tbuckley/cabot-search huggingface dataset:
EGFR mutations in tumor tissue and blood collected from lung cancer patients by Insight Onco NGS technique.
Authors: Jin-Hyoung Kang, Jung-Young Shin, Jeong-Oh Kim, Min Young Kim, Kyoung Hwa Son, Hwn Woo Lee, DoWon Kim
Journal: Journal of Clinical Oncology (2016)

e20017 Background: Activating or resistant somatic mutations (19 Del, L858R, T790M) occurring in the specific sites of EGFR gene are the powerful predictive biomarker for EGFR tyrosine kinase inhibitors (EGFR TKIs) in advanced non-small cell lung cancer (NSCLC). Even the serial monitoring of quantitative changes of these mutations is considered to be important for the continuation of EGFR TKIs treatment, it is not possible for doing multiple biopsy of tumor tissue in clinical practice. The quantitative measurement of mutant EGFR in peripheral blood is desperately in need of development of highly sensitive detection technique. Methods: We took measure of limitation of 3 mutant EGFRs by InsightTM Onco NGS and compared the results with conventional NGS in serial dilutions of PC9 (19Del) and H1975 (T790M,L858R) cells. We also extracted cell-free DNA (cfDNA) from paired peripheral blood and tumor tissues in 5 lung adenocarcinoma pts receiving EGFR TKIs. We measured % of mutant EGFRs by InsightTM Onco NGS and analyzed the correlation between accordance and sensitivity. Results: With conventional NGS, we were not able to detect any of 3 mutant EGFRs in serial dilution samples containing lower than 0.5% of mutant EGFR DNA.When InsightTM Onco NGS was applied, it enabled to detect three mutant EGFRs in much lower density of 0.01% of mutant DNA. The mean age of 5 pts was 59 (28-78) and M: F ratio 1:4. Four pts were stage IV. All five pts had 19 Del at the beginning of EGFR TKI treatment. Of 5 biopsied tumor tissues, both two detection technique discovered 19 Del in 2 cases. In cfDNA from serum samples, conventional NGS detected 19 Del only in 1 case (2.19%). However, InsightTM Onco NGS enabled to detect 19 Del in additional 2 cases (5.56% and 7.43%) in which conventional NGS did not. No T790M mutation was found in serum and tumor tissues, two detection technique. Conclusions: Taken together, our preliminary result suggest clinical potential of highly sensitive InsightTM Onco NGS for monitoring cf EGFR mutant DNA in peripheral blood of the unique subgroup of NSCLC pts receiving EGFR TKIs. Now, we are undergoing validation study of this high-sensitive genomics analysis technique in extension cohorts.
EGFR-targeted treatments in patients with metastatic colorectal cancer: Experience of panitumumab.
Authors: Mahmut Gumus, Caglayan Geredeli, Mahmut Ucar, Serap Kaya, Hacer Demir, Olcun Umit Unal, Mustafa Degirmenci, Gamze Gokoz Dogu, Nedim Turan, Nilgun Yildirim, Fatma Bugdaycı Basal, Erkan Arpaci, Mustafa Karaagac, Hakan Harputluoglu, Haci Mehmet Turk, Faysal Dane, Metin Ozkan
Journal: Journal of Clinical Oncology (2017)

e15028 Background: Overall survival times have been exceeded three years by the targeted treatments in metastatic colorectal cancer (MCC) . The sequence of these agents and the possible side effects constitute our discussions. We aimed to investigate the efficacy and tolerability of panitumumab use in this study. Methods: In this study 168 MCC patients from 15 different centers that were treated with panitumumab in first or second line settings were evaluated respectively. Progression free survival (PFS) and overall survival(OS) time were calculated in case of the patients treated with targeted treatments in first line setting. Results: The median follow-up time was 12(3-82) months. The median age was 60 (24-86) years and 36 % of the patients were female. Panitumumab as a component of first line treatment was used in 66 % of the patients. Median 6 (1-18) cycles treatment were given to the patients as first line chemotherapy. The median PFS was 11 (SE:2; 95% CI: 7-15) months in patients treated with panitumumab while 12 (SE:1; 95% CI: 10-14) months in patients treated with bevacizumab containing regimens as first line treatment (p:0.836). The median OS was 32 (SE:12; 95% CI: 7-56) months in patients treated with panitumumab containing regimen and the median OS has not been reached in bevacizumab group (p: NS). In univariate analysis, female gender and left-sided colon tumors have favorable PFS (p:0.030 and p:0.023 respectively). No difference between bevacizumab or panitumumab containing regimen in right- sided tumors have observed (p:0.812). But in left-sided tumors, the panitumumab containing regimens have favorable PFS (8 vs 13 months. p:0.023). Grade 2 or higher skin rash was observed in 49% . Diarrhea in 38%, neuropathy in 30%, different hematologic toxicity in 14% and infusion reaction in 2.2% of the patients were detected. The skin rash was associated to panitumumab containing regimen (p:0.000). Other toxicity frequencies were not statistically significant in both groups. Conclusions: Compilation of current life data in MCC treatment will reveal the efficacy and tolerability in our daily practice beyond as data in clinical trials. These data together with more experience will guide the optimization of the treatments.
Effectiveness and safety of lobectomy and sublobar dissection in Chinese elderly patients with non-small cell lung cancer: A real-world observational study.
Authors: Zhenrong Zhang, Xiaofei Li, Heng Zhao, Jian HU, Yang Liu, Lunxu Liu, Xiangning Fu, Yin Li, Lin Xu, Xike Lu, Haiying Yang, Deruo Liu
Journal: Journal of Clinical Oncology (2018)

e20522 Background: The golden surgery standard of early-stage non-small cell lung cancer (NSCLC) is lobectomy with dissection of mediastinal lymph nodes. Due to the risks of reduced pulmonary reserve, comorbidities, and incidences of complications, sublobar resection was demonstracted to be an alternative therapy in elderly patients. Given that the clinical data are limited, the study was designed to evaluate effectiveness and safety of lobectomy and sublobar resection in the target population. Methods: The study data on the elderly NSCLC patients (≥65 years) who received lobectomy vs sublobar resections [segment vs wedge resection]) from 2014 to 2017 were collected from the LinkDoc database. The Kaplan-Meier method and the Log-rank test were performed to evaluate overall survival (OS) based on the method of propensity score matching (PSM). Results: A total of 4490 NSCLC patients were enrolled in this study including 82.8% of patients with lobectomy, 17.2% with sublobar resections (4.9% segment resection and 12.4% wedge resection). After PSM, the 1, 2, and 3-year OS rates in patients with sublobar resection were 97.4%, 93.2%, and 93.2%, which were significantly higher than those with lobectomy (92.9%, 86.2%, and 82.0%). The OS of patients with lobectomy was inferior to that of patients with wedge resection (HR = 1.76, p < 0.05) and segment resection (HR = 4.00, p < 0.05). No significant OS differences was observed between the groups of the patients with wedge and segment resections. The percentage of postoperative mortality rate within 90 days after surgeries was higher in the patients with lobectomy (1.1%) than in those with sublobar resection (0.3%) (p < 0.05). The most common complications were pleural effusion (5.0%), pneumonia (4.9%), and pneumothorax (3.3%). Conclusions: Our results demonstrated that the OS of patients with sublobar resection was superior to that of patients with lobectomy in Chinese elderly patients with NSCLC,. The real-world evidences would offer complementary clinical evidences on the choice of surgical procedures for those elderly patients with early-stage NSCLC. Clinical trial information: ChiCTR1800014704.
Long-term results of the ADORE trial: Adjuvant oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) versus 5-fluorouracil and leucovorin (FL) after preoperative chemoradiotherapy and surgery for locally advanced rectal cancer.
Authors: Yong Sang Hong, Sun Young Kim, Ji Sung Lee, Byung-Ho Nam, Jeong Eun Kim, Kyu-Pyo Kim, Joon Oh Park, Young Suk Park, Ji Yeon Baek, Tae-You Kim, Keun-Wook Lee, Joong Bae Ahn, Kyung Hae Jung, Tae Won Kim
Journal: Journal of Clinical Oncology (2018)

3501 Background: To report the long-term survival outcomes of the ADORE, a randomized controlled trial, compared adjuvant FOLFOX vs FL in patients with resected rectal cancer whose pathologic stages of ypII/III after preoperative chemoradiotherapy (CRT). Methods: This is a randomized phase II study accrued patients with curatively resected rectal cancer patients whose postoperative ypStage II/III after preoperative CRT with fluoropyrimidines alone. Patients were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL or FOLFOX for 4 months. Randomization was centrally coordinated and stratified by the ypStage and participating sites. The primary endpoint was disease-free survival (DFS). Results: A total of 321 patients were randomly assigned between Nov 2008 and Jun 2012; 161 patients to FL and 160 to FOLFOX. At a median follow-up of 74.1 months (IQR, 56.2 – 88.0), 6-year DFS rate was 68.2% in the FOLFOX arm vs 56.8% in the FL arm with an adjusted hazard ratio (HR) of 0.63 (95% CI, 0.43–0.93, p= 0.018) by intention-to-treat analysis. In the subgroup analysis for DFS, patients with ypStage III (HR 0.59 [0.38-0.92], p= 0.019), ypN1b (HR 0.35 [0.14-0.83], p= 0.017), ypN2 (HR 0.47 [0.22-0.99], p= 0.048), high grade histology (HR 0.28 [0.08-0.97], p= 0.045), minimally regressed tumor (0.40 [0.19-0.85], p= 0.016), absence of lymphovascular (HR 0.55 [0.34-0.88], p= 0.013) or perineural invasion (HR 0.53 [0.33-0.86], p= 0.01), male gender (HR 0.62 [0.39-0.98], p= 0.039), and younger than 65 years (HR 0.64 [0.42-0.97], p= 0.034) benefited more from FOLFOX than FL. The 6-year overall survival (OS) rate was 78.1% in the FOLFOX arm vs 76.4% in the FL arm (HR 0.73 [0.45-1.19], p= 0.21). In the subgroup analysis for OS, those with ypN2 (HR 0.42 [0.18-0.96], p= 0.04) and minimally regressed tumor (HR 0.42 [0.19-0.97], p= 0.043) benefited from FOLFOX than FL. Conclusions: Adjuvant FOLFOX clearly demonstrated improved DFS in rectal cancer patients with ypStage II/III after preoperative CRT. Subgroup analyses provided additional information on the selection of adjuvant candidates. Clinical trial information: NCT00807911.
Programmed cell death ligands expression in pheochromocytomas (PCC) and paragangliomas (PGL): Relationship with the hypoxic response and malignant behaviour.
Authors: David James Pinato, James M Black, Sebastian Trousil, Roberto Dina, Pritesh Trivedi, Francesco A Mauri, Rohini Sharma
Journal: Journal of Clinical Oncology (2017)

11597 Background: The hypoxic response underlies the pathogenesis and malignant behaviour of PCC/PGL. Regulation of PD-1 receptor-ligand signalling, a therapeutically actionable driver of the anti-tumour immune response, is a hypoxic-driven trait across malignancies. We evaluated the prognostic role of PD ligands in association with biomarkers of hypoxia and angiogenesis in patients with PCC/PGL. Methods: Tissue microarrays sections including consecutive cases of PCC/PGL diagnosed between 1983-2011 were stained for PD-L1 &amp; 2, Ki-67, hypoxia inducible factor 1a (Hif-1a), Carbonic Anhydrase IX (CaIX), Vascular Endothelial Growth Factor-A (VEGF-A). Candidate biomarkers were assessed for correlation with clinical variables including overall survival. Results: In total, 100 patients, 10% malignant, 64% PCC, 29% familial with a median tumour size of 4.7 cm (range 1-14) were included. Median follow-up was 4.7 years. PD-L1 expression was observed in 18% of cases and was independent of adverse pathological features including capsular (CI), vascular invasion (VI), necrosis (N) and expression of biomarkers of hypoxia. We observed a trend towards association with malignancy (p = 0.08). PD-L2 expression was found in 16% of tumors. PD-L2 overexpression strongly correlated with CI, VI, N (p &lt; 0.01) and malignant behaviour (p = 0.009) and was associated with stronger Hif-1a and CaIX immunolabeling (p &lt; 0.01). PD-L2 but not PD-L1 expression was predictive of shorter survival (162 versus 309 months, HR 3.1 95%CI 1.1-9.2, Log-rank p = 0.03). Gene set enrichment analysis on the TGCA PCC/PGL RNA-seq dataset (n = 184) revealed a positive correlation between PD-L2 and a number of transcripts involved in angiogenesis and immunity including Interleukin-6 (Pearson R = 0.57) and CD-8a (R = 0.56). Conclusions: We report for the first time PD-1 ligands expression in PCC/PGL with a distinctive prognostic and clinicopathologic role. These findings support a potential therapeutic role for PD-1/PD-L1 targeted checkpoint inhibitors in these tumors.
Representation of African-American patients in clinical studies of prostate cancer.
Authors: Ohad Oren, Douglas Francis Beach
Journal: Journal of Clinical Oncology (2016)

e18057 Background: African-American (AA) men represent a unique subset of patients in prostate cancer. First, they are disproportionately affected by this cancer, with prevalence rates of 214.5 (per 100,000) compared with 130.4 for white men (1). In addition, their cancers tend to be more aggressive with higher mortality rates compared with other ethnicities (2). We sought to define the extent of inclusion of AAs in prostate cancer studies. Methods: We collected data from clinicaltrials.gov pertaining to all interventional (phase 3/4) clinical studies done in U.S men with prostate cancer. Participation of AA versus non-AA patients was assessed in its contribution to the individual study and to the global data. Results: 42 studies were found. Of those studies, 54.7% (23/42) had no ethnic stratification. In all trials that provided demographic information, there were 5,116 (9.8%) AA and 41,103 (79.4%) white participants. 4 (of 42) trials accounted for 91.6% of the total number of AA patients. Conclusions: AA males are under-represented in prostate cancer studies. Most studies fail to account for ethnicity when reporting the data. A small number of studies generates most of the clinical data about AAs. As a result, most prostate cancer clinical trials may not be optimally generalizable to AA patients. References: 1. SEER Stat Fact Sheets: Prostate Cancer. http://seer.cancer.gov/statfacts/html/prost.html 2. Williams H, Powell IJ. Epidemiology, pathology, and genetics of prostate cancer among African Americans compared with other ethnicities. Methods Mol Biol. 2009;472:439-53.
Early metabolic response as predictor for treatment outcome of pazopanib in patients with metastatic soft tissue sarcomas (the PREDICT study).
Authors: Winette T.A. Van Der Graaf, Myrella Vlenterie, Neeltje Steeghs, Ingrid Desar, Remy B Verheijen, Anne Miek Koenen, Willem Grootjans, Lioe-Fee de Geus-Oei, Wim J.G. Oyen, Nielka P. Van Erp
Journal: Journal of Clinical Oncology (2018)

11555 Background: Pazopanib is the first approved targeted treatment for non-GIST soft tissue sarcoma (STS) pts. In the PALETTE study 23% of pts had progressive disease as best response. This study correlates early metabolic response evaluated by FDG-PET/CT to treatment outcome assessed by RECIST and investigates the relation between metabolic response and pazopanib pharmacokinetics. Methods: Twenty STS pts recruited from sarcoma clinics in Radboud University Medical Centre Nijmegen and the Netherlands Cancer Institute Amsterdam, underwent FDG-PET scans at baseline, and 2 and 8 weeks after start of pazopanib. Blood samples were collected for pharmacokinetic (PK) assessment (Ctrough levels and AUC0-24h). We investigated the relation between early metabolic response after 2 weeks of therapy and pazopanib exposure at 2 weeks, and the relation between early metabolic response and treatment response assessed by RECIST1.1 at 8 weeks. The study was registered at ClinicalTrials.gov (NCT01995981) and approved by the regional medical ethics committee. All patients gave written informed consent. Results: After 8 weeks of therapy, 14 out of 20 pts had discontinued pazopanib due to radiological tumor progression (‘non-responders’ n = 12) or toxicity (n = 2). Quantitative FDG-PET scoring according to PERCIST guidelines at 2 weeks identified 25% (3 of 12) of all non-responders versus 42% (5 of 12) with visual response analysis by an independent evaluation from a nuclear medicine physician. No patient was incorrectly labeled as non-responder. PK results were not related to metabolic response. Conclusions: In this heterogeneous STS patients’ cohort we did not see a relation between pharmacokinetics and pharmacodynamics of pazopanib, but we did show that FDG-PET/CT identified a substantial part of pazopanib non-responders. The results of this study warrant a larger study, to enable future early and cost-effective decision making in STS pts treated with pazopanib. Funding: This academic investigator-initiated study was supported by a grant from GlaxoSmithKline/ Novartis to the institute. Clinical trial information: NCT01995981.
Variation in radiation oncology referral and adjuvant radiotherapy use following prostatectomy: A population-based study of health system performance.
Authors: Chunzi Jenny Jin, Timothy Hanna, Earl Francis Cook, Qun Miao, Michael Donald Brundage
Journal: Journal of Clinical Oncology (2017)

e16551 Background: Evidence-based guidelines confirm a survival advantage of adjuvant radiotherapy (ART) for prostatectomy (RP) patients with high-risk pathology. The efficacy of deferred salvage RT is under evaluation as an alternative strategy, and guidelines recommend radiation oncology (RO) referral for discussion of options. We report RO referral patterns, ART use, and factors associated with these patterns in a contemporary population-based RP cohort. Methods: Electronic treatment records were linked to Ontario's cancer registry. Multivariable regression was used to evaluate clinical and health systems factors associated with RO referral and ART use ≤ 6 months post-RP. Results: From January to November 2012, 2,663 prostate cancer patients received RP in Ontario. Among 1,261 with adverse pathology, 492 (39%) were referred to RO ≤ 6 months post-RP, of which 51% received ART. Multivariable analysis demonstrated that RO referral was more frequent for cases of T3b/T4 disease [OR 17.87; p &lt; 0.0001], T3a disease [OR 5.24; p &lt; 0.0001], Gleason score 8-10 disease [OR 11.32; p &lt; 0.0001], Gleason score 7 disease [OR 4.18; p &lt; 0.0001], at least one non-apex margin positive [OR 4.20; p &lt; 0.0001], an apex only positive margin [OR 2.60; p &lt; 0.0001], RO referral prior to RP [OR 1.95; p &lt; 0.0001], low RP volume hospitals [OR 2.50; p &lt; 0.0001], and increased distance of patient residence from cancer center [OR 1.73; p = 0.01]. There was wide geographic variation in RO referral rates (range 6%-66%; p &lt; 0.0001). Among patients seen by RO, only T3b/T4 disease [OR 5.37; p &lt; 0.0001], T3a disease [OR 2.72; p &lt; 0.0001], at least one non-apex positive margin [OR 2.81; p &lt; 0.0001], and an apex only positive margin [OR 1.32; p &lt; 0.0001] remained predictive of ART on multivariable analysis. Conclusions: Nonmedical factors are important determinants of whether patients are referred for discussion of ART post-RP. Post-RO consultation, treatment decisions are correlated with pathologic findings. Large inter-center variations persist in referral and treatment post-RP, suggesting that further understanding of the reasons for variation could improve access to potentially curative RT in this setting.
Galeterone to target proteasomal degradation of the androgen receptor in prostate tumor cells: A novel mechanism of action for treatment of AR-V7+ CRPC.
Authors: Daniel T. Dransfield, Douglas B Jacoby, Nivedita Namdev, Andrew Kwegyir-Afful, Vincent Njar
Journal: Journal of Clinical Oncology (2016)

e14092 Background: Galeterone is an oral small molecule that disrupts androgen receptor (AR) signaling via multiple pathways: AR degradation, CYP17 inhibition, and AR antagonism. By enhancing ubiquitin-mediated AR degradation within the cellular proteasome, galeterone is a first-in-class degrader of the full-length AR and the AR-V7 splice variant. AR-V7 expression is associated with resistance to abiraterone or enzalutamide in patients with castration-resistant prostate cancer (CRPC). Methods: Normally, proteins can be enzymatically flagged for proteasomal degradation with ubiquitin (Ub); however, proteins can be saved from degradation by the removal of Ub through deubiquitinating enzymes (DUBs). We utilized a series of biochemical and cell-based in vitro studies to further elucidate and characterize additional signaling molecules in the proteasomal dependent mechanism of galeterone-induced AR degradation. Results: Galeterone binds to 2 key DUBs involved in sparing the AR from degradation, USP12 and USP46, and inhibits their activity in a dose-dependent manner (IC50 3.4 μM, 4.2 μM, respectively). By comparison, abiraterone and enzalutamide do not inhibit USP12 or USP46 activity. Pre-clinically, the galeterone-mediated degradation appears to be specific for AR as there was no impact on the levels of other nuclear hormone receptors (ERβ, PR, RARα, RARβ). Galeterone also activates AKT, which then phosphorylates the E3 ligase enzyme Mdm2 and ubiquitinates the AR, further inducing proteasomal degradation Conclusions: By directly inhibiting the activity of the DUBs, and indirectly activating Mdm2, galeterone targets multiple points in the proteasomal degradation pathway. This results in a shift of the equilibrium from deubiquitination to ubiquitination of AR, enhancing degradation of both full-length AR and the AR-V7 splice variant. A Phase 3 trial, ARMOR3-SV, of galeterone vs. enzalutamide in AR-V7+ metastatic CRPC patients is underway.
Ibrutinib vs chlorambucil: Immunophenotypic and quantitative impacts on circulating immune cells in chronic lymphocytic leukemia (CLL).
Authors: Isabelle Solman, Hana You, Marlene Taylor, Jason A. Dubovsky, Thomas J. Kipps, Jan Andreas Burger, Indu Lal, Betty Y. Chang, Danelle Frances James, John Stephen Hill
Journal: Journal of Clinical Oncology (2017)

7524 Background: Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is indicated by FDA for treatment (Tx) of patients (pts) with CLL. Following the outcome of the RESONATE-2 trial, ibr was approved as the first chemotherapy-free Tx option for treatment-naïve (TN) pts. In this study, ibr reduced the risk of progression or death by 84% compared with chlorambucil (chl). To assess the impact of ibrutinib vs this traditional chemotherapeutic agent on the immune system, quantitative changes in circulating cells were studied throughout the first year of Tx. Methods: Immunophenotypic analyses were performed by flow cytometry on peripheral blood to assess lymphoid and myeloid cells of TN CLL pts who received 420 mg ibr once daily (n=50) or 0.5-0.8 mg/kg chl twice a month (n=30). Medians of statistically significant changes (p&lt;0.05, Wilcoxon test) in absolute counts of 1-year paired samples (pre-dose vs 1-year) are reported. Results: Chl progressively reduced circulating B, T, NK, NKT cells, myeloid derived suppressor cells (MDSC), and monocytes by 69%-99%. All development stages of CD4 + and CD8 + T cells, except stem cell memory T cells (T SCM ), decreased by 51%-90%. Regulatory T cells (Treg) and PD1 + T cells also decreased similarly; however, long-term activated T cells (T LA ) were not impacted. On the other hand, ibr mainly reduced B cells (90%), MDSC (61%) and some T cells, specifically T LA , PD1 + T cells, Treg and effector T cells (27-52%). Naïve T cells, T SCM , central memory T cells and NK cells were spared throughout the full year of Tx. Classical monocytes were increased (+187%), while non-classical monocytes and intermediate monocytes remained relatively steady. Conclusions: Chl, a traditional chemotherapy, affected non-specifically most immune cell subsets in circulation, although surprisingly it did not affect T LA which have been reported as dysfunctional in CLL. Ibr represents a more targeted Tx approach than cytotoxic chemotherapy; essentially B cells, abnormal T subsets (T LA , PD1 + T, Treg) and pro-tumor MDSCs were reduced. However, ibr preserved naïve T cells, NK cells and monocytes, which are important for mounting anti-tumor responses. Clinical trial information: NCT01722487.