bluuebunny/crossref_metadata_2025_split huggingface dataset:
An open label, nonrandomized, multi-arm, phase II trial evaluating pembrolizumab combined with cetuximab in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): Results of cohort 1 interim analysis.
Authors: Sacco Assuntina Gesualda , Chen Ruifeng , Ghosh Debanjali , Wong Deborah J.L. , Worden Francis P. , Adkins Douglas , Pittman Emily , Messer Karen , Gold Kathryn A. , Daniels Gregory A. , Swiecicki Paul , Sutton Brian , Natsuhara Amanda , Cohen Ezra E.W. 
Published: May 2019

6033 Background: Pembrolizumab (a humanized monoclonal antibody blocking programmed death receptor-1[PD-1]), and cetuximab (a chimeric monoclonal antibody inhibiting epidermal growth factor receptor) are both FDA-approved, second-line monotherapies for R/M HNSCC. This is the first trial to evaluate anti-tumor efficacy of dual therapy with pembrolizumab and cetuximab. Previously reported safety data demonstrated favorable toxicity. An interim futility analysis of cohort 1 (anti-PD-1/PD-L1 and cetuximab naïve) was completed per protocol. Methods: Patients (pts) with platinum-refractory/ineligible, R/M HNSCC were treated with pembrolizumab 200mg IV on day 1 and cetuximab 400mg/m2 loading dose followed by 250mg/m2 weekly (21-day cycle). Primary endpoint: overall response rate (complete and partial responses) by 6 months (mo). Secondary endpoints: 12-mo progression-free survival (PFS) probability, overall survival, response duration, safety, correlative analyses. Results: 14 evaluable pts were enrolled March 2017-October 2018. Median age 60y (range 47-86y), M:F 6:8, ECOG (0:1) 2:12, 14 mucosal primaries (9 oral cavity, 2 HPV-mediated oropharynx, 2 non-EBV-associated nasopharynx, 1 larynx). 11 pts (79%) had no prior lines of systemic therapy for R/M HNSCC (range 0-1). 6 pts (42.8%) had a partial response by 6 months, meeting pre-planned criteria for trial continuation. 4 pts (28.6%) had stable disease and 4 (28.6%) had progressive disease. Median PFS was 128 days (4.3 mo). Median duration of response was 160.5 days (5.4 mo) for partial responders and 133 days (4.4 mo) for pts with stable disease. Disease control rate (partial + stable) was 71.4%. There were 7 grade 3 treatment-related toxicities. 2 pts discontinued cetuximab due to toxicity, however, both continued pembrolizumab. Conclusions: Interim analysis indicates that pembrolizumab plus cetuximab is potentially active for platinum-refractory/ineligible pts with R/M HNSCC. These results meet protocol specifications for trial continuation. Final results will include PD-L1 expression data. Clinical trial information: NCT03082534.
COX-2 expression and mesenchymal-transition status on circulating tumor cells to predict survival in patients with nasopharyngeal carcinoma: A prospective analysis.
Authors: Li Yongjiang , Xie Xiaoqi , Zhang Hong , Lv Chen , Miao Dongyan , Guo Zhigui , Zhang Yumei , Li Changhu , Ge Wei , Wang Feng 
Published: May 2019

6042 Background: The prognostic significance of circulating tumor cells (CTCs) in head and neck cancer is still under active investigation. It remains unclear whether just CTC count alone is sufficient to predict outcomes or whether the functional status of the CTCs is also needed. We investigated the clinical significance of determining epithelial-to-mesenchymal transition status and geno-/pheno-typic biomarkers of aggressiveness of CTCs in predicting outcomes in nasopharyngeal carcinoma (NPC). Methods: The prospective study enrolled 131 patients with NPC. CTCs were isolated at baseline and at the end of concurrent chemoradiotherapy using the CanPatrol system. Subsequently, the epithelial-mesenchymal transition (EMT) biomarkers and cyclooxygenase-2 (COX-2) expression status of the CTCs were identified by RNA-in situ hybridization (ISH) method. Results: COX-2 expression was found in 87/131 (66.4%) patients at baseline and 53/115 (46.1%) patients post-treatment. Independent of initial COX-2 expression status, the patients with post-treatment COX-2 expression on CTCs had significantly poorer treatment response (P = 0.011), and higher risk of tumor relapse (P = 0.026) and metastasis (P = 0.007). Similarly, post-treatment mesenchymal transition was also associated with higher risk of tumor relapse and metastasis. In multivariate analysis, post-treatment COX-2 expression on CTCs remained an independent prognostic indicator of poorer overall survival (HR 2.41, 95% CI 1.12-5.19; P = 0.024). Post-treatment COX-2 expression and mesenchymal transition in CTCs was the strongest prognostic indicator of overall survival on multivariate analysis (HR 2.73, 95% CI 1.28-5.83; P = 0.009). Conclusions: Post-treatment COX-2 expression on CTCs, especially on the mesenchymal subtype, is a novel and promising prognostic indicator for NPC patients treated with chemoradiation therapy. Future studies are needed to validate our findings and further clarify the value of integrating the indicators with current clinical strategies in improving survival of NPC patients.
Development of a clinicomolecular risk stratification system for nonmetastatic nasopharyngeal carcinoma using Epstein–Barr virus DNA and TNM stage: A “Big data” analysis of 9,160 endemic cases.
Authors: Chen Fo-Ping , Zhou Guan-Qun , Luo Ying-Shan , Tan Kuan Rui Lloyd , Tan Sze Huey , Zheng Yu , Lin Li , Guo Ying , Ma Jun , Chua Melvin L.K. , Sun Ying 
Published: May 2019

6043 Background: To construct a clinicomolecular index integrating circulating Epstein-barr virus (cfEBV) DNA with T- and N- categories for better prognostication in nasopharyngeal carcinoma (NPC). Methods: Clinical and treatment records of 9,160 biopsy-proven, non-metastatic NPC cases were identified from an institutional “Big-data” platform. Decision tree modeling (DTM), recursive partitioning analysis (RPA) and adjusted hazard ratio (AHR) methods were used to generate clinicomolecular risk models. Outcome prediction of the models were compared against 8th edition TNM stage and two RPA-original models. Results: We observed linearity between cfEBV DNA and DFS; cfEBV DNA of > 2,000 copies was consistent for risk discretisation (HR > 1.0) for DFS, OS and DMFS in our cohort of 9,160 patients. DTM, RPA-new and AHR modelling using a two-tiered stratification by cfEBV DNA (≤2,000 and > 2,000 copies) and T- and N- categories yielded five risk groups with significantly disparate DFS (P < 0.001 for all subgroup comparisons). AHR model outperformed all other models and the TNM stage classification with better hazard consistency, hazard discrimination, explained variation, sample size balance and likelihood difference. Importantly, our clinicomolecular AHR groupings were significantly associated with the efficacy of different therapeutic regimes. Outcomes were comparable between concurrent chemoradiotherapy and intensity-modulated radiotherapy (IMRT) and IMRT alone for AHR1-2 (3-y DFS [AHR1] = 96.2% [IMRT] vs 95.3% [chemo-IMRT]; 3-y DFS [AHR2] = 91.1% vs 90.4%). Neoadjuvant chemotherapy and chemo-IMRT was superior to chemo-IMRT alone for AHR4-5 (AHRDFS 0.77[0.65-0.93], P = 0.005; 0.77[0.61-0.97], P = 0.027), but not for AHR3 (AHRDFS 1.07[0.86-1.34]). Conclusions: Here, we present a robust clinicomolecular risk stratification system that outperforms the TNM stage classification in non-metastatic NPC. Our clinicomolecular model is associated with the efficacy of different therapeutic regimes.
Correlation of angiogenic and immunomodulatory proteins with clinical outcomes of durvalumab (anti-PDL1) in recurrent/metastatic head and neck squamous cell carcinoma.
Authors: Guo Xiang , Higgs Brandon W. , Baverel Paul , Fan Jean , Morsli Nassim , Wrona Magdalena , Yovine Alejandro Javier , Chang Shao-Chun , Arends Rosalin , Roskos Lorin 
Published: May 2019

6048 Background: The potential for durvalumab, a PD-L1 blocking monoclonal antibody, to treat head and neck squamous cell carcinoma (HNSCC) is being evaluated in multiple clinical trials. We assessed circulating protein biomarkers in HNSCC patients prior to treatment to better understand pathways related to clinical outcomes and potentially relevant for targeting in combination with durvalumab. Methods: Sixty-six selected serum proteins were measured by multiplex immunoassay at baseline in HNSCC patients receiving durvalumab treatment: 106 patients with high PD-L1 (≥25% tumor cells; SP263 assay) in phase II HAWK trial and 52 patients with low/no PD-L1 in phase II CONDOR trial. Results: Multivariate Cox modeling demonstrated that higher baseline concentrations of angiogenic, pro-inflammatory, and myeloid-associated proteins (ANGPT2, CRP, IL6, S100A12) were associated with shorter overall survival (OS), while higher concentration of a bone formation marker and immunostimulatory hormone (BGLAP) correlated with longer OS in 158 durvalumab-treated HNSCC patients ( P< 0.05). These 4 proteins also showed higher baseline levels in patients with progressive disease (PD) compared to stable disease (SD) and partial or complete responses (PR/CR), while BGLAP had lower levels in PD compared to SD or PR/CR (Mann-Whitney P< 0.05). The 5 proteins remained significantly associated with OS in a multivariate model including PD-L1, ECOG, tumor size, and neutrophil count. Bone metastasis status had no impact on the association of BGLAP with OS, which has not been reported before in HNSCC. Interestingly, ANGPT2 level above median showed the highest hazard ratio (HR = 2.2, P <0.001) among all evaluated variables. Furthermore, higher levels of VWF, an angiogenesis-related protein, correlated with shorter OS by univariate survival analysis ( P < 0.001). Conclusions: Our results suggested an important role of angiogenesis in the resistance of HNSCC patients to durvalumab treatment, and ANGPT2 may have predictive utility for durvalumab combination with an anti-angiogenic agent. The predictive value of BGLAP remains to be evaluated in a randomized clinical study. Clinical trial information: NCT02207530; NCT02319044.
Phase 1b study of chemoprevention with green tea polyphenon E (PPE) and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (Erlotinib) in patients (pts) with advanced premalignant (AP) lesions of the head and neck.
Authors: Shin Dong Moon , Beitler Jonathan Jay , El-Deiry Mark , Steuer Conor Ernst , Chen Amy Y. , Baddour Harry Micael , Chen Zhuo Georgia , Roser Steve , Magliocca Kelly R. , Patel Mihir , Griffith Christopher C , Klein Adam , Owonikoko Taofeek Kunle , Khuri Fadlo , Nannapaneni Sreenivas , Saba Nabil F. 
Published: May 2019

6049 Background: Based on the strong synergistic effects between green tea polyphenon E (PPE) and EGFR-TKI in our preclinical studies (Int J Cancer, 2008; Cancer Prev Res, 2009; JCO, 2009), we conducted a phase 1b study with PPE and erlotinib combination for APL (mild-, moderate-, severe-dysplasia or carcinoma in situ [CIS]) of the oral cavity and larynx from 2/2011 to 11/2017 at Emory Winship Cancer Institute. Methods: All pts were enrolled after signing the IRB approved Informed Consent Form. Tissue biopsy before and at 6-months (6-M) treatment was mandatory, and cytobrushed samples of the APL and normal buccal mucosa at 3-, 6-, and 12-M were obtained for biomarker studies. Treatment included fixed dose of PPE (200 mg, P.O.,TID) and dose escalation of erlotinib P.O., (50mg [level 1], 75mg [level 2] and 100mg [level 3]) for 6-M. The primary endpoint was safety and toxicity, and secondary endpoints were evaluation of pathologic responses, cancer free survival (CFS) and biomarker modulation. Results: Out of 27 enrolled pts, 6 control subjects for biomarker studies, 2 ineligible, and 19 were treated with PPE and erlotinib for 6-M. Clinical characteristics of treated patients included median age, 63 yrs. (range,33-78); 9 M/10 F; 10 former or current smokers/9 never smokers; 15 severe dysplasia or CIS, 2 moderate dysplasia, 2 mild dysplasia; 13 had surgical resection; 17 oral cavity primary; and 2 at larynx. 3 pts were treated at dose level 1, 4 at level 2, and 12 at level 3. Toxicity (G0 or G1 excluded) were: skin rash (1 G3, 1 G2), pruritus/dry skin (1 G2), fatigue (1 G2), diarrhea (1 G2), epistaxis (1 G2), and hypertension (2 G3, 1 G2). Skin rash (associated with erlotinib) may be DLT and MTD has not been reached. The recommend doses for phase 2 or 3 studies will be PPE 200mg TID plus erlotinib 100mg QD. 17 pts were assessed for pathologic responses at 6-M: pCR 7/17 (41%), pPR 2/17 (12%), pSD 5/17 (29%) and pPD (3/17 (18%). The median follow up was 32 months. Median CFS has not been reached. 16 pts are alive at the time of data analyses and 1 pt died (by noncancerous reason). Biomarker studies are ongoing for tissues and/or cytobrushed samples. Conclusions: The treatment of the combination of green tea PPE plus erlotinib for 6-M was well tolerated in pts with APL of the head and neck, and showed significant pathologic response rates (pCR and pPR, 53%). This combination therefore deserves further investigation for efficacy testing. Clinical trial information: NCT01116336.
Connective tissue growth factor (CTGF) methylation status is associated with prognosis of patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy (RCHT): A multicenter study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
Authors: Tawk Bouchra , Schwager Christian , Zaoui Karim , Hess Jochen , Linge Annett , Budach Volker , Stuschke Martin , Balermpas Panagiotis , Grosu Anca , Zips Daniel , Combs Stephanie E. , Krause Mechthild , Kouchakji Elias , Lipson Kenneth , Herpel Esther , Belka Claus , Baumann Michael , Herold-Mende Christel , Debus Juergen , Abdollahi Amir 
Published: May 2019

6050 Background: CTGF plays a central role in tissue remodeling and has emerged as an attractive novel therapeutic target. We sought to investigate the impact of CTGF methylation status (CTGF-M) in predicting outcome of HNSCC patients undergoing RCHT. Methods: CTGF-M was discovered by applying Illumina 450K/850K arrays to DNA extracted from FFPE material of patients homogeneously treated with surgery followed by adjuvant cisplatin-based RCHT in frame of the DKTK-ROG multicenter retrospective trial (n = 194, training cohort). Methylation probes correlating with overall survival (OS) and progression were identified using random forest. Validation was done in 4 cohorts including DKTK-ROG definitive RCHT (n = 110) and 3 RCHT cohorts from Heidelberg, Dresden and Munich (n = 222). CTGF-M and RNAseq data from The Cancer Genome Atlas (TCGA) (n = 206) were analyzed to identify differentially expressed genes (DEG) as a function of CTGF-M. Results: Increased methylation of 2 probes (mapping to CTGF 3’UTR and gene body) was associated with significantly improved OS in the training cohort (HR = 0.51, p = 0.044) and the validation cohort (HR = 0.67, p = 0.016), in multivariate cox regressions adjusting for HPV status, age, T and N stages, location and treatment (adjuvant vs definitive RCHT). In the TCGA, probes’ methylation was significantly inversely correlated with CTGF gene expression (r = -0.18 and -0.51, p < 0.05). 1843 DEGs were found at FDR < 0.05 as a function of CTGF-M. Pathways mapping to tissue remodeling were significantly enriched for among downregulated genes in CTGF hypermethylated tumors. Increased CTGF methylation was inversely correlated with the mesenchymal subtype mRNA gene signature (r = -0.21, p = 0.0026) and correlated with the atypical subtype (r = 0.32, p = 0.000002). Conclusions: Implementation of CTGF-M in routine diagnostic is feasible and correlates well with CTGF gene-expression levels and activation of tissue remodeling pathways. Therefore, CTGF-M might be instructive for stratifying HNSCC patients for CTGF targeting therapies. CTGF emerges as a promising prognostic marker independently of HPV status.
Identifying adverse molecular features of HPV+ head and neck cancers using patient-derived models.
Authors: Basu Devraj , Facompre Nicole D , Gimotty Phyllis A. , Rajagopalan Pavithra , Sahu Varun , Pearson Alexander T. , Califano Joseph A. , Netto Frederico , Pickering Curtis R. 
Published: May 2019

6057 Background: Advancing therapy for human papilloma virus-related (HPV+) head and neck squamous cell carcinoma (HNSCC) is hindered by inadequate preclinical models and risk stratification tools. This study addresses both barriers by characterizing a panel of patient-derived xenografts (PDXs) that includes nine new models of HPV+ disease. Methods: Exome-sequenced genetic features of the PDXs were compared to their growth properties and the outcomes of their patients of origin. Genetic traits with potential prognostic utility were validated in multiple retrospective patient cohorts. Results: The HPV+ PDXs avoided known artifacts in HPV+ cell lines, including 3q amplifications and loss of PIK3CA mutants, while enriching for alterations in H3K4 methyltransferases and Notch pathway genes. A positive association emerged between PDX tumor mutational burden (TMB) and their growth efficiency both in vivo and as organoids. This finding led to identification in The Cancer Genome Atlas (TCGA) of an association between high TMB and worse survival of early-stage HPV-negative cancers but not HPV+ ones. Insight into aggressive HPV+ disease came from a PDX established from a patient before lethal relapse. The reduced levels of viral E7 and p16INK4A present in this model were also detected in early lethal HPV+ cases in TCGA as well as the recurrences in a second HPV+ HNSCC cohort (JHU). This observation suggested a diminished contribution of viral oncogenes to cell cycle dysregulation in aggressive cases. To evaluate this possibility, hierarchical clustering of both cohorts was performed based on expression of E2F target genes. This analysis discovered a distinct cell cycle-related transcriptional pattern in the clusters of cases containing the recurrences and early lethal events. Furthermore, a subset of these transcripts proved to be stage-independent predictors of survival for the HPV+ HNSCCs in both TCGA and JHU cohorts. Conclusions: Characterizing the most HPV+ patient-derived models described to date revealed novel prognostic utility for E2F target expression in HPV+ HNSCCs and TMB in HPV-negative HNSCCs. These features have potential for application to risk stratification, biomarker development, and trial design.
Depth of invasion in early oral cancers: Is it an independent prognostic factor?
Authors: Dhar Harsh , D'Cruz Anil , Vaish Richa , Hawaldar Rohini W , Gupta Sudeep , Pantvaidya Gouri , Chaukar Devendra , Chaturvedi Pankaj , Pai P. S. , Deshmukh Anuja , Kane Shubhada , Nair Deepa , Nair Sudhir Vasudevan , Laskar Sarbani , Agarwal Jaiprakash 
Published: May 2019

6058 Background: Depth of invasion (DOI) has been incorporated in the new AJCC TNM staging (8th edition) for oral cancers. We hypothesized that the negative effect of increasing DOI on outcomes was a result of an increased propensity to node metastasis and appropriate neck treatment would negate its detrimental effect on outcomes. Methods: Patients with T1/ T2 oral squamous cell carcinoma, clinically node negative, from a previously reported Randomized Controlled Trial (NCT 00193765) formed the cohort for this study. Patients were restaged according to the new staging system . Overall survival(OS) was estimated by the revised T stage for the entire cohort and separately for those who underwent END and those who did not (TND arm) using Kaplan Meier and log rank test . Multivariate analysis was performed using Cox proportional hazard model making adjustment for neck treatment, T stage, site, prognostic factors and the interaction between revised T stage and neck treatment. Results: Of the 596 patients 577 were evaluable, with a median follow up of 77.57 months. Initial pT staging was pT1, 389(67.4%); pT2, 181(31.4%); pT3, 7(1.2%) and was modified to pT1, 195(33.8%); pT2, 280(48.5%); pT3, 102(17.7%) on restaging . 288 patients underwent END and 289 did not (TND arm). For the entire cohort 5-year OS rates were 79.0% [95 %CI, 73.12-84.88] for pT1, 69.4% [95% CI, 63.91-74.89] for pT2 and 53.0% [95% CI, 43.2 -62.8] for pT3 with significant difference between the 3 groups (p < 0.001). In those without upfront neck treatment( TND ), OS difference was maintained between the pT1 and pT2 groups [81.1% (95%CI, 73.26-88.94) vs 65.0% (95%CI, 56.77-73.23)], p = 0.004. This difference was not apparent in the END arm ,pT1 -76.9% (95 %CI, 68.47-85.33) vs pT2 -73.7% (95%CI, 66.25-81.15), p = 0.73. T3 tumours had uniformly poor survival irrespective of neck treatment. On multivariate analysis of the revised pT1/T2 cohort (n = 475), pT stage, neck treatment and grade were independent prognostic factors impacting OS. There was a significant interaction between the T stage and neck treatment (p = 0.03). Conclusions: When DOI < 10 mm, END supplants the prognostic implication of depth with similar outcomes for T1 and T2 tumours (new AJCC staging). The exact role of DOI on outcomes warrants further research. Clinical trial information: NCT00193765.
Predictive biomarkers for response to nivolumab in head and neck squamous cell carcinoma (HNSCC) (NCT#03652142).
Authors: Psyrri Amanda , Gavrielatou Niki , Spathis Aris , Anastasiou Maria , Fortis Ekaterina , Gkotzamanidou Maria , Kladi-Skandali Athina , Kousidou Evgenia , Economopoulou Panagiota , Kotsantis Ioannis , Rusakiewicz Sylvie , Vagia Elena Mihal , Panayiotides Ioannis , Coukos George , Foukas Periklis 
Published: May 2019

6060 Background: Tumor immune cell compositions determine response to immunotherapy. For a better understanding of the mechanisms of resistance to nivolumab in HNSCC, we sought to investigate a prospective cohort of longitudinal HNSCC samples from recurrent/metastatic HNSCC pts treated with nivolumab and identify biomarkers of response and resistance. We will specifically focus on modulation of immune markers following two cycles of nivolumab. Methods: Patients with platinum-refractory HNSCC with no contraindication to nivolumab therapy are included in this study. Tumor biopsies are performed at baseline, 24-72 hours after the second cycle and at progression with appropriate written informed consent. Samples were assessed for the presence of Tertiary Lymphoid Structures (TLS), PD-L1 expression (TPS and CPS) and CD8 T cell infiltrates combined with Ki67 (CD8/Ki67 double IHC stain). The primary outcome measure of the study is change in the percentage of immune cells in post treatment compared to baseline biopsies. Secondary endpoints include safety of performing a second biopsy, best overall response rate, biomarker expression in association with response and survival. Evaluation of other biomarkers including tumor mutational burden, HLA class I and II expression and adaptive immunity cell populations using multiplex IF is ongoing. Results: Of 20 patients evaluable for response, 14 had PD (8 of whom showed hyper-progression) and 6 attained disease control (1 with PR). PD-L1 status (CPS or TPS) was not altered by treatment (p = 0.905) and CPS > 20 pre-treatment showed a favorable trend towards response (p = 0.117). Absence of tertiary lymphoid structures was associated with disease progression (p = 0.0374). Infiltrating plasma cell count remained unchanged pre- and post-treatment and was unrelated to response (p = 0.458). The percentage of proliferating CD8+ T cells (CD8+/Ki67+) increased in post-treatment biopsies in the entire population (p = 0.022) and especially in progressors (p = 0.039). Pre-treatment CD8+ T cell density was higher in patients with hyper-progression compared to progressors (p = 0.029). Conclusions: Increased percentage of proliferating CD8+ T cells in progressors might represent dysfunctional T cells as has been recently shown in melanoma pts (Li H et al Cell 2019) and clinical efforts to reactivate intratumoral T cells may augment the efficacy of PD1 checkpoint inhibitors. Clinical trial information: NCT03652142.