bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined regimen of inhalable STING agonist plus chemoimmunotherapy in platinum-resistant or platinum-refratory ovarian cancer: A randomized, open-label, phase II trial.
Authors: Zhang Yan , Mei Qian , Meng Yuanguang , Chen Meixia , Liu Yang , Yang Qingming , Han Weidong
Published: May 2020

6071

Background: Approximately 70% patients with advanced ovarian cancer have a relapse and ultimately succumb to their disease. Treatment options are limited in this context with an unacceptable low response (less than 20%). Immunotherapy with checkpoint inhibitors presented to date are not very convincing with 10-15% response because of inadequate immunity. We previously discovered the critical role of manganese in innate immune sensing of tumors by activating STING signaling. This ongoing, randomized, phase II study is to assess STING agonist plus nPP chemotherapy and anti-PD-1 antibody sintilimab in platinum-resistant/refractory ovarian cancer. Methods: Enrolled patients were 2:1 randomizedly assigned to receive nab-paclitaxel (180-220mg/m2), cisplatin (60-80mg/m2) and sintilimab 200mg per 3 weeks with (cohort 1) or without (cohort 2) inhalable MnCl2 (0.4mg/kg) daily. Safety was assessed by CTCAE v5.0, and clinical response by MRI or CT every 2 cycles referred to RECIST version 1.1. The primary endpoints were objective response rate (ORR) and safety. Key secondary end points were disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: 27 patients were enrolled, and 21 were included in efficacy population by the end of Jan. 2020. All enrolled patients were with heavily treated history, median 4 lines of prior therapy, median 19 cycles of multiagent regimens. The addition of MnCl2 to the combined chemo-immunotherapy did not appear to exacerbate treatment-related adverse events (AEs). The most common AEs are hematological toxicity (87%), nausea (56%) and vomiting (47%) in both two cohorts. All 14 evaluable patients (14/19) from cohort 1 had an effective control (11 PR [78.6%], 3 SD [21.4%]) . Ten patients (71.4%) achieved PR at the first tumor scan assessment. For 8 cases from cohort 2, 7 were assessable and all showed SD, 4 of whom exhibited SD with enlarged lesions and disease progression after 4-cycle treatment. Conclusions: MnCl2 administration induced encouraging objective clinical responses (78.6%) and disease control (100%) in relapsed/refractory ovarian cancer. The combined regimen showed accepted and manageable safety profile. Clinical trial information: NCT03989336.
Infiltration of tumor by T cells following treatment with DPX-Survivac and intermittent low dose cyclophosphamide (CPA) leads to clinical responses in advanced recurrent ovarian cancer (OvCa).
Authors: Dorigo Oliver , MacDonald Lisa Diana , Schindler Joanne , Bramhecha Yogesh , Torrey Heather , Kaliaperumal Valarmathy , Hrytsenko Olga , Dirk Brennan , Patterson Kelcey , Stanford Marianne , Fiset Stephan
Published: May 2020

6075

Background: DPX-Survivac is a novel T-cell activating therapy designed to elicit an effective immune response against survivin expressing tumors. Its unique mechanism of action (MOA) facilitates active and sustained uptake of target peptides by APC at the injection site. APCs subsequently present the antigen in local lymph nodes generating survivin-specific T cells that traffic to distant tumor sites and elicit effective tumor cell death. DPX-Survivac is used in combination with intermittent low dose CPA which acts as an immunomodulator of T-cell responses. Methods: The study enrolled 22 patients with recurrent, advanced platinum-sensitive and -resistant ovarian cancer. Patients received 2 subcutaneous injections of DPX-Survivac 3 weeks apart and every 8 weeks thereafter, and intermittent low dose CPA for up to 1 year. Paired tumor biopsies were performed prior to treatment and on treatment. Primary endpoints were ORR, DCR and safety. Secondary endpoints include cell mediated immunity, immune cell infiltration in paired biopsy samples, DOR, TTP, OS and biomarker analyses. Results: Twenty-two patients were enrolled in the study. Three patients were discontinued prematurely due to early progression leaving 19 patients for response evaluation. The population is heavily pre-treated with a median of 3 lines of prior treatment [range 1 to 8]; 77.3% of patients are platinum-resistant. At the time of data cut-off, 3/19 patients (15.8%) achieved PR and one additional patient met PR on target lesions but had a newly detected lesion; 10/19 patients (52.6%) showed tumor regression on target lesions at > 1 scan. The median time on study (N=19) is 131 days [63 to ˃295]. Six patients are still on trial. The clinical responses and benefits observed with treatment are associated with an increase in systemic survivin-specific T cells and tumor immune-infiltration. Moreover, RNAseq analysis on paired tumor tissue revealed an enrichment in cytolytic T-cell signature. The most common AEs were grade 1-2 injection site reactions; 4 treatment-related SAEs were reported. Conclusions: DPX-Survivac and intermittent low dose CPA shows promising clinical activity in heavily pre-treated patients with recurrent OvCa. The preliminary results, supported by strong translational data, link the observed clinical benefits with the unique MOA of DPX-Survivac. These clinical results suggest that DPX-Survivac/CPA is an active regimen in OvCa and warrant testing in an expanded cohort of patients. Clinical trial information: NCT02785250.
Elucidating resistance mechanism to PARP inhibitors for the development of novel therapeutic approaches in high-grade serous ovarian cancer.
Authors: Kulbe Hagen , Kassuhn Wanja Nikolai , Ringel Frauke , Welsch Gabriele , Treffkorn Peggy , Taube Eliane T , Horst David , Sehouli Jalid , Braicu Ioana ,   TOC (Tumor Bank Ovarian Cancer) Network
Published: May 2020

6078

Background: PARP inhibitors (PARPi) have been established as a targeted therapeutic approach not only in patients with high-grade serous ovarian cancer (HGSOC) that have genetic loss of function of BRCA1/2-associated DNA repair. However, treatment efficacy varies and neither BRCA mutation, nor homolog recombination deficiency (HRD) status seem to be optimal predictors. Moreover, mechanisms of treatment resistance are poorly understood and novel approaches are urgently required. Methods: Here we created gene expression data of HGSOC patients (n = 52) before PARPi treatment to elucidate key signaling pathways of resistance to increase their efficacy in combinatorial therapeutic strategies. We performed a comprehensive bioinformatics analysis of the differentially expressed genes between the 25% extreme responders (n = 26; 13 each group), including gene set enrichment analysis (GSEA) and causal inference analysis with the CARNIVAL pipeline to elucidate the underlying molecular and regulatory mechanisms governing treatment efficacy and resistance. Results: In accordance with recent publications, we found higher levels of MYC activity in non-responders and deregulation of the Wnt/ß-catenin signaling pathway resulting in PARPi treatment resistance. The pathway enrichment analysis also revealed specific pathways especially PDGFR, FGFR, PI3K/mTOR and MAPK signaling pathway associated with resistant phenotype. Furthermore, we have identified key kinases, particularly JAK1/2 and SRC that might mediate resistance to PARP inhibition. In addition, differential gene expression analysis revealed folate receptor 1 (FOLR1) to be significantly higher expressed in non-responders (logFC = 2.66; p < 0.0026) with the potential as a serum-based biomarker not only for ovarian cancer, as it correlates closely with CA125, but also PARPi treatment efficacy. Conclusions: In conclusion, these findings define a network of pathways, that are crucial to mediate mechanism of PARPi resistance and identified key signaling kinases as therapeutic targets in ovarian cancer.
Mutation in homologous recombination to predict a better prognosis in endometrial cancer.
Authors: Zhao Luyang , Yibo Dai , Hu Yuanjin , Wang Zhiqi , Li Chengcheng , Wang Guoqiang , Wang Jianliu
Published: May 2020

6082

Background: Endometrial cancers have been categorized into four genomic classes by The Cancer Genome Atlas Research Network (TCGA) with comprehensive genomic analysis. However, TCGA molecular subtypes are hard to utilize in clinic as the expensive cost and a simply version of POLE, TP53 genes cannot fully differentiate the four subtypes. Therefore, more convenient and reliable biomarkers need to be identified for clinical practice. Methods: Whole-exome sequencing and RNA sequencing data for 515 patients with endometrial carcinomas were downloaded from TCGA. Mutations in 48 genes of homologous recombination repair (HR) signaling were defined as HR mutation. Associations between HR mutation and survival and RNA expression were analyzed.Gene set enrichment analysis (GSEA) were used to invesgate the gene signaling. Results: HR mutation was associated with a prolonged disease specific survival (DSS) (HR, 0.39; 95% CI, 0.22-0.71; P = 0.002), progression-free survival (PFS) (HR, 0.46; 95% CI, 0.31-0.68; P < 0.001) and overall survival (OS) (HR, 0.45; 95% CI, 0.28-0.72; P = 0.001) in endometrial cancers. HR mutation was related with clinical characteristics including histological types (P < 0.05). In the multivariable cox proportional hazards regression model including FIGO 2008, histology types, tumor grade and TCGA subtypes, TP53 mutation, POLE mutation, the association between HR mutation and PFS was still significant (HR, 0.48; 95% CI, 0.27-0.86; P < 0.05), which indicating the HR mutation is an independent prognostic factor for PFS. HR mutations were associated with a higher tumor mutation burden. GSEA suggested that HR mutation was involved with the increase of genes related to activated T cells, immune cytolytic activity, and IFN-γ release. In MSS endometrial cancers, HR mutation still showed a longer PFS (HR, 0.57; 95% CI, 0.34-0.98; P = 0.04), suggested HR mutation may help predict the effect of immunotherapy in MSS endometrial carcinoma. Conclusions: HR mutation was related with a favorable prognosis through increasing T cells signature. Identification of HR mutation by genomic profiling provides a potentially novel and convenient approach for endometrial cancer patients to predict the prognosis independent of TCGA four subtype classifications and provides an inspiration for screening patients who may benefit from ICBs in endometrial cancer in the future.
Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort.
Authors: Erickson Britt Kristina , Najjar Omar , Klein Molly , Shahi Maryam , Dolan Michelle , Cimino-Mathews Ashley , Grandelis Anthony , Buza Natalia , Delaney Paris , Tymon-Rosario Joan , Santin Alessandro , Ferriss James Stuart , Stone Rebecca Lynn , Nickles Fader Amanda
Published: May 2020

6084

Background: Uterine serous carcinoma (USC) is a rare and aggressive malignancy, accounting for 40% of all endometrial cancer deaths. Human Epidermal Growth Factor Receptor 2 (HER2) has emerged as an important prognostic and therapeutic target in USC. Given recent randomized trial results, HER2-directed therapy is now recommended in advanced-stage or recurrent, HER2-positive disease. The significance of tumoral HER2 expression in early-stage disease has not yet been established. Methods: In this IRB-approved, retrospective, multi-institutional cohort, women diagnosed with stage I USC from 2000-2018 were identified. Patient demographic, treatment, and survival data were collected. Immunohistochemistry (IHC) was performed for HER2 and scored 0-3+. Equivocal IHC results (2+) were further tested with in-situ hybridization (ISH) per the 2007 ASCO-CAP HER2 breast cancer guidelines. HER2 overexpression (“positive”) was defined as 3+ IHC or ISH positive. Kaplan-Meier analyses and Cox-proportional hazards were used to compare survival between the cohorts. Results: In total, 173 patients with stage I USC were tested for HER2; 25% were HER2-positive, 77.4% had stage IA and 22.6% had stage IB disease. Adequate clinical follow up was available for 168 patients. There were no significant differences in age, race/ethnicity, body mass index, surgical management, sub-stage, tumor size, adjuvant therapy, or follow-up duration between the HER2-positive and negative cohorts. On univarite analysis, presence of lymph-vascular space invasion was correlated with HER2-positive tumors (p=0.003). After a median follow-up of 50 months, there were 41 (24.4%) recurrences. Significantly more recurrences were observed in the HER2-positive cohort (47.6% vs. 16.7%, p<0.001). HER2 overexpression was also associated with poorer progression-free (PFS) and overall survival (OS) (p<0.001 and p=0.012). After adjusting for prognostic factors including sub-stage and adjuvant treatment, those with HER2-positive tumors experienced inferior PFS (aHR 3.67, 95%CI 1.92-6.98; p<0.001) and OS (aHR 2.03, 95%CI 1.03-4.01; p=0.042) compared to HER2-negative tumors. Conclusions: Uterine serous carcinoma is a poor prognostic tumor, even in patients with early-stage disease. Given its significant association with worse survival outcomes, tumoral HER2 overexpression appears to be a prognostic biomarker in women with stage I disease. These data provide rationale for clinical trials with HER2-directed therapy in early-stage uterine serous carcinoma.
Evaluation of treatment patterns and prognosis in correlation with age in patients with vulvar cancer: A subset analysis of the AGO-CaRE-1 study.
Authors: Prieske Katharina , Woelber Linn Lena , Muallem Mustafa Zelal , Eulenburg Christine , Jueckstock Julia Kathrin , Hilpert Felix , de Gregorio Nikolaus , Iborra Severine , Ignatov Atanas , Hillemanns Peter , Fuerst Sophie , Strauss Hans-Georg , Baumann Klaus , Thiel Falk , Mustea Alexander , Meier Werner , Harter Philipp , Wimberger Pauline , Sehouli Jalid , Mahner Sven
Published: May 2020

6090

Background: Despite an increasing incidence with simultaneous decreasing age of onset, the impact of age on prognosis and treatment patterns in primary squamous cell vulvar cancer (VSCC) has not extensively been studied yet. Methods: This is a subgroup analysis of the AGO-CaRE-1 study. Patients (pts) with VSCC (FIGO stage ≥1B), treated at 29 cancer centers in Germany from 1998-2008, were included in a centralized database (n = 1618). In this subgroup analysis pts were analyzed according to age ( < 50yrs (n = 220), 50–69yrs (n = 506), ≥70yrs (n = 521)) with regard to treatment patterns and prognosis. Only pts with documented age, surgical groin staging and known nodal status were included (n = 1247). Median follow-up was 27.5 months. Results: At first diagnosis, women ≥70yrs presented with more advanced tumor stages ( < 0.001), larger tumor diameter ( < 0.001), poorer ECOG status ( < 0.001), higher tumor grading (0.048), as well as a higher rate of nodal involvement ( < 0.001). Older women ≥70yrs showed more commonly HPV negative tumors compared to the other age groups (54% vs. 36.5% in < 50yrs vs. 47.9% in 50-69yrs, p = 0.03). Disease recurrence occurred significantly more often in elderly women (48% vs. 21% in < 50yrs vs. 37.4% in 50-69yrs, p = 0.001). Particularly isolated vulvar recurrence was more frequent in the elderly in comparison to the younger groups (18.2% vs. 15.2% in 50-69yrs vs. 12.7% in < 50yrs, p = 0.001). Age was an independent prognostic factor for disease-free survival (DFS) (HR: 1.7, 95%CI: 1.24-2.46, p = 0.001) with 2-year DFS being 81.1% (< 50yrs), 65.8% (50–69yrs), and 59.3% (≥70yrs), respectively. Elderly women (age group ≥70) had a 221% higher risk for death or recurrence, compared to the youngest group (HR: 3.21, p < 0.001). In a multivariate analysis ECOG, tumor stage, grading, and receipt of (chemo)radiation were further independent prognostic factors for recurrence. Conclusions: Older women with VSCC present with advanced tumor stages at first diagnosis and have an increased risk of recurrence as well as a decreased 2-year PFS in comparison to younger pts groups. Potential reasons for delayed time of diagnosis could be self-awareness and/or more aggressive tumor biology due to HPV negative disease.
A prospective phase II open-label randomized controlled trial to compare mandibular preservation in upfront surgery to neoadjuvant chemotherapy followed by surgery in operable oral cavity cancer.
Authors: Chaukar D. , Pai P. S. , Chaturvedi Pankaj , Pantvaidya Gouri , Deshmukh Anuja , Nair Deepa , Thiagarajan Shivakumar , D'Cruz Anil , Prabash Kumar , Noronha Vanita , Patil Vijay Maruti , Laskar Sarbani
Published: May 2020

6518

Background: The study objective was to evaluate the non-Inferiority of survival and ability to preserve mandible with the use of neoadjuvant chemotherapy (NACT) in locally advanced oral cancers compared to upfront surgery alone without compromising survival. Methods: This study was a randomized, single centre, non-inferiority trial. Eligibility criteria included treatment naïve histologically confirmed cancer of the oral cavity; cancers requiring segmental resection for paramandibular disease without clinicoradiological evidence of bone erosion, clinical T2, T3 and T4, any N, M0 as per TNM (AJCC) 7th edition, age at least 18 years; and written informed consent. The patients were randomly assigned (1:1) to receive either upfront surgery followed by adjuvant treatment (Standard arm-SA) or receive two cycles of three drugs NACT (Docetaxel, Cisplatin, 5-Flurouracil) at three weekly interval (Intervention arm-IA). Depending on the response after two cycles, the patient would either receive an additional third cycle or undergo surgery followed by adjuvant treatment as decided by the tumour board. The primary endpoint was mandible preservation rate at 30% in the experimental arm. The secondary end points being Loco regional control and treatment related toxicity. Results: Between September 2010 and April 2013, 68 patients were enrolled and randomized to SA (34 patients) and IA (34 patients) with a median follow-up of 3.6 years (IQR 0.95- 7.05 years). Majority of the patients were T4 (n = 40, 58.8%) In the IA 28 patients had partial response (n = 28,82.4%), with a mandible preservation (Marginal Mandibulectomy) rate of 48% (n = 16/34). There were no close or positive margins in the IA. All patients received adjuvant treatment. The number of recurrences was similar in both the arms. All patients in the IA developed toxicities with the majority developing Grade III-IV toxicities (Grade III: 14, 41.2%, Grade IV: 11, 32.4%) (p = 0.739). The disease free survival (DFS) (p = 0.715, HR 0.911[0.516-1.607]) and overall survival (OS) (p = 0.747, HR 0.899[0.510-1.587]) were similar in both the arms. Conclusions: NACT seems to be a feasible option for mandibular preservation with acceptable toxicities in a select group of patients without compromising survival. However this needs to be tested in a larger phase III randomized trial. Clinical trial information: CTRI/2015/11/006396 .
Development and validation of a gene expression-based signature predicting efficacy of induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: A multicenter cohort study.
Authors: Lei Yuan , Li Ying-Qin , Jiang Wei , Hong Xiao-Hong , Ge Wen-Xiu , Zhang Yuan , Hu Weihan , Wang Ya-Qin , Liang Ye-Lin , Li Jun-Yan , Chen Lei , Xie Fangyun , Li Wen-Fei , Mao Yan-Ping , Liu Xu , Chen Yu-Pei , Tang Ling-Long , Sun Ying , Liu Na , Ma Jun
Published: May 2020

6522

Background: Induction chemotherapy (IC) followed by concurrent chemoradiotherapy is the mainstay treatment for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). However, some patients obtain little benefit and experience unnecessary toxicities from IC. We intended to develop a gene expression signature that can identify patients who will benefit from IC. Methods: We screened chemoresistance-related genes by comparing gene expression profiles of patients with short-term tumor response or non-response to IC (n = 95) using microarray analysis. Chemoresistance-related genes were quantified by digital expression profiling in a training cohort (n = 342) to obtain a gene signature. We then validated this gene signature in the clinical trial cohort (n = 187) and an external independent cohort (n = 240). Results: We identified 43 chemoresistance-related genes associated with the short-term tumor response to IC. In the training cohort, a 6-gene signature was developed that was highly accurate at predicting the short-term tumor response to IC (area under the curve [AUC] 0.87, sensitivity = 87.5%, specificity = 75.6%). We then apply the 6-gene signature to classify patients into the benefit group and the no-benefit group. In the benefit group, patients could benefit from IC in terms of failure-free survival (hazard ratio [HR] 0.54 [95% confidence interval 0.34-0.87]; p = 0.01), while patients in the no-benefit group could not (HR 1.25 [95%CI 0.62-2.51]; p = 0.53). In the clinical trial cohort, the developed 6-gene signature was also highly accurate at predicting the response to IC (AUC = 0.82; sensitivity = 87.5%; specificity = 71.8%). Additionally, IC conferred failure-free survival benefits only on patients in the benefit group (HR 0.37 [95%CI 0.18-0.75], p = 0.004) and not on those in the no-benefit group (HR 0.70 [95%CI 0.27-1.82]; p = 0.46). In the external independent cohort, similar results were observed. Conclusions: The 6-gene signature can help select patients who will benefit from IC and thus lay a foundation for a more individualized therapeutic strategy for LA-NPC patients.
Distinct transcriptional profiles in plasma exosomes associated with recurrence of nasopharyngeal carcinoma patients with standard treatment.
Authors: Li Yongjiang , Zheng Xue , Xie Xiaoqi , Hu Yukai , Kang Jingbo , Wei Jiyu , Wang Ruoyu , Mao Beibei , Qu Baolin , Yang Ying , Li Xianfeng , Fu Xueying , Li Qingyun , Zhang Henghui , Wang Junjie , Wang Feng
Published: May 2020

6534

Background: Nasopharyngeal carcinoma (NPC) is endemic with a high prevalence in Southern China, Asia,cetuximab and North Africa. Exosomes are small vesicles containing a wide range of functional proteins, mRNA and miRNA. In the progression of NPC, the tumor cells constantly release exosomes into the surrounding environment and also into the circulating blood. The aim of this study was to explore the association between RNA expression in plasma exosomes and prognosis of NPC patients after standard treatment. Methods: In this retrospective study, a total of 25 eligible NPC patients were included: 12 patients in the recurrence (R) subgroup and 13 patients in the no recurrence (NR) subgroup. RNA was extracted from the exosomes of plasma specimens which were collected at West China Hospital, Sichuan University. Gene expression profiles were conducted by using the RNA-sequencing platform. The DESeq2 package was used to analyze the differentially expressed genes (DEGs) between R and NR subgroups. The gene set variance analysis (GSVA) was performed to explore C5 gene sets enrichment related to the recurrence after standard treatment. Results: We observed 332 DEGs between R and NR subgroups, which include 125 up-regulated and 207 down-regulated genes (R vs. NR,∣log2fold change∣>1, p<0.05). Moreover, hierarchical clustering analysis of the 332 DEGs revealed that all samples clustered into two subgroups, with cluster 1 containing 82% (9/11) recurrence patients and cluster 2 containing 79% (11/14) no recurrence patients. Further, univariate Cox regression analysis showed that 293 out of 332 DEGs were significantly correlated with DFS ( p<0.05), such as TRAM1, CAPN1, SAT1 and ACTB. GSVA and Log Rank test of survival data demonstrated that a total of 824 pathways/biological processes were significantly different between R andNR subgroups ( p<0.05). Specifically, the top 9 pathways/biological processes, such lipoxygenase pathway, rough endoplasmic reticulum membrane and low density lipoprotein particle clearance, was mainly enriched in the NR subgroup ( p <0.001). Conclusions: Profiling of plasma exosomes RNA in NPC patients reveals distinctive gene expression pattern between patients with or without recurrence. Further functional analysis revealed that top enriched 9 pathways/biological processes may correlate with a favorable prognosis and are worth investigating. Moreover, for the prognosis of patients with NPC, RNA expression of plasma exosomes may be a potentially valuable research object.
Dendritic cell therapy with CD137L-DC-EBV-VAX in locally recurrent or metastatic nasopharyngeal carcinoma (NPC).
Authors: Walsh Robert John , Nickles Emily Pauline , Li Yating , Dharmadhikari Bhushan , Koh Mickey , Ho Liam Pock , Chan Marieta , Koh Liang Piu , Poon Michelle Li Mei , Tan Lip Kun , Huang Yiqing , Ang Yvonne Li'en , Chong Wan Qin , Asokumaran Yugarajah , Loh Kwok Seng , Soo Ross A. , Lim Chwee Ming , Schwarz Herbert , Goh Boon Cher
Published: May 2020

6535

Background: Epstein-Barr virus (EBV) is associated with non-keratinising (NK) NPC, a disease prevalent in Southeast Asia, and provides a potential target for dendritic cell (DC) vaccine therapy. CD137 ligand (CD137L) expressed on antigen presenting cells costimulates CD137 expressing T cells upon receptor/ligand interaction. CD137L signalling differentiates monocytes to CD137L-DC, a novel type of DC, which are more potent than classical DC in stimulating autologous T cells. Here, we explore the safety and efficacy of autologous CD137L-DC pulsed with EBV peptides spanning Epstein Barr nuclear antigen 1, latent membrane protein 1 (LMP1) and LMP2 (CD137L-DC-EBV-VAX) in patients with locally recurrent or metastatic NPC. Methods: In this single centre, phase I study, eligible patients (pts) with locally recurrent or metastatic NK-NPC and clinical benefit (CB) from their prior treatment (stable disease [SD], partial [PR] or complete response[CR]), underwent apheresis to isolate monocytes which were differentiated to CD137L-DC through CD137L agonist exposure. CD137L-DC were pulsed with EBV antigens during maturation to obtain CD137L-DC-EBV-VAX which was administered intradermally every 2 weeks (w) for up to 7 injections following site preconditioning with Tetanus and Diphtheria vaccine. Results: 14 pts were enrolled of which 2 progressed rapidly and did not begin treatment. Mean age was 58 years. Median lines of prior treatment for metastatic NPC was 1 (range 1-6), the most common being cisplatin and gemcitabine. 9 pts received 7 vaccine doses (range 2-7) with a mean administered cell count of 23.9x106. CB was seen in 5 cases (42%) with 1 PR and 4 SD beyond 1 year. Median progression free survival (mPFS) was 26w (95% CI, 23-43). The lowest PFS (8w) was in a pt with 6 prior lines of treatment including a checkpoint inhibitor. Mean pretreatment neutrophil: lymphocyte ratio (NLR) was 3.4 and a value of less than 3 was associated with prolonged mPFS (42 vs 14w, p = 0.01). Enzyme linked immune absorbent spot (ELISPOT) analysis in 5 pts with CB showed a rise in interferon-γ secreting peripheral T cells prior to the 3rd vaccine versus baseline. Treatment was well tolerated with only 4 cases of grade 1 related adverse events reported, most commonly injection site reaction (3pts). Conclusions: CD137L-DC-EBV-VAX is safe and exhibits promising efficacy when administered following CB from chemotherapy. A rise in activated peripheral blood mononuclear cells after 2 vaccinations in selected patients showing benefit suggests immunological correlates with efficacy. Clinical trial information: NCT03282617 .
Correlation of tumor mutational burden (TMB) with CDKN2A and TP53 mutation in HPV-negative head and neck squamous cell carcinoma (HNSCC).
Authors: Burtness Barbara , Deneka Alexander , Baca Yasmine , Serebriiskii Ilya , Parker Mitchell I. , Nicolas Emmanuelle , Lee Jong Woo , Wise-Draper Trisha , Sukari Ammar , Somer Bradley G. , Golemis Erica
Published: May 2020

6552

Background: The tumor suppressors TP53 and CDKN2A are commonly mutated or lost in HNSCC, impairing G1 checkpoints. This reduces ability to repair DNA damage arising from hypoxia, replication stress, and mutagen exposure, thus increasing TMB, a potential predictive biomarker for immunotherapy benefit. TP53 mutations can be classified as loss-of-function (LOF) with or without dominant negative (DNE) activity, gain-of-function (GOF) and benign. We investigated whether specific categories of TP53 mutation were associated with increased TMB, and whether these cooperated with CDKN2A mutation to elevate TMB. Methods: We analyzed 1010 HPV- HNSCC tumor samples (246 female) profiled with a 592-gene panel by Caris Life Sciences from 2015 to 2019. Predominant subsites were oral cavity (285), oropharynx (225) and larynx (153). TMB reflected all somatic nonsynonymous missense mutations detected. We report mean TMB per megabase (MB). Pathogenicity of TP53 and CDKN2A mutations was determined according to American College of Medical Genetics (ACMG) guidelines. We also used four alternative methods of characterizing TP53 mutations based on analysis of protein structure, public databases (IARC, ClinVar, InterVar), and publications (PMID: 25108461 and others) assessing structure-function relations. Results: 60% of cases had TP53 mutations ( TP53mut) designated pathogenic by ACMG guidelines. Estimates of frequency of LOF/DNE mutations ranged from 30-42.8% of cases among the alternative classification methods. Damaging CDKN2A mutations were present in 20%. Average TMB per MB varied from 8.2/8.6 (females/males) in oral cavity cancers to 26.5/27.7 (females/males) in cancer of the lip. Mean TMB was typically higher in the presence of damaging LOF/DNE TP53 mutations or CDKN2A mutations, but not TP53 GOF mutations. Based on ACMG, for tumors with TP53 and CDKN2A wild type (WT) TMB was 8.03, for those with CDKN2Amut-only 9.82, for TP53mut-only 10.56, and TP53 mut/CDKN2A mut 17.6 (p < 0.001). For disruptive TP53mut (Poeta algorithm), mean TMB for WT/WT was 8.67, for TP53mut 11.31, CDKN2Amut 17.9 and TP53mut/CDKN2A mut 15.83 (p < 0.001). Conclusions: Mutation of TP53 and/or CDKN2A is associated with increased mean TMB relative to WT; mean TMB was highest for tumors bearing damaging mutations in both genes. GOF TP53 mutation was not clearly associated with increased TMB. As TMB is evaluated as a predictive biomarker in the immunotherapy of HNSCC, specific TP53/CDKN2A mutational status should also be evaluated.
Does sinonasal cancer survival differ based on human papillomavirus status?
Authors: Pusapadi Ramkumar Shreya , Bukatko Aleksandr R , Simpson Matthew C , Adjei Boakye Eric , Ward Gregory M , Antisdel Jastin L , Osazuwa-Peters Nosayaba
Published: May 2020

6565

Background: The sinonasal tract is a lesser known “hot spot” for the human papillomavirus (HPV), compared with the oropharynx. Additionally, unlike the oropharynx, the role of HPV tumor status in the survival and overall prognosis of the sinonasal tract and other non-oropharyngeal head and neck cancer sites remains inconclusive. Understanding differences in survival based on HPV status could be useful clinically, as it has been for HPV-positive oropharyngeal disease. This study examined whether there are survival differences in sinonasal cancer based on HPV status. Methods: This study included adult sinonasal cancer cases diagnosed between 2010 and 2015 in the National Cancer Database. A multivariable Cox proportional hazards model estimated the association between sinonasal cancer HPV status (HPV-positive, HPV-negative) and all-cause mortality while controlling for covariates (sex, age, race/ethnicity, insurance status, urban/rural, county-level household income, county-level percentage without high school diploma, comorbidity score, stage, histology, facility type, and treatment). A second multivariable proportional hazards model stratified HPV-positive tumor status by high-risk HPV (16, 18, 26, 31, 33, 35, 36, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 70, 73, 82, and 85) vs. low-risk HPV (6, 11, 32, 34, 40, 42, 44, 54, 61, 62, 64, 71, 72, 74, 81, 83, 84, 87, and 89) and compared their all-cause mortality to HPV-negative patients. Results: There were 1,750 sinonasal cancer patients included in this study, and 484 (27.7%) had HPV-positive disease. Among patients with HPV-positive disease, 75.6% had high-risk types. Mortality risk among all HPV-positive patients combined was 23% lower than HPV-negative patients (aHR = 0.77; 95% CI 0.64, 0.93). After stratifying by high-risk vs. low-risk HPV, high-risk HPV positive patients had 30% lower mortality risk than HPV-negative patients (aHR = 0.70; 95% CI 0.57, 0.88) while risk of mortality did not significantly differ between low-risk HPV-positive patients and HPV-negative sinonasal cancer patients. Conclusions: Sinonasal cancer shows differential survival based on HPV status, and sinonasal cancer patients positive for high-risk HPV had a significantly greater survival advantage than low-risk strains and those with HPV negative disease. HPV status might yet play a role in prognostication of sinonasal cancer, if future studies confirm these findings.
Association of sarcopenia with higher toxicity and poor prognosis in nasopharyngeal carcinoma.
Authors: Hua Xin , Ling Guo , Lin Huan-Xin
Published: May 2020

6568

Background: Given the growing evidence that sarcopenia is associated with toxicity and survival in various cancers, we investigated its significance in patients with nasopharyngeal carcinoma (NPC) receiving concurrent chemoradiotherapy (CCRT). Methods: In this retrospective analysis, we studied 862 NPC patients who had received CCRT between 2010 and 2014. Sarcopenia was determined using routine pre-radiotherapy computed tomography (CT) simulation scans at the third cervical (C3) vertebral level. Receiver-operating characteristic (ROC) curve analyses were used to determine the optimal cutoff values. Propensity score matching (PSM) was applied to develop comparable cohorts of patients with or without sarcopenia. Results: A total of 862 patients were included as the primary cohort, and 308 patients were matched and regarded as the matched cohort. In the primary cohort, the five-year overall survival (OS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) rates for the sarcopenia group vs. non-sarcopenia group were 78.2% vs. 93.6% ( P <0.001), 89.4% vs. 87.9% ( P = 0.918), and 82.5% vs. 89.0% ( P = 0.007), respectively. Univariate and multivariate survival analyses revealed that sarcopenia was an independent predictor of OS ( P <0.001 and P <0.001) and DMFS ( P = 0.009, P = 0.034). Patients with sarcopenia experienced significantly higher rates of treatment-related toxicities compared with patients without sarcopenia ( P= 0.032). In addition, patients with sarcopenia also experienced significantly worse treatment response than those without sarcopenia ( P = 0.004). Similar results were found in a PSM cohort. Conclusions: The current findings support that sarcopenia is a promising indicator for predicting clinical outcomes in NPC patients receiving CCRT. A simple and rapid analysis on CT simulation images can provide information about the therapeutic toxicity and survival prognosis, consequently guiding personalized multi-modality interventions during CCRT.
Phase I trial of hafnium oxide nanoparticles activated by radiotherapy in cisplatin-ineligible locally advanced HNSCC patients.
Authors: Le Tourneau Christophe , Calugaru Valentin , Borcoman Edith , Moreno Victor , Calvo Emiliano , Liem Xavier , Salas Sebastien , Doger Bernard , Choussy Olivier , Lesnik Maria , Mirabel Xavier , Badois Nathalie , Krhili Samar , Blomkvist Josefin , Fakhry Nicolas , Wong-Hee-Kam Stéphanie , Hoffmann Caroline
Published: May 2020

6573

Background: The standard of care non-surgical approach for locally advanced head and neck squamous cell carcinoma (LA HNSCC) patients (pts) is concurrent chemoradiation with high dose cisplatin or cetuximab in case of contra-indication. Older age is a contra-indication to cisplatin, and cetuximab might not improve survival in older pts. It is therefore urgently needed to develop new treatment options for elderly pts with LA HNSCC. NBTXR3 are hafnium oxide nanoparticles that can enhance the efficacy of radiotherapy (RT) by increasing locally the deposited dose. In this phase I clinical trial we aimed to evaluate the feasibility and safety of NBTXR3 administered as intratumoral (IT) injection prior to RT in LA HNSCC elderly pts. Methods: Pts with stage III-IV LA HNSCC of the oropharynx or oral cavity ineligible for platinum-based chemoradiation received a single IT injection of NBTXR3 into a selected primary tumor and intensity modulated RT (IMRT; 70 Gy/35 fractions/7 weeks) [NCT01946867]. A 3+3 dose escalation design, tested NBTXR3 dose levels equivalent to 5, 10, 15, and 22% of baseline tumor volume, followed by a dose expansion at the Recommended Phase II Dose (RP2D). Primary endpoints included RP2D determination, and early dose limiting toxicities (DLT). NBTXR3 intratumoral bioavailability and anti-tumor activity (RECIST 1.1) were also evaluated. Results: Enrollment was completed at all dose escalation levels: 5% (3 pts), 10% (3 pts), 15% (5 pts), and 22% (8 pts). No early DLT or SAE related to NBTXR3 or injection were observed. The median follow-up from NBTXR3 administration is 7.6 months. One AE (Grade 1) related to NBTXR3 and four AEs (Grade 1-2) related to the injection were observed. RT-related toxicity was as expected with IMRT. CT-scan assessment showed a good dispersion of NBTXR3 throughout the injected tumor and not in surrounding healthy tissues. The RP2D was determined to be 22%. Preliminary efficacy was evaluated in pts who received the intended dose of NBTXR3 and RT. A complete response of the injected lesion was observed in 9/13 (69%) evaluable pts at doses ≥10% (2 unconfirmed) and an overall complete response in 5/13 (38%) evaluable pts at doses ≥10%. Preliminary safety and efficacy data of the dose expansion cohort at the RP2D will also be presented. Conclusions: NBTXR3 activated by RT was well tolerated at all tested doses and demonstrated promising preliminary anti-tumor activity. Recruitment is ongoing in the dose expansion cohort. These results demonstrate that further testing of NBTXR3 in this population is warranted. Clinical trial information: NCT01946867 .
Upfront DPYD genotyping and toxicity associated with fluoropyrimidine-based concurrent chemoradiotherapy for oropharyngeal carcinomas.
Authors: Desilets Antoine , Aubin Francine , Bahig Houda , Ballivy Olivier , Charpentier Danielle , Filion Edith , Jamal Rahima , Lambert Louise , Vadnais Charles , Weng Xiaoduan , Soulieres Denis
Published: May 2020

6580

Background: The combination of carboplatin and 5-fluorouracil (5-FU) is effective when used concurrently with radiotherapy for locoregionally advanced oropharyngeal carcinomas (Calais et al. 1999). DPYD polymorphisms can be associated with an increased risk of severe toxicity to fluoropyrimidines (Deenen et al. 2016). Upfront screening for the DPYD*2A allele is available in the province of Québec, Canada since March 2017. This study aimed to determine the effect of upfront genotyping on grade ≥3 toxicities. Methods: The studied population included all consecutive cases of oropharyngeal carcinomas treated with 5-FU based chemoradiotherapy one year before and after the implementation of upfront DPYD*2A genotyping. All patients were treated at the Centre Hospitalier de l’Université de Montréal (CHUM) between March 2016 and April 2018. Clinical data were extracted from chart review. Extended screening for 3 supplemental at-risk DPYD variants was also retrospectively performed in August 2019. Results: 181 patients were included in the analysis (87 patients before and 94 patients after DPYD*2A screening implementation). 91% of patients (n = 86) were prospectively genotyped for the DPYD*2A allele. Of those screened, 2% (n = 2/87) demonstrated a heterozygous DPYD*2A mutation. Those two patients received cisplatin-based treatment and thus avoided 5-FU toxicities. Extended genotyping of DPYD*2A-negative patients later allowed for the retrospective identification of 6 additional patients with alternative DPYD variants (two c.2846A > T and four c.1236G > A allele mutations). Conclusions: The DPYD*2A, c.2846A > T and c.1236G > A polymorphisms are associated with an increased risk of G3-4 toxicity to 5-FU, as well as higher hospitalization rates. Upfront DPYD genotyping can identify patients in whom fluoropyrimidine-related toxicity should be avoided. This represents an interesting addition in terms of pharmacovigilance. [Table: see text]
A novel multiple-catheter implantation method for advanced head and neck cancer.
Authors: Ohmae Masatoshi , Kato Itsuro , Fujita Yusei , Meshii Noritoshi , Motoki Ayako , Nakazawa Mitsuhiro , Uzawa Narikazu
Published: May 2020

6582

Background: We previously developed a super-selective intra-arterial chemotherapy (iaCT) approach for head and neck cancer (HNC), by which, an intra-arterial catheter is retrogradely inserted via either the superficial temporal artery (STA) or occipital artery (OA) and connected to a subcutaneous reservoir. As a result, since this approach overcomes the need for frequent fluoroscopy sessions, the infusion frequency can be increased and the therapeutic effectiveness improved. However, since the anticancer effect is limited to the region supplied by the selected blood vessel, it is often difficult to control an advanced HNC by single-catheter iaCT. Subsequently, a novel multiple-catheter implantation method (MCIM) for super-selective iaCT has been developed using, both, the STA and OA. Methods: A total of 21 patients with stage III or IV HNC were enrolled in this study and treated via MCIM for iaCT between 2009 and 2017. The catheters were super-selectively placed in the tumor-feeding arteries after having entered the STA or OA. The first catheter was introduced into one of the target branches. Next, a second catheter was introduced into another target branch. If a third catheter was required, the procedure was repeated. The extra-arterial portions of the catheters were subcutaneously connected to an implanted juxta-mastoidal infusion reservoir. Results: The response rate was 100%; particularly, 20 cases of complete response and 1 of partial response were confirmed. Although the partial responder underwent salvage surgery and two complete responders ultimately died (due to either delayed recurrence or brain metastases), the other 18 patients have been living cancer-free for 2-9 years. Conclusions: The MCIM method allows to expand the infusion region while maintaining the main advantages of super-selective iaCT. As a consequence, due to the lack of need for patient confinement in the catheter room and for frequent fluoroscopy sessions, patients’ mental and physical distress, medical expenses, and treatment time are all ultimately reduced.
ELLA01-1: A study to determine the utility of TP53 mutations as a prognostic biomarker in adenoid cystic carcinoma.
Authors: Metcalf Robert , Mubarak Khaireah , Bola Becky , Rack Samuel , Morgan David , Hussell Tracy , Wallace Andrew , Betts Guy , Harrington Kevin Joseph
Published: May 2020

6585

Background: TP53 mutations are reported in 5% of patients with adenoid cystic carcinoma (ACC). Whilst TP53 mutations are associated with adverse clinical outcomes across multiple tumour types, their prognostic significance in ACC is unknown. We sought to determine the utility of TP53 mutations as a prognostic biomarker in a prospective cohort of ACC patients. Methods: From April 2017 to September 2019, 146 patients with ACC were prospectively recruited to an ethically approved study. DNA was extracted from archival FFPE samples and underwent targeted next generation sequencing (Qiagen GeneRead DNAseq Targeted Panel V2 n = 134; Foundation Medicine; n = 12). Clinical, pathological and outcome data were collected on all patients and Kaplan-Meier survival analysis was performed to test for survival differences between TP53 mutated and wild-type ACC. Results: 146 ACC patients (mean age 48 years, range 16-79) underwent DNA extraction and next generation sequencing for TP53 mutations. The primary site was major salivary gland in 47% and minor salivary gland in 48% (other 5%). Analysis was successful in 122/146 patients (84%). Recurrent or metastatic disease was present in 94% (115/122) at study entry. TP53 alterations were identified in 9% (11/122), most frequently within the DNA binding domain (9/11). Non-pulmonary visceral metastases were seen more frequently in TP53 wild-type than in TP53 mutated ACC (44% vs. 10%; p = 0.042), and other clinical parameters were balanced between groups. During follow-up from diagnosis (median follow up 6.6 years), death occurred in 45% of patients with TP53 mutation and in 23% with TP53 wild-type ACC (p = ns). In TP53 mutated ACC, median overall survival was significantly shorter (5.3 vs. 16.3 years), and 10-year survival rate significantly lower (42% vs. 82%) than TP53 wild-type ACC (log-rank p = 0.013). Conclusions: In this cohort of patients with ACC, TP53 mutations were seen with a higher frequency than previously reported. This may be explained by the high frequency of recurrent or metastatic disease at study entry. TP53 mutation was associated with a statistically significant reduction in overall survival in patients with recurrent and metastatic ACC. These findings suggest that stratifying by TP53 status may be of clinical value to inform follow-up strategy in addition to established clinical, pathological and genomic biomarkers.
Radioiodine (RAI) in combination with durvalumab for recurrent/metastatic thyroid cancers.
Authors: Burman Bharat , Sherman Eric Jeffrey , Kriplani Anuja , Michel Loren S. , Dunn Lara , Fetten James Vincent , Warner Elizabeth , Grewal Ravinder K , Sabra Mona , Tuttle R. Michael , Boucai Laura , Fish Stephanie , Haque Sofia , Ostrovnaya Irina , Ghossein Ronald A , Knauf Jeffrey , Pfister David G. , Fagin James A , Ho Alan Loh
Published: May 2020

6587

Background: Immune checkpoint blockade (ICB) has limited efficacy for radioiodine-refractory thyroid cancer. The high incidence of autoimmune thyroid disease and ICB-induced hypothyroidism suggests that loss of T cell tolerance to thyroid protein epitopes is common and can be activated by ICB to induce immune responses. We hypothesize that RAI can enhance presentation of thyroid protein immunogens and putative neoantigens in thyroid cancers to amplify the effectiveness of ICB. We studied the safety and efficacy of RAI plus the anti-PD-L1 agent durvalumab (durva) in recurrent/metastatic (R/M) patients (pts). Methods: Pts. had at least one RAI-avid tumor on the most recent RAI scan or one tumor on FDG PET with an SUVmax < 10. RECIST measurable disease was required. Any number of prior therapies was allowed. Pts were treated with durva 1500 mg IV every 4 weeks with recombinant human TSH (rhTSH)-stimulated RAI (100 mCi) administered in Cycle 1. Treatment beyond progression was allowed. The primary objective was to assess safety. Durva related dose limiting toxicities (DLTs) were monitored for 6 weeks after the first dose. Since no durva DLTs were observed in the first 6 pts, per protocol rules the trial accrued 11 pts total. Secondary objectives were assessing best overall response (BOR) per RECIST and progression-free survival (PFS). Results: 11 pts (7 female) were enrolled. Eight had prior drug therapy. No DLTs or > Grade 3 durva related adverse events (AEs) were observed. The most common non-laboratory AEs (regardless of attribution) were cough (7), hypertension (7), pain (6), edema (5), and fatigue/nausea/diarrhea/arthralgia/dry skin/dyspnea/edema (4 each). As of 2/6/20, 2 had partial response, 7 stable disease, and 2 progression of disease as BOR. Six pts had tumor regression. Four pts received treatment for > 6 months. Six are still on treatment. Analyses of research biopsies (bxs) (8 had pre-treatment bxs, 6 had an additional on-treatment bx) will be presented. Conclusions: Durva plus RAI is safe and well tolerated. The preliminary efficacy signal in this small cohort is promising. Understanding how RAI plus PD-L1 targeting impacts the tumor immune microenvironment may guide how RAI should be evaluated in future ICB trials. Clinical trial information: NCT03215095 .