tbuckley/cabot-search huggingface dataset:
Variation in colorectal cancer (CRC) post-treatment surveillance intensity (SI) and detection of recurrence.
Authors: Amanda Cuddy, Chung-Yuan Hu, Rebecca A Snyder, Amanda B. Francescatti, Jessica R. Schumacher, Y. Nancy You, Daniel McKellar, David P Winchester, George J. Chang
Journal: Journal of Clinical Oncology (2016)

6579 Background: The optimal strategy for CRC post-treatment surveillance is unknown. Existing guidelines are based on limited evidence and not risk-based. The purpose of this study is to examine surveillance patterns and intensity in routine practice and the impact on recurrence detection. Methods: Primary records of a random sample of 10,885 Stage I-III CRC patients from Commission on Cancer accredited hospitals (2006-2007) were individually abstracted and detailed results of surveillance testing (advanced imaging, endoscopy and CEA) were reviewed. Data was merged with records in the National Cancer Database (NCDB). Incidence rate ratios (IRR) of tests were determined using multivariable negative binomial regression with an offset variable. SI quartiles were identified based on recurrence risk-independent factors and rates of recurrence detection assessed using Cox regression. Results: Testing rates per person-year were 0.69 (imaging), 0.22 (endoscopy), and 0.77 (CEA). No testing was performed for 20%, 17% and 13% of stage I, II, and III patients. Advanced stage (III vs I) was associated with imaging (IRR = 1.87), endoscopy (IRR = .8) and CEA (IRR = 1.68). After adjusting for cancer-related factors, SI of imaging (p = .007, Q4 vs Q1) but not endoscopy or CEA (all p > .1) was associated with detection of distant recurrence. The association with imaging SI was limited to stage III patients in the highest SI quartile only and insignificant for all other groups. Conclusions: Variation exists in the intensity of surveillance following curative treatment of CRC in routine practice. While there is significant variation associated with underlying recurrence risk (e.g. stage), after accounting for cancer-related factors, surveillance intensity was associated with rate of recurrence detection only among the highest risk cohort. These data inform the development of optimized, risk-stratified approaches to CRC surveillance.
Mutation detection in cell free DNA from healthy donors.
Authors: Anja Kammesheidt, Aaron Chen, Sean Li, Jair Jaboni, Megan Anselmo, Troy Viloria, Julie A Neidich, Glenn D Braunstein
Journal: Journal of Clinical Oncology (2016)

e23054 Background: Tumor cells release small DNA fragments into the bloodstream as circulating tumor DNA (ctDNA), a subset of cell-free DNA (cfDNA). CancerIntercept Detect is a CLIA validated, laboratory-developed blood test that can be used by physicians as a screening tool for the detection of biomarkers associated with specific cancer types in high-risk patients without a cancer diagnosis. The assay detects the presence of 96 mutations in nine genes (BRAF, CTNNB1, EGFR, FOXL2, GNAS, KRAS, NRAS, PIK3CA, TP53). To investigate the positive mutation rate in an unselected, general population, we initiated a small IRB-approved study in August 2015. Methods: Subjects were asymptomatic, had no personal history of cancer and filled out a health questionnaire. Ages ranged from 20-71 (mean 40 years); 55 females and 47 males participated. 20 ml of blood was collected in cfDNA blood tubes, plasma was separated, cfDNA isolated from 5 ml of plasma, and ctDNA enriched and then sequenced via next-generation methods. We report on as few as 2 copies of mutant ctDNA. Results: 98/102 (96%) subjects were negative for the 96 mutation panel. A single mutation was detected in 3 subjects at just above the detection threshold, and 2 mutations were detected in one individual. All 4 positive subjects were over 50 years old. We continue to test ctDNA levels every ~2-3 months and levels have remained steady with small copy number variations. Subject 4 underwent a CT scan of the lungs showing multiple lung nodules. Results at ~9 months follow-up will be presented. Conclusions: In our study, 3% of non-selected adults were found to have low levels of ctDNA detected without an underlying neoplasm found, while 1% had moderately elevated levels associated with lung nodules concerning for neoplasm. Subject Mutation 1st Blood Draw 2nd Blood Draw (within 1-2 months of first draw) Copy# Abundance (%) Copy# Abundance (%) 1 NRAS_G12S 2.19 0.010 3.5 0.032 2 TP53_R273H 3.70 0.037 4.1 0.048 3 GNAS_R201H 4.4 0.053 3.0 0.065 4 KRAS_A146T 76.2 0.457 30.1 0.7 5 TP53_R175H 4.1 0.025 5.5 0.128
Demethylating agents to upregulate HLAs and antigen presenting machinery (APM) related genes in HER2+ breast cancer (BC) cell lines.
Authors: Giampaolo Bianchini, Alberta Locatelli, Francesca Giannese, Lucia Viganò, Michela Riba, Marta Bini, Paolo Provero, Lorenzo Sica, Balazs Gyorffy, Luca Gianni
Journal: Journal of Clinical Oncology (2018)

e13012 Background: Low expression of HLAs genes was associated with high risk of relapse in HER2+ BC (Bianchini AACR 2016) and it was mainly driven by hypermethylation (Balazs ASCO 2016). We aimed to investigate if demethylating agents (decitabine [5AZA2d] and azacytidine [5AZA]) modulate HLAs and APM-related genes in BC cell lines Methods: We selected three BC cell lines (SKBr3, BT474, MDA-MB-361) characterized by a low, intermediate and high cell-surface expression of HLAs (HLA-A, B, C), respectively. Cells were exposed to 5µM 5AZA2d or 5AZA for 96h. Modulation of HLAs and Beta 2-μglobulin (B2M) protein expression was assessed at baseline, 96h and 168h with and without the addition of IFN-gamma. In SKBr3 treated with 5AZA2d, we also assessed HLAs and B2M mRNA expression and the genome wide methylation status (RRBS methodology and NextSeq500 (Illumina) platform) at the 3 time points Results: Exposure to 5AZA2d and 5AZA increased HLAs protein expression in cell lines with low (SKBr3) and intermediate (BT474) HLAs basal level (4.5 and 1.7 fold changes , respectively). The effect was more pronounced at 168h than 96h. Interesting, the cell line with high HLA basal level (MDAMB361) showed a decrease of HLA. The addition of IFN-gamma increased HLA basal expression in all cell lines, which was further increased after treatment with 5AZA2d and 5AZA. Similar results were observed for B2M protein expression. In SKBr3, treatment with 5AZA2d increased the mRNA expression of HLAs, but not B2M. In the same model, whole genome differential methylation analysis at single CpG resolution demonstrated a significant and extensive enrichment of hypomethylated regions (p < 0.001) after treatment. We also demonstrated a significant hypomethylation of CpG associated with APM-related genes. This effect was stronger at 168h than 96h Conclusions: Decrease of HLAs and APM-related genes is a general mechanism of immune escape associated with poor prognosis in HER2+ BC. Demethylating agents increased protein and mRNA expression of these genes in HER2+ BC cell lines. Combination of immunecheckpoints inhibitors and demethylating agents in HER2+ disease warrants clinical investigation
A randomized phase II trial of pazopanib (PAZ) vs. temsirolimus (TEM) in patients (pts) with advanced clear-cell renal cell carcinoma (accRCC) with intermediate or poor-risk disease (the TemPa trial).
Authors: Amado J. Zurita, Jeremy Aaron Ross, Catherine E Devine, Anuradha Chandramohan, Xuemei Wang, Zita Dubauskas Lim, Jennifer Wang, Paul Gettys Corn, Pavlos Msaouel, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2018)

4563 Background: TEM has level 1 evidence in aRCC with poor-risk disease. No previous trial compared a VEGFR-TKI with TEM as first-line (1L) therapy. Methods: We randomly assigned (1:1) treatment-naïve pts with accRCC and > = 3 risk factors (Hudes et al., NEJM 2007) to receive PAZ 800 mg po qd or TEM 25 mg iv qw. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. A blinded radiologist assessed the radiographic response using RECIST v1.1. A sample size of 90 pts was based on an assumption of improved median PFS from 3.8 mo (TEM) to 6.1 mo (PAZ). Pts were stratified by prior nephrectomy (Nx) and prior cytokine therapy. The Kaplan-Meier method was used for PFS/OS analysis, and the Fisher's exact test for comparison of ORR between PAZ and TEM. Results: TemPa was closed to new patient enrollment in Sept. 2017 after the results of CheckMate 214 and CABOSUN were released. A total of 69 pts were eligible and evaluable (median age 61, 52 males [75%], 44 [64%] with poor-risk by IMDC criteria). Thirty pts (43%) had prior Nx and 3 pts prior IL-2. Thirty-five pts received PAZ (intermediate-risk 15, poor-risk 20) and 34 pts TEM (intermediate-risk 10, poor-risk 24). Of the 69 pts, 67 had progressive disease or died. The median PFS was 5.2 mo (95% CI: 3.6 –7.4) for PAZ and 2.6 mo (95% CI: 1.9 –4.2) for TEM (p = 0.16). However, PFS was significantly longer with PAZ in IMDC intermediate-risk pts after adjustment for IMDC risk group (7.3 v 3.7 mo, HR 0.38, p = 0.03). Fifty-nine pts have died. The median OS was 12.0 mo (95% CI: 8.3–20.1) for PAZ and 7.3 mo (95% CI: 5.8–17.4) for TEM (p = 0.56). Sixty-eight pts were evaluable for response: 9/35 pts (26%) who received PAZ and 2/33 pts (6%) who received TEM had partial response (p = 0.046). Adverse events were consistent with the known safety profiles of PAZ and TEM, and resulted in treatment discontinuation in only 2 pts in each. Circulating biomarker analysis will be presented. Conclusions: PAZ extended PFS, particularly in intermediate-risk, and yielded a higher ORR than TEM as 1L therapy in pts with accRCC and poor prognosis features. Clinical trial information: NCT01392183.
RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation
Authors: Nan Zhou, Alvaro Gutierrez-Uzquiza, Xiang Yu Zheng, Renxu Chang, Dan T. Vogl, Alfred L. Garfall, Luca Bernabei, Anita Saraf, Laurence Florens, Michael P. Washburn, Anuradha Illendula, John H. Bushweller, Luca Busino
Journal: Leukemia (2019)

Ikaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and IKZF3. Although IMiDs have been used as first-line drugs for MM, the overall survival of refractory MM patients remains poor and demands the identification of novel agents to potentiate the therapeutic effect of IMiDs. Using an unbiased screen based on mass spectrometry, we identified the Runt-related transcription factor 1 and 3 (RUNX1 and RUNX3) as interactors of IKZF1 and IKZF3. Interaction with RUNX1 and RUNX3 inhibits CRBN-dependent binding, ubiquitylation, and degradation of IKZF1 and IKZF3 upon lenalidomide treatment. Inhibition of RUNXs, via genetic ablation or a small molecule (AI-10-104), results in sensitization of myeloma cell lines and primary tumors to lenalidomide. Thus, RUNX inhibition represents a valuable therapeutic opportunity to potentiate IMiDs therapy for the treatment of multiple myeloma.
P01.080 Individual diagnosis of adult diffuse gliomas into the EM/PM molecular subtypes
Authors: X Fan
Journal: Neuro-Oncology (2018)

We recently identified gene co-expression modules around EGFR or PDGFRA in glioma transcriptome, and established an EM/PM clustering framework that can assign adult diffuse gliomas of WHO grades II-IV into EM, PM and EMlowPMlow subtypes in a morphology-independent manner (PNAS 119:3538–43, 2014). Though the EMlowPMlow feature was caused by high contamination of normal brain tissues, the EM and PM subtypes are distinct in their prognosis, age at diagnosis, genomic changes and cellular origins. Here, we aimed to translate the EM/PM classification scheme into a diagnostic tool. By analyzing public datasets, we selected 31, 43, and 9 genes as candidate diagnostic markers for the EM, PM and EMlowPMlow. subtypes, respectively. Together with 13 candidate control genes, we designed a Taqman Low Density array (TLDA), measured the expression of these genes in 37 gliomas with known EM/PM subtype (based on mRNA-seq data) from the CGGA dataset, and filtered out nonspecific or low expressed genes. Forty-four diagnostic markers, 4 control genes were selected for a new 48-gene TLDA diagnostic array. With this new array, we analyzed 54 samples from CGGA with known EM/PM subtype and trained an EM/PM prediction model using support vector machine (SVM) algorithm. Meanwhile, another 31 glioma samples were tested by Affymetrix expression array and TLDA in parallel to generate a validation set. The performance of this diagnostic model was assessed using validation data and the model was furtherly applied to predict EM/PM subtypes for 100 samples in the test set without prior EM/PM subtype information. Whole genome sequencing was performed to acquire SCNA landscape of the samples tested. And IDH1/2 mutations were evaluated by Sanger sequencing. Cross-validation in the training set showed that SVM-based EM/PM prediction model has accuracies of 88%, 91% and 93% for EM, PM and EMlowPMlow glioma subtype, respectively. Applying this prediction model to the validation set, we found that only one PM glioma was wrongly predicted as EMlowPMlow subtype. In the test set, 36 EM, 51 PM and 13 EMlowPMlow samples were predicted. Clinical analysis of the patients in validation and test set combined showed that PM gliomas had a better survival (median survival time: 11.7 months for EM vs. not reached for PM, p=0.0001, log-rank test), younger age at diagnosis (47.4 ± 2.4 for vs. 60.1 ± 1.8 for EM, p = 0.0002, t test). Importantly, genomic analysis showed that IDH1/2 mutation and 1p19q co-deletion occurred nearly exclusively in the PM, while amplification of EGFR, deletion of PTEN and CDKN2A/B are highly enriched in EM gliomas. We developed a qRT-PCR array-based diagnosis platform that can individually assign adult diffuse glioma to EM/PM subtype with high accuracy. Our findings can predict the prognosis and genomic alterations of glioma.
Costs of skeletal-related events (SREs) in patients with metastatic castrate-resistant prostate cancer (mCRPC) treated with oral therapies.
Authors: Nicole Engel-Nitz, Ajay S. Behl, Cori Blauer-Peterson, Sophia S Li, Nancy Ann Dawson
Journal: Journal of Clinical Oncology (2017)

e16539 Background: SREs are associated with increased mortality and costs for mCRPC patients. The impact of mCRPC oral therapies on SREs is not well understood in the real world. This study examined the occurrence of and health care costs associated with SREs among mCRPC patients treated with abiraterone acetate + prednisone (ABI) or enzalutamide (ENZ). Methods: A retrospective study of a large national health claims database identified patients initiated on ABI or ENZ from 9/2012- 6/2015. Patients included had: ≥1 claim with prostate cancer diagnosis (ICD-9-CM 185.x) from 6 mo. pre- to 30 days post-index; ≥6 mo. pre- + ≥3 mo. post-index health plan enrollment. Index was date initiated on first oral therapy (ABI/ENZ). SREs (spinal cord compression, radiation to bone, pathological fracture, bone surgery) were assessed and health care cost calculated for patients with/without SREs in baseline/follow-up. Descriptive analyses and Cox proportional hazards examined SREs; generalized linear models assessed costs. Models adjusted for ABI/ENZ, age, region, baseline comorbidities, bone/brain/visceral metastases, docetaxel, and statin use. Results: The table below summarizes unadjusted results. Total all-cause per patient per month (PPPM) costs of 1,516 patients were highest for those with follow-up SREs. A significant difference in cost exists when comparing across all groups. Among patients without baseline SREs, adjusted analysis found greater hazards of follow-up SREs for baseline bone metastases (HR: 1.62, P = 0.003), baseline visceral metastases (HR: 1.68, P &lt; 0.001), prior docetaxel (HR: 1.46, P = 0.004), and ENZ (vs. ABI) as first treatment (HR: 1.35, P = 0.013). Patients with follow-up SREs (with/without baseline SREs) had 19% higher adjusted costs compared to those without baseline or follow-up SREs (P &lt; 0.001 each). Conclusions: SREs were common among mCRPC patients and associated with a significant financial burden. [Table: see text]
Phase Ⅲ randomized, multicenter trial comparing high-dose IFN-a2b with temozolomide plus cisplatin as adjuvant therapy for resected mucosal melanoma.
Authors: Bin Lian, Chuanliang Cui, Xin Song, Xiaoshi Zhang, Di Wu, Lu Si, Zhihong Chi, Xinan Sheng, Yan Kong, Li Li Mao, Li Zhou, Xuan Wang, Bixia Tang, Xieqiao Yan, Siming Li, Dan Li, Jie Dai, Xue Bai, CaiLi Li, Jun Guo
Journal: Journal of Clinical Oncology (2018)

9589 Background: Mucosal melanoma is rare and associated with extremely poor prognosis. Standard adjuvant therapy for mucosal melanoma has not been established. Based on the result of phase 2 trial which compared temozolomide-based chemotherapy, high-dose IFN-a2b (HDI) and observation, we compared HDI with temozolomide plus cisplatin as adjuvant therapy for resected mucosal melanoma in this phase 3 trial. Methods: In this multicenter, randomized, controlled, phase 3 trial, 204 patients of mucosal melanoma with stageⅠ-Ⅲ after completely resected were randomized 1:1 into two groups from Feb 2014 to Jun 2016: HDI group (101 patients, treated with i.v. 15×10^6U/m^2/d IFN-a2b on days 1 to 5 each week for 4 weeks, followed by s.c. 9×10^6U IFN-a2b three times per week for 48 weeks), and chemotherapy group (103 patients, per os 200 mg/m^2/d temozolomide on days 1 to 5 plus i.v. 75 mg/m^2 cisplatin divided into 3 days, which was repeated every 3 weeks for six cycles). The primary end point was relapse-free survival (RFS), Secondary end points included distant metastasis-free survival (DMFS), overall survival (OS), and safety. Results: At a median follow-up of 23.7 months, the median RFS was 15.53 months (95% CI, 11.37-19.69m) in the chemotherapy group, as compared with 9.47 months (95% CI, 8.49-10.45m) in the HDI group (HR for relapse, 0.56; 95% CI, 0.40 to 0.77; P < 0.001). The median DMFS was 16.80 months (95% CI, 9.35-24.25m) in the chemotherapy group, as compared with 9.57 months (95% CI, 7.46-11.67m) in the HDI group (HR for metastasis, 0.53; 95% CI, 0.38 to 0.74; P < 0.001). Estimated median OS for chemotherapy group and HDI group was 41.20, 35.73 months (P = 0.083). Toxicities were generally mild to moderate in two groups. Conclusions: Adjuvant chemotherapy with temozolomide plus cisplatin resulted in a significantly lower risk of relapse and metastasis in resected mucosal melanoma than high-dose IFN-a2b and was not associated with seriously toxic effects. Clinical trial information: BCHMMAT001.
Clinical trial accrual and patient survival in oncology.
Authors: Nicholas George Zaorsky, Ying Zhang, Vonn Walter, Leila T Tchelebi, Vernon M Chinchilli, Niraj Jaysukh Gusani
Journal: Journal of Clinical Oncology (2018)

e18513 Background: Our purpose is to characterize cancer patient accrual onto clinical trials and impact of accrual on survival. Methods: The National Cancer Database (NCDB) was queried for patients going onto a clinical trial, defined as an institutional or a double-blind study, among 46 disease sites. For the top 10 cancers with the highest trial enrollment, overall survival (OS) was analyzed via Kaplan-Meier graphical displays, log-rank tests, and stratified Cox proportional hazards. Strata were defined with 10 variables (including cancer subtype, stage, age, diagnosis year, race, comorbidity, insurance, treating facility, surgery, chemotherapy) to account for differences between the two groups. Results: From 2004 to 2015, 11,576 patients went on institutional or double-blind trials in the US, out of a total of 12,097,681 patients (0.1%) in the NCDB. Among those on trial vs not on trial, median age was 59 (interquartile range [IQR] 60 – 68) vs 64 (IQR 65 – 74). Most commonly, patients on clinical trials had breast cancer (2,252/2,445,870, 0.09%) followed by non-small cell lung cancer (1,088/1,393,073, 0.10%). Patients with acute myeloblastic leukemia had the greatest relative percent on trial, total 845/106,024 (0.90%). In contrast, patients with cancer of the lip, penis, nasopharynx, and testis had < 0.009% trial accrual. Patients on clinical trials vs those not on trials typically had metastatic disease (30.9% vs 16.4%, p < 0.0001), were of white ethnicity (88.0% vs 84.5%, p < 0.0001), and had private insurance (56.1% vs 42.2%, p < 0.0001). At a median follow-up of 64 months, enrollment onto a clinical trial was associated with improved OS on univariate and stratified analyses, with median survival time 60.0 vs 52.5 months, hazard ratio 0.876; 95% confidence interval 0.845 - 0.907, p < 0.0001. The stratified analysis with matched baseline characteristics of those on a clinical trial vs not a clinical trial demonstrated superior overall survival at 5 years (95.0% vs 90.2%) and 7 years (90.0% vs 78.0%), p < 0.0001. Conclusions: In this large contemporary analysis, cancer patients treated on clinical trials lived substantially longer than those not treated on trial. Further efforts are needed to increase clinical trial accrual.
Defining DDR defectiveness in pancreatic cancer.
Authors: Stephan Dreyer, Viola Paulus-Hock, Eirini-Maria Lampraki, Peter Bailey, David Kuang-Fu Chang, Andrew Biankin
Journal: Journal of Clinical Oncology (2017)

4115 Background: Recent whole genome sequencing analysis of Pancreatic Cancer (PC) revealed that up to 24% of PC may harbor defects in DNA damage response (DDR). There is increasing evidence that DDR defective tumors preferentially respond to DNA damaging agents, representing novel therapeutic strategy for PC using a synthetic lethality approach. The aim of this study is to define and refine DDR defective phenotypes in PC using next-generation preclinical model systems. Methods: From a panel of 40 patient-derived cell lines (PDCL) and 64 patient-derived xenografts (PDX), generated and extensively characterized as part of the International Cancer Genome Initiative (ICGC), we identified DDR defective models using recently described putative biomarkers of DDR defectiveness. Cytotoxic viability assays were performed using a panel of DNA damaging agents and inhibitors of key molecules in DDR pathway, including Cisplatin, PARP inhibitors, ATR inhibitor (AZD6738); and ATM inhibitor (AZD0156). Appropriate subcutaneous PDX models were also generated to test the hypothesis using various therapeutic regimens. Results: DDR defective PDCLs were selected based on a combination of an unstable genome, and/or a high BRCA mutational signature, and/or deleterious mutations in BRCA1/2, PALB2 or ARID1A. DDR defective PDCLs were significantly more sensitive to Cisplatin, PARP and ATR inhibitors. The ATR inhibitor AZD6738, and ATM inhibitor AZD0156 sensitized PDCLs with no putative biomarkers of DDR defectiveness to Cisplatin, demonstrating a ‘fabricated’ synthetic lethality. A BRCA1 mutant PDX model responded exceptionally to Cisplatin and the PARP inhibitor Olaparib monotherapy. Conclusions: This study provides proof of concept data that DDR deficiency represents an attractive segment to target in PC using a variety of DNA damaging agents and novel agents targeting key molecules of the DDR pathway in PC. In addition, the DDR defective segment may be significantly larger than just germline BRCA1/2 mutants, which is current clinical trial recruitment criteria. Robust molecular assays with clinical utility to define DDR defectiveness is urgently needed.