bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodality determination of HPV status in head and neck cancers (HNC) and development of an HPV signature.
Authors: Zuo Zhixiang , Keck Michaela K. , Khattri Arun , Patel Rajesh D. , Walter Kim , Lingen Mark W. , White Kevin P. , Hammerman Peter S. , Cohen Ezra E.W. , Stenson Kerstin , Blair Elizabeth A. , Shames David S. , Vokes Everett E. , Seiwert Tanguy Y. 
Published: March 2020

6008 Background: Determination of HPV status is prognostically important, and various testing modalities are commonly used. Discordant results are occasionally observed and a gold standard (for research purposes) is E6/E7 mRNA expression. We aimed to evaluate accuracy of multiple research HPV tests compared to p16 expression/anatomic site, and developed a new HPV signature that we hypothesize will capture HPV-related oncogenic processes independent for all HPV types. Methods: HNCsamples from 136 patients were evaluated by: 1) nested E6 PCR (DNA) (Sotlar 2004), 2) qPCR for E6, E7 (HPV16), E6, L1 (HPV18) (mRNA), 3) p16 expression by IHC and/or mRNA. Results were correlated with anatomic site. A gene expression (GE) signature was developed based on Agilent 4x44Kv2 data and validated in a second cohort. In equivocal cases mutational status of TP53 was evaluated. Results: p16/CDKN2A expression was unreliable outside the oropharynx (OP) (81% false-positives in non-OP tumors, compared to 12% for OP tumors). Anatomic site as described by clinical reports was unreliable. In our cohort, 52 out 77 OP (67.6%) were HPV positive by DNA and RNA based approaches, 3 only by DNA. DNA and RNA based approaches appeared to be similarly accurate and concordant in 97% of samples. The newly developed HPV-GE signature was highly accurate, and allowed to reconcile discrepant cases, suggesting that the DNA-based approach overcalled HPV(+) in 2 tumors while the RNA based approach underreported HPV status in two cases. Expression levels of E6/E7 mRNA showed extensive variability in HPV(+) samples. Interestingly the HPV-GE signature suggested continuous/overlapping biology for a minority of cases. Two tumors (1 supraglottis/HPV18, 1 oropharynx/HPV16) tested HPV(+) by DNA/RNA, p16/CDKN2A, and HPV-GE signature while at the same time having TP53 mutations. Conclusions: p16 should not be used outside the oropharynx and anatomic allocation may also be inaccurate. DNA and mRNA based approaches perform equally well and can be reconciled using the HPV-GE signature. The HPV-GE signature supports the hypothesis that HPV(+) and HPV(-) biology may overlap in a minority of cases.
An epithelial-mesenchymal transition (EMT) gene signature to predict resistance to EGFR inhibition and AXL identification as a therapeutic target in head and neck squamous cell carcinoma.
Authors: Cardnell Robert , Diao Lixia , Wang Jing , Bearss David , Warner Steven , Fan You Hong , Giri Uma , Story Michael D. , Weinstein John N. , Coombes Kevin R. , Williams Michelle D. , Genome Atlas Reseach Network The Cancer , Wistuba Ignacio Ivan , Mills Gordon B. , Myers Jeffrey , William William Nassib , Ang K. Kian , Heymach John , Byers Lauren Averett 
Published: March 2020

6011 Background: Epithelial-mesenchymal transition (EMT) has been associated with EGFR inhibitor resistance in preclinical studies of head and neck squamous cell carcinoma (HNSCC). Recently, we developed an EMT signature that predicts EGFR inhibitor resistance in lung cancer. Using this signature, we explored the association between EMT and drug response in HNSCC, focusing on the tyrosine kinase Axl as a potential therapeutic target. Methods: We conducted an integrated molecular and drug response analysis in HNSCC. A 76-gene EMT signature previously developed and validated in lung cancer was tested in HNSCC cell lines (n>50) and patient tumors from The Cancer Genome Atlas (TCGA) (n=113) and a MDACC cohort (n=105). Reverse phase protein array (RPPA) and proliferation assays were used to measure protein expression and sensitivity to erlotinib and the Axl inhibitors SGI-7079 and TP-0930. Results: The EMT signature identified distinct epithelial and mesenchymal subsets of HNSCC among cell lines and patient tumors. RPPA experiments revealed higher protein levels of the receptor tyrosine kinase Axl, vimentin, and N-cadherin and lower expression of E-cadherin and beta-catenin in mesenchymal HNSCC (p-values <0.02). Elevated Axl expression was also associated with significantly shorter overall survival in patients with locally advanced HNSCC (p<0.001 in TCGA cohort; p=0.003 MDACC). Consistent with previous studies, mesenchymal HNSCC cells exhibited resistance to erlotinib (IC50 >10μM); however, we discovered that mesenchymal HNSCC were highly sensitive to two Axl inhibitors, SGI-7079 and TP-0930 (IC50s ≤1.2μM and 0.2uM, respectively). Conclusions: Our EMT gene expression signature identified discrete epithelial and mesenchymal subgroups of HNSCC. Mesenchymal HNSCC cells expressed higher levels of Axl protein and exhibited sensitivity to Axl inhibition, but resistance to erlotinib. These results highlight differences in drug response between epithelial and mesenchymal cancers and support Axl as a potential therapeutic target and predictive marker of EGFR inhibitor resistance in HNSCC. (Funded in part by 5 P50 CA097007-10)
Efficacy of trastuzumab re-therapy in routine treatment of HER2-positive breast cancer patients who relapsed after completed (neo-)adjuvant anti-HER2 therapy.
Authors: Hanker Lars Christian , Hitschold Thomas , Hesse Tobias , Grafe Andrea , Foerster Frank Gerhard , Schroeder Jan Klaus , Janssen Jan , Reichert Dietmar Arno , Hielscher Carsten , Greinemann Jasmin , Borquez David Julian , Schmidt Marcus 
Published: March 2020

602 Background: Addition of trastuzumab (Roche; T) to chemotherapy (CT) has improved outcomes in patients (pts) with HER2+ breast cancer at all stages, including locally advanced and metastatic disease. Anti-HER2 re-treatment with T is an increasingly used therapy option for the treatment of recurrent/metastatic breast cancer (MBC). However, limited data on T re-treatment is currently available. Methods: Patients with locally recurrent and/or MBC who received T re-therapy were included in this non-interventional study. Among 232 pts enrolled at 121 sites in Germany, 174 pts (33 locally recurrent disease, 141 MBC) were already sufficiently documented to be analyzed for efficacy of T re-therapy in this ongoing study. Progression-free survival (PFS) was assessed by the investigator. Results: The median disease-free interval (calculated from the time of resection of the primary tumor to diagnosis of local recurrence/MBC) was 3.1 years. Median duration of re-therapy with T was 9.3 months. The median PFS of all patients was 10.1 months (95% confidence interval (CI), 8.5 to 13.1). PFS for pts with only locally recurrent disease (n= 33) was 23.6 months. PFS for MBC pts (n=141) was 8.9 months (95% CI, 7.4 to 10.6). For pts with visceral metastases (n=96) a PFS of 8.0 months compared to 10.1 months in patients with only non-visceral (n=45) was recorded. 104 pts were re-treated with T + CT (>70% paclitaxel, vinorelbine, capecitabine or docetaxel alone; PFS= 9.3 months), 26 pts with T + hormonal therapy (HT) (mostly anastrozole, fulvestrant, exemestane, letrozole or tamoxifen; PFS=10.1 months), 24 pts with T+CT+HT (PFS= 19.9 months) and 20 pts with T monotherapy (PFS= 9.4 months). Conclusions: This study provides clinical evidence that re-application of T in combination with either CT, HT or alone is effective in the routine treatment of patients with MBC and/or locally recurrent disease. The benefit observed for pts receiving first-line treatment with T in combination with taxane in pivotal trials as well as recently published data seems comparable to the presented results of pts receiving T re-therapy.
Phase II study of dovitinib (TKI258) in patients with progressive metastatic adenoid cystic carcinoma.
Authors: Dillon Patrick Michael , Moskaluk Chris , Fracasso Paula M. , Petroni Gina R. , Thomas Christopher Y. 
Published: March 2020

6021 Background: Adenoid cystic carcinoma (ACC) is an uncommon malignancy of secretory glands for which there is no standard systemic therapy. At least 90% of ACC tumors carry a t(6;9)(q22–23;p23–24) chromosome translocation that results in overexpression of the MYB oncogene that in turn upregulates FGF2 and other growth factors. Dovitinib is a multiple receptor kinase inhibitor that could potentially block autocrine activation of the FGFR and VEGFR-mediated angiogenesis. In a mouse model, dovitinib suppressed the growth of low passage ACC xenografts. Methods: In this open-label, single-arm trial, patients (n=21) with metastatic ACC that progressed in the last 6 months were treated with dovitinib 500 mg/d, 5-days on/2-days off. The primary endpoint was objective response rate using a two-stage design to test a null and alternative rate of 1% and 18%, respectively, with 90% power and type I error <5%. Secondary endpoints were progression-free survival, safety, quality of life, biomarker studies, and change in tumor growth rate. Results: All 21 patients (median age 54.3, range 29-74) had previous treatment with chemotherapy, radiotherapy or targeted agents. Median duration of treatment to date is 5.7 months (range 2-10 months) and is ongoing in 11 patients. Nine of 21 patients required dose reductions. Grade 3/4 drug-related adverse events included thromboembolism (4), hematuria (1), dehydration (1), pneumonia (2), hypertriglyceridemia (3), diarrhea (2), stomach pain (2), anxiety (1), transaminitis (3) and cytopenias (4). One death occurred unrelated to study drug. Among 19 evaluable patients, 2 had partial responses by RECIST criteria (1 with lung metastases and 1 with tracheal recurrence and stable bone metastases). Both experienced improvements in pain ratings and are free of disease progression at 8+ and 5+ months. Stable disease >6 months was observed in 9 patients while 6 others with shorter follow-up have not progressed. Four patients progressed early (<4 months) and two are too early to assess. Conclusions: Dovitinib produces objective partial responses and prolonged tumor stabilization with acceptable toxicity in patients with progressive ACC. Clinical trial information: NCT01524692.
A phase II study of everolimus in patients with aggressive RAI refractory (RAIR) thyroid cancer (TC).
Authors: Lorch Jochen H. , Busaidy Naifa , Ruan Daniel T , Janne Pasi A. , Limaye Sewanti Atul , Wirth Lori J. , Barletta Justine A. , Rabinowits Guilherme , Garraway Levi A. , Van Allen Eliezer Mendel , Wagle Nikhil , Hanna Glenn J. , Misiukiewicz Krzysztof , Suda Margaret , Haddad Tyler C , Devine Catherine E , Williams Amy , Warsi Ghulam , Posner Marshall R. , Haddad Robert I. 
Published: March 2020

6023 Background: We present results of an open label phase II study of the mTOR inhibitor Everolimus in patients (pts) with RAIR TC. Methods: Pts with metastatic, incurable RAIR TC who had shown radiographic progression within 6 months prior to enrollment received Everolimus 10mg orally once daily. Responses were monitored by CT's every two months. The primary endpoint was progression free survival. Sequential biopsies were obtained in selected pts. Results: Enrollment to the differentiated TC (DTC) cohort finished in Jan 2013 and included 33 pts, among them 11 with Hurthle cell TC. Exploratory cohorts enrolled 10 pts with medullary [MTC] and 5 with anaplastic [ATC] with 2 added openings remaining for ATC. For the DTC cohort, median time on study to date is 10 months (mo) (<1-23+). 31 pts are evaluable at this time. PFS in the DTC cohort by Kaplan-Meier (K-M) analysis is 16.0 mo (95%CI 10-NR). Currently, disease stability for 6 and 12 mo or more was achieved in 18 and 10/31 pts, respectively, 11 pts remain on study. Median OS was not reached but 1 year survival by K-M analysis was 76%. One pt achieved a PR. 3 pts with DTC underwent sequential biopsies which revealed activation of autophagy while markers for apoptosis were not detected. Among 10 MTC pts, one achieved a PR and 9 pts had stable disease for 6 mo or more (6-33+). Among 5 ATC pts, 3 progressed, one has ongoing disease stability for 5 mo. One patient achieved a complete response that lasted for 18 mo and whole exome sequencing revealed somatic loss of function mutation affecting the Tuberous Sclerosis 2 (TSC2) protein, a negative regulator of mTOR activity [TSC2 (Q1178*) and FLCN (R17fs)]. Most common treatment-related adverse events were as anticipated and included fatigue, stomatitis and infections. Grade (gr) 3 events included infection 5, weight loss 3, leukopenia 3, thrombocytopenia 3, fatigue 3, hypophosphatemia 2, stomatitis 2, pneumonitis 1 and thrombosis 1pts. One pt had gr 4 hypercholesterinemia and one pt had gr 4 leukopenia. Conclusions: Everolimus has significant anti-tumor activity in pts with advanced TC. Activation of autophagy could account for high rate of disease stability. Sequencing may identify mechanistic basis and predictive markers for treatment response. Clinical trial information: NCT00936858.
HPV prevalence in the different subsites of the oropharynx.
Authors: Attner Per 
Published: March 2020

6037 Background: Oropharyngeal cancer patients are often reported as one group in articles and studies regardless that within the subsites of the oropharynx, there are differences regarding clinical features, treatment and HPV prevalence. To investigate these differences, we wanted to further analyze HPV prevalence in the different subsites of the oropharynx. Methods: We identified all patients diagnosed with oropharyngeal cancer in Stockholm County, Sweden, between 2000 and 2007, using the Swedish Cancer Registry, a registry unique in its reliability. Using the ICD 10 codes C01.9 (base of tongue cancer), C09.0-C09.9 (tonsillar cancer) and C10.0-C10.9 (oropharyngeal cancer) and C50.1-C50.8 (cancer of the soft palate). The two last subsites were grouped together into the group Other Oropharyngeal Cancer (OOC). We retrieved pre-treatment biopsies and tested for HPV-DNA using PCR, both with general primers and HPV16 specific primers. Results: We identified 474 patients diagnosed with oropharyngeal cancer in Stockholm County, Sweden between 2000 and 2007; 290 diagnosed with tonsillar cancer, 109 diagnosed with base of tongue cancer and 75 diagnosed with other oropharyngeal cancer. Of these 474 patients, pre-treatment biopsies for HPV-testing were available for 400 patients (236, 95 and 69, respectively). In the tonsillar cancer group, 185 biopsies were HPV-DNA-positive (79%), in the base of tongue cancer group 71 (75%) and in the other oropharyngeal cancer group 17 were positive (25%) Conclusions: Tonsillar and base of tongue cancer share some similarities and HPV prevalence is similarly high in both groups. Other oropharyngeal cancer (OOC) does not share the high HPV-prevalence and it would then be preferred that the sub-sites of the oropharynx are reported separately.
Phase II randomized trial of radiotherapy (RT), cetuximab (E), and pemetrexed (Pem) with or without bevacizumab (B) in locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Authors: Argiris Athanassios , Ohr James , Kubicek Greg J. , Duvvuri Uma , Heron Dwight Earl , Kotsakis Athanasios Panayotis , Spencer Christina , Kim Seungwon , Grandis Jennifer R. , Johnson Jonas Talmadge , Bauman Julie E. , Gibson Michael K. , Ferris Robert L. 
Published: March 2020

6043 Background: We previously developed a novel regimen by the addition of Pem to RT and E (Ann Oncol 2011;22:2482). The current study evaluated PemE in the phase II setting and assessed the addition of B, an anti-VEGF monoclonal antibody, to PemE based on promising data with Pem/B (JCO 2011;29:1140) and E/B (Ann Oncol 2013;24:200) in recurrent/metastatic SCCHN. Methods: Patients (pts) with previously untreated stage III/IV SCCHN of the oropharynx, larynx or hypopharynx, performance status (PS) 0-1, no history of bleeding, and adequate laboratory parameters were randomized after stratification for PS, stage and site to: RT 2 Gy/day to 70Gy, E 250mg/m2 weekly, after a loading dose of 400 mg/m2 1 week prior starting RT, and Pem 500mg/m2 every 21 days x 3 cycles (arm A, PemE), or the same regimen plus B 15mg/kg every 21 days x 3 cycles during RT followed by B maintenance x 8 cycles (arm B, B-PemE), with antibiotic prophylaxis. The primary endpoint was progression-free survival (PFS) with a target of 64% at 2 years; planned sample size was 80. Results: 79 pts were randomized of whom 77 were eligible and analyzable (arm A/B:36/41); oropharynx 65/larynx 12; HPV+ 38/HPV- 15/HPV unknown 24; stage IV 54/stage III 23. 31 pts were enrolled in community centers. Treatment delivery of E and Pem was similar between arms: E, median number of doses 8 (range, 5-11); Pem 3 (2-3); and B 3 (1-3). 5 deaths occurred: 3 due to progression; 1 from unknown cause; 1 pt died from hemoptysis after bronchoscopy within 4 weeks of the 8th cycle of B leading to elimination of B maintenance after the 6th pt was enrolled. 9 pts (2 HPV+) progressed. With a median follow-up of 18 months, the 2-year PFS was 81% vs 87% and the 2-year overall survival (OS) was 96% vs 86% for arm A vs B. Grade 3/4 acute toxicities for arm A vs B (N=59) : dermatitis 3/1 vs 4/1; mucositis 13/2 vs 13/0; neutropenia 7/4 vs 7/3; rash 6/1 vs 8/1; fatigue 1/0 vs 3/0; weight loss 2/0 vs 5/0. Conclusions: Both regimens are feasible in academic and community practice settings with expected toxicities. Preliminary efficacy results are very promising and better than projected, however, the addition of B does not appear to improve outcomes. Clinical trial information: NCT00703976.
Predictive values of (18)f-FDG PET standardized uptake value for adjuvant chemotherapy in patients with nasopharyngeal carcinoma.
Authors: Lin Ching Chan , Hsieh Te-Chun , Chen Tzu-Ting , Hsieh Ching-Yun , Lin Chen-Yuan , Huang Hsin-Hui , Bai Li-Yuan , Lin Po-Han , Chiu Chang-Fang , Yeh Su-Peng , Liao Yu-Min , Lo Woei-Chung 
Published: March 2020

6052 Background: Concurrent chemoradiotherapy (CCRT) with or without adjuvant chemotherapy is the mainstay of treatment for locally advanced nasopharyngeal carcinoma (NPC). However the benefit of adjuvant chemotherapy has been controversial and search for adequate predictive factors is warranted. We conduct this study to evaluate the predictive values of mean standardized uptake value (SUV) measured in [(18)F]-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) for adjuvant chemotherapy in patients with locally advanced NPC. Methods: From January 2004 and July 2010, Data collection were performed in 108 NPC patients who underwent (18)F-FDG-PET before CCRT and adjuvant chemotherapy. The SUV was recorded for the primary tumor. All patients received intensity modulated radiotherapy. Concurrent chemotherapy was composed of cisplatin 100mg/m2 triweekly. Adjuvant chemotherapy was consisted of 3 cycles of cisplatin 75 milligrams/m2 and fluorouracil 1000 milligrams/m2for 4 days. Results: The median follow-up was 41months. The optimal cutoff value was 8.35 for SUV. 63.8% of patients had lower SUV (n=69), and 36.2% had higher SUV (n=39). Patients with a lower SUV had a significantly better 3-year overall survival (OS), disease-specific survival (DDS), and distant relapse-free survival (DRFS), but showed no difference in local relapse-free survival. Multivariate analysis showed only stage, SUV and adjuvant chemotherapy were significant in terms of overall survival. In patients with higher SUV, those receiving adjuvant chemotherapy had significantly higher 3-year OS, DDS, and DRFS compared with those without adjuvant chemotherapy. However, in those with lower SUV, there was no difference of OS, DDS and DRFS between patients with and without adjuvant chemotherapy. Conclusions: SUV of (18)F-FDG-PET for primary tumor could identify NPC patients who benefit from adjuvant chemotherapy. [Table: see text]
Use of gene expression signature to discriminate oropharyngeal cancers according to HPV16 status.
Authors: Mirghani Haitham , Ory Catherine , Ugolin Nicolas , Amen Furrat , Guigay Joel , Lacau Saint Guily Jean , Chevillard Sylvie , Lacave Roger 
Published: March 2020

6055 Background: Strong evidence supports the hypothesis that high-risk human papillomavirus (HPV), particularly HPV16, is a causative agent for an increasing subset of oropharyngeal squamous cell carcinomas (OPSCC). These tumors have distinct oncogenic mechanisms and a more favorable prognosis than tobacco induced OPSCC. Although these differences emphasize the need for a specific therapeutic approach, HPV status is still not used to guide treatment. A better understanding of the molecular profile related to HPV16 induced OPSCC may help to develop personalized treatments. Methods: To identify an HPV16-related molecular signature, we compared the gene expression profile of 15 transcriptionally active HPV16-positive and 15 HPV16-negative OPSCC. The study was conducted in two steps. First, a learning set of 16 OPSCC comprising 8 HPV16-positives and 8 HPV16-negatives OPSCC was analyzed in order to identify the signature. Potentially confounding factors of stage, sex and tobacco consumption were equally distributed in both groups. Secondarily, the robustness of this signature was further confirmed by blind case-by-case classification of an independent set of 14 OPSCC. Results: We identified a signature composed of 224 genes which discriminates HPV16-induced OPSCC from their tobacco induced counterparts. After the viral status was revealed, 13 out of 14 tumors were correctly classified according to tumor etiology, 1/14 was undetermined and none were misclassified. Interestingly, deregulated genes in HPV16-positive tumors are principally involved in innate immunity, in cell cycle regulation through the TP53/RB/E2F pathway, and autophagy through mTOR regulation. Well known targets of E6 and E7 proteins are also found to be deregulated. Conclusions: Our results demonstrate that a set of selected genes can distinguish OPSCC according to etiology. These genes shed light on HPV16 induced carcinogenesis since specific molecular pathways are deregulated. Further investigations are required for a better understanding of the differing natural histories and biological properties of these tumors. These properties may be exploited as a target of novel therapeutic agents in HPV-related OPSCC.