tbuckley/cabot-search huggingface dataset:
Definitive cetuximab-based (CRT-CX) vs. non-cetuximab based chemoradiation (CRT) in older patients with squamous cell carcinoma of the head and neck (HNSCC): Analysis of the SEER-Medicare linked database.
Authors: Dan Paul Zandberg, Kevin J. Cullen, Vinod Varki, Ikumi Suzuki, Søren Bentzen, Olga G. Goloubeva
Journal: Journal of Clinical Oncology (2018)

6001 Background: Overall survival (OS) after definitive CRT-CX vs. definitive CRT has not been adequately evaluated outside of younger more highly selected clinical-trial populations with locally advanced HNSCC. Methods: We used the SEER-Medicare linked database to evaluate OS in HNSCC patients diagnosed over 2005-2011, following FDA approval of cetuximab in combination with radiation therapy (RT) in March 2006. Results: 2135 beneficiaries were identified. Median age was 73 (66-104) years. Primary subsites were oropharynx (61%), hypopharynx (15%), nasopharynx (5%), and larynx (19%). CRT-CX was associated with worse OS compared to CRT (P < 0.005), and similar OS to RT (P = 0.21); 5-year OS was 46% for CRT, 35% for CRT-CX, 32% for RT. Median survival was 4.5(3.8-4.9), 2.5(2.2-3.0), and 2.2 (2.0-3.0) years after CRT, CRT-CX, RT, respectively. Patients were more likely to receive CRT-CX vs. CRT if they had oropharyngeal vs nasopharyngeal primary, Charlson comorbidity index 2 vs 0, older age at diagnosis. Multivariable Cox regression showed that CRT-CX was associated with a higher risk of death compared to CRT (HR = 1.23, 1.07- 1.42; p = 0.005), after stratifying by stage and primary site, and adjusting for gender, race, age, income, Charlson comorbidity index, marital status, hospital type, and year of diagnosis. Regarding treatment-related toxicity, CRT was associated with significantly higher hearing loss within the first 3 months compared to CRT-CX (9.3% vs. 4.1%, p < 0.001), but there were no differences in dysphagia, gastrostomy tube placement, pneumonia, and weight loss over the first 12 months after diagnosis. Conclusions: Definitive treatment with CRT-CX was associated with inferior OS compared to CRT even after adjustment for established prognostic factors, and with similar toxicity, in the SEER-Medicare patient population. Survival after CRT-CX was not significantly different from RT alone. Despite the limitations to comparative effectiveness evaluation in population-based registries, our data suggest that non-cetuximab based chemoradiation should be used for eligible older HNSCC patients.
Association of outcomes and co-occuring genomic alterations in patients with <i>KRAS</i>-mutant non-small cell lung cancer.
Authors: Gregory J. Riely, Emmet Jordan, Hyunjae Ryan Kim, Helena Alexandra Yu, Michael F. Berger, David B. Solit, Mark G. Kris, Ai Ni, Maria E. Arcila, Marc Ladanyi
Journal: Journal of Clinical Oncology (2016)

9019 Background: KRAS mutations define the largest subset of oncogene-driven lung cancers (~25%). Patients with KRAS-mutant lung cancers have a heterogeneous clinical course. The pattern of co-occuring mutations in other oncogenes and tumor suppressors has been hypothesized to describe different biological subsets of patients with KRAS-mutant lung adenocarcinoma. We used results of routine, clinical next-generation sequencing to comprehensively describe concurrent genetic alterations present in KRAS-mutant lung cancers and explore the effect of such alterations on patient outcomes. Methods: We identified patients with KRAS mutant lung cancers who underwent routine hybridization capture-based next-generation sequencing clinical assay, sequencing > 340 cancer-related genes, between January 2014 and September 2015. Fisher's exact test was used for association of frequencies and the association of concurrent mutations and overall survival was evaluated using Cox proportional hazard model. Results: Among 239 patients (women 153, men 86) with KRAS-mutant lung cancers, the predominant histology was adenocarcinoma (n = 221, 92%). KRAS mutation subtypes: G12C = 106, G12D = 37, G12V = 37, G12A = 19, G13D = 11, other = 29). 333 different genes were found mutated along with KRAS, median of 7 co-occuring mutations (range 0 – 55) per tumor. The most frequent mutations were found in TP53 (39%), STK11 (30%), KEAP1 (24%), RBM10 (15%), and PTPRD (15%). There was shorter overall survival (OS) in patients with concurrent mutations in STK11 (HR 2, 95%CI 1.2-3.4, p = 0.006) or KEAP1 (HR 2.8, 95%CI 1.7-4.7, p < 0.001). Neither TP53 status (HR 1.25, p = 0.4) nor number of concurrent mutations ( < 7 vs > 7, HR 1.5, p = 0.124) were associated with significant differences in overall survival. Conclusions: This is the largest series of KRAS-mutant lung cancers with a broad analysis of co-occuring molecular alterations and outcomes. Concurrent mutations in either STK11 or KEAP1 are associated with shorter survival, suggesting that information available from routine, clinical next-generation sequencing describes clinically relevant subtypes of KRAS-mutant lung cancer.
Multiplexed analysis of myeloid cell (MC) markers to characterize the innate immune composition and clinical features of human non-small cell lung carcinomas (NSCLC).
Authors: Brian S. Henick, Ila Datar, Franz Villarroel-Espindola, Miguel F. Sanmamed, Jovian Yu, Rasikh Tuktamyshov, Alice Chuan Li, Maria Toki, Konstantinos N. Syrigos, David L. Rimm, Lieping Chen, Roy S. Herbst, Kurt A. Schalper
Journal: Journal of Clinical Oncology (2018)

12002 Background: Despite innate immunity’s prominent role in the anti-tumor response, little is known about the MC composition of human NSCLC. We used multiplexed quantitative immunofluorescence (QIF) to determine MC subtypes’ distribution, functional state and clinical significance in large cohorts. Methods: We established a novel QIF panel to map distinct MC subsets in fixed human NSCLC including DAPI for all cells, pancytokeratin for tumor-epithelial cells, CD11b for all MCs, CD68 for M1-type macrophages and HLA-DR to interrogate maturation state/antigen-presenting potential. We interrogated 834 NSCLC represented in 5 tissue microarray-based cohorts: #1 (Yale, n = 55) with patient-matched NSCLC and morphologically-normal lung tissue; #2 (Yale, n = 379) and #3 (Greece, n = 230) with different/mixed NSCLC subtypes; #4 (Yale, n = 138) with molecularly annotated lung adenocarcinomas (ADC); and #5 (Yale, n = 32) including baseline samples from anti-PD-1-treated patients. We examined associations between marker levels, MC-profiles, clinicopathologic/molecular variables and survival. Results: Stromal CD11b-levels were significantly higher in tumor than in non-tumor lung tissues. HLA-DR was consistently higher in MCs from tumors with elevated CD68 expression, supporting a more mature phenotype. Stromal CD11b was significantly higher in squamous-cell carcinomas (SCC) than ADC across the cohorts. In SCC, increased stromal CD11b or HLA-DR expression was associated with shorter 5-year survival. EGFR-mutated lung ADC had significantly lower CD11b levels than KRAS-mutant ADC. In a limited sample set/preliminary analysis, MC markers did not significantly stratify clinical benefit to PD-1 axis inhibitors (cohort #5). Conclusions: NSCLCs contain more tumor-associated MCs than non-tumor lung and exhibit distinct myeloid compositions across histologies and presence of major oncogenic driver-mutations. ADC lacking EGFR variants and SCC display higher stromal MC content associated with worse outcome. Studies with larger datasets are ongoing to confirm the role of MC markers for prediction of sensitivity/resistance to PD-1 axis blockers.
Intratumoral activity of ONC201 in adult recurrent glioblastoma patients.
Authors: Isabel Arrillaga, Yazmin Odia, Joshua E. Allen, Varun V. Prabhu, Rohinton Tarapore, Wolfgang Oster, Minesh P. Mehta, Patrick Y. Wen, Tracy Batchelor
Journal: Journal of Clinical Oncology (2018)

e14034 Background: ONC201 is an antagonist of the G protein-coupled receptor DRD2 that crosses the blood-brain barrier and induces tumor cell apoptosis in preclinical models. The anti-tumor activity of ONC201 is pronounced in cells with low DRD5 expression and is associated with induction of the ATF4/CHOP/DR5-mediated integrated stress response pathway to trigger apoptosis. We previously reported the single agent activity of ONC201 in 17 adult patients with recurrent glioblastoma that demonstrated the safety, systemic pharmacodynamics, and a durable objective response when administered orally once every 3 weeks. Here, we evaluated the intratumoral drug concentrations and pharmacodynamic activity of ONC201 in adult recurrent glioblastoma patients who were treated on a weekly schedule. Methods: Six patients ≥18 years old with first recurrence of glioblastoma who were eligible for salvage surgical resection were enrolled. ONC201 was administered orally as 625 mg once a week. Salvage surgery was performed approximately 24 hours after the second dose of ONC201 and patients continued on ONC201 until radiographic and/or clinical progression. Tumor tissue was flash-frozen and formalin-fixed for assessments of intratumoral drug concentrations and pharmacodynamics, respectively. Results: Of the 6 enrolled patients, 5 had sufficient tissue for evaluation. Intratumoral drug concentrations exceeded therapeutic thresholds: median 1.5 µM (range 600 nM – 9.3 µM). Investigation of biomarkers related to downstream signaling induced by ONC201 revealed heterogeneous intratumoral induction of ATF4, CHOP, and DR5 expression along with tumor cell apoptosis (TUNEL). Stronger induction of the pharmacodynamic signaling biomarkers was associated with stronger induction of apoptosis and inversely associated with DRD5 expression, but not with drug concentration. No drug-related adverse events were reported in this cohort. Conclusions: ONC201 achieves intratumoral concentrations in recurrent glioblastoma patients that are well tolerated and result in pharmacodynamic signaling and tumor cell apoptosis.
Immunological microenvironment in the clinical outcome of head and neck squamous cell carcinoma.
Authors: Georgy M. Manikhas, Svetlana I. Kutukova, Natalia P. Belyak, Andrey I. Yaremenko, Gregory Raskin, Tatiana S. Ermakova, Svetlana S. Bozhor, Natalia V. Popova, Julia V. Ivaskova
Journal: Journal of Clinical Oncology (2016)

e17530 Background: The purpose of our study was to investigate some correlation between tumor and microenvironment infiltration by CD8(+) T-cells, eosinophils, neutrophils, p16 expression, on the one hand, and clinical parameters, treatment options and OS, PFS for patients with HNSCC, on the other hand. Methods: In the prospective study medical records and tumor samples of 60 patients with HNSCC with stage I - IVB (37 men, 23 women; median age 59) were analyzed. All patients were under standard clinical complex protocol. All patients were under our supervision from 2010 to 2015. Demographic data, clinical stage, tumor morphological characteristics and specific level of expression of CD8(+) T-cells, eosinophils and neutrophils in the tumor and microenvironment, eapression p16 in the tumor were examined. Results: Rate of neutrophils in tumor and microenvironment varied from 0 to 1000 cells in mm2 (average rate 266,1±67,9 cells, 95% CI from 23,23 to 308,89; p = 0,03). Rate of eosinophils varied from 0 to 872 cells in mm2 (average rate 12,88±4,4 cells, 95% CI from 3,5 to 22,23; p = 0.01). Expression of CD8(+) T-cells varied from 190 to 1380 cells in mm2(average rate 551,28±80,74 cells, 95% CI from 380,93 to 721,62; p < 0.0001). Neutrophils rate had inversely correlation with cornification (r = -0.63, 95% CI from -0,87 to -0,18, p = 0,0114). Expression of CD8(+) T-cells had inversely correlation with tumor size (T) (r = -0.53, 95% CI from -0,8 to -0,09, p = 0,0227), stage (r = -0.48, 95% CI from -0,77 to -0,01, p = 0,0461) and direct correlation with cornification (r = -0.54, 95% CI from 0,03 to 0,83, p = 0,0391). Expression of p16 was detected only in 10 samples (16,6%). Conclusions: Definition of intratumoral expression of CD8(+) T-cells and infiltration of eosinophils and neutrophils could be informative prognostic factors for patient with HNSCC.
Abstract 15299: TWIK-Related Acid-Sensitive K+ Channels Affect the Development of Aortic Root Aneurysms in Mice
Authors: Rachel D Torok, Dennis M Abraham, Clarice Gareri, Lan Mao, Howard A Rockman
Journal: Circulation (2016)

Introduction: Aortic aneurysms are a significant cause of morbidity and mortality, yet the genetics underlying aortic aneurysm formation remain poorly understood. TWIK-related acid-sensitive K+ (TA...
Abstract 18472: Enhancing the Therapeutic Potential of Induced Pluripotent Stem Cell Derived Cardiomyocytes Through Targeting the Hippo Signalling Pathway
Authors: Abigail C Robertson, Tamer Mohammed, Min Zi, Sukhpal Prehar, Nicholas Stafford, Elizabeth J Cartwright, Delvac Oceandy
Journal: Circulation (2016)

Cell based therapy using stem cell derived cardiomyocytes, has emerged as a potential therapeutic approach for cardiac diseases such as myocardial infarction and heart failure. Induced pluripotent stem cells (iPSC) could be an ideal source of cardiomyocytes (iPS-CM). However, challenges facing this approach include the high number of viable cells needed to survive in pathological conditions. The Hippo signalling pathway is a key pathway involved in regulating cardiomyocyte proliferation and survival in both embryonic and adult hearts. In this study, we target the Hippo pathway to enhance the therapeutic potential of iPS-CM.Skin fibroblasts were reprogrammed to iPSC and then differentiated to cardiomyocytes. The Hippo pathway was modified by genetic ablation of Mst1, a major upstream regulator of the Hippo pathway, or by overexpressing YAP, the main downstream effector of the pathway. We found that genetic ablation of Mst1 leads to significantly increased reprogramming efficiency by 43.8±2.4%. iPSC lacking...
Clinical characterization of long term survivors (LTS) in ovarian cancer (OC): Results of a propensity score matched (PSM) analysis of the international prospective tumor bank for ovarian cancer (TOC Network).
Authors: Elena Ioana Braicu, Hannah Woopen, Joanna Glajzer, Oliver Hunsicker, Linn Woelber, Aarne Feldheiser, Els van Nieuwenhuysen, Michael D Mueller, Nicole Concin, Patrick Achimas, Ilary Ruscito, Sven Mahner, Pierluigi Benedetti Panici, Maria Luisa Gasparri, Andrea Papadia, Michael J. Birrer, Ignace Vergote, Silvia Darb-Esfahani, Jalid Sehouli
Journal: Journal of Clinical Oncology (2017)

e17063 Background: OC has the highest mortality rate amongst gynecological malignancies. Nevertheless a small fraction of OC patients will survive longer than 8 years. Aim of our study was to analyze differences in the clinical appearance and management of LTS versus “classical” OC patients. Methods: OC patients living longer than 8 years were identified within the TOC Network between 1998 and 2008, representing the LTS subgroup. PSM analysis was used to select comparable groups of LTS and OC patients who died within first 5 years (control group - CG). PSM was conducted using nearest neighbor caliper matching without replacement to match LTS and CG for age, FIGO and residual tumor mass. All calculations were performed with the R project for Statistical Computing (R-packages used: “MatchIt”). Results: A total of 347 OC patients with different histological subtypes were included in the current analysis, i.e. 173 LTS and 174 in the CG. After PSM 114 patients remained in each group. Patients had similar age, FIGO stage and residual mass (p = 0.99, p = 0.35 and p = 0.88, respectively). Tumor spread in middle and upper abdomen (p = 0.002 and 0.013, respectively) was higher and diaphragm, mesentery and peritoneum (p = 0.009, 0.037 and 0.002, respectively) were significantly more often involved in CG than in the LTS. When only considering the HGSOC patients, 95 patients remained in each group. All patients received surgery and platinum based chemotherapy. The PSM analysis showed significant higher involvement of upper abdomen (p = 0.028), higher peritoneal spread (p = 0.002), higher ascites volume (p = 0.0007) and higher bowel resection rates (p = 0.002) in the CG compared to LTS. Neoadjuvant chemotherapy rate was similar in the LTS and CG (p = 0.5). Conclusions: Based on this PSM analysis, HGSOC-LTS seem to have mainly similar clinical pattern as the control group, however with lower rates of ascites and involvement of upper abdomen. Molecular characterization including analysis of clonal diversity might help elucidate mechanisms of tumor spread and good prognosis.
Impact of different MET alterations on the efficacy of crizotinib in non-small-cell lung cancer.
Authors: An Na Li, Jin-Ji Yang, Xuchao Zhang, Yi-Long Wu
Journal: Journal of Clinical Oncology (2016)

e20622 Background: We reported MET overexpression could be as a biomarker for de novo MET activated non-small cell lung cancer (NSCLC) last year, and the rs13223756 SNP variation (-648A > G) might be a candidate for primary resistance. The relationship between the efficacy of MET-TKIs and MET status, such as amplification and overexpression, has not been well established. Methods: Advanced NSCLC patients with de novo MET expression were detected by immunohistochemistry (IHC) and Sanger sequence for SNP . H-score ≥ 60 were defined as c-Met positive. Gene copy numbers were detected by FISH ( By Cappuzzo scoring system & MET/CEP7 ratio). ≥ 5 copies were positive or MET/CEP7 ratio ≥ 1.8 was defined as MET amplification with low ≥ 1.8- ≤ 2.2, Intermediate > 2.2- < 5 and High ≥ 5.The statuses of EGFR, ALK, KRAS and ROS1 were also tested. Results: From January 2013 to December 2015, 32 eligible patients with MET IHC overexpression received crizotinib treatment (4 females, median age 59 years), with 25 evaluable for response. EGFR, ALK, KRAS and ROS1 were negative for all patients. Sixteen of them (64%,16/25) achieved partial response (PR), 1(4%,1/25) was stable disease (SD) and 8(32%,8/25) were progressive disease (PD). All responders had high c-Met IHC status. Ten of 13 (77%) FISH–positive patients had PR. Exon 14 splicing mutation was observed in 2 patients (1 with PR and 1 with PD). The significant difference occurred in the ORR (objective response rate) between FISH-positive and FISH-negative (83.3% vs. 30% respectively; P = 0.032).The incidence of SNP was not different in patients with AG or GG when compared with those with AA genotype (47.8%. vs. 52.2% respectively; P= 0.4), and there was no significant difference in ORR (70%vs. 33.3% respectively; P = 0.27). Adverse events of grade 3 QT prolongation have been found in 1 patient. For one death with interstitial lung disease, causality to crizotinib was not ruled out. The other common drug-related AEs were grade1/2. Conclusions: MET amplification could be a remarkable biomarker for de novo MET overexpressed NSCLC. The combination of IHC and FISH predicted the efficacy of crizotinib more precisely. The SNP Q648 variant in the MET gene is not a significant predictor for primary resistance.
Treg Destabilization and Reprogramming: Implications for Cancer Immunotherapy
Authors: David H. Munn, Madhav D. Sharma, Theodore S. Johnson
Journal: Cancer Research (2018)

Regulatory T cells (Tregs) are an important contributor to the immunosuppressive tumor microenvironment. To date, however, they have been difficult to target for therapy. One emerging new aspect of Treg biology is their apparent functional instability in the face of certain acute proinflammatory signals such as IL6 and IFNγ. Under the right conditions, these signals can cause a rapid loss of suppressor activity and reprogramming of the Tregs into a proinflammatory phenotype. In this review, we propose the hypothesis that this phenotypic modulation does not reflect infidelity to the Treg lineage, but rather represents a natural, physiologic response of Tregs during beneficial inflammation. In tumors, however, this inflammation-induced Treg destabilization is actively opposed by dominant stabilizing factors such as indoleamine 2,3-dioxygenase and the PTEN phosphatase pathway in Tregs. Under such conditions, tumor-associated Tregs remain highly suppressive and inhibit cross-presentation of tumor antigens released by dying tumor cells. Interrupting these Treg stabilizing pathways can render tumor-associated Tregs sensitive to rapid destabilization during immunotherapy, or during the wave of cell death following chemotherapy or radiation, thus enhancing antitumor immune responses. Understanding the emerging pathways of Treg stabilization and destabilization may reveal new molecular targets for therapy. Cancer Res; 78(18); 5191-9. ©2018 AACR.
The functional MDM4 genetic variant is associated with clinical outcome of lung adenocarcinoma patients with gefitinib treatment
Authors: N. Zhang, M. Yang, L. Zhang, J. Liu, H. Xing
Journal: Annals of Oncology (2018)

Background: As a mostly used epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), gefitinib significantly prolongs survival of lung adenocarcinoma patients with EGFR mutations. However, more than 10% of EGFR mutation-positive patients do not respond and a substantial fraction of responded patients progress after 8-12 months' treatment. Identification of new biomarkers for EGFR-TKIs prognosis is vital. The objective of this study is to explore associations between MDM4 genetic variant and survival of lung adenocarcinoma patients treated with gefitinib. Methods: 384 patients with stage IIIB or IV lung adenocarcinoma were recruited between January 2009 and June 2013. Patients were treated with gefitinib orally at a daily dose of 250 mg as 1st-line monotherapy. MDM4 rs4245739 A>C genotypes were determined using MassArray system. Dual luciferase reporter gene assays evaluated the function of MDM4 rs4245739 genetic variant in lung adenocarcinoma cell lines A549 and H1299. The differences of patient clinical characteristics were calculated by student's t test or χ2 test. Survival differences were examined by log-rank test. Multivariate Cox regression analysis assessed prognostic factors for PFS or OS. Two-sided P < 0.05 indicated a significant difference. Results: Among 384 patients, EGFR mutations were positive in 181 patients (47.1%). Median progression-free survival (PFS) and overall survival (OS) for all patients with the rs4245739AC genotype were significantly longer than that of the AA carriers (PFS: 22.9vs.10.9 months, P < 0.001; OS: 27.3vs.16.5 months, P = 0.003). Notably, in the EGFR mutant subgroup, individuals with MDM4 rs4245739AC genotype showed 14.1 months prolonged PFS (28.8 months vs. 14.7 months; P = 0.022) and 12.2 months prolonged OS (31.4 months vs. 19.2 months; P = 0.047) compared to the AA group. Reporter gene assays showed that the rs4245739A allele leads to significantly increased MDM4 expression in lung adenocarcinoma cells compared to the C allele (P < 0.05). Conclusions: MDM4 rs4245739 genotypes may act as prognostic biomarker for patients' survival to gefitinib therapy and offer help to individualized treatment in lung adenocarcinoma patients with EGFR mutations. Legal entity responsible for the study: Nasha Zhang. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.