using Cistrome toolkit) and sc analysis using Seurat. Results: 35 patients with pre and post available samples were included in the analysis. The H3K27ac enhancer analysis revealed a signature predictive of treatment response to immunotherapy. Comparison with publicly available ChIP-seq datasets showed that enhancers more active in pre-treatment samples in responders were highly represented in lymphoid lineages. In contrast, the enhancers less active in responders were associated with squamous differentiation. When translated to a gene expression signature, we found enhancers at novel and known genes described in UC that included CYTOR, TGFBR2 and IKZF1( involved in immunotherapy response) and FYN, PDE4B and GPR174 involved in cell migration, microenvironment and EMT among the top ten genes. We projected the gene signature over a scRNAseq atlas resulting from 20 patients that includes all inflammatory lineages, and found an increase within specific T cell populations and a reduction of B and plasma cells in responders as compared to non-responders in the pre-treatment samples. Conclusions: Our combined epigenetic and scRNAseq strategy revealed the existence of specific microenvironment and tumor states in pre-treatment samples from MIBC. We also provided a novel gene signature predictive of response. Prospective validation is ongoing.
T-DM1 in Chinese patients with Her2-positive metastatic breast cancer: A multi-center, retrospective, real world study.
Authors: Ruyan Zhang, Huiping Li, Pin Zhang, Chunfang Hao, Wenhui Zhao, Xueli Mo
Journal: Journal of Clinical Oncology (2024)

e13026 Background: In the pivotal EMILIA and THRESA study, the proportion of Chinese patients in the clinical trials was very low (17% of Asian patients, 87 patients in EMILIA), and no patients in the trials were previously treated with pertuzumab. Methods: We enrolled patients with Her2-positive metastatic breast cancer who received T-DM1 in metastatic setting between March 2020 and August 2023 in Peking University Cancer Hospital and five other medical centers. The primary endpoint was progression free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: A total of 172 patients who had received at least two cycles of treatment were included in the efficacy and safety analysis. The median age was 53 years (range, 24–87years). The median number of treatment lines was three(range:1-12). 47(27.3%) patients were treated in first or second line and 125(72.7%) patients were treated in third- and above line. 79% and 61% patients had previously received pyrotinib/lapatinib and pertuzumab, respectively. With a median follow-up of 7.8 months (range: 1.3-42.2), progressive disease (PD) occurred in 103 of 172 patients (59.9%), and 26 deaths (15.1%) occurred. The median PFS was 5.1 months (95% CI: 3.9-6.3m). OS was not reached. The ORR was 17.4%, and DCR was 80.2%. Cox regression analysis showed that brain metastasis, lung metastasis and HER2 2+ in IHC were associated with shorter PFS. And the PFS of patients with previous pertuzumab treatment, liver metastasis, and more treatment lines tended to be shorter, but the difference was not statistically significant. Most AEs were grade 1–2 and manageable, grade 3 or higher adverse events were mainly thrombocytopenia(26 patients [15.1%]) and elevation of liver enzymes (7 patients [4.1%]). 36 patients (20.9%) experienced at least one dose reduction. Conclusions: In this real world study, in which more than half of the patients received pertuzumab previously, and more than 20% had brain metastasis, the median PFS was shortened as compared with the EMILIA trial and THERESA trial results. However, multivariate analysis suggested that previous exposure of pertuzumab did not affect the PFS of T-DM1, and patients with HER2 2+ and lung metastasis may not be the advantageous population for T-DM1 treatment. Thrombocytopenia was a dose-limiting toxicity of T-DM1, and most patients could tolerate it well after dose adjustment.
Patients with early-onset metastatic colorectal cancer as an emerging distinctive clinical and molecular phenomenon.
Authors: Andrea Pretta, Pina Ziranu, Eleonora Perissinotto, Filippo Ghelardi, Federica Marmorino, Riccardo Giampieri, Maria Caterina De Grandis, Paolo Ciracì, Marco Puzzoni, Krisida Cerma, Carolina Sciortino, Ada Taravella, Valeria Pusceddu, Camilla Damonte, Rossana Berardi, Sara Lonardi, Francesca Bergamo, Filippo Pietrantonio, Chiara Cremolini, Mario Scartozzi
Journal: Journal of Clinical Oncology (2024)

3531 Background: Despite a reduction of both incidence and mortality from CRC in the elderly population, several studies published in the last decade have shown an increase in the incidence of early-onset CRC (EO-CRC), conventionally defined as cancer that occurs in adults between the ages of 18 and 49. Clinical and prognostic data on this setting are limited and conflicting. The aim of our study was to evaluate the clinical, prognostic, and molecular profiles of metastatic EO-CRC patients (age at diagnosis ≤ 50) in order to identify potentially relevant differences compared to a control group late-onset CRC (LO-CRC). Methods: We retrospectively collected data from 1272 metastatic colorectal cancers from 5 different Italian Institutions: 693 (54.5%) EO-CRC and 579 (45.5%) LO-CRC as control group. All patients had one or more metastatic sites, molecular profiling available (including RAS, BRAF, and MSI status), and underwent at least one line of treatment for metastatic disease. The main objective of the study was to the evaluate clinical outcome for the global population of EO-CRC patients in different clinical and molecular subgroups according to RAS and BRAF status and in comparison to patients included in the control group. Results: In the EO-CRC group median age was 42.8 (20.0-50.9) and 66.7 (51.0-86.2) in the control group. M/F ratios were 1:1 and 2:1, respectively. In the overall population, mOS was 34,7 in EO-CRC pts vs 43,0 months (mo) ( p &lt; 0,0001 ) in the control group. In the RAS/BRAF mutated subgroup mOS in EO-CRC pts was 30,3 vs 34,0 mo in the control group ( p = 0,0156 ). In RAS/BRAF wild-type subgroup mOS in EO-CRC pts was 43,0 vs 50,0 mo ( p = 0,0290 ). Finally, in the BRAF V600E mutated subgroup EO-CRC pts showed a 16 mo mOS vs 26 mo ( p = 0,04 ). In the overall population, mPFS was 11,0 in EO-CRC pts vs 14,0 mo ( p &lt; 0,0001 ) in the control group. Furthermore, the overall response rate (ORR) was 63% in EO-CRC and 67% in LO-CRC. Conclusions: Findings from a large population of EO-CRC patients indicate a general worse prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly this seems to occur regardless of the molecular status. These observations might have a considerable impact on clinical practice and research. Subsequent investigations will be needed to further understand the specific clinical and molecular characteristics of this growing group of patients to better define the more appropriate treatment strategy.
Real-world data comparison of time to next treatment for patients with HER2 positive metastatic breast cancer treated in the second line of therapy with fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine.
Authors: Vikram C. Gorantla, Anna Rui, Stephan B. Rosenfeld, Fred J. Kudrik, Anupama Vasudevan, Teena Sura, Mike Gart, Doug Kanovsky, Dawn Brenneman, Prateesh Varughese, Jeffrey A. Scott, Rushir J. Choksi, Robert B. Geller, Simon Blanc
Journal: Journal of Clinical Oncology (2024)

e13025 Background: The Destiny-03 trial observed that a median progression-free survival was not reached in the patients (pts) treated with fam-trastuzumab deruxtecan-nxki (TDxd) and was 6.8 months in the pts treated with ado-trastuzumab emtansine (TDM1). We sought to evaluate the time to next treatment (TTNT), a surrogate for progression-free survival, between trastuzumab deruxtecan-nxki and TDM1 using real-world data to assess whether such pts see similar benefits beyond the clinical trial setting. Methods: We used the Integra Connect PrecisionQ real-world de-identified database of over 3 million cancer pts across 500 sites of care to identify 315 breast cancer pts for analysis. Each of the breast cancer pts was identified as HER2+ (IHC of 3+ or an ISH/FISH positive result) at the time of second line treatment initiation. The 315 pts were included so long as they started their second line treatment in the metastatic setting on or after 1/1/2022 through 12/31/2023. TTNT was measured from the treatment start to either the first of the initiation of a subsequent line of therapy or death. Descriptive analyses were used and TTNT was analyzed using a Kaplan-Meier analysis. Results: The median age was 62 (IQR 23-90) at time of treatment start. 100% of pts were female. 241 (76.5%) pts received TDxd with a median age of 62 at treatment start, while 74 (23.5%) pts received TDM1 with a median age of 62.5 at treatment start. The median TTNT was 19.0 months (95% confidence interval [CI], 14.1 to Not Reached [NR]) for pts who received TDxd compared to 9.2 months (95% CI, 6.7 to 13.0) for those who received TDM1 ( p &lt;0.01). The median overall survival was not reached in either TDxd or TDM1 treated pts. The percentage of TDxd pts who were deceased was 13.3% compared to 14.9% for TDM1 pts. The probability of pts on therapy after 12 months was found to be 66% (95% CI, 58.7% to 73%) for those who received TDxd compared to 38.9% (95% CI, 25.2% to 52.4%) for those who received TDM1 ( p &lt;0.01). Conclusions: HER2 positive metastatic breast cancer pts on second line treatment with TDxd experienced a statistically significant difference in TTNT compared those treated with TDM1. The real-world data shows that TDxd demonstrated superior clinical benefit to TDM1 in the treatment of HER2 positive second line pts. However, only 75% of pts received the recommended treatment option of TDxd, suggesting an opportunity to improve outcomes in HER2 positive pts.