tbuckley/cabot-search huggingface dataset:
Molecular panel sequencing of pre-treatment samples to reveal mechanisms of innate resistance to 3rd generation EGFR TKI treatment in T790M-positive NSCLC patients.
Authors: Sebastian Yves Friedrich Michels, Carina Heydt, Barbara Deschler-Baier, Vanessa Ruesseler, Jan Stratmann, Susanne Steinhauser, Rieke Nila Fischer, Matthias Scheffler, Jana Fassunke, Lucia Nogova, Vanessa Brandes, Anna Kostenko, Frank Griesinger, Oliver Gautschi, Martin Sebastian, Martin Hellmich, Lukas C. Heukamp, Sabine Merkelbach-Bruse, Reinhard Buettner, Juergen Wolf
Journal: Journal of Clinical Oncology (2017)

9041 Background: Resistance to early generation epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKI) inevitably develops in EGFR-mutant lung cancer. The secondary EGFR p.T790M mutation is the driving factor in 60% of cases and 3rd generation EGFR TKIs have been developed to overcome T790M-mediated resistance. However, besides T790M other genetic aberrations such as amplifications of MET may contribute to resistance to EGFR inhibition in the same patient. We here report on the systematic analysis of co-occurring genetic aberrations that may influence response to 3rd generation EGFR TKIs. Methods: Thirty-six patients were treated with 3rd generation EGFR TKIs in the setting of acquired resistance to EGFR inhibition in cancer centers in Germany and Switzerland. Pre-treatment samples were analyzed for co-occurring genetic aberrations in a subset of resistance-related genes including MET, HER2, RAS-gene family, PIK3CA, CTNNB1 and PTEN using next-generation sequencing and fluorescence in-situ hybridization assays. We investigated the association between clinical, epidemiological and molecular data and response to treatment (RECIST 1.1). Results: Co-occurring genetic aberrations were found in 68% of the pre-treatment samples where both, analyses by sequencing and FISH were feasible (N = 25). Efficacy of 3rd generation EGFR TKIs significantly dropped in the presence of high-level MET amplification as compared to wild-type MET (ORR, 0.0%; 95% CI, 0.0-60.4 vs. 70.0%; 95% CI, 45.7-87.2; p = 0.02; median PFS, 1.0 month; 95% CI, 0.37-1.72 months vs. 8.2 months; 95% CI, 1.69-14.77 months; p ≤ 0.001). No statistically significant association was found between treatment efficacy and the molecular status of the genes analyzed or the number of prior EGFR TKIs. Conclusions: Prevalence of additional genetic aberrations is frequent in the setting of acquired resistance to early generation EGFR TKIs and may not necessarily mediate resistance to 3rd generation EGFR TKIs. However, in our analysis high-level amplification of MET was associated with primary treatment failure and might be the main factor underlying resistance in this setting.
<i>RGS4</i> deficit in prefrontal cortex contributes to the behaviors related to schizophrenia via system x<sub>c</sub><sup>-</sup>-mediated glutamatergic dysfunction in mice
Authors: Min-Wei Huang, Yu-Jung Lin, Chi-Wei Chang, Fu-Ju Lei, En-Peng Ho, Ren-Shyan Liu, Woei-Cherng Shyu, Chia-Hung Hsieh
Journal: Theranostics (2018)

Rationale: Although molecular investigations of regulator of G-protein signaling 4 (RGS4) alterations in schizophrenia patients yielded partially inconsistent findings, the previous studies suggested that RGS4 is both a positional and functional candidate gene for schizophrenia and is significantly decreased in the prefrontal cortex. However, the exact role of RGS4 in the pathophysiology of schizophrenia is unclear. Moreover, a whole genome transcription profile study showed the possibility of RGS4-regulated expression of SLC7A11(xCT), a component of cysteine/glutamate transporter or system xc-. We hypothesized that system xc- is a therapeutic target of RGS4 deficit-mediated schizophrenia. Methods: Pharmacological and genetic manipulation of RGS4 in organotypic brain slice cultures were used as an ex vivo model to investigate its role in system xc- and glutamatergic function. Lentiviral-based mouse models with RGS4 deficit in the prefrontal cortex and treatment with system xc- activator, N-acetyl cysteine (NAC), were utilized to observe their impacts on glutamatergic function and schizophrenic behaviors. Results: Genetic and pharmacological inhibition of RGS4 resulted in a significant decrease in SLC7A11 (xCT) expression and hypofunction of system xc- and reduced glutamatergic function in organotypic brain slice cultures. However, NAC restored the dysregulation of RGS4-mediated functional deficits of glutamate. Moreover, knockdown of RGS4 specifically in the prefrontal cortex caused mice to exhibit behaviors related to schizophrenia such as increased stereotypy, impaired prepulse inhibition, deficits in social interactions, working memory, and nesting behavior, while enhancing sensitivity to the locomotor stimulatory effect of MK-801. These mice displayed glutamatergic dysfunction in the prefrontal cortex, which may have contributed to the behavioral deficits. RGS4 knockdown mice that received NAC treatment had improved glutamatergic dysfunction and schizophrenia behaviors. Conclusion: Our results suggest that RGS4 deficit induces dysregulation and dysfunction of system xc-, which further results in functional deficits of the glutamatergic system and subsequently to schizophrenia-related behavioral phenotypes. Activation of system xc- offers a promising strategy to treat RGS4 deficit-mediated schizophrenia.
ADAM9 to enhance CDCP1 protein expression by suppressing miR-218 for lung tumor metastasis.
Authors: Kuo-Liang Chiu, Ting-Ting Kuo, Qian-Yu Kuok, Liang-Chuan Lai, Yuh-Pyng Sher
Journal: Journal of Clinical Oncology (2016)

e23002 Background: A majority of lung cancer patients are diagnosed at late stage due to early metastasis. We conducted studies to demonstrate MicroRNA(miR)-218 is associated with overexpression of ADAM9, CDCP1, and hence could play a role of lung cancer metastasis. Materials and Methods: We used lung cancer cells with suppression and overexpression of miR-218, and measured ADAM9, and CDCP1 expression with the correlation of lung cancer cell migration and survival. Mutation of 3'-UTR of CDCP1 mRNA was performed to test the binding point of miR-218. Transfection of cancer cells in mice was also used to demonstrate in vitro effects. Results: Several lung cancer cell lines showed decreased expression of miR-218, and overexpression in ADAM9 and CDCP1. Suppression of miR-218 was associated with overexpression of ADAM9 and CDCP1, hence, increased cancer cell migration. Overexpression of miR-218, in contrast, suppressed expression of ADAM9 and CDCP1, hence, decreasing not only migration, but also anoikis resistance of cancer cells. Suppression of CDCP1 by miR-218 was inhibited after mutation of 3'-UTR of CDCP1 mRNA. Overexpression of miR-218 reduced tumor growth in mice. Conclusions: Suppression of miR-218 in lung cancer cells is associated with increased cell migration due to overexpiression of ADAM9 and CDCP1. Restoration of miR-218 inhibits tumor cell mobility, anchorage-free survival and tumor sphere formation, moreover, reduces tumor growth in mice.
Temporal trend in the use of surgery in the management of stage IIIa non-small cell lung cancer (NSCLC) between 2000-2013: A SEER analysis.
Authors: Veena Iyer, Hosam Hakim, Arindam Bagchi, Qiang Nai, Danae Hamouda, William Barnett, Roland T. Skeel
Journal: Journal of Clinical Oncology (2017)

8524 Background: The optimal treatment of patients with Stage IIIA NSCLC, a heterogeneous group comprised of T1-T4, N0-N2 disease, is controversial. Lack of clear data and guidelines allows several options for treatment, and hence there has been significant variability in clinical practice. The purpose of this study was to evaluate the nationwide trends in rates of surgery for Stage IIIA lung cancer diagnosed between 2000-2013. Methods: The study included patients with Stage IIIA NSCLC, 18 years and older diagnosed between 2000 and 2013. We used Z-tests in SEER*Stat to compare relative survival rates for patients diagnosed between 2000-2010. Results: Among the 27,697 patients with Stage IIIA NSCLC, 45% were females and median age was 67. 35% were treated with surgery. Multivariate analysis demonstrated that year of diagnosis, race, marital status, geographic region, tumor size, tumor grade, nodal status all were significantly associated with the use of surgery. Relative survival at 24 months (RS 24 ) was 62% for patients who had surgery and 29% for patients without surgery (z = -47.3). The proportion of patients receiving surgery decreased from 55.6% in 2000 to 32.6% in 2010 and 29.7 in 2013 (p &lt; 0.0001) while the relative survival at 24 months (RS 24) from 2000 to 2010 rose from 34.7% to 43.2% (z = -4.89). The RS 24 for patients who received surgery rose from 55.3% in 2000 to 77.6 % in 2010 (z = -3.58). Change in RS 24 for patients who did not have surgery also improved from 19.6% to 31.2%. The median RS of the surgical cohort changed from 28 m to 44 m. Conclusions: Based upon reporting within the SEER database, the proportion of stage IIIA NSCLC patients undergoing surgery has decreased over the study time period. However, the relative survival rates have improved significantly for both the overall group and those having surgery, suggesting that significant strides have been made both in selecting the group of patients who would benefit from surgical resection and in the overall management of this group of patients.
Thirty-day mortality following interventional line or drain placement among hospitalized cancer patients.
Authors: Kerry L. Kilbridge, Brett Glotzbecker, Sherri Oliver Stuver, Cecilia H. Rosenbaum, Susan Kiernan O'Horo, Angela Day, Joseph O. Jacobson
Journal: Journal of Clinical Oncology (2017)

e18222 Background: Percutaneous lines and drains provide a less invasive alternative to operative procedures for patients with cancer. We categorized outcomes for placements among solid tumor patients hospitalized on the medical oncology services of a tertiary care academic center. Methods: Consecutive cases (n=71, Mar-Sept 2016) were identified by electronic medical record orders for non-vascular lines and drains placed in solid tumor patients hospitalized on medical oncology services and confirmed by retrospective chart review. Percutaneous nephrostomy tubes, pleurx catheters (abdominal and thoracic), gastrojejunostomy/gastric tubes, biliary drains, and wound/abscess drains were included. Retrospective chart review was used to categorize 30-day outcomes including those deemed related or possibly related to the placement that resulted in a phone call, office visit, ED evaluation, or hospital readmission. Results: Mean age at placement was 62 years and 53% of patients were female. All patients had metastatic tumor. The majority of patients had an Eastern Cooperative Oncology Group Performance Status of 3-4 (63.4%). Patients with gastrointestinal, gynecological and genitourinary malignancies required more procedures than all other tumor types combined. The 30-day mortality rate following line and drain placement was 32.4%. Of these deaths, 43.5% occurred prior to discharge and 30.4% occurred within two weeks. 40.8% of patients required ED evaluation or hospital readmission and 29.6% of patients required an office visit or phone call within 30 days. Conclusions: Although percutaneous interventions are generally safe and minimally invasive, there is a high 30-day mortality rate associated with line and drain placement among hospitalized patients with advanced cancer. Among patients who expired, over forty percent of deaths occurred during the index hospitalization, suggesting placements are occurring at the end of life, may potentially reflect overuse and may represent a missed opportunity to address goals of care. [Table: see text]
Circulating tumor cells (CTCs) N-terminal androgen receptor expression to identify patients (pts) with castrate resistant prostate cancer (CRPC) who are more sensitive to chemotherapy.
Authors: Susan F. Slovin, Karen E. Knudsen, Susan Halabi, Emily Carbone, Celina Fernandez, Yu Chen, Karen A. Autio, Dana E. Rathkopf, Lewis J. Kampel, Michael J. Morris, Gabrielle Arauz, Ryon P Graf, James Kelvin, Ryan Vance Dittamore, Renee De Leeuw, Amanda Sullivan, Kin Tse, Ana M. Molina, Howard I. Scher, William Kevin Kelly
Journal: Journal of Clinical Oncology (2017)

5034 Background: Loss of the retinoblastoma tumor suppressor (RB) function was identified as a major means to develop CRPC; the expression of the androgen receptor (AR) is under stringent RB control; and tumors devoid of RB function are hypersensitive to treatment with chemotherapy. Exploratory analysis evaluated baseline N-terminal AR expression in CTCs in men with chemotherapy-naïve CPRC and correlated to changes in PSA, leading us to inquire if this biomarker may identify pts sensitive to chemotherapy. Methods: In a multicenter phase II randomized trial of approved doses of abiraterone acetate/prednisone (AA-Arm 1) or combination AA and standard doses of cabazitaxel (AA/CBZ-Arm 2). Patients on AA received CBZ upon progression. Baseline CTCs were obtained on all pts and expression of N-terminal AR expression was performed by Epic Sciences. Positive AR N-terminal expression (AR + ) was based on the presence of at least 1 CTC or CK - cell with AR N-terminal signal expression above the 3.0 positivity threshold. Serial PSAs were determined at baseline and every 3 weeks with routine labs and imaging every 12 weeks. Results: To date, 42 of 80 pts have been enrolled: 22 pts to AA, and 20 pts to AA/CBZ. Both regimens were well tolerated with 8/42 (19%) pts experiencing treatment-related grade 3 or 4 toxicities. Blood from 35 patients underwent CTC analysis. Seventy-seven percent of pts (27/35) had detectable CTCs; 11 of 35 pts (31%) had AR overexpression. Of the pts with AR+ CTCs, 1/5 pts treated with AA, and 5/6 pts treated with AA/CBZ had a PSA decline &gt; 50% from baseline. Conclusions: Real-time CTC analysis of N-terminal AR expression was feasible and data suggests that this may identify a cohort of pts who may benefit from the combination of CBZ with AA. Further studies are ongoing to evaluate whether cellular heterogeneity and RB expression in CTCs play a role in identifying pts who would benefit from chemotherapy. The trial is coordinated by the Prostate Cancer Clinical Trials Consortium, LLC and funded by Sanofi US Services Inc. and Prostate Cancer Foundation. Clinical trial information: NCT02218606.
A phase 3 study of androgen annihilation in high-risk biochemically relapsed prostate cancer: An Alliance Foundation trial (AFT-19).
Authors: Rahul Raj Aggarwal, Scott E. Eggener, Ronald C. Chen, Glenn Heller, Akash Patnaik, Han Xiao, Douglas Weckstein, James Mohler, Mark Watson, Mary-Ellen Taplin, Linda A. Skoog-Sluman, Meryl Pereji, Eunice Aikins-Afful, J Kellogg Parsons, Charles J. Ryan, Michael J. Morris
Journal: Journal of Clinical Oncology (2018)

TPS5090 Background: Men with biochemically relapsed prostate cancer (BRPC) following prior radical prostatectomy (RP) and a short PSA doubling time (PSADT) are at high risk for the development of metastatic disease and prostate cancer-related mortality. Intermittent androgen deprivation therapy (ADT) is a commonly applied treatment in this disease setting, but fails to achieve prolonged progression-free and treatment-free intervals for the majority of patients (pts). Apalutamide is a next generation androgen receptor (AR) antagonist that has efficacy in non-metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate, a prodrug of the CYP17 androgen synthesis inhibitor abiraterone, has been shown to prolong survival in both CRPC and metastatic hormone-sensitive prostate cancer. We hypothesize that the addition of apalutamide with or without abiraterone acetate/prednisone, as compared to ADT alone, will prolong disease suppression and potentially eradicate micrometastatic disease with a finite duration of treatment in pts with BRPC. Methods: AFT-19 is a randomized, open-label, three arm phase 3 study (first patient enrolled March 2017) of a) degarelix monotherapy compared to each of two experimental arms: b) degarelix plus apalutamide, and c) degarelix plus apalutamide plus abiraterone acetate/prednisone, in pts with BRPC following prior RP without metastases on conventional imaging, and a PSADT of ≤ 9 months. Pts are treated for up to 52 weeks in the absence of progression or unacceptable toxicity, and subsequently followed off treatment until PSA progression, defined as serum PSA > 0.2 ng/mL. The primary endpoint is PSA progression-free survival (PFS). Secondary endpoints are 36-month PSA PFS rate, metastasis-free survival, time to CRPC, overall survival, and quality of life. Planned accrual is 504 pts, estimated to provide 85% power to detect a hazard ratio of 0.63 in the comparison of PSA PFS between each experimental arm versus the control arm, with an overall two-sided type I error rate of 0.025 for each comparison. The DSMB last reviewed the trial in November 2017 and recommended that the trial continue as planned. Clinical trial information: NCT03009981.
First-in-human phase I trial of BI 836880, a vascular endothelial growth factor (VEGF)/angiopoietin-2 (Ang-2)-blocking nanobody, given every 3 weeks (q3w) in patients (pts) with advanced/metastatic solid tumors.
Authors: Christophe Le Tourneau, Rainer Claus, Francesco Ricci, Björn Hackanson, Christoph Rummelt, Oliver Fietz, Thomas Arnhold, Dooti Roy, Zohra Oum'Hamed, Ralph M Fritsch
Journal: Journal of Clinical Oncology (2018)

12024 Background: VEGF and Ang-2 inhibitors have demonstrated clinical activity in various tumor types. Given the overlap of the VEGF/VEGFR2 and Ang-2/Tie-2 signaling pathways there is a rationale for dual inhibition. BI 836880 is a humanized bispecific nanobody (engineered antibody fragment of variable antibody domains) that inhibits VEGF and Ang2 and has demonstrated preclinical activity in cancer models. Methods: Pts with solid tumors refractory after standard therapies/for whom no established treatment options were available received BI 836880 q3w (IV; starting dose 40 mg). Dose escalation followed a Bayesian logistic regression model with overdose control. The maximum-tolerated dose (MTD; primary endpoint) was evaluated based on dose-limiting toxicities (DLTs) in the first 21-day cycle. Treatment-related AEs (TRAEs) leading to dose reduction/discontinuation, exposure/disposition kinetic measures (both secondary endpoints) and best overall response were also assessed. Results: 29 pts were treated: median age 57 yrs (range 28–79); 62% female. The MTD was determined as BI 836880 720 mg q3w (Table). All pts had at least 1 AE, most commonly (all grade/grade ≥3): hypertension 86%/34%, asthenia 48%/10%, nausea 45%/3% and vomiting 38%/3%. 23 (79%) pts had TRAEs; none led to dose reduction. One patient had a TRAE leading to discontinuation (pulmonary embolism DLT at 1000 mg). Two (7%) pts (nasopharyngeal [n = 1] and breast [n = 1] carcinoma) had a partial response and 9 (31%) pts had stable disease. PK/PD analysis of 14 evaluable pts showed dose-proportional plasma kinetics of BI 836880, complete peripheral target inhibition at doses ≥360 mg q3w and predicted required trough values at doses ≥720 mg q3w. Clinical trial information: NCT02674152. Conclusions: The MTD/recommended phase 2 dose of BI 836880 was determined as 720 mg q3w based on safety and PK/PD analyses. Early signs of antitumor activity were observed. Dose, mg Pts, n Pts with DLT, n 40 3 0 120 2 0 360 2 0 720 17* 0 1000 5 1: G3 pulmonary embolism *No DLT in first 2 pts; expanded to 7 after DLT at 1000 mg; 10 more patients enrolled after MTD determined at 720 mg.
A phase II study of irinotecan as single agent in the third-line treatment of unresectable or metastatic gastric cancer.
Authors: Zhe Zhang, Zhiyu Chen, Xiaodong Zhu, Xiaowei Zhang, Xiaoying Zhao, Wen Zhang, Lixin Qiu, Mingzhu Huang, Chenchen Wang, Weijian Guo
Journal: Journal of Clinical Oncology (2018)

e16084 Background: There is no relative standard chemotherapeutic regimen in the third line therapy except oral anti-angiogenesis drug-Apatinib. This study was designed to determine the efficacy and toxicity of irinotecan as a third-line therapy for patients with unresectable or metastatic gastric cancer who have undergone initial platinum combined with fluoropyrimidines and second-line taxanes regimens. Methods: We analyzed 44 patients who had been histologically diagnosed with adenocarcinoma of the stomach and who had progressed after initial platinum combined with fluoropyrimidines and second line taxanes regimens. Patients were treated with cycles of 180 mg/m(2) irinotecan on day 1 every 2 weeks. Results: From April 2015 to May 2018, 44 patients were enrolled in this trial and 29 patients were evaluated in terms of tumor response: 1 (3.6%), 11 (35.7%), and 17 (60.7%) patients experienced a partial response, stable disease, and progressive disease, respectively. The median time to progression was 3.1 months (95% confidence interval [CI], 1.72 to 4.48), and overall survival was 5.8 months (95% CI, 2.68 to 8.92), from the start of the irinotecan regimen. Conclusions: Irinotecan is a feasible third-line therapy regimen for patients with advanced gastric cancer after first line platinum combined with fluoropyrimidines and second line taxanes regimens Clinical trial information: NCT02662959.
High frequency mismatch repair (MMR) pathway mutations in adrenocortical carcinoma: Indication for routine MMR-deficiency (MMR-D) testing.
Authors: Omobolaji Oyekunle Akala, Virginia Kelly, Vivian E. Strong, Anuradha Gopalan, Diane Lauren Reidy, Nitya Prabhakar Raj
Journal: Journal of Clinical Oncology (2018)

e16195 Background: Adrenocortical carcinomas (ACC) are rare cancers with overall poor prognosis and limited treatment options. We sought to use molecular profiling to predict tumor biology and define possible targeted treatment options. Methods: Next generation sequencing (NGS) was performed using MSK-IMPACT, a matched tumor-normal sequencing platform that interrogates 468 cancer-related genes. Immunohistochemistry (IHC) staining for MSH2, MSH6, PMS2, and MLH1 was performed on FFPE tissue. Microsatellite instability (MSI) testing was performed from tumor specimen and normal, comparing the pattern of 5 standard microsatellite markers via PCR. MSIsensor score was determined by MSIsensor program that interrogates the length distribution of all genomic microsatellite loci across tumor and matched normal. Results: Since 2014, NGS was performed in tumor samples from 54 patients (41% metastatic, 59% primary). The most commonly altered genes were TP53 (30.4%), CTNNB1 (25%), CDKN2A deletion (16%), APC (12.5%), NF1 (12.5%), ATRX (12.5%), TERT amplification 12.5%, TERT (10.7%). Mutations in MMR pathway genes were found in 8/54 patients (15%) and did not overlap. The somatic mutation rate was: PMS2 (1.8%), MSH6 (1.8%), MSH2 (5.4%), and MSH3 (1.8%). The germline mutation rate was: MSH2 (1.8%), MSH6 (1.8%), both of which were confirmed by IHC. One patient with a somatic MSH2 mutation was confirmed MSI-high by MSIsensor and microsatellite PCR. A second patient with a somatic MSH6 mutation had an indeterminate MSIsensor but confirmed MSH6 loss by IHC. Two patients with MSH2 somatic mutations had indeterminate MSIsensor scores (IHC not available). Conclusions: We found a combined frequency of 15% mutations in MMR pathway genes in ACC (11% somatic, 4% germline). This data argues for routine determination of MMR-D status in all ACC patients that present for disease management. Our institution is conducting an ongoing phase II study with pembrolizumab in advanced ACC testing the efficacy of immune checkpoint inhibitors.