bluuebunny/crossref_metadata_2025 huggingface dataset:
Initial results from the 21-gene breast cancer assay registry: A prospective observational study in patients (pts) with ER+, early-stage invasive breast cancer (EBC).
Authors: Vacirca Jeffrey L. , Tsai Michaela L. , Brufsky Adam , Michaelson Richard Alan , Smith Frederick P. , Schwartzberg Lee Steven , Butler Steven M , Jamshidian Farid , Sing Amy Pratt
Published: March 2020

565

Background: Genomic assays such as the 21-gene breast cancer assay (Oncotype DX), have improved the ability to individualize pt treatment based on their individual tumor’s biology. Since 2004, when the 21-gene assay became commercially available, more than 300K assays have been ordered. While several studies have been conducted assessing the impact of having the Recurrence Score (Score) result on treatment decisions, most have been retrospective or evaluating the treatment recommendation. The Oncotype DX Breast Cancer Registry is a large prospective study conducted in clinical practices evaluating the types of pts having the assay ordered and the actual treatments delivered. We report here the first set of analyses. Methods: Pts with ER+ EBC were eligible to enroll. Data collected at baseline (BL) included age, size, grade, ER, PR and HER2 status. Data collected at the 6-month visit included Score and treatment given. Pt demographics, Score distribution, and associations with clinicopathologic (CP) factors are described. Results: A total of 890 pts were enrolled at 15 U.S. sites between 11/09-3/12. 803 eligible pts were included in the analyses. The Table shows BL characteristics, Score distribution and %CT given. Distribution of Score values across the CP factors was similar to the cohort overall. 30% of pts received CT. Among low Score patients, CT was given in 17% of pts <50y, 9% of Grade 3 tumors and 11% of tumors >2cm. Conclusions: A large, prospective registry for pts with EBC receiving the 21-gene breast cancer assay examined the application of the Score to treatment. The Score distribution is consistent with other retrospective cohorts. The association between the Score and the CP factors was modest. The CP factors did not predict the Score. In general, CT decisions followed the Score with the exception of younger pts; 17% received CT despite a low Score. These findings from a real-world cohort underscore the importance of understanding breast cancer biology in order to make more informed and individualized treatment decisions. [Table: see text]
Phase I clinical trial of bavituximab (Bavi) and paclitaxel (P) in patients (pts) with HER2-negative metastatic breast cancer (MBC).
Authors: Chalasani Pavani , Marron Marilyn , Clarke Kathryn , Schmidt Kathy , Powell Alisa , Iannone Maria , Stopeck Alison
Published: March 2020

567

Background: Bavituximab is a novel tumor vascular targeting agent. It is an unconjugated, chimeric immunoglobulin G1 monoclonal antibody directed against phosphatidylserine (PS). PS is externally expressed on endothelial cells when exposed to hypoxia and/or other physiological stressors frequently observed in tumor-associated vasculature. On attaching to PS, Bavi triggers antitumor effects by inducing antibody-dependent cellular cytotoxicity and promoting antitumor immunity. Methods: We conducted a phase I clinical trial of Bavi in combination with P in pts with HER-2 negative MBC. Pts were treated with weekly P (80mg/m2 for 3/ 4 weeks) and weekly Bavi (3mg/kg for 4/ 4 wks). Microparticle generation, activation and circulating endothelial cell apoptotic markers were measured by flow cytometry. Results: 14 pts with MBC were enrolled. Median age at MBC diagnosis was 50yrs. Seven pts had triple negative MBC; 4 pts presented with de-novo metastatic disease. Prior treatments included chemotherapy in the adjuvant/neoadjuvant setting (8); metastatic setting (2); adjuvant hormonal therapy (3). Best responses to date include complete response (1), partial response (6), stable disease (1), progressive disease (2) and too early to evaluate (4). Bavi related toxicities include grade2/3 infusion related reactions in 2 pts (1 discontinued Bavi). Bone pain, fatigue, headache and neutropenia were the most common adverse effects. 1 pt had a catheter associated upper extremity thrombosis requiring anticoagulation. Laboratory correlative studies revealed no evidence of platelet activation of PAC-1 or P-Selectin. Median platelet and endothelial microparticles decreased from baseline in response to therapy. Conclusions: Bavi is a novel vascular targeting agent that is well tolerated in combination with P. Early results show promise in terms of clinical responses with 8 of 10 evaluable patients having clinical benefit. Early biomarker results suggest no effect of therapy on platelet activation but decreases in circulating microparticles is observed. Clinical trial information: NCT01288261.
Periodontal health in early-stage postmenopausal breast cancer survivors on aromatase inhibitors.
Authors: Taichman L. Susan , Inglehart Marita , Giannobile William , Braun Thomas , Kolenic Giselle , Van Poznak Catherine
Published: March 2020

568

Background: Aromatase inhibitors (AIs) are associated with profound estrogen deprivation resulting in reduced bone mineral density (BMD). Periodontal diseases and tooth loss are associated with estrogen withdrawal and decreased systemic BMD. Little is known as to the impact of AIs on oral health. To investigate oral health as a breast cancer (BCA) survivorship concern, a prospective study was initiated to determine the prevalence of periodontal diseases in postmenopausal early stage (I-IIIA) BCA survivors on adjuvant AI therapy. Baseline assessments are presented here. Methods: Women within 6 months of initiating adjuvant AI for hormone receptor positive BCA were eligible to participate in this study of serial assessments of oral health. A control group of women without BCA and not on AI underwent parallel assessments. Periodontal status was evaluated by the following established dental techniques; (1) periodontal pocket depth (PD), (2) number of teeth with bleeding on probing (BOP), (3) the number of teeth with clinical attachment loss (CAL). Questionnaires regarding socio-demographic and dental utilization were administered to all participants. Linear regression modeling was used to analyze the outcomes. Results: The study met its target accrual of 58 postmenopausal women; 29 with BCA on AI and 29 controls. Demographics were similar regarding age, education, income level, frequency of dental visits, and dental insurance status across both groups. Baseline assessments demonstrated no differences in PD (2.0 mm vs. 2.0 mm; p < 0.95) or the number of teeth (26.6 vs 26.1; p< 0.39). Interestingly, the AI group had significantly more sites of BOP (27.9 vs 16.7; p < 0.02), and higher CAL (5.2 mm vs 4.0 mm; p < 0.01) than did controls. In linear regression analysis adjusted for income, AI use increased CAL by 1 mm (95% CI: 0.15 -1.88). There was also a trend for decreased CAL in subjects with incomes over $75,000 per year (p< 0.06). Conclusions: This first investigation of the periodontal status of women initiating adjuvant AI therpay identifies this population to have signs of increased risk for periodontal disease. Serial oral health assessments are being conducted to assess AI therapy and periodontal changes over time. Clinical trial information: NCT01693731.
Evaluation of microRNA-10b expression as a novel predictive marker of metastases development and patients’ survival in breast cancer.
Authors: Parrella Paola , Barbano Raffaela , Pasculli Barbara , Fontana Andrea , Copetti Massimiliano , Valori Vanna Maria , Poeta Maria Luana , Perrone Giuseppe , Castelvetere Marina , Coco Michelina , Balsamo Teresa , Pellegrini Fabio , Onetti-Muda Andrea , Maiello Evaristo , Murgo Roberto , Fazio Vito Michele
Published: March 2020

576

Background: MicroRNA-10b was found highly expressed in metastatic breast cancer cell lines and able to generate metastases in mice models. The aim of this study is to evaluate the putative association between miR10b expression and disease progression. Methods: We selectedfrom our tumor bank 150 consecutive breast cancers with at least three years follow up. For each case frozen paired tumor and normal tissue and complete clinical data were available. Pathological examination was performed to ensure that each tumour sample contained more than 70% of cancer cells resulting in 114 samples suitable for RNA extraction. RNA quality was measured and only samples with RIN≥7.0 were analyzed (n=101) by a relative quantification method. Results: miR10b relative expression in tumor to normal samples (RERs) was significantly higher in the subgroup of patients with metastases (median 0.25 IQR 0.11-1.02) as compared with patients without metastases (median 0.09 IQR 0.04-0.29) (P=0.023 Mann Whitney Test). The association between miR-10b RERs and survival was evaluated in the group of patients without metastases at diagnosis (n=90). In univariate Cox regression model, patients with high miR-10b RERs had a higher risk of distant metastases development (HR 4.91, P=0.02) and disease related death (HR 6.02; P=0.01). In a multivariate Cox regression model adjusted for tumor size, lymph node metastases, grade, ER, PgR status, and Ki67 labeling index (n=79), higher miR-10b RERs were still associated with increased risk of distant metastases development (HR18.84; P<0.001) and disease related death (HR 13.39; P=0.003) (Table). Conclusions: We show that in breast cancer patients miR-10b expression is associated with worse prognosis on a short term follow up. These results suggest that miR-10b expression could be used for individual patient’s risk assessment and perhaps as potential therapeutical target. [Table: see text]
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.
An open-label single-arm, phase II trial of zalutumumab, a human monoclonal anti-EGFR antibody, in patients with platinum-refractory squamous cell carcinoma of the head and neck.
Authors: Saloura Vassiliki , Cohen Ezra E.W. , Licitra Lisa F. , Billan Salem , Dinis Jose , Lisby Steen , Gauler Thomas Christoph
Published: March 2020

6065

Background: Treatment for patients with platinum-refractory metastatic squamous cell carcinoma of the head and neck (SCCHN) is limited. Cetuximab has been approved in the US in this patient population based on a phase II trial that demonstrated 13% response rate (RR) and 5.9 months median OS. A recently conducted phase III trial of zalutumumab, a human monoclonal IgG1k antibody against EGFR, versus best supportive care showed significant increase in PFS. Here, we present the results of a companion phase II trial in the same patient population. Methods: Patients with platinum-refractory recurrent or metastatic SCCHN received weekly infusions of zalutumumab starting at a loading dose of 8mg/kg. The dose was then reduced to 4mg/kg and individually titrated by increments of 4mg/kg every 2 weeks based on skin rash evaluation up to a maximum of 16mg/kg aiming at a grade 2 skin rash. Primary objective was OS. The analysis was based on the intent-to-treat principle and OS was estimated using the Kaplan-Meier method. Results: Between January 2008 till August 2011 90 patients were enrolled in 57 centers in the United States, Europe and South America. 23% of patients had WHO PS 2 and 74% had distant relapse metastases. Grade 3-4 adverse events (AEs) related to zalutumumab were observed in 19% of the patients and included skin rash (5%), hypomagnesemia (4%) and pneumonitis (1%). Infusion-related reactions occurred in 33% of patients. The frequency of all-cause grade 3-4 AEs was 62% and included infections (14%), gastrointestinal disorders (12%), hypokalemia (6%), dyspnea (9%) and anemia (6%). Two deaths secondary to cardiac arrest in a patient with history of myocardial infarction, and respiratory acidosis in a patient with a pleural effusion and hypomagnesemia were deemed related to zalutumumab. CR was observed in one (1%) patient and PR in four (5%) patients. The median PFS was 8.6 weeks (95% CI [8.0, 10.4]) and the estimated median OS was 5.3 months (95% CI [4.1, 7.1]). Conclusions: Zalutumumab showed reasonable efficacy in platinum-refractory recurrent or metastatic SCCHN patients and dosing titration based on skin rash evaluation was feasible. Clinical trial information: NCT00542308.
The association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer.
Authors: Campian Jian Li , Sarai Guneet , Ye Xiaobu , Marur Shanthi , Grossman Stuart A.
Published: March 2020

6068

Background: Severe treatment-related lymphopenia (TRL) occurs in 50% of glioblastoma and pancreatic cancer patients and is associated with early death from tumor progression. We sought to determine if similar findings were seen in head and neck squamous cell carcinoma (HNSCC). Methods: Eligible patients for this retrospective study had: 1) HNSCC cancer diagnosed in 2007-2009, 2) good performance status, 3) platinum-based chemoradiation, and 4) follow-up at Johns Hopkins. Serial total lymphocyte counts (TLC), overall survival (OS) and progression-free survival (PFS) were analyzed accounting for known prognostic factors. Results: Fifty-six adults met eligibility criteria: median age: 57 years, female: 21%, HPV+: 61%, surgery prior to chemoradiation: 16%, stage IVA-IVB: 77%, T stage 3-4: 40% and N stage 2b-3: 56%. Changes in TLC are shown below (Table). 14/56 patients (25%) had tumor recurrence and 9 (16%) died of their tumor. HPV+ patients had longer PFS (p=0.01) and OS (p=0.006) than HPV- patients. 10/22 HPV- patients had disease progression and 7 died. HPV- patients who developed grade III-IV TRL two months after beginning chemoradiation had a strikingly higher hazard rate for disease progression than those whose TLC remained higher (multivariate analysis HR 6.2, 95%CI: 1.1-35.2; p=0.039). Too few events occurred in the HPV+ cohort for analysis. Conclusions: TLCs were normal before chemoradiation. However, two months after chemoradiation ~60% of patients had severe TLC regardless of HPV status. HPV- patients with severe TRL were much more likely to have disease progression than those without TRL. Prospective studies are needed to confirm these findings which are similar to those reported in other cancers. Preservation of the immune system during chemoradiation may be important to improving PFS and OS. [Table: see text]
Evaluating the cost-effectiveness of low-level laser therapy (LLLT) in head and neck cancer patients submitted to concurrent chemoradiation.
Authors: Antunes Heliton Spindola , Herchenhorn Daniel , Small Isabele Avila , Araujo Carlos Manoel , Cabral Elida , Rampini Mariana Pereira , Rodrigues Pedro Carvalho , Silva Tereza Giannini Pereira da , Ferreira Elza Maria de Sa , Dias Fernando Luiz , Teich Nelson , Teich Vanessa , Schluckebier Luciene Fontes , Ferreira Carlos G. M.
Published: March 2020

6071

Background: Oralmucositis (OM) is a main factor for increasing treatment costs in head and neck squamous cell carcinoma (HNSCC) patients (pts) treated with chemoradiation (CRT). This study was designed to estimate the cost-effectiveness of LLLT to prevent oral mucositis in HNSCC patients submitted to CRT. Methods: From June 2007 to Dec 2010, 94 patients with HNSCC of nasopharynx, oropharynx and hypopharynx entered a prospective, randomized, double blind, placebo-controlled, phase III trial (47 LLLT (LG) and 47 placebo (PG)). CRT consisted of conventional RT 70.2 Gy (1.8Gy/d, 5 times/wk) + concurrent cisplatin 100 mg/m2 every 3 wks. The LLLT used daily was a diode InGaAlP (660nm-100mW-4J/cm²). OM evaluation was done by WHO and OMAS scale. The resources used by patients in both groups were documented during the trial. Unit costs for procedures were obtained from a public reference list (SIGTAP / SUS) as of Jan 2012 and unit costs for drugs were based on ex-factory prices. The cost per laser session was US$ 34.00 (exchange rate from Brazilian currency to US dollar = 1.95) for the baseline analysis. Costs of RT, chemotherapy, fluconazole and chlorhexidine 0.12% were equivalent in both groups and therefore not included in the analysis. Hospitalization rates associated with the treatment of oropharyngeal or oral mucositis were not documented in the study and were estimated according to previously published data. Results: Under the perspective of the Brazilian public healthcare system (SUS), total costs were higher in PG than LG on opioide use (LG= US$ 29.45; PG= US$143.72, gastrostomy (LG= US$ 41.69; PG= US$107.22 ) and hospitalization (PG= US$ 63.59). In LG costs were higher with laser therapy (US$ 1,549.50). The total incremental cost associated with the use of LLLT was US$ 1,306.61 per patient. The incremental cost-effectiveness ratio (ICER) was US$ 3,838.16 per case of grade 3 and 4 mucositis avoided when compared with no treatment. Conclusions: Our results indicate that laser group had a smaller morbidity during treatment and LLLT is cost-effective when compared to pacebo under a threshold of at least US$ 4,000 per avoided mucositis case. Clinical trial information: NCT01439724.
Clinical utility of CT and FDG PET/CT in assessing the neck in node-positive head and neck cancer after chemoradiotherapy.
Authors: Nakahara Susumu , Takenaka Yukinori , Yamamoto Yoshifumi , Yasui Toshimichi , Hanamoto Atsushi , Inohara Hidenori
Published: March 2020

6082

Background: Concurrent chemoradiotherapy has been widely accepted to treat locoregional advanced head and neck cancer, but the need for subsequent neck dissection remains controversial. Our objective was to determine whether CT or fluorodeoxyglucose (FDG) PET/CT is superior in the evaluation of persistent nodal disease after chemoradiotherapy in patients with node-positive head and neck squamous cell carcinoma (HNSCC). Methods: Study entry criteria included node-positive HNSCC treated with concurrent chemoradiotherapy, a local complete response, and post-treatment CT and FDG PET/CT studies 11 weeks after chemoradiotherapy. Fifty-eight patients with 68 node-positive necks were eligible. Nodes larger than 1 cm (minor axis), or with central necrosis on CT, or any visually hypermetabolic nodes on FDG PET/CT were considered clinically positive. Regardless of PET/CT findings, necks with positive CT were subjected to neck dissection, whereas those with negative CT were observed without neck dissection. Results: Seventeen necks showed positive CT, 13 and 4 of which underwent neck dissection and fine needle aspiration cytology, respectively, resulting in pathologic evidence of persistent nodal disease in 5 necks. Four of 51 necks with negative CT developed regional recurrence. Diagnostic accuracy of CT and PET/CT is shown in table. In general, the negative predictive value (NPV) was equivalent between CT and FDG PET/CT, whereas FDG PET/CT was better than CT in the specificity and accuracy. Conclusions: In patients with HNSCC, both CT and FDG PET/CT after chemoradiotherapy have a high NPV for excluding residual regional disease and avoiding unnecessary neck dissection. Although the NPV is similarly high, PET/CT has superior utility compared with CT because the number of false positive findings is less in PET/CT than CT. [Table: see text]
miRNA analysis between malignant and benign tissue and circulating exosomes (CE) in patients (pts) with tongue squamous cell carcinoma.
Authors: Rabinowits Guilherme , Flores Ludmila , O'Neill Anne M. , Stevenson Kristen , Ghobrial Irene M. , Vergara Victoria , Jo Vickie Y , Verselis Sigitas Jonas , Chau Nicole Grace , Lorch Jochen H. , Haddad Robert I.
Published: March 2020

6088

Background: The identification of a specific miRNA pattern in HNSCC is challenging given the heterogeneity of this disease and different methodologies used in prior studies. Here we chose to group pts according to primary tumor location and used Nanostring as a larger miRNA platform. Methods: CE-miRNA was isolated from 500ul of plasma collected in Heparin/EDTA tubes. Samples were pretreated with Pacific Hemostasis Thromboplastin D. Supernatant was treated with ExoQuick. Exosomal pellet was resuspended in 1ml of QIAzol Lysis Reagent. Formalin fixed paraffin embedded (FFPE) samples were deparaffinized and digested with proteinase K. miRNA from plasma and FFPE were isolated with miRNeasy Mini Kit. Samples were processed by Nanostring Technology. In this analysis, only tongue cancer pts were selected due to availability of paired tumor and benign tissue miRNA in conjunction with CE from the same pts and others with tongue cancer. Results: 21 HNSCC pts and 32 age-matched controls have enrolled to date. For homogeneity we analyzed only patients with tongue cancer (n=9): 8 males, median age 55.5 years (range 24-64), all had stage IVA tongue cancer (6 base of tongue), 6 HPV/p16 positive. Nine pts received chemoradiation; 4 also had surgery; 8 had clinical and radiological complete response. Of the 800 miRNAs tested 62 were overexpressed and 15 were suppressed in the tumor compared to benign tissue in the same pts. Of those overexpressed and suppressed in tumor tissue, 4 (miR23a-3p; miR150-5p; miR199a-5p; miR203) had a post/pre treatment average ratio (PPTAR) less than 1, while 4 (miR720; miR1253; miR145-5p; miR1283) had PPTAR greater than 1, respectively on CE of pts. miR150-5p was suppressed and miR1283, miR145-5p and miR1253 were overexpressed on CE of control samples compared to pre treatment samples of pts. Conclusions: Of the 800 miRNAs, 8 appear to correlate with treatment response. The average levels of 4 of those miRNA mirror the average levels of tumor tissue miRNA and is in an inverse relationship with benign tissue and control blood samples, suggesting this may be a unique signature for tongue cancer. This observation needs to be validated in larger studies.
Survival in patients with HPV-positive oropharynx squamous cell carcinoma with distant metastases.
Authors: Price Katharine Andress Rowe , Okuno Scott H. , Garcia Joaquin J. , Molina Julian R. , Olsen Kerry D. , Kasperbauer Jan C. , Price Daniel L. , Garces Yolanda I. , Ma Daniel , Neben-Wittich Michelle A. , Shull Shastin E. , Foote Robert Leonard , Moore Eric J.
Published: March 2020

6095

Background: Prognosis for patients (pts) with locally-advanced, HPV-positive oropharynx squamous cell carcinoma (HPV+OPSCC) is significantly better than for pts with HPV-negative head and neck squamous cell carcinoma (HNSCC). Historic survival of pts with metastatic HNSCC is 6-9 months with palliative therapy. However, the prognosis and survival of pts with HPV+OPSCC with distant metastases is not known. Methods: Pts with HPV+OPSCC with distant metastatic disease were identified from databases from the departments of surgery, radiation, and medical oncology. Demographic and clinical data was abstracted from the medical record. All pts had confirmed HPV/p16+ disease. Results: Fifteen pts with metastatic HPV+ OPSCC were identified. The median age was 57 years (range 42-78, 15 male). The median pack-year smoking was 0 (range 0-120). Primary site included 10 tonsil and 5 tongue base. At diagnosis, one pt had stage III and 14 had stage IV disease (IVA: 9, IVB: 2, IVC: 3). T- and N-stage included T1 (1), T2 (10), T3 (3), T4 (1) and N1 (1), N2a (1), N2b (9), N2c (3), N3 (1). Extracapsular extension was seen in 8 pts, absent in 2, and unknown in 5. Seven pts had lymph node (LN) involvement at level IV/V. Initial therapy for locally-advanced disease included surgery followed by adjuvant radiation (RT) in 1 pt and chemoRT in 8, and definitive chemoRT in 3 pts. Three pts were metastatic at initial diagnosis. Of 6 pts with an isolated metastatic site, 3 pts are alive > 2 years from diagnosis of metastasis (median 1.97 years, range 0.49-2.29). Palliative therapy included surgery (3), RT (9), platinum chemo +/- cetuximab (8), cetuximab alone (2) or with a taxane (2). The most common sites of metastasis included bone (6), lung (5), and LNs (5). The 1-year survival rate after diagnosis of metastatic disease was 92%. The median time to diagnosis of metastatic disease after definitive therapy was 0.47 years (95% CI 0.19-1.29); 75% of pts who developed metastatic disease did so within 1 year of definitive therapy. Of note, 2 of the 15 pts developed a secondary immune-mediated malignancy (melanoma and non-HIV associated Kaposi’s sarcoma). Conclusions: The survival of pts with metastatic HPV+OPSCC is significantly better than that of historic controls.