tbuckley/cabot-search huggingface dataset:
Survey of long term survivors of oral cancer: Looking beyond cancer biology.
Authors: Sudhir Vasudevan Vasudevan Nair, Manasi Bavaskar, Hitesh Singhavi, Rathan Shetty, Arjun Singh
Journal: Journal of Clinical Oncology (2024)

6087 Background: While surgery is the main stay of treatment for early stage oral cancers, advanced stages require adjuvant treatments in the form of radiotherapy or concurrent radiotherapy. Yet, the effectiveness of these interventions is not solely determined by clinical measures but also by personal factors such as individual motivation, support from loved ones, and financial security. These aspects might explain the survival rate variations among patients who, despite having similar prognostic categories and stages of disease, show differing outcomes. The role of social determinants in influencing patient survival, apart from the acknowledged impact of disease biology, is not well understood. Methods: All treatment-naive oral cavity cancer patients who underwent definitive treatment during 2014 to 2018 at our institute and are alive for more than five years were selected for this study. A custom investigator-administered questionnaire was developed and it had 32 questions under six domains- personal, habit history, financial, social, functional, and emotional. The study was approved by the institutional ethics committee. Of the 1787 potential participants, we found that 219 had expired, only 442 patients agreed to answer the questionnaire, while 45 refused to participate. The rest of the patients were not reachable telephonically. Results: This survey had 442 patients, of which 90% were males, with a mean age of 52.1 years. The most common site of the presentation was buccal mucosa (60%), and 59% presented in the locally advanced stage. Post-operatively, 71% received adjuvant therapy. All patients were motivated to undergo the radical treatments and had their family support. However, post-treatment, about 10% of individuals experienced a change in marital status. Financial constraints did affect 20% of patients during and after treatment, and more than 70% had their out-of-pocket expenditure above 50% of the total cost. While 80% did not have trouble attending social functions, 46% reported trouble eating socially. However, this was more common for patients who received adjuvant treatment (p &lt; 0.001). About 21% reported shoulder dysfunction and body discomfort. However, no statistically significant associations could be drawn for any of the domains of the questionnaire when compared to patients between the early and late stages. Shoulder discomfort was experienced more by patients who were treated for tongue cancer (p-value 0.010). Conclusions: The results of this study shed light on the challenges faced by long-term survivors of oral cancer following radical treatment regimens. More than half of patients reported that out-of-pocket expenses constituted more than half of their total treatment costs. A notable minority of people suffer from shoulder dysfunction, suggesting there is a clear opportunity for advancements in reconstruction and rehabilitation.
MR radiomics and neoadjuvant chemo-responsiveness with insights into selective treatment de-intensification in HPV-positive oropharyngeal carcinoma.
Authors: Xueguan Lu, Xin Zhou, Jing Gong, Tingting Xu, Chunying Shen, Yu Wang, Chaosu Hu, Yajia Gu, Lin Zhu, Wenjiao Lv
Journal: Journal of Clinical Oncology (2024)

6085 Background: In HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), patients with good response to neoadjuvant chemotherapy (NAC) exhibit superior prognosis. Accurate prediction of NAC response allows for NAC candidate selection and personalized treatment de-intensification in HPV-positive OPSCC. In this study, we aimed to apply baseline magnetic resonance (MR) radiomic features to predict NAC response and prognosis. Methods: Pre-treatment MR images and clinical data of 131 patients with HPV-positive OPSCC were retrieved from Fudan University Shanghai Cancer Center. Radiomic features of both oropharyngeal lesions and metastatic nodes were extracted on T2WI and contrast-enhanced T1WI sequence. Patients were divided into training cohort (n=47), prospective validation cohort (n=49) and real-world validation cohort (n=35). Following radiomic feature selection, a linear support vector machine (SVM) model was built and validated for NAC response prediction. Nomograms that combined radiomics and clinical characteristics were then developed to predict survival outcomes. The performance of response models was assessed by the area under the curve (AUC), accuracy, sensitivity, specificity and prognostic models were measured by C-index. RNA-seq and proteomic data were further leveraged and compared to interpret the molecular features underlying radiomic signatures with differential NAC response. Results: For NAC response prediction, the fusion model with both oropharyngeal and nodal radiomic signatures on multi-sequence MR images achieved encouraging performance to predict good responders in the training cohort (AUC 0.89, 95% CI, 0.79-0.95) and prospective validation cohort (AUC 0.71, 95% CI, 0.59-0.83). For prognosis prediction, radiomics-based nomograms exhibited satisfactory discriminative ability between low-risk and high-risk patients in training cohort and two validation cohorts (PFS, C-index: 0.85, 0.76 and 0.83; OS, C-index: 0.79, 0.76 and 0.87). An exploratory analysis in the prospective validation cohort showed that de-intensified radiotherapy after NAC in low-risk patients yielded 100% in both PFS and OS. Furthermore, expression analysis unveiled distinct molecular phenotypes in relation to NAC response, where poor responders had predominantly enhanced keratinization while good responders were featured by stronger innate and adaptive immune response. Conclusions: The MR-based radiomic models and subsequent prognostic models efficiently discriminate among patients with different NAC response and survival risk. This study provides a new strategy for patient selection in HPV-positive OPSCC that are suitable for personalized de-intensification. Integration of radiomics in future trials is warranted.
The role and mechanism of circadian clock gene BMAL1 in the proliferation and metastasis of nasopharyngeal carcinoma by inhibition TGF-β1/Smads pathway.
Authors: Zhao Chaofen, Feng Jin, Lina Liu, Qianyong He, Yue Chen, Kai Shang, Xiaomei Li, Xinyu Xu, Xunyan Luo
Journal: Journal of Clinical Oncology (2024)

6027 Background: To explore the molecular mechanism of biological clock gene BMAL1 inhibiting the proliferation and metastasis of nasopharyngeal carcinoma(NPC). Methods: 1. IHC detected the expression of BMAL1 in 41 cases of nasopharyngeal chronic inflammatory tissue and 71 cases of NPCtissue. PCR and Western blot measured the expression levels of BMAL1 in NP69 in NPC cells and human immortalized nasopharyngeal epithelial cells, respectively. 2. To detect the effect of BMAL1 on the proliferation capacity of NPCcells in vitro and in vivo; Scratch healing and Transwell invasion migration experiments detected the effect of BMAL1 on the invasion and migration ability of NPCcells in vitro. Fluorescence in vivo imaging and HE staining to determine the transfer of nude mouse tail intravenous injection model. PCR and Western blot detect the effect of BMAL1 on the expression of EMT-related markers at the transcriptional and protein levels in NPC cells. 3. A series of molecular biological means such as bioinformatics technology, ChIP experiment, double luciferase reporter gene experiment, immunofluorescence colocalization experiment and Co-IP were used to verify its mechanism. Results: 1. The expression of BMAL1 in NPCtissues and cells is reduced. The expression of BMAL1 in NPC tissues was associated with the M stage of nasopharyngeal carcinoma patients (p=0.006). 2. Overexpression of BMAL1 can inhibit the proliferation, invasion and migration ability of nasopharyngeal cancer cells, while knocking down BMAL1 is the opposite. Overexpression of BMAL1 inhibits EMT of NPCcells. 3. There are 5 BMAL1 binding sites in the TGF-β1promoter region, and BMAL1 can directly bind to the TGF-β1promoter region, which can inhibit the transcriptional activity of TGF-β1. Overexpression of BMAL1 inhibits TGF-β1/Smads pathway activity. Under the induction of recombinant human TGF-β1, the proliferation ability of NPC cells was enhanced, the activity of TGF-β1/Smads signaling pathway was enhanced, and nasopharyngeal cancer cells underwent EMT, and cell invasion and migration capacity increased. After overexpression of BMAL1, TGF-β1 no longer promotes TGF-β1/Smads signaling pathway activity, EMT is inhibited, and cell invasion and migration ability is weakened. BMAL1 combined with TGF-β1 has certain diagnostic value in predicting whether nasopharyngeal carcinoma metastasis. Conclusions: BMAL1 expression is downregulated in nasopharyngeal carcinoma, and its expression level is related to the development and metastasis of nasopharyngeal carcinoma. BMAL1 can inhibit the proliferation, epithelial-mesenchymal transformation and invasion and metastasis ability of NPC cells, and its mechanism is related to the inhibition of TGF-β1/Smads signaling pathway activity. It is speculated that it may become a new prognostic marker and therapeutic target for nasopharyngeal carcinoma.
Pembrolizumab plus nab-paclitaxel and platinum as first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): A prospective, single-arm, open-label, phase 2 study.
Authors: Lin Gui, Xinrui Chen, Zucheng Xie, Xiaohui He, Jianliang Yang, Peng Liu, Yan Qin, Yuankai Shi
Journal: Journal of Clinical Oncology (2024)

6023 Background: Based on KN-048, pembrolizumab combined with PF regimen has become the first-line standard treatment for R/M HNSCC. KN-B10 confirmed pembrolizumab combined with carboplatin and paclitaxel has a promising effect with manageable safety. This study aims to supplement the efficacy and safety data of pembrolizumab combined with nab-paclitaxel and platinum in the Chinese population. Methods: Untreated R/M HNSCC patients were treated with pembrolizumab 200mg, nab-paclitaxel 260mg/m 2 , plus cisplatin 75 mg/m 2 or carboplatin AUC 5 (only if patients have cisplatin contraindications) on day 1 every 21 days for up to six cycles, followed by pembrolizumab maintenance therapy until progression or intolerable toxicity or completion of 35 cycles. Efficacy was evaluated according to RECIST 1.1, and survival analysis was performed using the Kaplan-Meier method. Adverse events were assessed using the CTCAE 5.0. The primary endpoint was ORR. Secondary endpoints include safety, DCR, OS, and PFS. High-resolution sequencing based on probe capture was performed on eligible patients. Results: Between Sep 15, 2020, and Nov 8, 2023, 67 R/M HNSCC patients were enrolled. Baseline characteristics are shown in the table. The median follow-up time was 12.7 months at the data cut-off date of January 8th, 2023, the ORR was 62.7%, and the DCR was 88.1%. The median PFS and OS were 11.6 months and 18.7 months, respectively. The median DOR was 14.7 months. The most common TRAEs of grade ≥3 were leukopenia (22.4%) and neutropenia (28.4%). Grade≥3 immune-related AEs were pneumonitis (1.5%), hepatitis (1.5%), and enteritis (1.5%). Of the 35 patients with sequencing results, the most common alterations were the TP53 mutation (86%), CDKN2A mutation (22%), FGF19 (26%), FGF4 (20%), FGF3 (20%), and CCND1 (20%) amplification. FGF19, FGF4, FGF3, and CCND1 amplification were associated with poor ORR, and CDKN2A mutation was associated with poor OS. Conclusions: Pembrolizumab combined with nab-paclitaxel and platinum shows encouraging antitumor activity accompanied by a manageable safety profile in untreated R/M HNSCC patients in China. CDKN2A mutation was a potential independent prognostic factors for this patient population. Clinical trial information: NCT04857164 . [Table: see text]
Safety and efficacy of iparomlimab and tuvonralimab in combination with gemcitabine and cisplatin as first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma: A multicenter, single-arm, phase 2 trial (DUBHE-N-302).
Authors: Yan Huang, Shen Zhao, Song Qu, Ying Guan, Yuanyuan Zhao, Jie Wang, Ting Wu, Xiaokui Yu, Shilin Xue, Xiaoyan Kang, Li Zhang
Journal: Journal of Clinical Oncology (2024)

6026 Background: Programmed cell death 1 (PD-1) inhibitor plus chemotherapy has been the standard first-line (1L) treatment for patients with recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). Iparomlimab and tuvoralimab (QL1706), a novel bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen 4, indicated promising anti-tumor activity for advanced solid tumors including NPC in phase 1/1b trial. This study aimed to evaluate the safety and efficacy of QL1706 combined with chemotherapy as 1L treatment in R/M NPC. Methods: This multicenter, single-arm, phase 2 study (NCT05576272) recruited patients with NPC who had no prior systemic therapy in the R/M setting. Intravenous injection of QL1706 5 mg/kg (day 1) combined with gemcitabine 1000 mg/m² (days 1 and 8) and cisplatin 80 mg/m² (day 1) was administered for four to six cycles (21 days per cycle), followed by maintenance treatment of QL1706. The primary endpoint was safety and tolerability. Key secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). Results: From May 19 2022 to Dec 9 2022, 29 patients were included. The median age was 50 years (range, 25-65), with 24 (83%) being male. Seven patients (24%) had an Eastern Cooperative Oncology Group Performance Status of 1. Nineteen (66%) had recurrent disease. As of the data cut-off on Dec 31 2023, the median follow-up was 15.5 months. Treatment-related adverse events (TRAEs) occurred in 29 patients (100%). TRAEs of grade 3 or 4 occurred in 18 patients (62%), with the most common being decreased neutrophil count (41%), decreased white blood cell count (35%), anemia (21%), and decreased platelet count (21%). Twenty patients (69%) experienced immune-related adverse events, with the most common being grade 1-2 hypothyroidism (38%). Serious TRAEs occurred in five patients (17%). Three patients (10%) discontinued treatment due to adverse events. No treatment-related deaths occurred. Among the 28 evaluable patients, the ORR was 82.1% (95% confidence interval [CI], 63.1% to 93.9%), including one achieving complete response. The DCR was 96.4% (95% CI, 81.7% to 99.9%). The median PFS was 12.5 months (95% CI, 5.7 to not evaluable [NE]), and the median DoR was 14.1 months (95% CI, 7.6 to NE). In 14 patients with high expression level of programmed cell death ligand 1 (combined positive score≥50), the median PFS was 16.2 months (95% CI, 9.9 to NE). The median OS was not reached. Conclusions: Iparomlimab and tuvoralimab combined with chemotherapy showed tolerable safety and promising efficacy as 1L treatment for patients with R/M NPC. Clinical trial information: NCT05576272 .
Comparative analysis of pembrolizumab and cetuximab-based therapy in patients with recurrent/metastatic head and neck squamous cell carcinoma: Real-world data.
Authors: Zahra Hamedi, Andrea Yachee Lo, Jonathan David Berkman, Erin R. Alesi
Journal: Journal of Clinical Oncology (2024)

6022 Background: The preferred treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) not amenable to localized/curative treatment is pembrolizumab, either monotherapy or in combination with chemotherapy based on the results of KEYNOTE-048. Since the FDA’s approval of pembrolizumab in 2019, real-world data has been scarce. Using the TriNetX platform, we retrospectively compared survival outcomes between patients treated with pembrolizumab vs. cetuximab-based treatment. Methods: Cohorts were identified on TriNetX platform using the US Collaborative Network, which includes anonymous clinical information of patients between 2007-2023. Three cohorts were selected: patients treated with pembrolizumab monotherapy (P), patients treated with pembrolizumab and platinum+5-FU chemotherapy (P+CT), and patients treated with cetuximab and platinum+5-FU chemotherapy (C+CT). All patients had non-nasopharyngeal R/M HNSCC with no prior systemic therapy. The study objective was to compare overall survival (OS) between these three cohorts using the Kaplan-Meier method. Results: Our analysis identified 409 patients in cohort P, 161 patients in cohort P+CT, and 176 patients in cohort C+CT. Median age at initiation of treatment was 69.8, 62.2, and 57.7 years in cohort P, P+CT, and C+CT, respectively. Male percentage was 61%, 75%, and 77%, respectively. The most common primary tumor sites for cohorts P, P+CT, and C+CT were as follows: oropharynx 28%, 37%, and 48%, hypopharynx 10%, 19%, and 11%, larynx 31%, 29%, and 40%, and oral cavity 4%, 6% and 9% respectively. Information on PD-L1 and HPV (Human Papillomavirus) status was not available. Median OS was 13.7, 15, and11.4 months in cohorts P, P+CT, and C+CT, respectively. Survival probability at 5 years was 25.7% in cohort P, 32.2% in cohort P+CT, and 9.9% in cohort C+CT. Based on our analysis, patients treated with pembrolizumab (P or P+CT) demonstrated superior OS compared to those who received cetuximab-based therapy (P-Value &lt;0.05). There was no statistically difference in median OS between P and P+CT group. (P-Value 0.6). Conclusions: Our retrospective analysis of real-world data from a large national database shows superior OS with pembrolizumab- based treatment compared to cetuximab-based treatment in the first line setting for patients with R/M HNSCC. This analysis is consistent with KEYNOTE-048 outcomes. we found no difference in OS between Pembrolizumab alone or in combination with chemotherapy. Limitations include unknown PD-L1 and HPV status. Further long-term and prospective analysis is imperative to enhance the care and outcomes of patients with metastatic HNSCC. [Table: see text]
Correlation between irAEs and treatment efficacy of anti-PD-1 single agent in patients with recurrent/metastatic head and neck squamous cell carcinoma: A monocentric real-world observational study.
Authors: Chiara Gottardi, Giuseppe Anile, Ilaria Micheletto, Marco Krengli, Andrea Luigi Camillo Carobbio, Badr El Khouzai, Stefano Taboni, Greta Pretto, Valentina Guarneri, Maria Grazia Ghi
Journal: Journal of Clinical Oncology (2024)

6029 Background: Immune-related adverse events (irAEs) are associated with efficacy of ICIs-based treatment in various cancer types. The aim of this retrospective study was to assess the relationship between irAEs and outcomes in patients with recurrent/metastatic Head and Neck squamous cell carcinoma (R/M-HNSCC) treated with immune checkpoint inhibitors (ICIs) monotherapy. Methods: We retrospectively reviewed data from patients with R/M HNSCC treated with ICIs single-agent between January 2018 and June 2023 at the Istituto Oncologico Veneto of Padua. Common Terminology Criteria for Adverse Events v.5.0 was used to assess irAEs evaluation. Patients were stratified into irAEs (any grade) and non-irAEs groups. Overall survival (OS) and progression free survival (PFS) were assessed using the Kaplan-Meier method. Univariate and multivariate Cox-regression were used to compare survival outcomes. The chi-square test was used to assess the association between irAEs and objective responses (ORR). Results: A total of 89 patients were eligible for the analysis. Patients with platinum-refractory disease received nivolumab (64 patients, 72%). All the 25 patients (28%) with platinum-sensitive disease were PD-L1 positive (CPS≥1) and received pembrolizumab as first line treatment for R/M disease. Median follow-up was 8.7 months. IrAEs (any grade) were observed in 60 patients (67%), including 9 patients (10%) with grade ≥3 AEs. The most common irAEs were endocrinopathies (35%), skin events (15%), hepatic events (13%), diarrhea/colitis (10%) and lipase/amylase elevation (10%). The ORR was higher in the irAEs group than in the non-irAEs group (19.5% vs 2%, p=0.017). PFS and OS were also significantly longer in the irAEs group: median PFS was 3.9 months vs 2.1 months (HR 0.48 95% CI 0.30-0.77; p=0.003) and median OS was 12.5 months vs 4.3 months (HR 0.36 95% CI 0.21-0.60; p=0.000). The statistically significant benefit for both PFS and OS was confirmed at the multivariate analysis (Table1). Patients who experienced endocrine-related irAEs (p=0.004), diarrhea/colitis (p=0.040) and lipase/amylase increase (p=0.005) had significantly longer OS than those without the corresponding toxicity. A positive trend was observed for skin toxicity (p=0.051). Conclusions: The occurrence of irAEs was a predictor of response and survival outcomes in patients with R/M HNSCC treated with ICIs single-agent.[Table: see text]
Off-label use of checkpoint inhibitor (CPI) monotherapy in PD-L1–negative or unknown recurrent/metastatic head and neck cancer (R/M HNSCC).
Authors: Margaret Stalker, Kewen Qu, Wei-Ting Hwang, Roger B. Cohen, Ronac Mamtani, Lova Sun
Journal: Journal of Clinical Oncology (2024)

6025 Background: The KN-048 study established that the CPI pembrolizumab with chemotherapy should be used for PD-L1 negative R/M HNSCC, while CPI monotherapy has limited efficacy (ORR 4%) in PD-L1 negative disease and should be reserved for PD-L1 positive disease. National patterns of PD-L1 testing and PD-L1 guided treatment selection are unknown. We examined PD-L1 testing rates, the use of CPI overall, and the use of CPI monotherapy in PD-L1 negative or unknown R/M HNSCC (“off-label”), and associated factors. Methods: This retrospective analysis included adult patients starting treatment for R/M HNSCC from 2019-2023 in the Flatiron Health electronic health record (EHR)-derived de-identified national database. Demographics, treatment type, and PD-L1 test results were summarized using descriptive statistics. Specifically, first-line therapy was categorized as CPI monotherapy, CPI with chemotherapy, or chemotherapy and/or cetuximab without CPI. “Off-label” use of CPI was defined as single-agent use without concurrent chemotherapy in patients with negative or unknown PD-L1. Factors associated with “off-label” use were identified using multivariable logistic regression analysis. Results: Our cohort included 3,395 patients with median age 66 (IQR 59-73), 65% White, 77% treated in a community setting, 76% with smoking history, 37% HPV positive, and 72% ECOG PS 0-1. Almost half of patients (44%) did not have a recorded PD-L1 test result; of those with known PD-L1 status (n=1886), distribution of combined positive score (CPS) 0, 1-19, and 20 was 19%, 41%, and 40%, respectively. The most common frontline treatment was CPI monotherapy (43%), followed by chemotherapy/cetuximab (33%) and CPI with chemotherapy (25%). CPI monotherapy use was highly prevalent in patients aged ≥75 (54%) and with ECOG PS ≥ 2 (52%). Among the subgroup of PD-L1 negative or unknown patients (n=1831), 37% (678) received CPI monotherapy (“off-label”). Factors associated with “off-label” CPI monotherapy use included ECOG PS ≥ 2 (OR 1.3), age ≥ 75 (OR 1.3), community practice (OR 1.7), and earlier year (HR 1.2) (all p&lt;0.05). Conclusions: Most US patients with R/M HNSCC are now receiving CPI-based therapy in the frontline setting, but PD-L1 testing rates remain suboptimal. Use of CPI monotherapy in PD-L1 negative or unknown HNSCC is common, particularly in elderly patients and those with poor performance status.[Table: see text]