tbuckley/cabot-search huggingface dataset:
A haploid genetic screen identifies the key determinant of response to novel combination therapy with gemcitabine and entinostat in pancreatic cancer.
Authors: Yuk Ting Ma, Sarah Leonard, Naheema Gordon, Jennifer Anderton, David Huen, Ciaran Woodman, Daniel H. Palmer
Journal: Journal of Clinical Oncology (2016)

e15685 Background: Pancreatic cancer is known to be highly resistant to systemic therapy. Recently epigenetic changes have been shown to be a key determinant in the maintenance of subpopulations of cancer cells with high-level resistance to cytotoxic therapy. We have thus investigated the effect of the potent class I histone deacetylase inhibitor, entinostat, on gemcitabine sensitivity in vitro. We have also performed a genome-wide haploid genetic screen to identify the key determinants of sensitivity to this combination therapy. Methods: Six human pancreatic cancer cell lines were treated with gemcitabine and entinostat. Cell proliferation was determined using a XTT assay. Apoptosis was assessed using flow cytometry. Acetylated histone H3 and p21 expression were confirmed using immunoblot analysis. Haploid KBM7 cells mutagenized with a retroviral gene-trap vector were then exposed to gemcitabine and entinostat and resistant clones expanded as a pool. High throughput sequencing was used to map insertions in the resistant population to the human genome. Genes with the highest degree of insertional enrichment were selected for validation using the CRISPR/Cas9 gene editing system. Results: Entinostat treatment resulted in a dose-dependent increase in gemcitabine-induced inhibition of cell proliferation. This effect was observed in both gemcitabine-sensitive and resistant cell lines. Entinostat also enhanced the apoptotic effect of gemcitabine. Increased expression of p21 and acetylated histone H3 following treatment were confirmed. Deoxycytidine kinase(DCK) was identified as one of the genes with the highest degree of insertional enrichment from the haploid genetic screen. Immunoblotting confirmed loss of DCK protein expression in the resistant KBM7 cells. CRISPR/Cas-9 inactivation of DCK in pancreatic cancer cell lines resulted in resistance to gemcitabine and entinostat treatment. Conclusions: We have identified gemcitabine and entinostat as a potential new combination therapy in pancreatic cancer, and using a genome-wide screening approach we have identified DCK as the critical gene in determining resistance to this combination treatment.
Response by Soliman et al to Letter Regarding Article, “Derivation and Validation of a Novel Right-Sided Heart Failure Model After Implantation of Continuous Flow Left Ventricular Assist Devices: The EUROMACS (European Registry for Patients With Mechanical Circulatory Support) Right-Sided Heart Failure Risk Score”
Authors: Osama Soliman, Sakir Akin, Rahatullah Muslem, Kadir Caliskan
Journal: Circulation (2018)
The prognostic role of PD-L1 expression according to MSI status in stage III colon cancer after curative resection.
Authors: Sang-Hee Cho, Jun Eul Hwang, Woo Kyun Bae, Ik-Joo Chung
Journal: Journal of Clinical Oncology (2019)

555 Background: Tumors expressing PD-L1 can render immune inactivated via triggering of PD-1 receptor on T cells with various pathways. Based on these mechanism, the blockade PD-1/PD-L1 pathway based been used as a therapeutic target for metastatic CRC. In the present study, we evaluated the prognostic role of PD-L1 expression associated with microsatellite status in surgically resected stage III colon cancer patients. Methods: PD-L1 expression was performed by immunohistochemistry from 182 stage III colon cancer patients after curative resection. Using the immunohistochemical stain, percentages of PD-L1 positive tumor cells and staining intensity were evaluated and categorized as ‘strong’ and ‘weak’ positive group. Clinical and histopathologic parameters including of MSI status and survival outcomes were analyzed with IDO expression which stands for the suppressive immune environment. Results: Strong PD-L1 expression was observed in 29% of all patients. PNI and lymphocyte response response were more frequently shown in strong PD-L1 patients. Among these patients, MSI was shown in 23 patients (12%). Although there was no significant difference between MSI and PD-L1 status, strong PD-L1 tended to better OS in MSS colon cancer (P = 0.056). In contrast, strong PD-L1 expression significantly correlated with significantly worse prognosis in disease free survival (P = 0.001) and overall survival (P &lt; 0.001) than weak PD-L1 expression inMSI patients regardless of adjuvant chemotherapy. In MSI patients, the strong IDO expression was tended to be more frequently shown in strong PD-L1 expression patients (36.4%) than weak PD-L1 expression patients (14.3%). Conclusions: The expression of PD-L1 is differently affected on the survival according to the status of microsatellite. There is no significant relationship between the expression of PD-L1 and prognosis in MSS stage III colon cancer patients. However, in MSI colon cancer which has been well known as a highly immunogenic property, strong PD-L1 expression is significantly associated with poor prognosis on survival outcomes reflecting of immunosuppressive microenvironment in curative resected stage III colon cancer patient.
Patients’ willingness to pay for blood-based EGFR T790M testing: Results from a Canadian validation study of circulating DNA T790M testing.
Authors: Tristan Alexandra Barnes, Janessa J. Laskin, Parneet Kaur Cheema, Geoffrey Liu, Mussawar Iqbal, Jeffrey Rothenstein, Ronald L. Burkes, Scott Peter Owen, David Laurence, Ilda Carvalhana, Leslie Markin, Linda Wong, Nicole Perera-Low, Magdalena Sawczak, Ming-Sound Tsao, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2017)

e18329 Background: Detection of EGFRmutations in circulating tumor DNA (ctDNA) in peripheral blood has been shown to have high concordance with definitive tumor biopsy samples. Patients’ perceived value and willingness to pay for novel technology can help inform policy and funding decisions in the public healthcare system. Methods: Canadian patients undergoing screening for the ASTRIS clinical trial (NCT02474355) were invited to participate in a national Canadian validation study of blood-based ctDNA T790M testing. All participants had metastatic EGFRmutant lung cancer with acquired resistance to EGFR kinase inhibitors. In addition to collection of blood samples and demographic data, patients completed a structured interview measuring their perceived value of blood-based ctDNA testing as an alternative to tumor biopsy and willingness to pay for testing using both open-ended and iterative bidding approaches. The study was supported by a grant from AstraZeneca. Results: 55 patients have been accrued of a planned 60. As of 01/31/2017, demographic data for 55 and willingness to pay data for 52 patients were available, the rest are pending. The median age of the cohort is 64 years (range 31-87), 68% are Asian (36/53), 56% female (31/55). Patients received a median of 1 prior line of treatment (range 1-7); all received prior EGFR kinase inhibitor therapy (66% gefitinib), and 34% also received prior cytotoxic chemotherapy (18/53). All but one patient preferred to have the blood test over repeat tumor biopsy. Patients were personally willing to pay a median of $400 CAD for the test (IQR $600, range 0-$10000). Patients estimated that a reasonable price for the test was a median of $150 (IQR $300, range 0-$2500). Conclusions: Lung cancer patients value ctDNA testing highly and prefer it to tumor biopsy. Despite the expectation that services like molecular testing should be covered through the Canadian public healthcare system, patients expressed willingness to pay out of pocket for ctDNA blood testing, reflecting perceived major value of this technology.
Meta-analysis exploring the effect of oncogenic driver mutations on outcome of metastatic non-small cell lung cancer (mNSCLC) patients (pts) treated with immune checkpoint inhibitors (ICI) or docetaxel (doc).
Authors: Abena Agyeman, Jonathon Joseph Vallejo, Adrian Myers, Gideon Michael Blumenthal
Journal: Journal of Clinical Oncology (2018)

9029 Background: Recent reports suggest that pts with mNSCLC with tumor EGFR mutations (EGFRm) receiving ICI as second line-plus (2L+) therapy may have better clinical outcomes with doc compared to ICI. We aimed to further investigate the role of ICI in pts with oncogenic driver mutations. Methods: We performed a patient-level meta-analysis on 4 randomized controlled, 2L+ trials of ICI versus doc controlling for EGFRm status, PD-L1 status, as well as common prognostic factors (e.g. race). A separate analysis was performed to assess the effect of KRASm, excluding EGFRm as a covariate. If EGFRm or KRASm status was unknown, pts were excluded from these analyses. A Cox proportional hazards model stratified by trial was used to estimate hazard ratios (HR) for EGFRm and KRASm. Median OS was estimated using Kaplan-Meier methods on aggregate data. Results: Treatment effect was evaluable in 2752 patients; 76% had EGFR mutation data and 17 % had KRAS mutation data. Of the 2078 pts with known EGFR status, 246 (12%) had EGFRm and 1832 (88%) had EGFR wildtype (wt). Of the 477 pts with known KRAS status, 136 (29%) had KRASm and 341 (71%) had KRASwt. The results of subgroup comparisons are summarized in the table. Conclusions: Pts with EGFRwt tend to have better outcomes than pts with EGFRm when treated with ICI. Pts with EGFRm may have longer OS when treated with doc than ICI, although this finding is inconclusive. The KRAS data is limited by small numbers, but it appears that KRASwt derive the expected benefit from ICI. Future studies should include full data capture of key oncogenic driver status on all NSCLC pts, and clarify the role of ICI on different biomarker subsets. Subgroup comparison Median OS; HR (95% CI) EGFRm vs EGFRwt (Doc) 12.8 vs. 9.3; 0.86 (0.65, 1.13) EGFRm vs EGFRwt (ICI) 9.4 vs. 12.8; 1.40 (1.10, 1.78) ICI vs Doc (EGFRwt) 12.8 vs. 9.3; 0.72 (0.60, 0.87) ICI vs Doc (EGFRm) 9.4 vs. 12.8; 1.18 (0.83, 1.68) KRASm vs KRASwt (Doc) 8.8 vs. 11.0; 1.29 (0.92, 1.80) KRASm vs KRASwt (ICI) 14.3 vs. 12.1; 0.79 (0.54, 1.16) ICI vs Doc (KRASwt) 12.1 vs. 11.0; 0.64 (0.41, 0.99) ICI vs Doc (KRASm) 14.3 vs. 8.8; 1.03 (0.75, 1.41)
Alterations in the Β-catenin pathway in non-small cell lung cancer to define a distinct molecular subtype with prognostic and therapeutic implications.
Authors: Saveri Bhattacharya, Aswin Somasundaram, Fei Ding, Autumn Gaither-Davis, Arjun Pennathur, William A LaFramboise, Sanja Dacic, Brenda F Kurland, Laura P. Stabile, Timothy Francis Burns
Journal: Journal of Clinical Oncology (2017)

11584 Background: The treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the development of targeted therapy for distinct molecular subsets. Activation of the β-catenin pathway is essential for colorectal carcinoma tumorigenesis and has been implicated in hepatocellular, thyroid and ovarian cancer. The β-catenin pathway is involved in the cell adhesion complex and Wnt signaling. While mutations in this pathway have been reported in NSCLC and β-catenin overexpression correlates with worse survival, its role in lung tumorigenesis is poorly understood. Methods: We performed targeted next generation sequencing using the Ion Torrent Hotspot Cancer Panel v.2 on tumor tissue from 244 NSCLC patients in which we have defined key demographic and clinical parameters including stage and survival. This cohort contained 91 Stage I cases with mRNA expression data using an Illumina platform. Co-occurrence of genes in the β-catenin pathway and 27 other genes in the panel were assessed by Fisher’s exact test, with Benjamini-Hochberg adjustment for multiple comparisons. Results: Seventeen of 244 tumors had mutations in the β-catenin pathway (APC, CTNNB1, and NOTCH1): 10/170 non-squamous NSCLC (6%, 95% CI 3%-10%), and 7/70 squamous NSCLC (10%, 95% CI 5%-19%). The rate of EGFR and RB1 mutations was higher in tumors with b-catenin pathway mutation (5/17 and 2/17) than in those without (13/227 and 0/227, adjusted p = 0.06 for both). The presence of an APC mutation was also associated with higher mRNA expression of the pro-survival protein, BCL2 (n = 91; 5/41 vs. 0/50, unadjusted p = 0.022, adjusted p = 0.3). Furthermore, APC mutations were more frequently observed in tumors with higher levels of EMT markers (high VIM 8% vs. low VIM 0%, unadjusted p = 0.16) and EMT transcription factors (10% vs. low expression 2%, unadjusted p = 0.16). Finally, we observed a trend toward worse overall survival in non-squamous tumors with mutations in the β-catenin pathway (n = 170, log rank test p = 0.07). Conclusions: These studies suggest that tumors with b-catenin pathway alterations are defined by a more mesenchymal and potentially drug resistant subtype which portends a poor prognosis.
Upfront next generation sequencing in NSCLC: A publicly funded perspective.
Authors: Kirstin Perdrizet, Tracy Stockley, Ming Sound Tsao, Joshua Morganstein, Suzanne Kamel-Reid, Laura Ranich, Frances A. Shepherd, Geoffrey Liu, Penelope Ann Bradbury, David Hwang, Prodipto Pal, Joerg Schwock, Scott L. Boerner, Jennifer H Law, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2018)

12062 Background: A growing number of actionable targets in non small cell lung cancer (NSCLC) have led to the need for molecular profiling beyond the standard of care (SOC) EGFR/ALK. Here we present actionable targets, impact on patient treatment, clinical trial opportunities and costs using the Illumina TruSight Tumour 15 panel (TST15) for NSCLC samples. Methods: In addition to immunohistochemistry for ALK and PDL-1, tissue-based next generation sequencing using the TST15 was reflexively performed on all new non-squamous NSCLC specimens at the University Health Network (Toronto, Canada) between February and December 2017. The panel identifies hot spot mutations in KRAS, EGFR, TP53, PIK3CA, BRAF, ERBB2, FOXL2, GNA11, GNAQ, KIT, NRAS, PDGFRA, RET, AKT1 and MET, but not fusions, copy number variations (CNV) nor MET exon 14 skipping mutations. Patient age, stage, pathologic subtype and genotyping results were collected prospectively. Treatment changes as a result of TST15 and clinical trial opportunities (using clinicaltrials.gov) were identified. Incremental testing costs were based on direct laboratory costs, but not personnel and administration costs. Results: Testing included 284 samples from 282 patients. The TST15 panel identified 343 mutations from 284 samples. Sample demographics include: male/female 53/47%, stage 1/2/3/4 33/7/16/44%. Incremental actionable targets beyond EGFR and ALK were identified in 2.6% of specimens (ERBB2 1.7%, BRAF V600E 0.9%). Most mutations occurred in TP53 (43%), EGFR (25%) and KRAS (24%), with co-mutations in 31% (TP53, KRAS, EGFR). To date, one patient has had a treatment change as a result of TST15 beyond targeting EGFR. Above SOC clinical trial options were identified for 73% of stage IV and 25% of stage III patients. 3.6 samples were needed to identify one actionable mutation, predominantly in EGFR, at an estimated cost of $1919 CAD per target. Conclusions: Extended genotyping with TST15 in NSCLC identifies many actionable mutations and improves clinical trial options for patients. Despite this, impact on patient treatment beyond targeting EGFR is minimal. To enhance the number of targets and minimize costs, population-based comprehensive testing with a panel that includes fusions/CNV is needed.
P01.004 New techniques in Radiotherapy for brain tumors, brain metastasis and pediatric gliomas, VMAT (volumetric modulated arc therapy) and SIB technique (simultaneous integrated boost) - Neuroaxis Radiation
Authors: M Theodorou
Journal: Neuro-Oncology (2018)

With the VAMT technique we radiated the brain tumors such as Glioblastomas, Astrocytomas, low grade Gliomas, Gliomas -Recurrence, meningiomas, acustic neurinomas, pituitary adenomas, brain metastasis and pediatric gliomas and Neuroaxisradiation for PNET and Medulloblastoma. With the VMAT plan the PTV coverage is higher compared the 3D conformal technique and the radiation for the OAR (organs at risk) is less so the safety for the organ at risk is a significant factor to choose the VMAT technique. Due to the lower dose in the organ at risks the rate for acute side effects and late side effects is lower such as the radionecrosis risk. The Neuroaxis Radiation (Brain and whole spine) in VMAT technique delivers high coverage in the target and a good toleration of the treatment without significant side effects such as gastrointestinal symptoms. Mild fatigue and nausea is mentioned and alopecia at the end of radiation. The simultaneous integrated boost (SIB) delivers higher dose for the macroscopic tumor daily and at the same time the whole target inclusive safe margin takes lower dose. The toleration is also good without significant side effects. In conclusion we can suggest the New techniques in Radiotherapy using the VMAT technique for brain tumor due to the high coverage of the targets, the safety for the OAR and the short time radiation especially for little children in order to avoid sedation.
Well differentiated / dedifferentiated liposarcoma: Are patients at risk of developing a second cancer?
Authors: Eric E. Jung, Shefali Chopra, Ann S. Hamilton, William W. Tseng
Journal: Journal of Clinical Oncology (2016)

e22542 Background: Well differentiated / dedifferentiated (WD / DD) liposarcoma is one of the most common subtypes of soft tissue sarcomas. There are no known risk factors and a genetic predisposition has never been reported. We examined a case series of patients at our institution with WD / DD liposarcoma to determine the occurrence of a concurrent or subsequent second cancer and also determined the risk of second cancers among WD/DD liposarcoma cases included in the large, population-based National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database. Methods: For the case series, patient demographics and clinicopathologic data were collected from the available medical records at our institution from July 2014 to December 2015. For the SEER database analysis, we selected all adult patients from 9 combined registries who were diagnosed with WD / DD liposarcoma between 1973-2012. Observed/expected (O/E) ratios of concurrent or subsequent primary malignancies were calculated by comparing to the age-adjusted cancer incidence in the general population using the multiple primary standardized incidence ratio session of SEER*stat software. Results: At our institution, 5 out of 20 consecutive patients (25%) with WD / DD liposarcoma had a concurrent second cancer: T cell lymphoma, papillary thyroid cancer, renal cell carcinoma, gallbladder cancer and colon cancer. Genetic testing was completed in 3 of these patients without identification of any known hereditary cancer syndromes. In the SEER database, among 1,845 patients diagnosed with WD / DD liposarcoma, 269 patients (14.6%) had 314 concurrent or subsequent second cancers with an O/E ratio of 1.33 (99% CI = 1.15-1.54). In 69 patients (3.7%), this event occurred within 2 years of the liposarcoma diagnosis with an O/E ratio of 1.81 (99% CI = 1.33-2.40). Conclusions: In some patients with WD / DD liposarcoma, there appears to be an increased risk of developing a second cancer compared to the general population. The etiology of this novel observation is unclear, however close screening for additional cancers may be beneficial in these patients. Further studies including whole genome sequencing, are ongoing.
First-in-human, first-in-class phase 1a study of BXQ-350 for solid tumors and gliomas.
Authors: Olivier Rixe, John Charles Morris, Vinay K. Puduvalli, John L. Villano, Trisha Michel Wise-Draper, Carolyn Muller, Angela N. Johnson, Robert Wesolowski, Xiaoyang Qi
Journal: Journal of Clinical Oncology (2018)

2517 Background: BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C and phosphatidylserine. BXQ-350 demonstrated antitumor effects in vitro and in vivo, particularly in glioma and pancreatic cancer models. Methods: A phase 1a dose-escalation trial (NCT02859857; Phase 1b ongoing) was conducted in refractory solid tumors/high-grade glioma (HGG) patients (Pt) by administering escalating IV BXQ-350 doses of 0.7, 1.1, 1.4, 1.8, or 2.4 mg/kg on days 1-5, 8, 10, 12, 15, 22 (cycle 1) and at 28-day cycles thereafter. Response was assessed at day 113 by RECIST or RANO. Results: 17 Pt (age 24-67) with a median 7 (range, 2-12) prior systemic therapies completed a median 2 (range, 1-6) cycles without DLTs or treatment-related serious adverse events (AEs). Moderately severe related AEs occurred in 3 (100%), 1 (33%), 1 (33%), and 2 (25%) Pt at 1.1, 1.4, 1.8, and 2.4 mg/kg cohort doses, respectively. The most common treatment-related AEs was transient fatigue (n = 4, 23.5%). At 2.4 mg/kg, 1 Pt had moderate blood pressure elevation. Best response in 7 Pt completing to day 113 was 1 PR (appendiceal carcinoma) at 2.4 mg/kg, and 6 SD (1 HGG Pt at 0.7 mg/kg had stable disease >12+ months, and 6 had improved day 113 RANO/RECIST). BXQ-350 pharmacokinetics was dose proportional with half-life and Cmax, consistent with preclinical data. Conclusions: BXQ-350 showed clinical activity in heavily pre-treated patients with advanced solid and brain tumors. BXQ-350 has a tolerable safety profile with no significant DLT at the highest planned dose, supporting continued monotherapy dose expansion at 2.4 mg/kg. Clinical trial information: NCT 02859857.DOSE (mg/kg) N 0.7 1 1.1 3 1.4 3 1.8 3 2.4 8 Mean Age, F:M 64, 0:1 53, 0:3 58, 2:1 49, 1:2 54, 2.2 Prior systemic therapy, # cycles, range 7, 6 5-7, 2-4 2-12, 1-3 3-8, 2-6 4-12, 1-4 Solid Tumor n, Improved RANO n/N D 113 1, 0 2, 1/1 1, 1/2 1, 0 5, 0 HGG n, Improved RECIST, n/N D 113 1, 1/1 1, 0 2, 0 2, 0 3, 2/2 Adverse Event (n case, n event) 1, 15 3, 54 3, 37 3, 32 8, 80 Moderate severity related 3, 6 1, 1 1, 2 2, 2 Fatigue 2, 2 1, 2 1, 1 Neutropenia, EKG, Balance, Nerv, Dysarthria, Urin, BP 3, 4 Serious non-related – GI, hyponatremia, weak 1, 1 1, 4 1, 3 1, 3 3, 5