tbuckley/cabot-search huggingface dataset:
Peripheral blood-based genetic signatures for early diagnosis of micro-nodular lung cancer.
Authors: Baohui Han, Changming Cheng, Huiming Wang, Min Wang, Choong-Chin Liew
Journal: Journal of Clinical Oncology (2016)

e20051 Background: Small pulmonary nodules less than 10 mm are difficult to diagnose lung cancer, but it is also the best opportunity to cure lung cancer. The national lung cancer screening test (NLST) confirmed: low dose CT screening could reduce lung cancer mortality. However, LDCT screening for lung cancer has some limitations, such as the detection of lung cancer is mostly around the adenocarcinoma, the early detection of central type of lung cancer is relatively difficult, relatively high false positive rate, it is difficult to accurately measure the growth rate of small nodules. In a recent lung cancer screening study launched in Shanghai China, 25.6%(742 cases ) peoples were identified with pulmonary nodules among 2892 participants using LDCT. 91.7% pulmonary nodules were benignant. More than 70% pulmonary nodules identified were micro-nodule that has the size less than 10 mm, making fine needle biopsy sampling difficult for further diagnosis. There is an urgent need to develop a non-invasive and cost-effective method to discriminate micro-nodular lung cancer from benign pulmonary diseases. Our previous reports and other studies have found that gene expression profiles derived from peripheral blood samples convey information as to the presence and status of a number of diseases, including cancers. Methods: In this study we compared blood gene expression data in72 patients with micro-nodules surgically and pathologically diagnosed as lung cancer and 42 health controls and 34 benign pulmonary diseases. Results: We were able to identify a six-gene panel that could discriminate the micro-nodular lung cancer from the health controls and benign pulmonary diseases with 81% accuracy, 78% sensitivity,84% specificity and 0.92 of ROC AUC value. Independent validation testing confirmed this performance with 72% accuracy, 72% sensitivity,72% specificity and 0.81 of ROC AUC value. Conclusions: Our results indicate the feasibility of using blood based genetic signatures to identify micro-nodular lung cancer and may find use as a blood test in screening for lung cancer at very early stages. idation testing confirmed this performance with 72% accuracy, 72% sensitivity,72% specificity and 0.81 of ROC AUC value.
A randomized phase 2, multicenter, open-label study of trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing gastric cancer.
Authors: Kensei Yamaguchi, Yung-Jue Bang, Daisuke Sakai, Hisateru Yasui, Yoshinori Kawaguchi, Masahiro Sugihara, Kaku Saito, Rita Dalal, Kohei Shitara
Journal: Journal of Clinical Oncology (2018)

TPS4133 Background: There is no HER2-targeted therapy for patients with HER2-positive gastric cancer who progressed on trastuzumab-based therapy. DS-8201a is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker (deruxtecan), and with a high drug-to-antibody ratio of 7 to 8. In the ongoing phase 1 DS8201-A-J101 trial, DS-8201a showed a manageable safety profile and promising antitumor activity in salvage-line subjects with gastric cancer who previously received trastuzumab (confirmed objective response rate [ORR] of 45.5% at Oct 16, 2017 data cutoff) (Iwasa et al, ASCO-GI 2018). Methods: The randomized, phase 2, multicenter, open-label, DESTINY-Gastric01 study will assess the efficacy and safety of DS-8201a in HER2-expressing gastric cancer subjects. The primary cohort, HER2-positive (IHC 3+ or IHC 2+/ISH+) subjects who progressed after ≥2 prior regimens and previously received trastuzumab, will be randomized (2:1) to DS-8201a (6.4 mg/kg dose; once every 3 weeks) or physician’s choice (irinotecan or paclitaxel). Two nonrandomized exploratory cohorts will assess the efficacy and safety of DS-8201a in subjects with HER2-low gastric cancer (IHC 2+/ISH- and IHC 1+, respectively) who are treatment-naïve to HER2-targeted therapies. The primary endpoint is ORR assessed by an independent central review; secondary endpoints include overall survival (OS), progression-free survival, duration of response, disease control rate, pharmacokinetics, and safety (as shown in ClinicalTrials.gov). The primary analyses for ORR and interim OS analysis will occur after all subjects complete tumor assessments on week 18 and when approximately 108 OS events are observed, whichever comes later. The primary cohort will enroll 180 subjects; providing 92.9% power to detect a difference between the ORR of 40% for DS-8201a vs 15% for physician’s choice. Each exploratory cohort will enroll a maximum of 20 subjects. Enrollment began in October 2017. As of Feb 13, 2018, 12 of 180 subjects have been enrolled. Clinical trial information: NCT03329690.
Preliminary safety of deep/visceral (D/V) image guided (IG) intratumoral injection (ITI) of IMO-2125.
Authors: Hani M. Babiker, Erkut Hasan Borazanci, Vivek Subbiah, Adi Diab, Gregory Woodhead, Charles Hennemeyer, Ankit H Shah, Rolf Hultsch, Ravi Murthy, Christopher Miller, Suzanne Swann, Shah Rahimian, James Geib, Melissa Catlett
Journal: Journal of Clinical Oncology (2018)

e15150 Background: Patients without palpable lesions who are candidates for intratumoral immunotherapy may need D/V IG agent delivery. Novel immuno-oncology (I-O) agents requiring ITI highlight the need to demonstrate its safety. IG percutaneous access to D/V structures is common for oncology procedures in which biopsies, in situ tumor ablation or delivery of therapeutics are necessary. IMO-2125, a TLR-9 agonist, is delivered by ITI into lymph node (LN), palpable, or D/V lesions. We hypothesize that D/V ITI with IMO-2125 with IG is safe and should be investigated. Methods: Two Ph1 dose escalation trials of IMO-2125 studied safety. Subjects with advanced metastatic disease were enrolled. Maximum Tolerated Dose has not been reached; dose escalation continues. IG was required for D/V ITI. Although 25 Ga was recommended, the final selection of needle size (20-25 Ga) and method (real time ultrasound/CT-guided) was decided by the performing Interventional Radiologist (IR). Performed under local anesthetic with or without IV sedation, ITI (1-4 ml) occurred weekly during cycle 1 and then every 3 wks. Biopsies occurred at screening, 24hr after 1st dose, and at 1st imaging response assessment (18-19 Ga coaxial). All subjects were monitored for safety. Results: Accrual occurred 12/2015 – 11/2017. As of 08Jan2018, a total of 35 subjects received IMO-2125 via ITI [median # of inj: 5 (2-6)]. Most common treatment associated adverse events (TAE): pyrexia (17). Injection Site Reactions (ISR): pain (4), erythema (1), hypersensitivity (1), soreness (1). Of these, 13 subjects received IMO-2125 via D/V ITI [median # of inj: 4 (2, 6)]. Most common TAE: pyrexia (8). ISR: pain (2), soreness (1). Site of D/V ITI Clinical trial information: NCT03052205, NCT02644967. Conclusions: Early experience suggests that D/V ITI of IMO-2125 with real time IG by IR is safe. This method is currently used in ongoing clinical trials. Site N # Inj CRC Esophageal Pancreatic Melanoma Liver 9 36 1 6 2 Adrenal gland 1 6 1 Back/Abdomen/Chest mass 2 11 2 Retroperitoneal LN 1 5 1 Total 13 58 1 1 6 5 No DLTs and no complications to D/V ITI of IMO-2125 were reported.
Prognostic factors of malignant paraganglioma and pheochromocytoma: A SEER database review.
Authors: Lin Mei, Francesco Celi, Steven Smith, Le Kang, Taha Al-Juhaishi, Sosipatros Alexandros Boikos
Journal: Journal of Clinical Oncology (2018)

e23538 Background: Paraganglioma (PGL) and pheochromocytoma (PCC) are rare malignancy while pathogenesis is strongly influenced by genetics. The prognostic factors of these patient remain poorly defined. We aim to study the epidemiology and survival pattern by analyzing the Survival, Epidemiology, and End Result (SEER) database. Methods: SEER database was reviewed for patients whom has histological diagnosis of PGL or PCC between 1973 and 2013. Multiple variables including age, gender, race, primary location, laterality, stage, tumor marker, and prior radiotherapy or surgical resection were investigated. Primary outcome was overall survival (OS) and disease specific survival (DSS). These were estimated by using Kaplan-Meier survival curve and log-rank test. Hazard ratios (HR) were calculated using Cox models. Results: A total of 1074 patients with PGL or PCC were identified, of which 1014 were analyzed. Younger age was associated with better outcomes. The median OS of patients younger than age of 30, 30-60 and > 60 were 298, 114 and 63 months respectively (P < 0.01). Male showed shorter survival than female with median OS of 108 vs. 117 months (HR: 1.26, P = 0.01). The incidence of second primary malignancy in PGL/PCC patients was about 14.6%. This population had a significant longer DSS (HR: 0.19, P < 0.01), rather than OS (HR: 0.78, P = 0.07). In univariate analysis, other factors, including surgical resection (HR: 0.41, P < 0.01) and origin from of aortic/carotid bodies (HR: 0.62, P < 0.01) conferred remarkable OS and DSS survival advantage. In contrast, prior radiotherapy (HR: 1.66, P < 0.01) and distant spread (HR: 2.82, P < 0.01) portended worse prognosis. Laterality, race, high levels of serum catecholamines did not demonstrate a significant association with OS and DSS. Conclusions: PGL and PCC have distinct demographics related to its underlying genetics. In these patients, younger age, female sex, origin from aortic/carotid bodies, complete surgical resection, local/regional disease, as well as concomitant second primary malignancy were associated with better prognosis. The observed potential negative impact of radiotherapy warrants further investigation.
Use of phenotypic profiling to determine sensitivity of gemcitabine with nab-paclitaxel for front-line treatment of pancreatic cancer.
Authors: Mark Ricigliano, Brandon Cooper, Andrew Bartlett, Kenneth H. Yu
Journal: Journal of Clinical Oncology (2017)

e15749 Background: Standard of care treatment for pancreatic adenocarcinoma (PDAC) consists of FOLFIRINOX (FFX) or gemcitabine with nab-paclitaxel (G/nab-P) in the front-line setting. The decision to use FFX or G/nab-P is a physician choice as there are no standardized assays to guide treatment selection. Here we report the results of a prospective clinical trial to evaluate a blood-based assay to select patients for G/nab-P in the front line setting. The assay was developed on the premise that if two patients have the same genomic profile, they will have the same response to chemotherapy. Methods: In a prospective study, 37 PDAC patients were pre-selected to receive G/nab-P at Memorial Sloan Kettering as a front-line treatment. Circulating tumor and infiltrating cells (CTICs) were isolated from peripheral blood samples using a cell invasion matrix. RNA was isolated and cDNA synthesized for qPCR gene expression. 83 drug transport genes were used as classifiers to create four treatment templates, one each for G/nab-P, GAX, FFX and FOLFOX. Nearest Template Prediction was used to match the genomic profile of the PDAC patient sample to one of the four a priori defined treatment templates. Results: Front-line PFS was correlated to treatment phenotype with G/nab-P (8.6 mos.), GAX (6.7mos.), FFX (5.6 mos.) and FOLFOX (5.0 mos.). Patients with a positive sensitivity (S+) to G/nab-P demonstrated a median PFS of 7.7 mos. vs. 4.7 mos. compared to those with a negative sensitivity (S-) to G/nab-P (p-value = 0.027). Contingency analysis demonstrated sensitivity (78%), specificity (64%), and likelihood ratio (2.139) with p-value = 0.048. Correlation between G/nab-P sensitivity and PFS was significant as measured by linear regression (R 2 = 0.90, p-value = 0.013). Conclusions: Phenotype profiling for selecting front-line treatment to G/nab-P is feasible in PDAC. Clinical trial information: NCT01474564.
Incidence of hypersensitivity reactions to carboplatin or paclitaxel in patients with ovarian, Fallopian tube, or primary peritoneal cancer with or without <i>BRCA1</i> or <i>BRCA2</i> mutations.
Authors: Andrew Garcia, Corey Frahm, Joanne M. Jeter, Ivo Abraham, Setsuko K. Chambers, Janiel M. Cragun, Ali McBride
Journal: Journal of Clinical Oncology (2018)

e18758 Background: Platinum-based regimens have been shown to yield favorable outcomes for women with BRCA1 or BRCA2 mutations and metastatic ovarian, fallopian tube, or primary peritoneal cancers. As cumulative carboplatin exposure rises, incidence of hypersensitivity reactions (HSRs) to carboplatin rises as well, sometimes requiring cessation of therapy. Recent data have shown an association between cumulative carboplatin exposure and greater incidence of HSRs in individuals carrying a BRCA mutation. Many of these patients also receive combination chemotherapy with taxanes such as paclitaxel, which are known to cause significant hypersensitivity reactions. Methods: Retrospective chart review involving ovarian, fallopian tube, and primary peritoneal cancer patients at the University of Arizona Cancer Center who underwent treatment with a carboplatin-containing regimens between January 2012 and April 2016. Of these, 62 patients with BRCA test results constituted the evaluable sample. Fisher’s Exact test was used to analyze development of HSRs to carboplatin or paclitaxel. Results: Out of the 62 BRCA-tested patients, 15 were treated with carboplatin monotherapy and 47 with combination therapy containing carboplatin, including 44 with paclitaxel-containing regimens. HSRs occurred in 4/13 (30.8%) BRCA-mutated patients and 22/49 (44.9%) BRCA wild-type patients (p = 0.5291). In the paclitaxel group, HSRs were observed in 1/13 (7.7%) BRCA-mutated patients and 26/49 (53.1%) BRCA wild-type patients (p = 0.0039). Overall, there were 11 grade 1 reactions, 14 grade 2 reactions, and 16 grade 3 reactions to carboplatin, based on the CTCAE v4.0. All reactions to carboplatin in BRCA-mutated patients were grade 1. BRCA wild-type patients with grade 2 or 3 HSRs often presented with 2 or more symptoms. For those with paclitaxel HSRs, all events manifested as grade 2 reactions. Conclusions: Presence of a BRCA1 or BRCA2 mutation was not associated with a higher incidence of HSRs in patients receiving carboplatin. Further studies are needed to clarify the association between BRCA mutations and development of carboplatin or paclitaxel HSRs.
Additional value of tumour growth rate (TGR) in patients (pts) diagnosed with well-differentiated neuroendocrine tumours (NETs) achieving RECIST-defined stable disease (SD): Subgroup analysis of the GREPONET study.
Authors: Angela Lamarca, Joakim Crona, Maxime Ronot, Marta Opalinska, Carlos Lopez Lopez, Daniela Pezzutti, Luciana Carvalho, Regis Franca, Pavan Najran, Louis de Mestier, Hector Vidal Trueba, Niklaus Schaefer, Anders Sundin, Frederico Costa, Marianne Pavel, Clarisse Dromain
Journal: Journal of Clinical Oncology (2018)

4094 Background: Response evaluation with RECIST has limitations when applied to slow growing malignancies with low objective response rates, such as NETs, when most pts achieve SD as best response. TGR represents the percentage of change in tumour volume per month and is postulated to overcome such limitations. Methods: Pts from 7 centres with advanced, grade (G) 1/2 NETs from the pancreas (P) or small bowel (SB) initiating systemic treatment (ST) or watch and wait (WW) and who achieved SD as best response were eligible. Baseline and follow-up scans were retrospectively reviewed for TGR calculation (%/month) at 3 (+/-1) months (m) of study entry (TGR3m). A previously identified TGR3m cut-off of 0.8 %/m was applied to assess impact of TGR3m on progression-free survival (PFS) (Kaplan-Meier/Cox Regression). Results: Out of 222 pts in the GREPONET study, 81 were eligible and included in this analysis: 54.3% SB, 45.7% P; 87.7% metastatic; 61.7% G2; 70.4% treatment-naïve). STs were; somatostatin analogues 34.6%, chemotherapy 22.2%, targeted therapies 12.4%, radionuclide therapy 4.9%; WW 25.9%. Median (med) PFS was 22.9m (95%CI 17.3-30.6); median follow-up 39.8m. TGR3m was available for all 81 pts [med 0 (95%CI -28.7-71.5)]; TGR3m cut-off of 0.8 %/m stratified SD pts in two groups with different outcomes: the pts with TGR3m< 0.8 (55 pts; 67.9%; med TGR3m -0.8 [95%CI -1.7-0]) had a significantly longer med PFS (27.4m (95%CI 19.7-39.1)) vs. pts with TGR3m≥0.8 (26 pts; 32.1%; med TGR3m 3.8 [95%CI 2.9-6.2]; med PFS 9.8m (95%CI 6.4-23.6)); p 0.003. TGR3m and treatment were significant in univariate Cox regression and included in multivariable Cox regression: TGR3m≥0.8 (HR 3.6 [95%CI 1.9-6.6]; p < 0.001) was independent factor related to shorter PFS. Conclusions: TGR3m is able to subclassify patients otherwise defined as SD by RECIST in two groups with different outcomes. By applying TGR we identify pts at higher risk of early progression who may require closer radiological follow-up, even if initially defined as SD by RECIST.
Overall survival results of ICON6: A trial of chemotherapy and cediranib in relapsed ovarian cancer.
Authors: Jonathan A. Ledermann, Andrew C. Embleton, Timothy Perren, Gordon C. Jayson, Gordon J. S. Rustin, Stanley B. Kaye, Hal W. Hirte, Amit M. Oza, Michelle Margaret Vaughan, Michael Friedlander, Antonio Gonzalez Martin, Elizabeth Clark, Babasola O Popoola, Laura Farrelly, Ann Marie Swart, Adrian Cook, Richard S. Kaplan, Mahesh K B Parmar
Journal: Journal of Clinical Oncology (2017)

5506 Background: ICON6 is a three-arm double-blind, placebo-controlled phase 3 trial of cediranib in platinum-sensitive relapsed ovarian cancer (NCT00532194). The primary analysis (Ledermann et al Lancet 2016) showed a significant (p &lt; 0.0001), 2.3 month extension in progression-free survival (PFS) using cediranib with chemotherapy and as maintenance compared to chemotherapy and placebo. We present the final overall survival (OS) results. Methods: The trial was originally designed to recruit 2000 patients with OS as the primary endpoint. AstraZeneca discontinued cediranib development in Sep 2011, leading to an unplanned redesign prior to analysis. The sample size was reduced and primary outcome became PFS, comparing two arms, placebo (A) to cediranib given with chemotherapy and as maintenance (C). In arm B cediranib was given with chemotherapy followed by placebo maintenance. Analysis of PFS was performed on a sample size of 456 patients receiving a 20mg dose of cediranib. At the primary analysis, 52% patients had died; this mature OS analysis was performed after 85% patients died. Results: The OS analysis was performed at a median 25.6 months follow up; 102/118 (86%) died in A and 140/164 (85%) in C. In A the median survival was 19.9 months (95% CI: 17.4, 26.5) and in C 27.3 months (24.8, 33.0). Using the logrank test the Hazard Ratio estimate was 0.85 (0.66, 1.10) in favour of cediranib (p = 0.21). Evidence of non-proportionality of the survival curves was observed (p = 0.0029), so we measured the Restricted Mean Survival Time as an alternative to the median. Over 6 years, there was a 4.8 month (-0.1, 9.8) increase in time to death in C compared to A, from 29.4 to 34.2 months. The mean for arm B (32.0 months) was consistent with a benefit of increased use of cediranib. Conclusions: Cediranib has demonstrated a significant effect in increasing PFS. The mature survival analysis (85%) shows an improvement in median OS of 7.4 months, and an incremental benefit with increased cediranib use. The previously published significant PFS benefit coupled with the increase in OS highlights the potential value of cediranib in platinum-sensitive recurrent ovarian cancer. Further exploration of cediranib in this setting is underway. Clinical trial information: NCT00532194.
Phase I study of DKN-01, an anti-DKK1 antibody, in combination with gemcitabine (G) and cisplatin (C) in patients (pts) with advanced biliary cancer.
Authors: Jennifer Rachel Eads, Lipika Goyal, Stacey Stein, Anthony B. El-Khoueiry, Gulam A Manji, Thomas Adam Abrams, Steven B. Landau, Cynthia A. Sirard
Journal: Journal of Clinical Oncology (2016)

e15603 Background: DKK1 is an inhibitor of the canonical Wnt/β-catenin pathway and a direct modulator of non-canonical signaling. DKK1 is thought to enhance the invasive properties of cholangiocarcinoma tumor cells, promoting lymph node metastasis by induction of MMP9 and VEGF-C. High tissue DKK1 expression in intrahepatic cholangiocarcinoma is associated with advanced stage and shorter survival. DKN-01 (D) is a humanized monoclonal antibody to DKK1 with clinical activity in non-small cell lung and esophageal cancers. This study evaluated the maximum tolerated dose (MTD), safety and early activity of D in combination with GC in pts with advanced biliary cancer. Methods: In Part A (3+3 design), pts received D at either 150 or 300 mg with G 1000 mg/m2 and C 25 mg/m2 on days 1 and 8 of each 21 day cycle. Part B (300 mg D expansion) is ongoing. Adverse events (AEs) assessed using CTCAEv4.03 and responses assessed using RECISTv1.1. Results: 7 pts were enrolled: 4 treated at 150 mg and 3 treated at 300 mg; 6 pts had DKK1+ tumor tissue. Median age: 66; Male: 57%; White: 100%. Median prior therapies: 0 (range 0, 2). No dose limiting toxicities or related serious AEs were seen. Treatment emergent AEs (TEAEs): anemia, thrombocytopenia (n = 5 each), fatigue, neutropenia (n = 4 each), hypoalbuminemia, hypocalcemia, hyponatremia, increased ALT, increased alkaline phosphatase (AP), and leukopenia (n = 3 each). DKN-related TEAEs: anemia, thrombocytopenia, fatigue, neutropenia (n = 3 each) and hyponatremia, increased AP and leukopenia (n = 2 each). Majority of D related TEAEs were Grade 1/2; only D related grade 3/4 TEAE in > 1 pt was neutropenia (n = 3). The MTD of D + GC was 300 mg. Among 4 pts treated with 150 mg D, 3 pts had stable disease (SD), 1 pt had progressive disease (DKK1- tumor tissue). In 3 pts treated with 300 mg D, 1 pt had a partial response (PR), 2 pts SD. Median number of cycles: 4 (range 1, 8), 3 pts still on therapy. Conclusions: Part A is complete. D + GC is well tolerated and D does not appear to alter the known GC safety profile. Early clinical activity with D + GC suggests possible prolonged SD, with one PR occurring after 4 cycles. Further investigation is ongoing. Clinical trial information: NCT02375880. Clinical trial information: NCT02375880.