bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective comparison of uPA/PAI-1 and EndoPredict-clin score in ER-positive, HER2-negative breast cancer: Impact on risk stratification and treatment decisions.
Authors: Ettl Johannes , Grosse Lackmann Kirsten , Hapfelmeier Alexander , Klein Evelyn , Paepke Stefan , Petry Christoph , Specht Katja , Hoefler Heinz , Kiechle Marion 
Published: March 2020

581 Background: Adjuvant therapy decisions in breast cancer patients are based on accurate risk assessment. UPA/PAI-1 can be used for risk evaluation. Recently, the EndoPredict-clin score (EPclin), a second generation multigene test has been introduced into clinical practice. Aim of this prospective study is to compare risk assessment by uPA/PAI-1 and EPclin and to determine, how these parameters influence treatment decisions. Methods: 100 consecutive cases of ER-pos, HER2neg, intermediate risk breast cancer cases were enrolled in this study. EPclin and uPA/PAI-1 (for G2-tumors) were obtained by central pathology assessment of the patients´ surgical specimen. Type of adjuvant treatment was chosen after case discussion in an interdisciplinary tumor conference. Results: 94 Patients (pt) have been evaluated. Tumor grading within the presented cohort was as follows: G1: 15 pt (16%), G2: 66 pt (70%), G3: 13 pt (14%). 20 pt (21%) had positive axillary lymph node involvement. Tumor size was less than 1 cm in 27 pt (29%). EPclin could be assessed in 94 pt (100%). 32 pt (34%) were classified as “high risk” whereas 62 pt (66%) were classified as “low risk”. uPA/PAI was obtained from 54 pt (57%). 36 pt (67%) out of these 54 pt had high uPA/PAI-1 levels whereas 18 pt (33%) showed low uPA/PAI-1 levels. Only 2 pt (4%) with low uPA/PAI-1 levels were classified as “high risk” with EPclin, whereas 17 pt (32%) with high uPA/PAI-1 were classified as “low risk” via EPclin (p=0,003). In 29 cases (31%) treatment decision was influenced by EPclin: In 26 pt (28%) adjuvant chemotherapy (ctx) was omitted whereas in 3 pt (3%) ctx was added following the EPclin. Conclusions: This prospective study shows for the first time, that high risk status according to the EPclin score is strongly associated with a high risk status as defined by uPA/PAI-1. Providing analytically valid results for all patients evaluated EPclin’s clinical practicability was clearly superior to uPA/PAI-1. This finding, combined with the fact that EPclin assigns twice as many patients to the low risk group indicated that EPclin is a more versatile and powerful tool to help spare patients from chemotherapy than uPA/PAI-1.
CYP2D6 genotype related to tamoxifen efficacy: An analysis with exclusion of potential false CYP2D6 genotype assignment caused by loss of heterozygosity in tumor tissue.
Authors: Dezentje Vincent O. , van Schaik Ron H.N. , Vletter - Bogaartz Judith M. , van der Straaten Tahar , Wessels Judith A.M. , Meershoek – Klein Kranenbarg Elma , Berns Els M. J. J. , Seynaeve Caroline , Putter Hein , Van De Velde Cornelis J. H. , Nortier J. W. R. , Gelderblom Hans , Guchelaar Henk-jan 
Published: March 2020

597 Background: The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Methods: Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in the Tamoxifen Exemestane Adjuvant Multinational trial (TEAM) were genotyped for 5 CYP2D6 variant alleles. CYP2D6 genotypes and phenotypes were related to disease free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing three microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. Results: Analysis of the CYP2D6 alleles and the microsatellite markers demonstrated heterozygosity for at least one of the CYP2D6 alleles or microsatellite markers in 97.7% of patients with a specified CYP2D6 phenotype. The 14 patients (2.3%) with a homozygous CYP2D6 genotype in which no heterozygosity could be demonstrated for the microsatellite markers were excluded from the analysis. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t. Conclusions: In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype was associated with DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded.
The Cancer Genome Atlas: Integrated analysis of genome alterations in squamous cell carcinoma of the head and neck.
Authors: Hayes David N. , Grandis Jennifer R. , El-Naggar Adel K. 
Published: March 2020

6009 Background: Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer death in worldwide. Methods: The Cancer Genome Atlas (TCGA) is conducting DNA, RNA and miRNA sequencing along with DNA copy number profiling, quantification of mRNA expression, promoter methylation, and reverse-phase protein arrays on surgically resected samples from previously untreated patients with HNSCC. We report for the first time the integrated genomic alterations for 279 HNSCC patients. Results: The demographics of 279 patients enrolled in the study show a median age of 61 years (range: 19-90); 27% female, and history of tobacco smoking in 80%. Over 30 sites of significant somatic copy number alteration were identified as well as 15 significantly mutated genes at the false fiscovery rate of <0.01, including: CDKN2A, TP53, PIK3CA, FAT1, MLL2, TGFBR2, HLA-A, NOTCH1, HRAS, NFE2L2, and CASP8. Evidence of the human papilloma virus (HPV) was observed by sequencing in up to 25% of samples. Integrated genomics data supported expected patterns including the predominant role of HPV type 16 infection in nonsmoking patients with tumors of the oropharynx which are wild-type for the tumor suppressor genes p16, Rb, and p53. In addition, striking atypical cases and viral infections will be presented as well as novel anti-correlation of HPV infection with focal copy number alterations including EGFR amplification and chromosome 11q. By contrast co-occurrence of HPV with focal deletions of TRAF3 and mutations of the oncogene PIK3CA will be described. Integrated tumor subtypes defined by gene expression, methylation, and miRNA will be presented in conjunction with associated mutations exclusive to tumor subtypes. For example, alterations of the “antioxidant response elements” transcription activators NFE2L2 and KEAP1 will be documented in association with the “classical” expression subtype of HNSCC, as has been shown in lung squamous cell carcinoma. By contrast, co-occurrence of CASP8 and HRAS will be documented in the “Basal” subtype. Conclusions: While, HNSCC is a heterogeneous tumor, coordinated tumor alterations are observed, including potentially targetable genes and pathways. Results presented on behalf of TCGA.
Postoperative detection of circulating EGFR transcripts as a surrogate marker for circulating tumor cells to predict tumor recurrence after adjuvant radio(chemo)therapy in locally advanced squamous cell carcinoma of the head and neck (LASCCHN).
Authors: Tinhofer Inge , Konschak Robert , Stromberger Carmen , Keilholz Ulrich , Budach Volker 
Published: March 2020

6014 Background: The prognostic role of circulating tumor cells (CTCs), occurring in up to 35% of LASCCHN patients, is still largely undetermined. In this prospective study we tested whether the detection of CTCs was associated with treatment outcome of adjuvant radio(chemo)therapy. Methods: Patients with LASCCHN (N=64) of the oropharynx (N=40), oral cavity (N=15), hypopharynx (N=3) or CUP (N=6) presenting after tumor surgery for adjuvant treatment were enrolled in this study. Peripheral blood samples were collected before start and at the end of adjuvant radio- (N=22) or radiochemotherapy (N=42). Transcripts of epidermal growth factor receptor (EGFR) were detected using RT-PCR. Samples positive in at least 2 of 3 PCR replicates were considered CTC-positive, according to previous studies. CTC detection was correlated with failure-free (FFS) and overall survival (OS). Results: CTCs were detected in blood samples from 21 of 64 patients (33%) whereas all 30 samples from healthy donors used as control were negative. The CTC+ and CTC- patient cohorts were comparable with relation to sex, age, smoking history, T and N stage, tumor localization, type of adjuvant treatment and the median follow-up for OS and FFS. Detection of CTCs before or after adjuvant treatment was not predictive for OS. However, the presence of CTCs at the start of adjuvant radio(chemo)therapy identified patients with reduced FFS (CTC- vs CTC+ [% of patients without relapse at 2 years]: 89% vs. 60%, HR: 0.30, 95% CI: .08-.92, p=.037). Multivariate Cox regression analysis revealed that the prognostic value of the CTC status was not influenced by the T and N stage and independent of whether the adjuvant treatment consisted of radio- or radiochemotherapy. Conclusions: Persistence of CTCs after tumor resection as detected by EGFR transcripts was established as an independent marker for tumor recurrence in LASCCHN. Postoperative detection of CTCs might prove useful for risk stratification in future clinical trials for optimization of adjuvant treatment, especially for the poor-prognosis group of CTC+ patients.
Re-differentiation of radioiodine-refractory BRAF V600E-mutant thyroid carcinoma with dabrafenib: A pilot study.
Authors: Rothenberg Stephen M. , McFadden David G , Palmer Edwin , Daniels Gilbert H , Wirth Lori J. 
Published: March 2020

6025 Background: Resistance to radioactive iodine is a leading cause of mortality in differentiated thyroid carcinoma. The MAPK pathway is a major determinant of iodine uptake into thyroid carcinoma cells. Mutations in BRAF activate this pathway, resulting in resistance to radioactive iodine. A pilot study using the MEK1/2 inhibitor, selumetinib, (Ho, ASCO 2012) increased radioiodine uptake in a subset of thyroid cancers. Methods: This is a single institution, single arm pilot study investigating the potential for the BRAF inhibitor dabrafenib to induce radioiodine uptake in metastatic, BRAF-mutant, radioiodine-refractory papillary thyroid carcinoma (PTC). The primary endpoint is increased radioiodine uptake demonstrated on a 4mCi 131-I whole body scan. Patients with increased uptake receive 14 additional days of dabrafenib followed by treatment with 150mCi 131-I. Secondary endpoints include safety and tolerability and clinical benefit as measured by decreases in serum thyroglobulin and objective response rate per modified RESIST 1.1. Results: To date, 7 patients have been enrolled. All had negative 131-I scans within 14 months of enrollment. No dose adjustments for toxicity have been needed. One patient developed reversible hypophosphatemia and a second developed a benign skin lesion. 3 of 5 evaluable patients developed radioiodine uptake after 28 days of dabrafenib, and new radioiodine-avid lesions were demonstrated in all three after receiving a therapeutic dose of 131-I. All three patients demonstrated increases in thyroglobulin levels during treatment with dabrafenib. Conclusions: This initial data suggests that a subset of patients with radioiodine-resistant BRAF-mutant PTC demonstrate new iodine uptake following treatment with dabrafenib. Reuptake may correlate with increases in thyroglobulin, suggestive of re-differentiation. It is not yet known whether increased uptake of radioactive iodine will translate into a radiographic response. Two patients failed to convert to radioiodine-sensitive disease; it is possible that BRAF inhibition was incomplete in these patients and/or determinants other than BRAF mutation status contribute to radioiodine sensitivity. Clinical trial information: NCT01534897.
A preliminary cost-effectiveness analysis of human papillomavirus vaccination in males for the prevention of oropharyngeal cancer.
Authors: Graham Donna M. , Isaranuwatchai Wanrudee , Habbous Steven , de Oliveira Claire , Liu Geoffrey , Siu Lillian L. , Hoch Jeffrey S. 
Published: March 2020

6033 Background: Many western countries have established female human papillomavirus (HPV) vaccination programmes for prevention of cervix cancer. Efficacy against additional HPV-related disease is proven in both sexes, but cost-effectiveness of male vaccination remains controversial. Projected figures suggest incidence and prevalence of oropharyngeal cancer (OPC) in North America will exceed that of cervix cancer by 2020 due to HPV-related cases. Two cost-effectiveness analyses evaluating male HPV vaccination have included OPC, with contrasting results. The Canadian government recommends, but does not fund, male vaccination. In order to assess the value for money of male HPV vaccination in Canada with respect to OPC, we performed a preliminary cost-effectiveness analysis. Methods: Following extensive literature review regarding HPV-related OPC in Canadian males, healthcare cost and clinical effectiveness estimates were obtained from published studies. A Markov model was used to compare potential costs and effectiveness of HPV vaccination against no vaccination among males aged 12 years old. A 3-month cycle length was used with a ‘lifetime’ time horizon. The outcome of the analysis was the incremental cost per quality-adjusted life-year (QALY). Sensitivity analyses were conducted on variables such as vaccine uptake rate and efficacy. Results: Assuming 99% vaccine efficacy and 70% uptake, the use of HPV vaccine produced 0.05 more QALYs and saved $204 Canadian dollars (CAD) per person compared with no vaccine (QALYs and costs discounted at 5% per year). Assuming 50% vaccine efficacy and 50% uptake, use of HPV vaccine produced 0.01 more QALYs and saved $43 CAD. Based on a population of 12 year old males of 192,940 in 2012, male HPV vaccination may potentially save $8.3-39.4 million CAD for this cohort over its lifetime. Conclusions: Knowledge gaps exist regarding male HPV vaccination for OPC prevention. Due to practical limitations, including lack of identifiable precursor lesions in OPC, clinical trials to evaluate this issue may not be feasible. Without considering the effects of herd immunity, this preliminary analysis highlights potential savings from male vaccination.
Validation of late oral health outcomes, an oral health subscale of the Vanderbilt Head and Neck Symptom Survey in post-radiation therapy head and neck cancer patients.
Authors: Kolnick Leanne , Deng Jie , Epstein Joel Brian , Migliorati Cesar A. , Rezk Julie , Dietrich Mary S. , Murphy Barbara A. 
Published: March 2020

6040 Background: The Vanderbilt Head and Neck Symptom Survey (VHNSS) version 2.0 oral symptom subscale was developed to address potentially overlooked and underreported oral health issues. We report the validation of questions pertaining to xerostomia (4 items), dental health (4 teeth), dentures (1 item) and trismus (1 item). Methods: Between May 2011 and April 2012, 50 patients treated with chemoradiotherapy for head and neck cancer completed the 50-item VHNSS survey, underwent an oral health assessment by a dentist, salivary flow and inter-incisal opening (IIO) measurements. Results: Patient reported “problems with dry mouth” correlated with unstimulated salivary flow rates (-0.43, p = 0.002). “Cracked teeth” (-0.55, p = < 0.001) or “difficulty chewing due to teeth” (-0.43, p = 0.004) correlated with urgent or emergent dental care issues identified on exam. Using a cut off of >4 on any of four the dental questions, we were able to identify 83% of patients with urgent or emergent dental issues. The ROC curve was useful (0.89, p< 0.001) for separating patients with and without urgent/emergent dental issues. “Limitations” in jaw movement correlated with IIO (-0.43, p = 0.002). Small numbers of patients with dentures precluded meaningful analysis of this subsample. Conclusions: Clinically significant oral health issues pertaining to xerostomia, dental health and trismus may be identified using the oral health subscale of the VHNSS version 2.0. Patients who score > 4 on any of the teeth related items should be referred for immediate dental evaluation; and for trismus should be referred for physical therapy.
Validation of the Vanderbilt Head and Neck Symptom Survey Version 2.0.
Authors: Niermann Kenneth J. , Dietrich Mary S. , Ridner Sheila H , Kolnick Leanne , Zatarain Lauren Azure , Gilbert Jill , Murphy Barbara A. 
Published: March 2020

6049 Background: We previously reported the development and preliminary testing of the Vanderbilt Head and Neck Symptoms Survey version 2.0 (VHNSS 2.0 ) for assessment of symptom burden in head and neck cancer (HNC) patients who are undergoing or completed primary or adjuvant radiation based therapy (Cooperstein et al., Head and Neck, 2012, 24(6): 797-804). In addition to expanding items on existing domains, version 2.0 includes new domains such as dental health, mucosal sensitivity, and joint range of motion. Herein we report the results of initial validation of the instrument. Methods: 159 unique patients with HNC completed the 50 item VHNSS 2.0 as a part of one of three supportive care studies. Since each of these studies was prospective and longitudinal with repeated application of the VHNSS 2.0, we chose to utilize the first complete questionnaire for each patient for this analysis. Results: Patient characteristics: median age 57 (range 28-81 years), male 74.8%, Caucasian 91.8%, T3 or T4 46.5%, N2 or N3 66%, Site: pharynx 57.9%, oral cavity 15.1%, larynx 11.3%, 15.7%. Analysis identified 10 distinct clusters with 3 single items. The internal consistency of the clusters was good to excellent. Cronbach’s alpha coefficient, a statistical measure of reliability is shown in the Table. Conclusions: The VHNSS 2.0 is a robust, reliable measure of acute and late toxicities in patients undergoing radiation for HNC. These results provide a platform for administering appropriate interventions, which would ultimately provide for effective management of adverse oral health outcomes. [Table: see text]
A phase II study of radiation therapy (RT), paclitaxel poliglumex (PPX), and cetuximab (C) in locally advanced head and neck cancer (LA-HNC).
Authors: Hahn Seung Shin , Bogart Jeffrey , Chung Chung Taik , Hsu Jack , Kellman Robert , Lacombe Michael Andrew , Kim Jung-AH , Graziano Stephen L. , Martin Dena , Gajra Ajeet 
Published: March 2020

6059 Background: RT + cisplatin in LA-HNC showed a survival benefit over RT alone, but with significant toxicity. Addition of C to RT demonstrated survival benefit without increased RT-related toxicity. PPX consists of paclitaxel linked to a biodegradable, water-soluble polymer of glutamic acid. PPX has a radiation enhancement factor of ≈8 in a radiocurability murine model. This study addresses the combined use of intensity modulated RT (IMRT), PPX, and C in patients with LA-HNC. Methods: Eligible patients had untreated stage III/ IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, larynx, or unknown primary, ECOG PS 0-1, and adequate bone marrow function. Patients received C 400 mg/m2 day 1 and 250 mg/m2 weekly for 7 weeks. PPX was administered at 40 mg/m² weekly for 7 weeks. IMRT began on day 8 consisting of 69.96 Gy delivered in 2.12 Gy daily. Results: 38 patients with LA-HNC are included in this report and evaluable for response. 24 (63%) had CR and 14 (37%) had PR. HPV status is 21+, 11- and 8 unknown. Pre-therapy, 36 patients had nodal disease, 9 underwent neck dissection post-treatment and 1/ 9 patients had microscopic involvement by cancer. Locoregional tumor control occurred in 36/38 (95%) patients with two patients developing locoregional recurrence after completion of therapy. Two patients have died from metastatic disease and two patients are alive with distant metastases. Two additional deaths were unrelated to therapy (sudden cardiac death and COPD exacerbation with respiratory failure). The majority of adverse events (AEs) were grade 1/2 and consistent with known toxicities of individual agents. The most common grade 3 AEs were mucositis (n=28), radiation dermatitis (n=15), dehydration (n=8) and cetuximab rash (n=9). The median overall survival and progression free survival have not been reached. Updated numbers will be presented. Overall survival rate is 34/38 (89%) by intent-to-treat analysis, with a median follow up of 13 months. Conclusions: The combination of IMRT, PPX, and C is tolerable and shows promising clinical activity in patients with LA-HNC. An expansion cohort of HPV negative patients on this protocol is in progress. Clinical trial information: NCT00660218.
Is there an interaction between epidermal growth factor receptor (EGFR) inhibition and p16-status in patients (pts) with oropharyngeal squamous cell cancer: A retrospective analysis.
Authors: Nwizu Tobenna Igewonu , Rybicki Lisa A. , Chute Deborah , Rodriguez Cristina P. , Koyfman Shlomo A. , Greskovich John , Saxton Jerrold P. , Scharpf Joseph , Lorenz Robert , Burkey Brian , Wood Benjamin J. , Khan Mumtaz , Al-khudari Samer , Hoschar Aaron P. , Ives Denise I. , Bodmann Joanna , Adelstein David J. 
Published: March 2020

6061 Background: Conflicting data exists about whether EGFR inhibition is more or less effective in pts with p16 positive or negative oropharynx cancer (OPC). We update results from two institutional clinical trials in pts with locoregionally advanced head and neck squamous cell carcinoma (LRA HNSCC) given chemoradiotherapy either with or without the oral EGFR inhibitor gefitinib (G), with specific attention to the subset of pts with p16-defined OPC. Methods: Between 1996-2000, 44 pts with LRA HNSCC were treated on a Cleveland Clinic IRB-approved protocol using concurrent cisplatin, fluorouracil and radiation without G (G- cohort). Between 2003-2007, 60 similar pts were treated using the same chemoradiotherapy regimen with the addition of G 250 mg daily for 2 years beginning on day 1 of radiation (G+ cohort). Available biopsy material from 64 OPC pts (23 G-, 41 G+) was retrieved and tested by immunohistochemistry for p16 (as a surrogate for human papillomavirus) positivity. Kaplan-Meier outcome projections were compared using the log-rank test. Results: With a median follow-up in excess of 7 years for all pts, survival and patterns of failure did not differ between the two trials. The 5-year overall survivals (OS) were 68% vs. 64% (p=0.73) and relapse-free survivals (RFS) 65% vs. 63% (p=0.85) in the G+ and G- cohorts respectively. OPC was more frequent in the more recently treated G+ cohort (68% vs. 53%). Excluding 14 pts for whom tumor was unavailable, OPC p16-positivity was also more frequent in the G+ cohort (74% vs. 63%). As expected, outcomes in the p16+ OPC pts were significantly better than in the p16- OPC pts including OS (66% vs. 58%, p=0.049) and RFS (69% vs. 56% p=0.027). However, in comparing the G+ and G- cohorts, the use of G did not significantly alter any survival outcome or pattern of failure in either the p16+ or p16- OPC pts. Conclusions: Although the retrospective nature of this analysis limits the strength of our conclusions, in the definitive management of LRA HNSCC, we could identify no effect of oral EGFR inhibition on any outcome. In subset analysis there was also no differential impact found in either the p16+ or p16- OPC pts. Clinical trial information: NCT00352105.