tbuckley/cabot-search huggingface dataset:
Weekly paclitaxel (P), carboplatin (CP) plus pembrolizumab (PMB) as first-line treatment of recurrent or metastatic (R/M) or locally very advanced (LVA) head and neck squamous cell carcinoma (HNSCC): A retrospective study in 39 patients (pts).
Authors: Christian Borel, Hélène Carinato, Carole Pflumio, Elodie Poprawa, Youssef Brahimi, Marine Oriel, Clara Vacheret, Delphine Ravily, Pierre Coliat, Thierry Petit, Mickael Burgy
Journal: Journal of Clinical Oncology (2024)

e18018 Background: Since the results of the KN-048 trial, the combination of platinum/5FU plus PMB has become the standard of care (SOC) for R/M HNSCC pts. The KN-B10 study shows that 5FU can be replaced by P with a favorable response rate and toxicity profile. Weekly use of P reduces hematologic toxicity and increases dose-intensity. Methods: We retrospectively reviewed all records of patients with R/M or LVA (T4b and/or N3b) HNSCC, ECOG-PS 0 to 2, PDL1 CPS ≥ 1, treated in first-line with weekly P (80 mg/m2) and CP (AUC 2: maximum total dose of 250 mg and systematic G-CSF at D3 and D4) for up to 12 infusions plus PMB every 3 weeks for up to 35 administrations. Results: From July 2020 to April 2023, 39 pts (median age 63 years, 74% male, 18% PS2) were treated. Primary tumors: oropharynx 44%, larynx 23%, hypopharynx 18% and oral cavity 15%. Disease setting: LVA 20%, local recurrence in irradiated area 54%, local recurrence and distant metastases 10% distant metastases only15%. With a median follow-up of 19 months (m), median Overall Survival (mOS) was 17.2 m (95%CI: 10.8-NR). 31/39 (79%) pts achieved an objective response (OR): 7 CR and 24 PR. For the 8 LVA pts, all achieved an OR, with a median Event Free Survival of 10 m (95%CI: 6.27-NR): the 4 progression-free pts (8.6 m+ to 25 m+) were treated with radiotherapy after neoadjuvant immuno-chemotherapy. For the 31 R/M pts, ECOG-PS was a significant prognostic factor of OS, mOS: 19.3 m (95%CI: 14.4-NR) for ECOG-PS 0-1 pts vs. 10.3 m (95%CI: 5.4-13.9) for ECOG-PS 2 pts (p = 0.02). For R/M pts, median Progression Free survival was 6.9 m (95%CI: 4.4-8.6) and the ORR was 74%, with a median duration of response of 6.5 m (95%CI: 3.13-8.56). Toxicity was manageable, with 20 (51%) pts experiencing at least one grade 3-4 adverse event: hematologic 18% (including one febrile neutropenia), infection 5%, neuropathy 8%, diarrhea 8%, infusion reaction 8%, electrolyte disturbances 8%, renal failure 3% and no toxic deaths. Conclusions: The combination of weekly P and CP plus PMB produces a high ORR and increased OS consistent with the results of the Frail-Immune study (J. Fayette ASCO 2023). This regimen deserves further consideration not only in the R/M setting, but also in the neoadjuvant setting for locally advanced patients.
Efficacy and safety of selpercatinib in advanced RET-altered thyroid cancers: A meta-analysis and systematic review.
Authors: - Muhibullah, Nouman Shafique, Navneet Kaur, Jawad Ahmed, Sarmad Zain, Syed Mujtaba Ali Naqvi, Shammas Bajwa, Hassan Nawaz, Atta Ur Rehman, Ali Haider, Ali Ghaffar, Zainab Javeed, Abdul Ghani Iqbal, Amna Ehsan, Prajjwal Khanal, Adeena Shafique, Iqra Shafiq, Besham Kumar, Rida Hussain, Umer Rizwan
Journal: Journal of Clinical Oncology (2024)

e18073 Background: Selpercatinib is a highly selective RET inhibitor that is used for the treatment of RET-mutant medullary thyroid cancers, but its efficacy and safety is not fully understood. Our objective is to summarize available literature on the safety and efficacy profile of Selpercatinib. Methods: A search was conducted on PubMed, Embase and Cochrane from foundation to 31st January 2024. Patients aged above 18 with Advanced RET-Altered Medullary Thyroid Cancers who received Selpercatinib were identified. Data abstraction was done based on objective response rate, complete response rate, any grade adverse effect (AE) and grade ≥3 AE. Analysis was done using R (v.4.3) and reported as proportions with respective 95% confidence intervals (CI) on forest plots. Results: Four studies were identified that reported the use of Selpercatinib in Advanced RET-Altered Medullary Thyroid Cancers. Our analysis showed that the pooled proportion of objective response rate and complete response rate was 74.8% (95% CI: 70.1% – 79%) and 4.9% (95% CI: 3.1% – 7.7%) respectively. Pooled proportion of patients experiencing any grade AE and grade ≥3 AE was 93.4% (95% CI: 90.4% – 95.6%) and 46.2% (95% CI: 41.1% – 51.3%) respectively. Conclusions: Selpercatinib is a novel RET inhibitor which has potential use against RET-Altered Thyroid Cancers. It has an overall acceptable safety and efficacy profile. However it requires further studies to establish its adverse effects and clinical application. [Table: see text]
Time restricted eating (TRE) and immunotherapy outcomes in head and neck squamous cell carcinoma (HNSCC) via modulation of microbial butyrate and tryptophan metabolic pathways.
Authors: Shahla Bari, Mostafa Eysha, Muhammad Alhomsi, Mahmoud Hathout, Krupal Patel, Lucas Li, Humaira Sarfraz, Jose Conejo-Garcia, Jameel Muzaffar
Journal: Journal of Clinical Oncology (2024)

e18028 Background: Metastatic HNSCC continues to have very poor prognosis. Only a fraction of patients respond to immune checkpoint blocker therapy (ICB), with no effective treatment options for non-responders. Gut microbial composition and diversity have been associated with response to ICB in many cancers including HNSCC. We have previously demonstrated that TRE significantly improved progression free survival via modulation of gut microbiota. We herein report our mechanistic data demonstrating critical role of microbially mediated butyric and tryptophan metabolic pathways in augmenting antitumor immune response to ICB. Methods: Paired blood and stool samples, at baseline and at first response assessment, from 43 HNSCC patients enrolled in the TRE study (NCT05083416) was collected and analyzed using untargeted and targeted metabolomics, focusing on tryptophan and short chain fatty acid pathway. Further shot gun metagenomic sequencing was conducted on stool samples. Finally, we performed an in vitro luciferase cytotoxicity assay using SCC-4 human cancer cells to demonstrate TRE mediated antitumor immune response. We co-cultured MHC-I and NY-ESO-1, and NY-ESO-1-specific TCR-transduced T cells. tumor cells and the T cells under different conditions of butyrate concentration and T cell-to-tumor cell ratio (1:5, 1:10) and evaluated T cell mediated tumors killing. Results: We noted significantly higher abundance of clostridium butyricum (OR-1004, p-0.0002) with corresponding higher expression of butyrate kinase enzyme in stool of patients who observed TRE (OR-1.9, p-0.0003) vs those who did not, leading to higher concentration of fecal butyric acid and hydroxy indole acetic acid (HIAA) (OR-4.2, p-0.003), both of which were independently associated with longer progression free survival (HR-0.9, p&lt;0.01). Higher abundance of butyric acid in gut is known to enhance the gut barrier function with consequent decrease in plasma butyrate and HIAA, lower systemic levels of which, was found to be associated with longer progression free survival in our cohort (OR-0.9, p-0.05). Both butyrate and 5HIAA are known activators of immunosuppressive aryl hydrocarbon receptor (AhR) expressed on cytotoxic CD8T cells, inhibiting CD8 mediated antitumor response. In line with our hypothesis, we observed that butyrate and 5HIAA impaired CD8 T mediated T cell killing of tumor cells in a dose-dependent manner. Conclusions: These results suggest that TRE favorably modulates ICB response via enrichment of gut microbiota with butyrate producing microbial organism, leading to increased abundance of gut butyrate and microbial tryptophan metabolites and their consequent reduction in systemic circulation, ultimately enhancing antitumor immune response.
Primary tracheal cancer: Demographics, histology, and treatment outcomes in the United States from 2000-2018.
Authors: Kristen Armel, Taylor Stamey, Andrew W. Ju, James E. Speicher, Aidan Michael Burke, Musharraf Navaid, Michael Casmer Larkins, Arjun Bhatt
Journal: Journal of Clinical Oncology (2024)

e18060 Background: Primary tracheal cancers (PTC) account for 0.2% of all respiratory malignancies and have an estimated incidence of 2.6 new cases per one million people in the US. Given the rarity of these cancers and paucity of data in the literature, we sought to determine the demographic and treatment patterns of PTC in the US. Methods: A retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results (SEER) database sponsored by the National Cancer Institute (NCI) was conducted for patients with a diagnosis of PTC between 2000 and 2018. Univariate, multivariate, and survival analyses were performed using 95% confidence intervals [CI] and a p-value &lt; 0.05 indicating significance. Results: 689 patients with PTC were identified, with 53% of these cases being squamous cell carcinoma (SCC) and 17% being adenoid cystic carcinoma (ACC). Comparison of five-year overall survival (OS) stratified by treatment modality, disease stage, and histology can be found in the table. Multi-factor analysis demonstrated significance with only disease histology (p=0.005). Asian patients with SCC had decreased five-year OS compared to White or Black patients (n=12; hazard ratio (HR)=0.19 and 0.20, and p=0.003 and 0.006, respectively). Patient age &lt; 65 years was associated with increased survival (hazard ratio (HR)=0.48; p&lt;0.001); no difference in survival based on sex or marital status was seen (sex: HR=1.03; p=0.733, marital status: HR=1.07; p=0.568). Conclusions: Patients with tracheal ACC had greater five-year OS compared to patients with tracheal SCC. Those with local or regional SCC that received surgery or RT saw survival benefit; patients with regional SCC had survival benefit with chemotherapy. Patients with ACC had no survival benefit from any treatment modality regardless of stage. Patients aged &lt; 65 years had increased survival and Asian patients with SCC had decreased survival. Further investigation into the potential differences in survival among various chemotherapeutic regimens and socioeconomic factors is warranted.[Table: see text]
Impact of tertiary lymphoid structures in response to immune checkpoint blockade in patients with head and neck squamous cell carcinoma.
Authors: Daniel A. Ruiz Torres, Shun Hirayama, Ross D. Merkin, Thomas J. Roberts, Manisha Jayandra Patel, Jong Chul Park, Lori J. Wirth, Peter Sadow, Moshe Sade-Feldman, Shannon Stott, Daniel Faden
Journal: Journal of Clinical Oncology (2024)

e18021 Background: Immune checkpoint blockade (ICB) is the standard of care for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), yetefficacy remains low. Current assessment for tumor response relies on a single proportional biomarker expressed in immune and tumor cells (Combined Positive Score, CPS) without differentiation by cell type, potentially explaining its limited predictive value. Tertiary Lymphoid Structures (TLS) have shown a stronger association with improved ICB response than PD-L1. However, their exact composition, size, and spatial biology in HNSCC remain understudied, and there is a need for a deeper examination of TLS biology in HNSCC and its link with clinical response to ICB. Methods: Pre-ICB tumor tissue sections (formalin-fixed, paraffin-embedded) were obtained from 10 responders (complete response, partial response, or stable disease) and 10 non-responders to ICB (progressive disease). A custom multi-immunofluorescence (mIF) staining assay was designed, optimized, and applied to characterize tumor cells (pan-cytokeratin), T cells (CD4, CD8), B cells (CD19, CD20), myeloid cells (CD16, CD56, CD163), dendritic cells (LAMP3), fibroblast (alpha Smooth Muscle Actin), proliferative status (Ki67) and immunoregulatory molecules (PD1). Following imaging and tissue classification using machine learning techniques, spatial profiling was performed, including proximity, density, and infiltration analysis. Response status was assessed via RECIST 1.1. Spatial metrics were compared among groups based on response to ICB. An unpaired t-test was used to compare mean densities. Multivariable logistic regression was used to measure the effect of TLS size on achieving response to ICB (CR, PR or SD). Results: A higher density of dendritic cells (LAMP3) was found in responders compared to non-responders to ICB (p=0.0415). A positive correlation was observed between mIF and pathologist identification of TLS (r 2 =0.51; p=0.0039). TLS trended toward more prevalent in responders to ICB (p=0.0906). There was no association of high CPS (&gt;20) with improved PFS (HR=0.91; p-value=0.8538 C.I.= 0.3538-2.369). Multivariate logistic regression analysis showed that total TLS area &gt; 5.8 (mm²) (mean TLS size in this cohort) in pretreatment tissue biopsies was associated with 2.4 increased odds of achieving objective response (OR= 2.4, p=0.05, 95% C.I.=1.2-275.1) independent of CPS score. Conclusions: Tertiary Lymphoid Structures play a critical role in the immune response to HNSCC, are quantifiable through histopathologic assessment by a pathologist, and may potentially outperform CPS as a predictor of ICB response.
Immune system evaluation in a cohort of Brazilian patients with head and neck squamous cell carcinoma who are non-smokers and alcoholic beverages abstainers.
Authors: Gilberto Castro, Ana Paula Lepique, Lorraynne Letycia Prado Cruz, Fatima Solange Pasini, Simone Maistro, Rosimeire Aparecida Roela, Maria Lucia Hirata Katayama, Ana Carolina Prado Ribeiro, Alexandre Bezerra dos Santos, Maria A. A. Koike Folgueira, Luiz Paulo Kowalski
Journal: Journal of Clinical Oncology (2024)

e18030 Background: Smoking and alcohol abuse are the main risk factors for head and neck squamous cell carcinoma. However, some patients do not present clear risk factors. We are studying a cohort of Brazilian patients that are non-smokers and alcoholic beverage abstainers. Brazilian people have peculiar ethnic characteristics, reflecting a miscegenation of Europeans, Africans and Amerindians. There is evidence that ethnic background may influence germline and somatic mutations, as well as tumor behavior. One of the aims is to evaluate the immune system of this cohort of miscegenated head and neck squamous cell carcinoma patients who are non-smokers and alcoholic beverages abstainers. Methods: In this prospective study, until now we have included 16 patients: 10 women and 6 men, who were non-smokers and alcoholic abstainers. All patients answered a questionnaire and collected blood, saliva and tumor samples before treatment for analysis. Self-declared skin color was mainly brown (n=8,) followed by white (n=6), black (n=1) and yellow (n=1). The median age was 56.5 years. Patients were diagnosed with oral (n=10), glotic (n=1), oropharyngeal (N=1,) lip and gingiva (n=4) carcinoma; clinical stages I (n=3), II (n=6); III (n=1) and IVA (n=5). Fourteen patients were already operated on. Results: Peripheral blood analysis revealed that within the mononuclear cell population CD16+CD66b-HLA-DR- cells, possibly NK, were significantly more frequent in patients with cancer stage III and IVA, than in patients with cancer stages I and II. There was also a significant negative correlation between the frequency of CD16+ cells in the mononuclear population and age of the patients. Finally, we observed that in the granulocyte population, patients with lesion grade I and II have 20-fold more CD16+CD66b+PD-L1+ cells than patients with lesions grade III and IV. It is possible that an IFN gamma driven response may be, in part, responsible for the induction of PD-L1 expression in granulocytes. This hypothesis is corroborated by the positive correlation between PD-L1 expression level in the granulocyte population and the frequency of CD16+CD66b- population (p=0.01, Pearson correlation 0.62). No other parameter, which included lymphocytes T and B, and monocytes, displayed correlation with clinical data. Conclusions: Our results suggest NK and myeloid cell frequency may vary in our cohort according to lesion grade as a consequence of immune responses. However, these are preliminary results, and other parameters acquisition, as well as a larger sample, will be needed for definitive conclusions.
A phase II umbrella clinical trial of advanced salivary gland cancer based on molecular typing.
Authors: Dongmei Ji, Yanjing Guo, Xin Liu, Yanan Yang, Youzhou Sang, Guangliang Chen, Shu Dong, Yulong Wang, Xiayun He, Hongmei Ying, Xueguan Lu, Yu Wang, Chaosu Hu, Qinghai Ji, Lu Zhang
Journal: Journal of Clinical Oncology (2024)

e18062 Background: Salivary gland cancers (SGCs) exhibit high heterogeneity in molecular and genomic characteristics, which provides a basis for targeted therapies of SGCs. Until recently, the gene targets of precision therapy drugs mainly included HER2, NTRK, TROP2, androgen-receptor (AR), etc. Herein, we report the preliminary result of a single-center, open-label, phase II umbrella clinical trial evaluating the efficacy and safety of molecular subtype-guided precision therapy for advanced salivary gland cancer (NCT05924256). Methods: Patients (pts) diagnosed as advanced SGC were recruited into 3 arms according to genetic subtypes. Pts with HER2 mutation/amplification or HER2 overexpression (IHC 3+ or IHC 2+/ISH+) will be assigned to arm 1 and receive SHR-A1811(anti-HER2) 4.8 mg/kg i.v. on day 1 of each 21-day cycle. IHC AR+ pts will be assigned to arm 2 and will receive rezvilutamide 240mg p.o. qd plus leuprolide 3.75mg s.c. on day 1 of each 28-day cycle. Pts with HER2 negative and AR negative will be assigned to arm 3 to receive SHR-A1921(anti-TROP2) 3.0 mg/kg or 4.0 mg/kg i.v. on day 1 of each 21-day cycle. A Simon’s two-stage optimal design was applied to each arm. The primary endpoint was the objective response rate (ORR) per RECIST1.1. Secondary endpoints included adverse events (AEs), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), etc. Results: Between Aug 2, 2023, and Jan 21, 2024, 21 pts were enrolled (arm 1/2/3: 9/5/7 pts, respectively). All pts were included in the safety set. In arm 1, of 6 evaluable pts, the unconfirmed ORR and DCR accounted for 100.0% and 100.0%, respectively. The most common treatment-related adverse events (TRAEs) in arm 1 were decreased lymphocyte count, neutrophil count, and decreased appetite (44.4% each). In arm 2, of 5 evaluable pts, the unconfirmed ORR and DCR were 20.0% and 100.0%, respectively. Rash, alanine aminotransferase increased, aspartate aminotransferase increased, and gamma-glutamyltransferase increased (20% each) were the most common TRAEs. In arm 3, of 6 evaluable pts, the unconfirmed ORR and DCR were 33.3% and 66.7%, respectively. In this arm, the most common TRAEs were stomatitis and vomiting (42.9% each). Conclusions: This molecular subtype-guided precision therapy for advanced salivary gland cancer showed promising results with acceptable toxicity. Clinical trial information: NCT05924256 .
Treatment of iodine refractory well differentiated thyroid carcinoma: Real world data from a tertiary center in Mexico.
Authors: Cristhel Cervin, Patricia Elvira Sánchez Valencia, Karina Del Valle Delgado, Eduardo Cardenas, Guadalupe Cervantes
Journal: Journal of Clinical Oncology (2024)

e18064 Background: Sorafenib and lenvatinib are the only drugs approved based on phase III clinical trials as first-line treatment in radiation-refractory, progressive, differentiated thyroid carcinoma, with limited data available for a direct comparison of these tyrosine kinase inhibitors. We aimed to evaluate the progression-free survival between the two groups treated with both medications in a Mexican tertiary center. Methods: In this retrospective study conducted from December 2015 to June 2024, we evaluated the outcomes of 38 patients with metastatic/locally advanced, progressive, RAI-refractory DTC/PDTC, treated with sorafenib or lenvatinib. The primary outcome was the probability of progression-free survival (PFS) between both groups. Results: Eighteen patients treated with sorafenib and twenty patients with lenvatinib were included. The median age was 64.5 years, and 76% were women. Papillary histology was the most frequent (81%), and they were diagnosed at stage IV in the majority of cases (82%). More than half of the patients had previously undergone surgery, radiotherapy, and/or radioactive iodine treatment. After a median follow-up of 13.2 months, no difference in PFS was observed between the sorafenib and lenvatinib arms (HR 1.53, 95% CI 0.38-6.05, p=0.54). Conclusions: Sorafenib and lenvatinib have shown comparable efficacy in prolonging progression-free survival in Mexican patients with metastatic/locally advanced, progressive, RAI-refractory DTC/PDTC, leading to markedly superior outcomes compared to pivotal studies.
Differential gene expression and methylation of upper aerodigestive tract and lung squamous cell carcinoma between European ancestry (EA) and African ancestry (AA) patients.
Authors: Hannah Thomas, Vera Mukhina, Anirudh Saxena, Ranee Mehra, Daria Gaykalova
Journal: Journal of Clinical Oncology (2024)

e18031 Background: Pan-cancer analysis of cancer disparities revealed both head and neck and lung cancer are among the top cancers with significant disparities in overall survival outcomes between EA and AA patients. Analysis of The Cancer Genome Atlas (TCGA) for all cancer in EA and AA found genetic signatures associated with noted disparities, such as somatic copy number alterations, TP53 mutations, CCNE1 amplification, and overexpression of genes correlated with chromosomal instability. To inform whether epigenetic and transcriptomic factors could be driving the disparities seen in squamous cell carcinoma (SCC) of the upper aerodigestive tract (UADT) and lung, we sought to analyze genomic data to identify differentially methylated and expressed genes between EA and AA patients and determine whether these affected survival. Methods: TCGA was queried to extract data from self-identified EA and AA patients with head and neck, esophageal, and lung SCC. Literature suggests that SCC tumors share genetic and epigenetic signatures and can be analyzed as a group. Human papillomavirus positive patients were excluded. Patients were separated into EA and AA groups matched for age, stage, and smoking to account for clinical biases of biological analysis. DNA methylation (Epic array) and gene expression (RNA-Seq) profiles were compared between tumor tissue samples in EA patients, tumors in AA patients, and normal tissue. The genes that were identified to be differentially methylated were then analyzed to compare overall survival between hypomethylation and hypermethylation of each identified gene, with and without subgrouping by race. Differentially expressed genes were similarly analyzed between high and low expression. Overall survival was estimated by the Kaplan-Meier method and compared using the log-rank test. Results: A comparison of DNA methylation profiles found 79 genes that were differentially methylated when comparing EA tumor, AA tumor, and normal tissue samples. Survival analysis was performed on top 21 of the differentially methylated genes. Of these, 9 were found to have significant differences in overall survival when stratifying by race and methylation status. Differentially methylated genes included MAD1L1 (Mitotic Arrest Deficient 1 Like 1), which is known for its role in the spindle assembly checkpoint in mitosis and tumor suppression. Similar analysis revealed 404 genes that were differentially expressed comparing EA tumor, AA tumor, and normal tissue. Candidate genes based on expression level will be discussed. Conclusions: Differential DNA methylation and gene expression were noted between EA and AA groups with lung and UADT SCC. This difference may contribute to the disparity in overall survival seen between these groups that persists even when controlling for variables commonly associated with worse survival.