tbuckley/cabot-search huggingface dataset:
First experiences with an AI-assisted clinical evidence system to evaluate clinical consensus among clinical trial publications.
Authors: Fernando Jose Suarez Saiz, Alexandra Urman, Corey Sanders, Michael W Britt, Robert Nielsen, Rick J Stevens
Journal: Journal of Clinical Oncology (2018)

e18583 Background: The ability to review the most current evidence is pressured by the volume and rapid growth of new and sometimes inconsistent medical information. IBM Watson Evidence Service (WES) is being developed to provide a level of confidence in published findings based on patient cohorts and treatment outcome consensus. Methods: A set of 60,000 articles for 12 cancer types are defined using PubMed query language for WES. The resulting corpus is processed for extraction by natural language processing (NLP) using deep learning and term disambiguation as well as extraction of Medical Subject Headings (MeSH) from the Medline record. Extraction of comparative statements related to efficacy is done for survival, response, toxicity and quality of life along with 18 oncology relevant attributes. Then a set of abstracts that report relevant outcomes for a therapy and for a patient cohort are extracted. The number of positive, negative and neutral outcomes are aggregated over the set of articles relevant to a given treatment. A summary is produced outlining the degree of concordance seen in each type of reported outcome over the set of studies involving the therapy of interest. Results: The WES runs though the corpus and measures both the volume and degree of consensus across all studies reported for each patient cohort/treatment combination and each type of reported outcome. The system measures the degree to which specific treatments have been evaluated for efficacy and how consistent the findings are for each type of outcome across the identified set of published study results. For example, fora stage IV, NSCLC patient cohort, 69 articles were found evaluating use of carboplatin + docetaxel vs other treatments. Over 51% of the studies reported relatively less favorable survival outcomes for this treatment while over 77% of these studies reported favorable toxicities for this treatment regimen. Conclusions: Here we present a novel approach that can read and clinically interpret vast amounts of unstructured and structured data, extract clinical outcome statements from clinical research publications and classify the degree to which observed outcomes are consistent across a set of clinical studies.
Fibroblast kinase 1-3 inhibitor BGJ398 in patients with <i>FGFR1</i> amplified squamous non-small cell lung cancer treated in a phase I study: Evaluation of tumor tissue and response at a single center.
Authors: Lucia Nogova, Florian Malchers, Elisabeth Bitter, Sebastian Yves Friedrich Michels, Rieke Nila Fischer, Matthias Scheffler, Masyar Gardizi, Vanessa Brandes, Andreas H. Scheel, Karl-Otto Kambartel, Stefan Krüger, Monika Heidi Serke, Randi Isaacs, Dale Porter, Reinhard Buettner, Roman K. Thomas, Juergen Wolf
Journal: Journal of Clinical Oncology (2017)

e20664 Background: Fibroblast growth factor receptor 1 ( FGFR1) amplification in squamous cell non-small cell lung cancer (sqNSCLC) has been described as potential oncogenic and targetable driver in cell lines and murine models. However, a phase I study evaluating FGFR 1-3 inhibitor BGJ398 showed moderate response rate of 11% in FGFR1amplified sgNSCLC treated with dose ≥ 100mg. To identify underlying mechanisms of resistance, we analyzed tumor tissues of selected patients. Methods: Within the phase I BGJ398 study, patients (pts) with FGFR1amplified sqNSCLC were treated orally with escalating dose (5 to 150mg) of BGJ398 once daily (QD) or 50mg twice a day. In the expansion phase, pts received BGJ398 either continuously QD or on a 3-weeks on/1-week off schedule. CT scans for response were performed every 8 weeks. Available tumor tissue of pts treated with BGJ398 at our center was analyzed using hybrid capture–based massively parallel sequencing (CAGE). Results: Twenty-one pts with FGFR1 amplified sqNSCLC were treated with ≥ 100mg BGJ398 at our site. As best response, 3 pts showed partial response (PR), 7 pts stable disease (SD) and 7 pts progressive disease (PD). Two pts withdrew their consents and 2 pts died ahead of first CT scan: one due to infection and one due to sudden death. We performed CAGE covering 256 genes on 9 patients: on 3 pts with PR, 2 pts with SD, 2 pts with PD and 2 pts who died before first CT scan. All analyzed patients harbored mutations in TP53. Additionally, we detected two CDKN2A (one patient with PR and one patient who died before first CT) and three MLL2 stop codon and frame shift mutations (two patients with SD and one patient with PD). Of interest, we identified three patients with two canonical (one patient with SD and one patient who died before first CT) and one non-canonical mutations in PIK3CA(one patient with SD). Conclusions: In our analysis, MLL2 and PIK3CA mutations seem to have a negative impact on response in FGFR1 amplified pts treated with BGJ398. Further analysis with higher patient number is needed to identify the role of MLL2 and PIK3CA mutations in FGFR1 amplified sqNSCLC. Clinical trial information: NCT01004224.
Impact of intravenous cancer drug wastage on economic evaluations.
Authors: Judy Truong, Matthew C. Cheung, Helen Mai, Jessa Letargo, Alexandra Chambers, Mona Sabharwal, Maureen E. Trudeau, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2017)

6607 Background: Intravenous drugs administered through body-surface area (BSA) or weight-based dosing may cause wastage due to large and/or limited fixed vial sizes, and vial sharing restrictions. Drug wastage leads to incremental costs without incremental value to patients. Bach et al. (2016) estimated 10% of revenue ($1.8 billion) from cancer drugs would result from wastage in 2016. The pan-Canadian Oncology Drug Review (pCODR) committee provides recommendations on which drugs to publicly reimburse by reviewing clinical and economic evidence. There is considerable potential that drug wastage could impact the economic evaluations. We sought to determine the impact of modeling cancer drug wastage on the results of economic evaluations. Methods: Economic evaluations submitted by drug manufacturers and reviewed by the pCODR Economic Guidance Panel (EGP) were assessed for frequency of wastage reporting and modeling. Cost-effectiveness analyses and budget impact analyses were conducted for scenarios in which “no wastage” and “wastage” of drugs occurred. Sensitivity analyses were performed to determine the effects of BSA and weight variation. Results: 12 drugs for use in 17 indications were analyzed. Wastage was reported in 71% and incorporated in 53% of manufacturer’s models, resulting in a mean incremental cost-effectiveness ratio (ICER) increase of 6.1% (range: 1.3% to 14.6%). EGP reported and incorporated wastage for 59% of models, resulting in a mean ICER increase of 15.0% (2.6% to 48.2%). When maximum wastage (i.e. the entire unused portion of each vial is discarded) was incorporated in our independent analysis, the mean ICER increased by 24.0% (0.0% to 97.2%) and the mean 3-year total incremental costs increased by 26.0% (0.0% to 83.1%). Over a 3-year period, wastage can increase the total incremental drug budget cost by CAD $102 million nationally. Changing the mean BSA or body weight caused 45% of the drugs to use a different vial size (if available) and/or quantity, resulting in further increased drug costs. Conclusions: Wastage can have an under-recognized and significant impact on economic evaluations of intravenous chemotherapy drugs. Guidelines are needed to promote uniform and optimal modeling of drug wastage in economic evaluations.
Beyond <i>BRCA1</i> and <i>BRCA2</i>: Implementation of a multigene panel for the upfront testing of germline mutations in ovarian cancer.
Authors: Maria Beatriz Mira, Isalia Margarida Campos Miguel, Sofia Fragoso, Ana Luís, Ana Clara, Sandra Bento, Ana Gaspar Opiniao, Patricia Machado, Sidonia Santos, Paula Rodrigues, Joana Parreira, Ana Francisca, Fatima H. Vaz
Journal: Journal of Clinical Oncology (2018)

1542 Background: Germline mutations impacting homologous recombination repair have been associated with predisposition to breast (BC) and ovarian cancer (OC). OC, even if no family history (FH) confers a 10% combined probability of BRCA1/2 mutations, being a criteria for testing. BRCA1/2 detection rate may vary FH and pathology. Besides BRCA1/2, other genes have also been associated with hereditary OC. Methods: all index, consecutive, OC patients (pts) counselled between September 2016-December 2017 were tested upfront for a panel testing (PT) including BRCA1, BRCA2, RAD50, RAD51C, RAD51D and BRIP1 (BRCA Hereditary Cancer MASTER Plus methodology). All pts were required to have a pathology confirmation of OC (mucinous cases excluded). In here, we analyze the molecular results and discuss the clinical potential of PT for OC. Results: 109 female pts consented to PT (108 OC pts and 1 BC pt with a first degree relative with OC). Medium age at testing was 58.1 years (26-83). Pathogenic variants were found in 20 pts (18.3%): BRCA2 – 8 (40%), BRCA1 – 5 (25%), RAD51C – 3 (15%), RAD51D – 2 (10%), RAD50 – 1 (5%), BRIP1 – 1 (5%). Of the 8 BRCA2 pts, 2 were diagnosed with the c.156_157insAlu mutation. 13 pts (65%) had high grade serous OC and 4 pts endometrioid OC (20%). 2 pts had low grade OC, both stage III at diagnosis – one with a RAD51C mutation (c.404G > A, p.C135Y) and other with a pathogenic BRCA2 variant (c.156_157insAlu). All of these pts (except the one with BRIP1 mutation) had a personal history of OC and 3 of them had had BC and OC (1 BRCA1, 2 BRCA2). The pt with the BRIP1 mutation (c.484C > T; p.Arg162Ter) was the only one without OC: she was as BC survivor with a FH of OC. Conclusions: With this panel, and without restrictions relating to non-mucinous pathology, we observed a high (18%) germline mutation detection rate for OC. Adding 4 genes to BRCA1/2 testing increased the mutation detection rate by 53.8%. Even if counselling is complex in families harbouring variants in moderate penetrance genes, our results suggest clinical utility for OC prevention. Other genes will be included in our upfront OC panel.
TCT-547 Initial Experience With Ultrathin Strut Biodegradable Polymer-Coated Everolimus-Eluting Coronary Stent in Coronary Artery Disease Patients
Authors: K. Sivaprasad, Jaspal Singh Arneja, Dilip Kumar, Parneesh Arora, Madanmohan Balakrishnan, T.R. Raghu, Deepak Davidson, Sanjeeb Roy, Subhash Chandra
Journal: Journal of the American College of Cardiology (2018)
Spectrum of pediatric and young adult cancer survivors at risk of developing subsequent sarcomas.
Authors: Diana M. Merino, Rochelle E. Curtis, Amy Berrington De Gonzalez, Margaret A. Tucker, Lindsay M. Morton
Journal: Journal of Clinical Oncology (2016)

10572 Background: Survivors of certain pediatric cancers, particularly first primary sarcomas, have increased risks of developing subsequent sarcomas. However, understanding of the full spectrum of pediatric cancer survivors with increased risk and the magnitude of risk for young adult survivors is limited. Methods: We evaluated risk of subsequent bone and soft tissue sarcomas (STS) in > 1 year survivors aged < 40 years at first primary cancer diagnosis, as reported in SEER registries during 1975-2012. Risks were estimated among survivors of the most common malignancies other than first primary sarcomas, including cancers of the breast (n = 30,858), thyroid (n = 21,736), testis (n = 16,313), cervix (n = 14,102), central nervous system (CNS, n = 13,408), and gastrointestinal tract (n = 10,361); melanoma (n = 24,893); Hodgkin lymphoma (HL, n = 14,969), non-Hodgkin lymphoma (NHL, n = 11,776), and acute lymphoid leukemia (ALL, n = 8,261). We calculated standardized incidence ratios (SIR), comparing observed cases (O) to that expected in the general population. Results: Risks for both bone and STS were among the highest for survivors of hematologic malignancies, including NHL [bone: O = 11, SIR = 10.7 (95% CI = 5.4-19.2); STS: O = 32, SIR = 3.5 (2.4-5.0)], HL [bone: O = 13, SIR = 8.3 (4.4-14.1); STS: O = 57, SIR = 4.1 (3.1-5.3)], and ALL [bone: O = 7, SIR = 8.0 (3.2-16.5); STS: O = 7, SIR = 3.3 (1.3-6.8)]. Survivors of CNS tumors also exhibited increased risk [bone: O = 12, SIR = 10.6 (5.5-18.5); STS: O = 28, SIR = 4.3 (2.9-6.3)]. Survivors of breast cancer and melanoma exhibited modestly elevated risk of developing STS only [breast: O = 40, SIR = 2.0 (1.5-2.8); melanoma: O = 44, SIR = 1.8 (1.3-2.4)], whereas thyroid carcinoma survivors only exhibited increased risk of bone sarcomas [O = 6, SIR = 2.8 (1.0-6.2)]. In contrast, survivors of cancers of the gastrointestinal tract, testis, and cervix were not at increased risk of developing subsequent sarcomas. For certain primary cancers, risks were more pronounced among survivors exposed to radiotherapy. Conclusions: Our findings highlight a broad spectrum of pediatric, and young adult cancers with distinct risks for subsequent sarcomas, requiring awareness to improve long-term health management guidelines.
Antiangiogenetic-induced hypertension and improved outcome in cancer patients.
Authors: Sandro Barni, Giuseppina Patrizia Dognini, Fausto Petrelli, Karen Borgonovo, Mara Ghilardi, Mary Cabiddu, Maurizio Destro
Journal: Journal of Clinical Oncology (2017)

e21651 Background: Hypertension (HTN) is one of the most common adverse events observed during treatment with antiangiogenetic drugs (AAG) inhibiting the Vascular Endothelial Growth Factor Pathway. It may rise few days after anti-AAG starting, is dose dependent and reversible after its withdrawal. Some reports seem to suggest an improved outcome in patients (pts) developing HTN after AAG initiation (AAG-HTN). The aim of this study was to evaluate the impact of AAG-HTN on ORR, OS and EFS in pts receiving AAG, particularly tyrosine kinase inhibitors. Methods: All consecutive pts referred to ASST Bergamo Ovest between March 2012 and January 2017, and receiving sunitinib, sorafenib, regorafenib, pazopanib or axitinib, were evaluated. AAG- HTN was defined either as ex novo HTN or worsening of a pre-existing and pharmacologically controlled HTN, arising after AAG starting, and graded according to the NCI CTCAE 4.03. Overall survival was estimated using the Kaplan-Meyer method and hazard ratio with 95% CI was calculated, the primary endpoint was analyzed with a stratified log-rank test. Overall response rates were compared applying the chi-square test. Results: Overall 43 pts (male/female = 30/13, median age = 65yrs, range: 49-84) were evaluated. The AAG used were: sunitinib (n = 20), sorafenib (14), regorafenib (4), axitinib (3), pazopanib (2). Hypertension was present and pharmacologically controlled before AAG in 35 pts. Antiangiogenetic-related hypertension was developed in 27 pts (62.8%). Thirty-four pts were evaluable for ORR, which was observed in 44% of pts developing AAG-HTN versus 9% of those not developing AAG-HTN (p = 0.045). A trend to improved OS (hazard ratio [HR] 0.71 95%CI 0.33-1.5; P = 0.33) and EFS (HR 0.7, 95%CI 0.33-1.49; P = 0.29) in pts developing HTN was observed too. Conclusions: the development of AAG-HTN is related to an increased ORR. An improvement in OS and EFS has been postulated too, but the small number of this series did not allow to find a statistical correlation. For its potential impact on pts’ prognosis, further studies to better explore this issue should be performed and, importantly, AAG-HTN should be early recognized and properly managed.
Evaluation of screening interval and mastectomy rates among rural U.S. women with newly diagnosed breast cancer.
Authors: Jeffrey M. Peppercorn, Kevin Leo Houck, Nora Horrick, Julia Rabin, Victor Villagra, Stephanie B. Wheeler
Journal: Journal of Clinical Oncology (2016)

6542 Background: Mammography screening reduces breast cancer mortality, but there is ongoing controversy over optimal target population and interval. We sought to explore the association between screening interval and type of surgery among a population of insured rural U.S. women. Methods: Using claims data, we identified women ages 40 to 65 insured by the National Rural Electric Cooperative Association with a new diagnosis of breast cancer between 2000 and 2012. We characterized screening intervals based on mammoraphy claims prior to diagnosis. Mammography within 3 months of diagnosis was viewed as the index mammogram and we then evaluated prior screening. Mammograms within 14 months were characterized as annual, 26 months biennial, and greater than 26 months less than biennial. We evaluated the correlation between screening interval on type of surgery; mastectomy or breast conservation. We also evaluated correlation between screening interval and mastectomy plus radiation as an indicator of more intensive local therapy and possible proxy for more advanced stage of disease. Results: We identified 517 women with newly diagnosed invasive breast cancer. Two hundred twenty (42%) women were screened annually, 117 (22%) biennially, and 180 (35%) less than biennially. Overall, 120 women received mastectomy, 397 breast conserving surgery, and 59 mastectomy plus radiation therapy. Mastectomy rates were significantly lower for annual screening vs. less than biennial (17% vs. 29%, p = 0.006), but not biennial screening (24%). Mastectomy plus radiation rates were also significantly lower for annual vs. less than biennial screening (7% vs. 17%, p = 0.001), but not biennial (11%). Overall, 26% of women were age 40 to 49 at the time of diagnosis and 40% had undergone annual mammography, 15% biennial, and 45% less than biennial. Despite small numbers, the difference in mastectomy rate between annual and biennial screening among young women was significant (15% vs. 40%, p = 0.02). Conclusions: Annual mammograpy screening may improve surgical options and lower treatment intensity for women diagnosed with breast cancer. These potential benefits should be considered when discussing screening preferences with patients.
Comprehensive genomic profiling of 724 gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
Authors: Alberto Puccini, Kelsey Poorman, Mohamed E. Salem, Richard M. Goldberg, Anthony Frank Shields, Joanne Xiu, Wolfgang Michael Korn, Andreas Seeber, Martin D. Berger, Ryuma Tokunaga, Madiha Naseem, Francesca Battaglin, Afsaneh Barzi, Syma Iqbal, Wu Zhang, Shivani Soni, Jimmy J. Hwang, Philip Agop Philip, John Marshall, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2018)

4098 Background: GEP-NETs are rare malignancies and their molecular characteristics are largely undefined. Here, we explored the underlying biology of GEP-NETs and the differences between gastrointestinal (GI) and pancreatic (PNET), high grade (HG) and low grade (LG) tumors. Methods: GEP-NETs were analyzed using NextGen sequencing (MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry, and in-situ hybridization. Tumor mutation load (TML) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Results: In total, 724 GEP-NETs were examined and categorized by location and grade: GI (N = 469), PNET (N = 255), HG (N = 135), and LG (N = 336). Demographics were as follow: female/male 51%/49%, median age 59 (19-90 yr). Among LG tumors, the most frequently mutated genes were ATRX (13%), ARID1A (10%) and MEN1 (10%). Among HG, TP53 (51%), KRAS (30%), APC (27%), ARID1A (23%) and RB1 (11%). Immune-related biomarkers showed lower prevalence in LG tumors compared to HG: TML-high 1% vs 7% (P = .05), MSI-H 0% vs 4% (P = .04), PD-L1 overexpression 1% vs 6% (P = .03). Compared to LG, HG NETs showed a higher mean TML (9.5mut/MB v 5.1, P < .0001), higher mutation rate in BRAF (5.4% v 0%, P < .0001), KRAS (29.4% v 2.6%, P < .0001) and PI3KCA (7% v 0.3%, P < .0001). When compared to GI, PNET carried significantly higher frequency of MEN1 (25.9% v 0.0%, P < .0001), FOXO3 (8.6% v 0.8%, P = .005), ATRX (20.6% v 2.0%, P = .007), and TSC2 (6.3% vs 0.0%, P = .007), but lower frequency of mutations in APC (1.0% v 13.8%, P < .0001). Comparison between LG GI vs LG PNET is reported in the table. Conclusions: Significant molecular differences were observed in GEP-NETs by tumor location and grade, indicating differences in carcinogenic pathways and biology, as well as response to therapy. HG tumors may benefit more from immunotherapy than LG tumors. Mutations in several targetable genes may provide novel therapeutic options and suggests the utility of genomic profiling in this tumor type. Gene Platform LG GI LG PNET P-values MEN1 NGS 0% 24% < 0.001 ATRX NGS 0% 33% 0.001 FOXO3 NGS 0% 12% 0.005 TSC2 NGS 0% 7.5% 0.03 CTNNB1 NGS 0% 2.2% 0.047 PR IHC 3% 56% < 0.001 TOP2A IHC 4% 17% < 0.001 TS IHC 2% 13% < 0.001
Gene-signature based prediction of relapse-free survival in melanoma patients with known sentinel lymph node status.
Authors: Thilo Gambichler, Uwe Reinhold, Konstantinos Tsagoudis, Erhard Bierhoff, Thomas Dirschka, Heiko Sülberg, Matthias Borowski, Axel Hinke, Georg Brunner, Eggert Stockfleth
Journal: Journal of Clinical Oncology (2017)

e21037 Background: Staging of cutaneous melanoma (CM), as defined by the American Joint Committee on Cancer (AJCC), includes determination of the sentinel lymph node (SLN) status as a major prognostic factor. We have previously identified and validated a gene expression risk score (GRS) in primary CM and adjacent stroma, consisting of 7 protective genes and 1 risk-associated gene, which predicts patient survival, independently of AJCC stage. This external validation study evaluated single and combined performance of GRS and SLN in predicting relapse-free survival (RFS). Methods: The study cohort included 203 formalin-fixed, paraffin-embedded (FFPE) -primary CMs (AJCC stages IA-IIIC, n=31 RFS events). Tissue samples and clinical data were provided by two centers, and gene expression was determined externally using real-time RT-PCR (double-blind study). External prospective data analysis followed a pre-specified protocol. Results: Integration Discrimination Improvement (IDI) analysis demonstrated non-inferiority of GRS vs. SLN status in predicting RFS (IDI estimate=-0.8%, p=0.040). In univariate Cox regression analysis, GRS and SLN status predicted RFS (GRS: p=0.011, HR=2.44 [1.2-4.95]; SLN: p=0.038, HR=2.12 [1.03-4.38]). Multivariate Cox regression demonstrated independent contribution of prognostic information by both parameters (GRS: p=0.015, HR=2.40 [1.18-4.89]; SLN: p=0.046, HR=2.11 [1.02-4.37]. IDI analysis demonstrated that combining GRS and SLN status improved prognostic performance, as compared to SLN status alone (IDI estimate=3.2%, p=0.044). When complementing SLN status with GRS (SLN positive or high GRS), sensitivity of relapse detection increased from 38.7% for SLN alone to 67.7%. Conclusions: GRS is a non-invasive predictor of RFS, complementary to SLN analysis. Combining GRS and SLN status significantly improves accuracy of melanoma prognosis and, therefore, may guide follow-up care as well as treatment decisions regarding new adjuvant therapies, e.g. of SLN positive patients with high GRS. [Table: see text]