bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final results of the multicenter, open-label, randomized phase II trial PAZOTHYR evaluating continuous versus intermittent administration of pazopanib in radio-iodine-refractory thyroid cancers (NCT01813136).
Authors: De La Fouchardiere Christelle , Godbert Yann , Dalban Cécile , Do Cao Christine , Illouz Frederic , Zerdoud Slimane , Wassermann Johanna , Bardet Stephane , Rodien Patrice , Chougnet Cecile N , Benisvy Danielle , Niccoli Patricia , Ravaud Alain , Lebosse William , Bourne-Branchu Valérie , Gautier Julien , Leboulleux Sophie ,   Tuthyref
Published: May 2020

6540 Background: Multikinase inhibitors (MKI) targeting angiogenesis, including pazopanib (P), have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC) but are accompanied by adverse effects, leading to dose adjustments/interruptions. We aimed to investigate the efficacy and tolerance of a discontinuous scheme of pazopanib administration in this situation. Methods: This randomized phase II study enrolled RAIR-TC patients (pts) in first or second-line of MKI with documented disease progression within 12 months (m). After a 6-m pazopanib continuous induction phase, pts with stable disease (SD) or tumor response were randomly assigned in a 1:1 ratio to receive continuous pazopanib (CP) or intermittent pazopanib (IP) until progression and restart. They were stratified by best tumor response [stable disease vs. objective response] and prior MKI treatment [yes vs. no]). Primary endpoint was time to treatment failure (TTF) defined as time between randomization and permanent discontinuation of pazopanib (either for disease progression or intolerance); secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and safety. Results: 168 pts (66.5 years median age; 51.8% female) were included and 100 pts randomized (CP: 50, IP: 50). The median number of metastatic sites was 2.0 (1-7) and 50 pts (29.8%) were pretreated with MKI. With a median follow-up of 31.3 m, we did not show any statistically significant difference in the TTF, 80% (66.0-88.7%)] of the pts being under P at 6 m after randomization in the IP arm versus 78% (63.8-87.2%) in the CP arm. Median TTF was 14.7 m 95% CI [9.3; 17.4] and 11.9 m 95% CI [7.5; 15.6] respectively (HR 0.79 [0.49-1.27]). The best response with P was 35.6% (95% CI [28.2; 43.6]) and the disease control rate was 89.4% 95% CI [83.5; 93.7]. Median time to progression under P was not statistically different between 2 arms (5.7m 95% CI [4.8;7.8] in the IP arm vs. 9.2m 95% CI [7.3;11.1] in the CP arm (HR 1.36 [0.88; 2.12]). 36/100 pts (36%) experienced pazopanib-related grade 3/4 AEs (CP:17; IP: 19) mainly represented by gastrointestinal disorders, hypertension, cardiac disorders and asthenia. Five pazopanib-related deaths were reported (CP:1;IP: 4). Conclusions: The intermittent administration of pazopanib study did not significantly demonstrate superiority in efficacy or tolerance over continuous treatment. Continuous administration of MKI remains the standard in RAIR-TC. Clinical trial information: NCT01813136 .
Overall survival modeling and association with serum biomarkers in durvalumab-treated patients with head and neck cancer.
Authors: Pierre Vadryn , Guo Xiang , Gonzalez-Garcia Ignacio , Morsli Nassim , Yovine Alejandro Javier , Li Weimin , Narwal Rajesh , Roskos Lorin , Baverel Paul 
Published: May 2020

6549 Background: Optimal patient selection for immunotherapy remains a challenge as most patients fail to respond. We aim to assess baseline factors for association with long-term survival from durvalumab treatment in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)1,2. Methods: Pooled longitudinal tumor size, survival, and dropout data from four trials (1108: NCT01693562, CONDOR: NCT02319044 , HAWK: NCT02207530, and EAGLE: NCT02369874) involving 467 HNSCC patients were used to develop tumor size-driven hazard models. A panel of 66 serum protein biomarkers at baseline and 4 relevant clinical markers from 346 out of 413 patients treated with durvalumab (all studies except 1108) were initially screened to select a pool of 21 candidate covariates. The criteria for dimensionality reduction comprised correlation strength between biomarkers and pharmacological hypotheses pertaining to a prior analysis3 (inflammation, immunomodulation, tumor burden and angiogenesis). Results: The final tumor model highlighted that high tumor burden, elevated LDH and neutrophil-lymphocyte ratio were associated with faster tumor growth while patients with lower baseline tumor burden had an increase in net tumor shrinkage. For overall survival, the model suggested that high levels of immunomodulators (IL23, Osteocalcin), low inflammation (IL6, NLR), low tumor burden, and low angiogenesis factors (von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1)) were associated with survival benefits for patients treated with durvalumab. Specifically, these patients had baseline serum IL23 > 2.1 pg/mL and Osteocalcin > 32 pg/mL or serum PAI-1 < 229 pg/mL and serum IL6 < 5.4 pg/mL which corresponded to a hazard ratio estimate (HR and 95%CI) of 0.36 (0.27- 0.47), logrank p-value: 2.3x10−14. The median (n, 95%CI) overall survival time for the patients with favorable biomarker profile was 14.6 months (n = 129, 11.2-21.4) vs. 4.4 months (n = 217, 3.6-5.3). Conclusions: Our results corroborate the prior hypothesis highlighting the prognostic value of inflammation, disease burden, tumor angiogenesis, and immunomodulatory factors on the clinical outcomes of HNSCC patients treated with durvalumab3. Collectively, we identified a serum biomarker profile of HNSCC patients with median survival times exceeding 1 year which may potentially be used for patient enrichment following further validation in prospective studies. References: 1Yanan CPT 2017, 2Baverel, 2018 ENA, 3Guo, X, 2019 Asco P6048 Clinical trial information: NCT01693562, NCT02319044, NCT02207530, NCT02369874 .
Immune functional portraits of head and neck cancer using next generation sequencing.
Authors: Raju Paul Susan , Kotlov Nikita , Svekolkin Viktor , Frenkel Felix , Almog Nava , Tsiper Maria , Nomie Krystle , Fowler Nathan Hale , Lin Derrick , Valine Laura , Sluder Ann , Bagaev Alexander , Ataullakhanov Ravshan , Poznansky Mark C , Wirth Lori J. 
Published: May 2020

6561 Background: The addition of biomarkers as companion diagnostics and Next Generation Sequencing (NGS) have dramatically increased therapeutic efficacy and have aided precision medicine development. The unique genomic profile and tumor microenvironment (TME) composition of each patient can be ascertained through NGS. Using TCGA and Geo datasets, we characterized head and neck cancers (HNC) according to the cellular and functional state of their TME and conducted a pilot validation study using prospectively collected HNC tumors. Methods: To stratify the TME of HNC tumors into molecular functional portraits, we analyzed the sequencing data of 1,486 HNC tumor samples and 143 controls (normal, oral leukoplakia) from TCGA and GEO data sets. For the prospective pilot study, resected tissue from oropharyngeal carcinomas independent of HPV status were processed for whole exome (WES) and RNA-seq (n = 6; HPV-positive = 1). Results: To characterize the cellular composition and functional state of HNC tumors and their TMEs, we created 26 separate molecular signatures related to functional processes such as immune checkpoint inhibition, immune infiltration, immunosuppression, and stromal activities represented by angiogenesis and mesenchymal stromal cells. Unsupervised clustering of these signatures delineated tumors into 4 types: immune infiltration with increased stromal signatures (type A), immune infiltration with decreased stromal signatures (type B), no immune infiltration with increased stromal signature (type C), and no immune infiltration and decreased stromal signatures (type D). Most HPV-positive tumors were type B (p = 1e-27) and associated with increased survival compared to the HPV-negative tumors (types C and D; p = 3e-05). Type B HPV-positive tumors had reduced FAT1 and TP53 mutations, whereas type B HPV-negative tumors had increased caspase 8 mutations/loss. In the validation cohort, actionable mutations were found in PI3KCA and TSC2 in types A and B HPV-negative tumors. Moreover, while the HPV-positive tumor was classified as type C, we identified a caspase 8 homozygous deletion and absence of FAT1 and TP53 mutations, supporting the TCGA and GEO analysis. Conclusions: Exome and transcriptome analyses with cellular deconvolution from bulk RNA-seq enrich tumor characterization by including major TME components, providing a comprehensive biomarker profile for precision therapy and clinical decision making. Our prospective analysis identified TME parameters comparable with the large datasets and revealed targetable genomic alterations.
18 FDG PET/CT prediction of treatment outcomes in patients with p16-positive, non-smoking associated, locoregionally advanced oropharyngeal cancer (LA-OPC) receiving deintensified therapy: Results from NRG-HN002.
Authors: Subramaniam Rathan M , Demora Lyudmila , Yao Min , Yom Sue S. , Gillison Maura L. , Caudell Jimmy J. , Waldron John , Xia Ping , Chung Christine H. , Truong Minh-Tam , Harrison Louis B , Chan Jason , Geiger Jessica Lyn , Mell Loren , Seaward Samantha A. , Thorstad Wade , Beitler Jonathan Jay , Sultanem Khalil , Blakaj Dukagjin , Le Quynh-Thu 
Published: May 2020

6563 Background: To determine the negative predictive value (NPV) of 12-14 week post-treatment PET/CT for 2-year progression-free survival (PFS) and 2-year locoregional control (LRC) in NRG-HN002, which is a two-arm phase II trial for patients with low-risk, non-smoking associated p16-positive LA-OPC randomized in a 1:1 ratio to reduced-dose IMRT with or without cisplatin. Methods: PET/CT scans were reviewed both centrally and locally by participating institutions. Tumor response evaluations for primary site, right neck, and left neck were carried out using a 5-point ordinal scale (‘Hopkins Criteria’). Overall scores were then assigned as ‘Negative,’ Positive,’ or ‘Indeterminate.’ Patients who had a ‘Negative’ score for all three evaluation sites were given an overall score of ‘Negative.’ The endpoints were NPV for LRC and PFS at 2 years testing NPV ≤ 90% vs > 90% (1-sided alpha 0.10 and 76% power). Results: There were 316 patients enrolled, of whom 306 were randomized and eligible. Of these, 131 (42.8%) patients consented to a post-therapy PET/CT, and 117 (89.3%) patients were eligible for PET/CT analysis. The median time from end of treatment to PET/CT scan was 94 days (range 52-139). The rates of 2-yr PFS and LRC in the analysis subgroup were 91.3% and 93.8%, respectively. Based on central review, post-treatment scans were negative for residual tumor for 115 patients (98.3%) and positive for 2 patients (1.7%). The NPV for 2-year LRC was 94.5% (90% lower confidence bound [LCB] 90.6%; p = 0.07). NPV for 2-year PFS was 92.0% (90% LCB 87.7%; p = 0.30). Similar NPV results were obtained based on analysis of local reviews. Conclusion: Within the context of deintensification with reduced-dose radiation, the NPV of a 12-14 week post-therapy PET/CT for 2-year LRC is statistically > 90%, similar to that reported for patients receiving standard chemoradiation. However, in this study, there was not enough evidence to conclude that the NPV of a 12-14 week post-therapy PET/CT for 2-year PFS is > 90%. Grant acknowledgement: This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA180803 (IROC), UG1CA189867 (NRG Oncology NCORP) from the National Cancer Institute (NCI). This project is funded, in part, under a Grant with the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. Clinical trial information: NCT02254278 .
Effect of mammography screening frequency on false-positive biopsy rates and detection of local recurrence among breast cancer survivors.
Authors: McGuinness Julia E , Manley Haley , Yuan Sarah , Pan Samuel M , Zhao Ziyi , Ha Richard D. , Genkinger Jeanine M , Crew Katherine D. 
Published: May 2020

7016 Background: Current guidelines recommend that women with a history of early-stage breast cancer treated with breast-conserving therapy (BCT) continue screening mammography after treatment. One strategy is semi-annual ipsilateral mammography for the first 3 years after diagnosis, when risk of local recurrence is highest. However, a potential harm of more frequent screening is false-positive breast biopsy. We examined the association between screening frequency and rates of false-positive biopsy and local recurrence among breast cancer survivors. Methods: We conducted a retrospective cohort study at Columbia University Irving Medical Center (CUIMC) in New York, NY, of women diagnosed with stage 0-III breast cancer from 2007 to 2017, who were treated with BCT and had at least 2 screening mammograms at CUIMC within the first 3 years after diagnosis. Demographic and clinical information were collected from the electronic health record. Frequency of mammography screening was defined as the median interval between two consecutive mammograms (every 6 months vs. yearly). False-positive biopsy and local recurrence were identified by review of breast pathology reports. A false-positive biopsy was defined as a breast biopsy without evidence of invasive or non-invasive cancer. Descriptive statistics and logistic regression models were conducted to examine relationships between covariates and either false-positive biopsy or local recurrence. Results: In our study cohort (n = 1404), the median age at breast cancer diagnosis was 61 years (range, 24-94), including 45% white, 14% black, 32% Hispanic, and 8% Asian. Eighty percent of women had screening mammography of the ipsilateral breast every 6 months during the first 3 years after diagnosis. Comparing women who screened every 6 months vs. yearly, there was no difference in local recurrence rates (4.0% vs. 4.1%), including screen-detected and invasive recurrences, but a higher rate of false-positive biopsy (13.5% vs. 7.5%). In multivariable analysis, women who screened every 6 months had about a 2-fold increased risk of having a false-positive biopsy (OR 1.93; 95% CI 1.17-3.19); no other factors were significantly associated with false-positive biopsy. Conclusions: We observed that women with early-stage breast cancer treated with BCT who underwent more frequent screening mammography had more false-positive breast biopsies, but no difference in local recurrence rates. Future studies are needed to determine optimal screening strategies for breast cancer survivors.
Effect of shorter time to treatment on survival in rural patients with breast cancer.
Authors: Kamath Suneel Deepak , Wei Wei , Tullio Katherine , Cooper Gregory S. , Khorana Alok A. 
Published: May 2020

7027 Background: Rural cancer care in the United States has unique challenges from variable access to care. This study examined differences in time to first treatment (TTT), a potential surrogate for access, and predictors of overall survival (OS) between rural and non-rural patients with breast cancer. Methods: Women with stage I-III breast cancer from 2004-2012 in the National Cancer Database of Commission on Cancer (CoC)-accredited facilities were included and categorized as rural and non-rural. Differences in demographic, disease and treatment characteristics, socioeconomic factors and TTT (< 4 weeks, 4-8 weeks and > 8 weeks) between rural and non-rural patients were assessed by Chi-square test. The effect of age, insurance status, cancer center type, community median income, community % no high school, and TTT on OS were assessed using univariate and multivariate Cox models. Results: The study included 1,205,031 patients, 18,417 (2%) of whom were rural. Compared to non-rural patients, rural patients were more likely to be age > 65, Caucasian, receive care at non-academic centers, have government insurance, have lower income and less education (p < 0.0001 for all). Significant demographic and socioeconomic differences are shown in Table. Rural patients had shorter mean TTT (3.72 vs. 4.35 weeks, p < 0.0001). More rural patients had TTT < 4 weeks (67% vs. 57%) and < 8 weeks (94% vs. 90%), p < 0.0001 for both. Shorter TTT (both < 4 weeks vs. 8 weeks and 4-8 weeks vs. > 8 weeks) was associated with improved OS (HR: 0.84, 95% CI: 0.82-0.86, p < 0.0001 and HR: 0.82, 95% CI: 0.81-0.83, p < 0.0001, respectively). After adjusting for demographic, socioeconomic, disease stage and treatment factors, rural status was associated with significantly better OS compared to non-rural status (HR: 0.92, 95% CI: 0.89-0.96, p < 0.0001). Conclusions: Despite several adverse socioeconomic factors, rural patients with breast cancer with access to CoC-accredited facilities had significantly shorter TTT and better OS compared to non-rural patients. These data suggest improving TTT can mitigate disparities in rural cancer care. It is unclear whether our data apply to non-CoC-accredited facilities in rural United States. [Table: see text]
Morbidity, mortality and healthcare use among siblings of children with cancer: A population-based study.
Authors: Desai Aditi , Lau Cindy , Sutradhar Rinku , Lee Douglas , Nathan Paul C. , Gupta Sumit 
Published: May 2020

7040 Background: Siblings of children with cancer are at increased risk of adverse mental health outcomes; impact of the childhood cancer experience on these siblings’ physical health is unclear. We characterized the long-term risk of adverse physical health outcomes and healthcare use among siblings of children with cancer. Methods: Pediatric cancer patients in Ontario diagnosed between 1988 and 2016 were linked to their biological siblings to form the siblings/case cohort. Cases were matched to population controls based on sex, age, and residence area. Index date for cases was the date of their brother’s or sister’s cancer diagnosis (controls had the same index date as cases). After individual linkage to health services data, we compared several outcomes between these two groups: 1) physical health conditions (e.g. cancer, hypertension, injuries, death); 2) acute healthcare use (hospitalization, emergency department [ED] visits), and; 3) preventative healthcare use (periodic health checkups, influenza vaccinations). Predictors of outcomes, including demographics and characteristics of the cancer-affected child, were examined in cases. Cox proportional hazards, recurrent event, or logistic regression models were used as appropriate. Results: We identified 8,529 cases and 30,364 matched controls [median age at index: 6 years, interquartile range (IQR) 0-10; median follow-up time: 9 years, IQR 5-15]. Compared to controls, cases had increased risk of hypertension [hazard ratio (HR) 1.8; 95% confidence interval (95CI) 1.1-2.9; p = 0.01]. They also had higher rates of ED visits [rate ratio 1.1; 95CI 1.1-1.2; p < 0.001] and increased risk of hospitalization [HR 1.1; 95CI 1.1-1.2; p < 0.001]. Cases were more likely to undergo periodic health checkups [odds ratio (OR) 1.1; 95CI 1.0-1.1; p = 0.01] and influenza vaccinations [OR 1.5; 95CI 1.4-1.6; p < 0.001]. In multivariable analysis restricted to cases, rurality and bereavement, among other predictors, were associated with increased use of acute healthcare. Conclusions: Increased risk of hypertension and hospitalization in cases suggests that these siblings are experiencing poorer physical health compared to their peers. Increased rates of ED visits and preventive healthcare suggests parental anxiety surrounding these siblings’ health. Siblings at highest risk of adverse outcomes could be identified through demographic characteristics, among others. Siblings would benefit from targeted surveillance and further investigation to elucidate underlying mechanisms influencing their health.
Breast cancer patients’ insurance status correlates with their adherence to endocrine therapy: Analysis of ECOG-ACRIN TAILORx trial.
Authors: Sadigh Gelareh , Gray Robert James , Yanez Betina , Wagner Lynne I. , Garcia Sofia F. , Sparano Joseph A. , Cella David , Carlos Ruth 
Published: May 2020

7041 Background: Cancer patients spend substantial amounts on their healthcare services, and are at high risk for financial toxicity, a patient-reported outcome shown to be associated with care non-adherence. Even with insurance, cancer patients often face unpredictable or unmanageable costs. In women with breast cancer enrolled in TAILORx trial, we investigated the association between study entry insurance status and adherence to endocrine therapy (ET). Methods: Women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer enrolled in TAILORx clinical trial who started ET within a year of study entry were included. Early discontinuation was defined as stopping ET within 4 years of start for reasons other than distant recurrence or death, and the rate was calculated using Kaplan-Meier estimates. Cox proportional hazards model was used to analyze association between the patients’ insurance status at study entry and early discontinuation of ET incorporating patients’ treatment, age, race and Recurrence Score in the model. Results: A total of 9,475 patients were included (mean age: 55.6; 84% white; 9% Hispanic). A total of 58.0% had private insurance, while 11.7% had Medicare; 5.8% had Medicaid; 0.98% had military/VA insurance; 3.8% were self-pay, and 19.1% were patient recruited from international sites. The rates of 4-year early discontinuation were highest among self-pay (18.7%) and Medicaid patients (18%) and lowest among patients with military/VA insurance (8.6%) and international sites (9.8%). In multivariable analysis, compared to private insurance patients with Medicaid (HR 1.6; 95% CI 1.3-2.0) and self-pay (HR 1.6; 95% CI 1.3-2.1) had higher probability of discontinuing ET within 4 years of start and those at international sites had lower probability of early discontinuation (HR 0.8; 95% CI 0.7-0.9) (All p values < 0.05). Conclusions: Patients’ insurance status plays an important role in adherence to ET with uninsured and underinsured having a high rate of treatment non-adherence. Early identification of patients at risk and enrollment in insurance optimization programs may improve adherence to therapy. Clinical trial information: NCT00310180 .