tbuckley/cabot-search huggingface dataset:
A phase II study of talimogene laherparepvec (T-VEC) and pembrolizumab in patients with metastatic sarcoma.
Authors: Ciara Marie Kelly, Timothy Geoffrey Bowler, Rodrigo Ramella Munhoz, Ping Chi, Mark Andrew Dickson, Mrinal M. Gounder, Mary Louise Keohan, Reena Dholakia, Mercedes M. Condy, Samuel Singer, Aimee Marie Crago, Sam S. Yoon, Charlotte Eielson Ariyan, Sinchun Hwang, Joseph Patrick Erinjeri, Cristina R. Antonescu, Li-Xuan Qin, William D. Tap, Sandra P. D'Angelo
Journal: Journal of Clinical Oncology (2018)

11516 Background: T-VEC is an oncolytic immunotherapy derived from HSV type-1 that is modified to selectively replicate within tumors and produce GM-CSF. Pembrolizumab (P) demonstrated activity in selective sarcoma (SAR) subtypes. The combination of T-VEC and P has shown favorable safety and efficacy in melanoma. We performed an open-label, single-center, phase II study evaluating T-VEC and P in patients (pts) with advanced SAR who failed at least one standard systemic therapy where available. Methods: Pts received P (200mg/dose) and ≤4ml of T-VEC injected into palpable tumor site(s). Both drugs were administered on day 1 of a 21-day cycle. The primary endpoint was best objective response rate (RR) (complete response and partial response [PR]) at 24 weeks by RECIST 1.1, with 30% as promising and 5% as not promising. If ≥ 3 responses were observed in 20 pts the combination would be claimed to be positive. Secondary endpoints included adverse events (AEs), RR by irRECIST, progression free and overall survival. Correlative studies included PD-L1 expression by IHC (Qualtek), multiplex IHC, characterization of tumor infiltrating lymphocytes, mutational burden/neoantigen analysis, and T cell receptor clonality. Results: 20 pts were enrolled [median age 63.5 yrs (range, 24-90), 60% female]. Represented histological subtypes included: leiomyosarcoma (25%), cutaneous angiosarcoma (15%), SAR not otherwise specified (15%), undifferentiated pleomorphic SAR (10%) and “other” SAR subtype (35%). Pts were refractory to 0 (10%), 1 (20%), and ≥ 2 (70%) prior regimens. Grade (G) 3 treatment related AEs (TRAEs) occurred in 2 pts (10%); fever from TVEC & pneumonitis from P. No G4/5 TRAEs were seen. 1pt stopped P due to G3 TRAE. Among 19 evaluable pts 4 confirmed PRs (21%), 9 stable diseases (SD) (47%) and 6 progressions (32%) were observed by RECIST 1.1. Two of the SDs had decrease in tumor burden of 17% and 28.6% at their first (week8) interval scan. PRs were seen in 3 histologies. The time to PR ranged from 8 to 32 weeks (wks) and all PRs are ongoing (range 1 -36 wks). Conclusions: TVEC and P demonstrated acceptable safety and promising anti-tumor activity across a range of SAR histologies. 4 pts maintain a PR. Correlative analyses are ongoing. Clinical trial information: NCT03069378.
Co-isolation and analysis of extracellular vesicle (EV)-associated DNA and cell free DNA (cfDNA) to improve the diagnostic and prognostic value of circulating BRAF <sup>V600E</sup> in metastatic melanoma patients.
Authors: Davide Zocco, Simona Bernardi, Mauro Novelli, Natasa Zarovni, Francesco Martino Carpi, Ottavia Malavenda, Pietro Quaglino, Domenico Russo, Antonio Chiesi, Maria Teresa Fierro
Journal: Journal of Clinical Oncology (2018)

e21564 Background: Detection of BRAF V600E on cell free tumor DNA (cfDNA) is emerging as a promising means to improve patient’s stratification or enable BRAFi therapy monitoring in a minimally invasive manner. Here, we evaluate extracellular vesicle-(EV)-associated-DNA (EV-DNA) as an alternative and valuable source of circulating BRAF V600E. To do so, we identified a clinically compatible protocol for the isolation of EV-DNA and assessed BRAF gene status on plasma samples from metastatic melanoma (MM) patients at the beginning and during BRAFi therapy. Methods: EV isolation by peptide-mediated affinity-(PA) was selected after protocol benchmarking and compared to the reference protocol for cfDNA isolation (CF). DNA was extracted from plasma samples of MM patients (n = 50) at baseline and during BRAFi treatment with both protocols and BRAF gene status was assessed by digital PCR (dPCR). Results: PA isolation captured more BRAF V600E-positive EVs than ultracentrifugation in a spike-in model. Most of the isolated DNA was found to be associated to the outer side of the EV membrane as EV-DNA or co-purified as cfDNA. PA isolation improved the detection of BRAF V600E gene copies from plasma samples of mutation-positive MM patients in comparison to CF, increasing the diagnostic and prognostic value of this circulating mutation (AUC PA = 0.72; CF = 0.66; Log-rank test, OS: P valuePA = 0.0046; P valueCF = 0.04; PFS: P valuePA = 0.091; P valueCF = 0.25). Conclusions: Co-isolation of EV-DNA and cfDNA improves the clinical value of circulating BRAF V600Ein comparison to the current reference protocol for liquid biopsy.
Impact of BRAF Mutation Class on Disease Characteristics and Clinical Outcomes in BRAF-mutant Lung Cancer
Authors: Ibiayi Dagogo-Jack, Pablo Martinez, Beow Y. Yeap, Chiara Ambrogio, Lorin A. Ferris, Christine Lydon, Tom Nguyen, Nicholas A. Jessop, A. John Iafrate, Bruce E. Johnson, Jochen K. Lennerz, Alice T. Shaw, Mark M. Awad
Journal: Clinical Cancer Research (2018)

Abstract Purpose: BRAF mutations are divided into functional classes distinguished by signaling mechanism and kinase activity: V600-mutant kinase-activating monomers (class I), kinase-activating dimers (class II), and kinase-inactivating heterodimers (class III). The relationship between functional class and disease characteristics in BRAF-mutant non–small cell lung cancer (NSCLC) has not been fully explored. Experimental Design: We performed a retrospective analysis of BRAF-mutant NSCLCs treated at 2 institutions from 2005 to 2017 to determine clinicopathologic characteristics, progression-free survival (PFS) on chemotherapy, and overall survival (OS). Results: We identified 236 patients with BRAF-mutant NSCLC (n = 107 class I, n = 75 class II, and n = 54 class III). Patients with class II or III mutations were more likely to have brain metastases (P ≤ 0.01) and RAS coalterations (P ≤ 0.001) than class I. Compared with class I, PFS on chemotherapy was shorter for class II (P = 0.069) and class III (P = 0.034). OS was shorter for class II and III (class I, 40.1 months; class II, 13.9 months; and class III, 15.6 months; I vs. II, P &amp;lt; 0.001; I vs. III, P = 0.023); however, this difference was driven by fewer extrathoracic metastases and higher use of targeted therapies in class I patients. When patients treated with targeted therapy and those with thoracic-only metastases were excluded, there was no difference in OS across the 3 classes. Conclusions: BRAF-mutant NSCLC is a heterogeneous disease that encompasses 3 distinct functional classes. Classes II and III have more aggressive clinical features leading to less favorable outcomes. The distinct biological characteristics of class II and III tumors suggest that class-specific therapies may be necessary to effectively target these molecular subsets.
The economic impact of the transition from branded to generic oncology drugs.
Authors: Winson Y. Cheung, Nicole Mittmann, Natasha B. Leighl, Matthew C. Cheung, Penelope Ann Bradbury, Raymond C.H. Ng, Bingshu E. Chen, Keyue Ding, Joseph L Pater, Dongsheng Tu, Annette E. Hay
Journal: Journal of Clinical Oncology (2016)

6520 Background: Economic evaluations are an integral component of many clinical trials. Costs used in these analyses are based on prices of branded drugs when the agents first enter market. The impact of genericization on cost-effectiveness (CE) or cost-utility (CU) of an intervention is unknown as economic analyses are rarely updated with the costs of generic drugs. Methods: We re-examined the CE or CU of regimens previously evaluated in Canadian Cancer Trials Group studies that included prospective economic evaluations and where genericization has occurred or is anticipated. We incorporated new costs of generic drugs and current day resource utilization to characterize changes in CE or CU. We also determined acceptable cost levels of generic drugs that would make regimens reimbursable in a publicly funded healthcare system. Results: A total of 4 randomized controlled trials consisting of 1,979 patients were included: BR.10 (early lung; adjuvant vinorelbine/cisplain vs observation; N = 172), BR.21 (metastatic lung; erlotinib vs placebo; N = 731), CO.17 (metastatic colon; cetuximab vs best supportive care; N = 557), and LY.12 (relapsed/refractory lymphoma; GDP vs DHAP; N = 519). Since the initial publication of these trials, the genericization of erlotinib, cetuximab, and cisplatin has taken place or is expected. Costs of generics improved the CE and CU of treatment significantly. For example, genericization of erlotinib ($1460.25 per 30 days) resulted in an ICER of $45,746 CAD per life year gained as compared to $94,638 for branded erlotinib. Likewise, genericization of cetuximab ($275.80 per 100 mg) produced an ICER of $261,126 CAD per quality adjusted life year (QALY) gained in comparison to $299,613 for branded cetuximab. Decreases in the cost of generic cetuximab to $129.39 and $63.51 would further improve the ICER to $150,000 and $100,000 per QALY, respectively. Conclusions: Genericization of costly oncology drugs can modify CE and CU of regimens significantly. Failure to revisit economic analyses with costs of generics may be a missed opportunity for funding bodies to optimize value-based allocation of healthcare resources. The current cost levels of generics may not be sufficiently low to sustain publicly funded healthcare systems.
Oncogenes expand during evolution to withstand somatic amplification
Authors: X. Wang, X. Li, L. Zhang, S.H. Wong, M.H.T. Wang, G. Tse, R.Z.W. Dai, G. Nakatsu, O.O. Coker, Z. Chen, H. Ko, J.Y.K. Chan, T. Liu, C.H.K. Cheng, A.S.L. Cheng, K.F. To, D. Plewczynski, J.J.Y. Sung, J. Yu, T. Gin, M.T.V. Chan, W.K.K. Wu
Journal: Annals of Oncology (2018)

Cancer-related genes are under intense evolutionary pressure. We conjectured that gene size is an important determinant of amplification propensity for oncogenes and thus cancer susceptibility and therefore could be subject to natural selection.Gene information, including size and genomic locations, of all protein-coding genes were downloaded from Ensembl (release 87). Quantification of gene amplification was based on Genomic Identification of Significant Targets in Cancer scores obtained from available The Cancer Genome Atlas studies.Oncogenes are larger in size as compared with non-cancer genes (mean size: 92.1 kb versus 61.4 kb; P < 0.0001) in the human genome, which is contributed by both increased total exon size (mean size: 4.6 kb versus 3.4 kb; P < 0.0001) and higher intronic content (mean %: 84.8 versus 78.0; P < 0.01). Such non-random size distribution and intronic composition are conserved in mouse and Drosophila (all P < 0.0001). Stratification by gene age indicated that young oncogenes have been subject to a stronger evolutionary pressure for gene expansion than their non-cancer counterparts. Pan-cancer analysis demonstrated that larger oncogenes were amplified to a lesser extent. Tumor-suppressor genes also moved toward small oncogenes in the course of evolution.Oncogenes expand in size whereas tumor-suppressor genes move closer to small oncogenes in the course of evolution to withstand oncogenic somatic amplification. Our findings have shed new light on the previously unappreciated influence of gene size on oncogene amplification and elucidated how cancers have shaped our genome to its present configuration.
Effects of pazopanib (PAZ) and sunitinib (SUN) dose modification on safety and efficacy in patients with metastatic renal cell carcinoma (mRCC) from COMPARZ.
Authors: Georg A. Bjarnason, Christian K. Kollmannsberger, Qasim Ahmad, Luca Dezzani, Mohamed Elmeliegy, Jackie Han, Paul D. Nathan
Journal: Journal of Clinical Oncology (2017)

4574 Background: COMPARZ was a randomized, controlled, open-label, phase 3 trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of life profiles for PAZ in patients (pts) with mRCC (NEJM 2013;369:722). We evaluated the relationship between dosing, safety, and efficacy in PAZ- and SUN-treated pts who did or did not undergo dose reduction or interruption resulting from adverse events (AEs) and other reasons. Methods: The AEs and median progression-free survival (mPFS) of PAZ and SUN were evaluated for pts with no, any, 1, and ≥2 dose reductions or dose interruptions lasting ≥7 days. Results: Similar percentages of pts in the PAZ and SUN groups had a dose interruption (44% vs 49%, respectively) or reduction (44% and 51%, respectively). The incidence of AEs in pts from the PAZ and SUN groups with dose modifications was higher compared to those with no dose modifications. Longer mPFS was observed in pts with dose modification (Table). Pts treated with PAZ or SUN with no dose reductions had mPFS of 7.3 months (mos) and 5.5 mos, respectively, whereas pts with any dose reduction had mPFS of 12.5 mos and 13.8 mos, respectively. Similarly, pts treated with PAZ or SUN with no dose interruptions lasting ≥7 days had mPFS of 8.2 mos and 5.6 mos, respectively, whereas those with any dose interruption lasting ≥7 days had mPFS of 12.6 mos and 13.8 mos, respectively. Pts with 2 or more dose interruptions or reductions had mPFS &gt; 16 mos with both SUN and PAZ. Conclusions: Consistent with previous data for SUN, the current analyses showed longer mPFS with PAZ and SUN when dose modification is required to manage toxicity, suggesting that pts are not disadvantaged by such dose reductions or interruptions. Pts not requiring dose modification may have sub-optimal therapeutic drug exposure. Clinical trial information: NCT00720941. [Table: see text]
Preclinical profile of GM102, a first-in-class antibody targeting AMHRII in ovarian cancers.
Authors: Jean-Marc Barret, Andre Pelegrin, Didier Decaudin, Christophe de Romeuf, Marie-Eve Duclos, Anne Bousseau, Catherine Combot-PlÃ Â©tan, Jean-François Prost
Journal: Journal of Clinical Oncology (2016)

e23196 Background: Expression of anti-Müllerian hormone receptor (AMHRII) is described in gynecologic cancers, tumors which are largely infiltrated by immune myeloid cells. Based on these observations, a humanized glyco-engineered monoclonal antibody (GM102) able to increase effector cells engagement has been developed displaying a high affinity towards AMHR2 (subnanomolar) and CD16 (nanomolar), and triggering enhanced ADCC and phagocytosis by M1 and M2 macrophages. Methods: In vivo antitumor activity of GM102 alone and in combination with first line combo (Paclitaxel + Carboplatin) has been evaluated in a panel of AMHRII+ ovarian PDXs. Safety profile of GM102 was documented during a regulatory toxicology study in cynomolgus with repeated IV infusions up to 300 mg/kg/day every two weeks for eight weeks, associated with ancillary pharmacokinetics (PK) studies. Human and monkey tissues were tested for tissue cross reactivity (TCR) studies. Results: A meta-analysis of the fivePDXs studied showed a significant effect on response rate (p = 0.018) in favor of combo + GM102 versus combo alone. The overall CR rates reached 32% with GM102 versus 12% with combo alone. In cynomolgus, GM102 did not elicit any signs of toxicity with a NOAEL ≥ 300 mg/kg. Very low levels of Anti-Drug Antibodies were found in two females indicating no immunogenic potential. TCR studies showed GM102 positive binding in reproductive organs. Few off-target binding (myocardium, lens) were observed and shown of no toxicological significance. The PK of GM102 consisted of low clearance and distribution volume, prolonged half-life (177 hours), and dose-proportional increase in exposure. Conclusions: Altogether, this preclinical profile supports the current clinical development (Phase I) of GM102 in gynecological malignancies expressing AMHRII, a novel target not yet addressed by cancer therapeutics.
Health related quality of life following breast reconstruction compared to breast conserving surgery and mastectomy among breast cancer survivors: A systematic review and meta-analysis.
Authors: Sadaf Zehra, Frank Doyle, Mitchel Barry, Malcolm R. Kell
Journal: Journal of Clinical Oncology (2018)

e22119 Background: Breast reconstruction following mastectomy for breast cancer aims to maintain and promote health related quality of life (HR-QOL). This meta-analysis evaluates the effect of breast reconstruction (BR) versus breast-conservation surgery (BCS) or mastectomy (MRM) among breast cancer survivors, on HR-QOL Methods: : A comprehensive literature search was conducted using predefined search terms within 5 databases. Data were extracted for global health, physical, social and emotional health, body image and sexual health for 3 comparative groups BR, BCS and MRM. The quality of studies was assessed by MINORS scale. Effect size (ES) were pooled using standardized mean differences (SMD) with associated 95% confidence intervals from random-effects. Sensitivity analysis was performed for different questionnaires and study designs. Results: Sixteen of eighteen eligible studies were included for quantitative analysis. Comparisons, were made on 1474 patients of BR, 1458 of MRM and 2612 patients of BCS. Small effect size (ES) emerged in favor of BR over MRM, for physical (Cohen’s d = 0.1), social (0.1), sexual (0.2) and global health (0.1) and negligible results (-0.08) favors MRM over BR for emotional health. While moderate ES emerged for body image favoring BR over MRM (d = 0.50, 95% CI 0.10, 0.89). Negligible results for body image favored BCS over BR (d = -0.06, 95% CI -0.55, 0.42, p = 0.01). Small ES was evident in favor of BCS over BR, for, social (-0.33) and global health (-0.26) however moderate ES for emotional health (d = -0.53, 95%CI -1.10, 0.04, p = 0.06) in favor of BCS was found. Small to negligible ES, favoring BR over BCS for physical (0.09) and sexual health (0.32).Significant heterogeneity was evident. Conclusions: Mastectomy was least favoured for across HR-QOL domains. Women in BR and BCS group do not differ significantly in terms of body image. These meta-analysis results confirm HRQOL is better following BR and BCS compared to MRM. Key words: HR-QOL, Breast reconstruction, breast conserving surgery, mastectomy.
Enrolling patients in clinical trials: Advice from close family and friends.
Authors: François Eisinger, Thibault De La Motte Rouge, Jerome Viguier, Morgan Roupret, Chantal Touboul, Christine Lhomel, Laurent Greillier, Jean F. Morere, Sebastien Couraud
Journal: Journal of Clinical Oncology (2018)

2533 Background: Clinical research is a major aspect of drug development and requires patient participation. Family and friends are known to play a role in medical decision-making, the extent of which depends on factors such as timing (onset or end of the disease), type of disease, the legal situation (e.g., patients under guardianship, or minor), and cultural aspects. The role of the close circle in inciting patients to enroll in clinical trials therefore warrants further study. Methods: The French nationwide observational survey, EDIFICE 6, was conducted online from 26 June-28 July 2017 on a core sample of 12 046 individuals (age, 18-69 years). Representativeness was ensured by quota sampling on age, gender, profession, and stratification by geographical area and type of urban district. Multivariate stepwise logistic regression analysis was conducted to identify factors likely to incite close relatives of cancer patients to urge them to enroll in a clinical trial. The present analysis included 11 307 individuals with no history of cancer and focused on the question
Abstract 17719: A New Termination-of-resuscitation Rule for Out-of-hospital Cardiac Arrest in the Japanese Population
Authors: Katsutaka Hashiba, Yoshio Tahara, Kazuo Kimura, Satoshi Yasuda, Naohiro Yonemoto, Hiroshi Nonogi, Keijirou Saku, Ken Nagao
Journal: Circulation (2015)

Background: Termination of resuscitation (TOR) rules for out-of-hospital cardiac arrest (OHCA) have been constructed for better utilization of hospital healthcare resources and increasing the availability of care for other patients. However, TOR rules in the prehospital settings are not legally implemented in Japan. Thus, almost all OHCA patients are transported to the hospital, regardless to the possibility of successful resuscitation. Objective: To validate the TOR-ALS rule in the Japanese population and to establish a new TOR rule for terminating ongoing resuscitation just after hospital arrival. Methods: The Fire and Disaster Management Agency (FDMA) of Japan developed a nationwide database of a prospective population-based cohort using an Utstein-style template for OHCA patients since January 2005. Data from January 2005 to December 2012 of this database was used for the current analysis. We constructed a new TOR rule consisting of 5 factors (no-witness, no-ROSC, asystole for the initial rhythm, no-defibrillation, age). Positive predictive value(PPV), negative predictive value(NPV), sensitivity, specificity and receiver operating characteristic(ROC) curve to predict Cerebral Performance Category(CPC) 3 to 5 at one-month for the TOR-ALS rule (no-witness, no-bystander, no-return of spontaneous circulation (ROSC), no-defibrillation before hospital arrival) and the new rule. Results: In the database, 925,288 patients were documented for the study period. Adult patients 18 years or older with OHCA without external causes of arrest were included, resulting in 708,933(77%) patients in the present analysis. Values were as followed for the TOR-ALS rule, PPV99.88%, NPV3.27%, sensitivity31.41%, specificity98.39%, Area Under Curve(AUC)-ROC0.649, and for the new rule, PPV99.96%, NPV3.40%, sensitivity33.45%, specificity99.40%, AUC-ROC0.664. Conclusion: The new TOR rule has a higher PPV and specificity to predict unfavorable outcome of OHCA in a Japanese population. Validation is required to prove the clinical utility of the rule.