tbuckley/cabot-search huggingface dataset:
The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies
Authors: Matthew C. Stubbs, Timothy C. Burn, Richard Sparks, Thomas Maduskuie, Sharon Diamond, Mark Rupar, Xiaoming Wen, Alla Volgina, Nina Zolotarjova, Paul Waeltz, Margaret Favata, Ravi Jalluri, Huiqing Liu, Xuesong Mike Liu, Jun Li, Robert Collins, Nikoo Falahatpisheh, Padmaja Polam, Darlise DiMatteo, Patricia Feldman, Valerie Dostalik, Pramod Thekkat, Christine Gardiner, Xin He, Yanlong Li, Maryanne Covington, Richard Wynn, Bruce Ruggeri, Swamy Yeleswaram, Chu-Biao Xue, Wenqing Yao, Andrew P. Combs, Reid Huber, Gregory Hollis, Peggy Scherle, Phillip C.C. Liu
Journal: Clinical Cancer Research (2018)

Bromodomain and extraterminal domain (BET) proteins regulate the expression of many cancer-associated genes and pathways; BET inhibitors have demonstrated activity in diverse models of hematologic and solid tumors. We report the preclinical characterization of INCB054329, a structurally distinct BET inhibitor that has been investigated in phase I clinical trials.We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations.In addition to c-MYC, INCB054329 decreased expression of oncogenes FGFR3 and NSD2/MMSET/WHSC1, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of FGFR3 sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor in vivo. In addition, we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 receptor (IL6R) leading to reduced levels of IL6R and diminished signaling through STAT3. Combination with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK-STAT signaling and synergized to inhibit myeloma cell growth in vitro and in vivo. This combination potentiated tumor growth inhibition in vivo, even in the MM1.S model of myeloma that is not intrinsically sensitive to JAK inhibition alone.Preclinical data reveal insights into vulnerabilities created in myeloma cells by BET protein inhibition and potential strategies that can be leveraged in clinical studies to enhance the activity of INCB054329.
P01.155 Verbal fluency analysis may support diagnosis of patients with brain tumours
Authors: K Zienius, P M Brennan, R Grant
Journal: Neuro-Oncology (2018)

It is difficult to identify patients who may have a brain tumour based on symptoms alone. Previous work in a group of pre-operative brain tumour patients identified an association between poor verbal fluency score and incapacity. We examined verbal fluency in an unselected cohort of brain tumour patients presenting for surgery to describe the characteristics of the neurocognitive test in this population. We recruited 180 consecutive patients with intracranial tumour who consented to cognitive testing with Addenbrookes Cognitive Examination (ACE) prior to neurosurgery in a regional Neurosurgical centre (Edinburgh) between August 2016 and February 2018. Semantic (animal) and phonemic (letter P) verbal fluency tasks were performed as part of the ACE. Years of education were recorded and the hospital anxiety and depression scale was completed. Fluency performance was assessed as a total score, mean cluster and switching score. Cluster and switching are qualitative aspects of fluency test, which are thought to specify contribution of executive and semantic processes during task production. Mean age was 56.8 years (SD 13.5). Tumour patients comprised 37.2% glioblastoma multiforme (GBM), 22.8% meningioma, and 15.6% cerebral metastases. Tumour patients obtained low scores on all fluency test across all measures (mean, SD). Animals: total=12.6, 5.62, mean cluster=1.12, 0.73, switching=5.62, 3.25; letter P: total=8.5, 4.77, mean cluster=0.28, 0.39, switch=6.4, 4.1. Seventy-two (40%) tumour patients had subjective memory disturbance, but this did not correlate with performance (animal total, p=0.84, letter P total, p=0.73). Malignant histology (p<0.001), tumour in the frontal lobe (p=0.03), midline shift of more than 10mm (p=0.048) and larger size (p=0.003) but not lesion laterality (p=0.08) were associated with a lower total animal score. Older patients (70+ years-old vs 16–69 years-old) named significantly lower animals (10 vs 13, p=0.008) and letter P words (6.8 vs 8.8,p=0.03). Both clustering (r=0.34) and switching (r=0.78) scores highly correlated with a total animal fluency score (p<0.001), while for letter P task, only switching was significantly associated with a total score (r=0.42, p<0.001) The verbal fluency test is low in patients across a spectrum of brain tumours. Effect of frontal lobe on fluency tasks confirm the role of executive function. For patients, both clustering and switching were strategies needed to generate semantic fluency performance, while switching was principally required for a letter P task. This test might be a useful adjunct to clinical history and examination in identifying patients at risk of a brain tumour who would benefit most from urgent imaging.
Abstract 19939: Familial Hypercholesterolemia: Classification of Mutation Severity According To Percentile Low-Density Lipoprotein Cholesterol Useful for Predicting Coronary Artery Disease Risk
Authors: Merel L Hartgers, G. K Hovingh, John J Kastelein, Roeland Huijgen
Journal: Circulation (2016)

Introduction: The clinical variability in patients diagnosed with familial hypercholesterolemia (FH) is largely related to severity of the underlying mutation. International guidelines advise to gr...
The effect of Genetic Cancer Risk Assessment (GCRA) on the uptake of risk-reducing surgeries (RRS) in Hispanic women with breast cancer (BC).
Authors: Yanin Chavarri Guerra, Kai Yang, Julio Abugattas, Sandra Brown, Annette Campbell Fontaine, Alicia Cock-Rada, Marcia Cruz Correa, Adrian Daneri-Navarro, Azucena Del Toro-Valero, Paul R. Duncan, Ian K. Komenaka, Analí Pamela Mora Alferez, Charite Ricker, Yeny Rodriguez, Gary Walter Unzeitig, Cynthia Villarreal-Garza, Bita Nehoray, Rosa Mejia, Sharon Sand, Jeffrey N. Weitzel
Journal: Journal of Clinical Oncology (2018)

1548 Background: The management of women with BC includes GCRA for those at risk of carrying deleterious BRCA mutations. GCRA can aid decisions regarding RRS, including contralateral risk reducing mastectomy (CRRM) and risk reducing salpingoophorectomy (RRSO). The uptake of RRS among Hispanic women with BC is unknown, partly due to disparities in access to GCRA. We hypothesized that these disparities may be accentuated in Latin America (LA). Methods: Hispanic women from the US & LA (Mexico, Colombia, Peru & Puerto Rico) with history of BC who underwent GCRA, enrolled in the Clinical Cancer Genomics Community Research Network registry from 1997-2016 were included. Demographic characteristics and data regarding RRS were obtained from chart reviews and self-reported surveys. Data was analyzed using Fisher’s and x2 tests. An adjusted logistic regression model including a set of selected factors was used to predict the likelihood of undergoing RRS. Results: RRS data was collected on 1,517 Hispanic women with BC. 270 (17.7%) were BRCA carriers and 1247 (82%) non-BRCA carriers. Median age at GCRA was 44 years (y)(range 17-87). Median follow-up was 2.6 y. RRS were more common among BRCA carriers (34% CRRM and 27.7% RRSO) compared to non-BRCA carriers (18.6% CRRM and 4.1% RRSO). Of those that had CRRM, it occurred after GCRA for 79% of BRCA carriers and 50% of non-BRCA carriers. Factors associated with CRRM in BRCA carriers were: ≥1 pregnancies (OR 0.3, p 0.01), and living in the US (OR 5.2, p < 0.01). Factors associated with CRRM among non-carriers were: older age (OR 0.9, p < 0.01), ≥1 pregnancies (OR 1.4, p 0.4), family history of cancer (OR 1.9, p > 0.1), living in the US (OR 30.6, p < 0.01) and previous ipsilateral mastectomy (OR 2.9, p < 0.01). Conclusions: RRS uptake among Hispanic women with BC in LA was lower than previously reported in other populations. GCRA may influence risk appropriate RRS uptake, especially for BRCA carriers. CRRM and RRSO can prevent new primary cancers, and RRSO can improve survival for BRCA carriers, so a better understanding of behavioral factors is needed to inform interventions to improve risk appropriate uptake of RRS among Hispanics.
Outcomes of patients with advanced sarcoma enrolled in clinical trials of pazopanib in combination with histone deacetylase, mTOR, Her2, or MEK inhibitors.
Authors: Vikas Dembla, Siqing Fu, Jennifer Wheler, David S. Hong, Filip Janku, Ralph Zinner, Sarina Anne Piha-Paul, Vinod Ravi, Robert S. Benjamin, Shreyaskumar Patel, Neeta Somaiah, Cynthia E. Herzog, Daniel D. Karp, Funda Meric-Bernstam, Vivek Subbiah
Journal: Journal of Clinical Oncology (2016)

11057 Background: Pazopanib is approved for treatment of advanced soft tissue sarcomas; however, all patients ultimately develop resistance to therapy. The mechanisms of resistance can include activation of the mTOR, histone deacetylase (HDAC), MAPK, ERBB4 pathways and others. We hypothesized that combining pazopanib with targeted agents inhibiting these pathways may increase response rates. Methods: We retrospectively analyzed patients with advanced sarcoma enrolled in phase 1 trials of pazopanib + vorinostat (HDAC inhibitor; NCT01339871), pazopanib + everolimus (mTOR inhibitor; NCT01430572), pazopanib + lapatinib or trastuzumab (Her2 inhibitor; NCT01454804), and pazopanib + a MEK inhibitor (NCT01438554). RECIST was used for response assessment. The molecular correlates of response were analyzed when available. Results: Of the 45 advanced sarcoma patients, 27 (60%) were males; 18 patients (40%) had bone sarcoma (Ewing sarcoma, n = 11; osteosarcoma, n = 5; chondrosarcoma n = 2), and 27 (60%) had soft tissue sarcoma (leiomyosarcoma, n = 6; alveolar soft part sarcoma, n = 3; liposarcoma, n = 2; other = 16). Twenty-three (51%) patients received pazopanib + vorinostat, 6 (13%) pazopanib + everolimus, 1 (2%) pazopanib + trastuzumab, 2(4%) pazopanib + lapatinib and 13(28%) pazopanib + a MEK inhibitor. The best response was a partial response (PR, -30%) in a patient with pleomorphic sarcoma with a TP53H193R mutation and stable disease (SD) in 20 patients. Five of the six patients with TP53 mutations in the pazopanib +vorinostat trial had a PR or SD > 6 months. The median progression-free survival (PFS) was 67.5 days (14–772 days). The median PFS for soft tissue sarcoma and bone sarcoma patients was 101.5 and 62.5 days, respectively (p = 0.0001). The most common adverse events were grade 3/4 thrombocytopenia, grade 3 diarrhea, and grade 3 skin rash. Conclusions: Pazopanib combinations demonstrated efficacy in refractory soft tissue sarcomas. No unexpected toxicities were seen for any pazopanib combinations. Preliminary evidence supports further evaluation of the pazopanib-vorinostat combination in sarcoma patients and the association of mutated TP53 with response.
Cost-effectiveness of chimeric antigen receptor T-cell therapy in pediatric relapsed/refractory acute lymphoblastic leukemia.
Authors: Reith Sarkar, Nicholas Joseph Gloude, James Don Murphy
Journal: Journal of Clinical Oncology (2018)

6610 Background: Chimeric antigen receptor T-cell (CAR-T) therapy is a new class of cancer therapy with promising results, but comes at a high upfront cost. We sought to evaluate the cost-effectiveness of CAR-T therapy among pediatric patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL). Methods: We built a microsimulation model for pediatric patients with r/r ALL who received either CAR-T therapy or standard of care chemotherapy. Outcomes modeled included costs, quality of life (health utility), treatment complications, and survival, all of which were estimated from published literature. Long-term survival beyond the time-frame of clinical trial data was estimated using Social Security actuarial life-tables adjusted with standardized mortality ratios. Cost-effectiveness was measured with the incremental cost-effectiveness ratio (ICER), with ICERs under $100,000 per quality-adjusted life year (QALY) considered cost-effective. One-way and probabilistic sensitivity analyses were used to assess overall stability of the model. Results: Compared to standard of care chemotherapy CAR-T increased the total cost of treatment by $378,600 and increased effectiveness by 6.72 QALYs, resulting in an ICER of $56,300 per QALY. The model was sensitive to assumptions about long-term CAR-T survival, the cost of CAR-T, and duration of IVIG required in CAR-T responders. The base model assumed a 79% one-year survival with CAR-T therapy, though if the one-year survival decreased to 61% then the ICER of CAR-T increased above $100,000 per QALY. If the cost of CAR-T infusion increased from $475,000 to $781,000, or if the duration of IVIG infusions extend beyond 12 years then the ICER of CAR-T therapy increased above $100,000 per QALY. In the probabilistic sensitivity analysis CAR-T was cost-effective in > 99% of iterations at a willingness to pay of $100,000 per QALY. Conclusions: Despite its high cost, CAR-T therapy has an acceptable cost-effectiveness profile for pediatric r/r ALL. Additional follow-up of this cohort is required to establish long-term outcomes and further inform questions about the cost-effectiveness of CAR-T therapy.
Symptom clusters in patients with advanced prostate cancer.
Authors: Shing Mirn Lee, Emerson Lim, Dawn L. Hershman, Joseph M. Unger, Xiaobo Zhong
Journal: Journal of Clinical Oncology (2015)

e20647 Background: Numerous studies have evaluated the relationship among patient reported symptoms in many types of cancer, but only one study has focused on patients with early stage prostate cancer. No research has been performed to identify symptom clusters in patients with advanced prostate cancer or has used clinician reported adverse event data. Methods: The adverse event data from a randomized clinical trial conducted by SWOG comparing Docetaxel plus Estramustine versus Mitoxantrone plus Predinsone in patients with advanced prostate cancer were utilized to identify symptom clusters. A variable-based hierarchical cluster analysis was conducted using the CTCAE for the 323 patients who reported at least one grade 3 or higher toxicity. Clusters were formed such that symptoms within a cluster were more similar and those from different clusters were more dissimilar. The aggregation criterion was the decrease in homogeneity of the clusters, measured as the sum of the correlation between symptoms. Results: A total of 109 adverse event types were reported among the 323 patients. Of these, only 23 had 10 or more reported events. Using a correlation of 0.10 as cutoff, six clusters were identified: (1) nausea, vomiting, anorexia and dyspnea (n = 47); (2) joint/bone and muscle weakness (n = 26); (3) fatigue, malaise, lethargy and dehydration (n = 66); (4) anemia and PRBC transfusion (n = 20); (5) neutropenia/granulocytopenia, leukopenia/lymphopenia and febrile neutropenia (n = 114); (6) constipation/bowel obstruction, infection without neutropenia and cramping (n = 35). Conclusions: Our approach identified six adverse events clusters in patients with advanced prostate cancer using the clinician reported CTCAE. Clusters (1) and (3) have been previously reported in other cancer patients. The others are unique to our study given the use of the CTCAE. These clusters are relevant because they help us understand symptom pathophysiology and indicate that symptoms within each cluster should be treated and managed together to improve symptom management which may result in greater therapeutic benefit.
Some characteristics of invasive candidiasis pathogens.
Authors: Olga Yu. Kutsevalova, Oleg Ivanovich Kit, Natalia I. Panova, Irina B. Lysenko, Viktoria V. Dmitrieva, Dmitry Rozenko, Yuri Gevorkyan, Vladislav Legostaev, Olga N. Shatokhina, Elena E. Pak, Nadezhda V. Nikolaeva, Yuliya Yu. Kozel, Sergei A. Kuznetsov, Olga V. Kozyuk, Elena A. Kapuza, Gulnara A. Mkrtchyan, Aleksandra I. Bespalova, Maria V. Starzhetskaya, Vera A. Kovalenko, Larisa Yu. Shashkina
Journal: Journal of Clinical Oncology (2017)

e14084 Background: The purpose of the study was to determine the etiology of invasive candidiasis (IC) and investigate in vitro activity of caspofungin and azoles for blood isolates of Candida fungi. Methods: We performed a multidisciplinary prospective study of isolates of patients with clinical signs of IC obtained in intensive care units (ICU), oncohematology and oncology departments of hospitals in Rostov-on-Don and Rostov region in 2012-2015. Candida fungi were identified using MALDI-TOF MS; interpretation was performed according to CLSI 2012, M27-S4 criteria. Sensitivity testing was performed using the Sensititre system (Trek Diagnostic Systems, England). Results: 92 Candida isolates were obtained from blood culture: C.albicans - 31.5% (29) and non-albicans - 68.5% (63), including C.tropicalis 30.2% (19), C.parapsilosis 28.6% (18), C.glabrata 19.0% (12), C.krusei 15.9% (10) and C.guilliermondii 6.3% (4). C. albicans were found mostly in oncological departments (44%) compared with ICU – 30% (р=0.003) and departments of oncohematology – 26%. The table demonstrates comparative activities of caspofungin, fluconasole and voriconasole (susceptible – S, intermediate – I, resistant – R) in % to Candida spp. Conclusions: Candida non albicans prevailed among IC pathogens (68.5%), which could be associated with the use of azole antifungal agents for prophylaxis and empirical therapy. Dominating isolates showed decreased activity to caspofungin and azoles. Acquired resistance to azoles was noted for C. parapsilosis and C. albicans. All cases of invasive candidiasis require susceptibility testing for caspofungin and azoles before starting therapy with these agents. [Table: see text]
Association of CDKN2A gene alteration with high expression of PD-L1.
Authors: Yan Zhang, Julian A. Marin-Acevedo, Abdel Ghani Azzouqa, Rami Manochakian, Yanyan Lou
Journal: Journal of Clinical Oncology (2018)

9102 Background: Gene CDKN2A, which encodes for p16INK4a/p14ARF is known to be important growth suppressor gene. CDKN2A gene alteration has been reported in non-small cell lung cancer (NSCLC). However, the demographic and clinical features of NSCLC with CDKN2A, coexisting gene alteration and association with immunotherapy biomarkers such as PD-L1 and tumor mutation burden are unknown. Methods: Tumor next-generation sequencing data from 197 NSCLC patients who are diagnosed at Mayo Clinic FL are retrospectively analyzed. Patients with CDKN2A gene alterations are identified. Data including demographic feature, clinical feature, coexisting gene alteration and association with immunotherapy biomarkers such as PD-L1 and tumor mutation burden are investigated. Results: One hundred ninety-seven patients with NSCLC were identified, and 49 (24.8%) had CDKN2A gene alteration, including 32 gene loss, 4 somatic mutations and 3 deletions. The medium age of patients with CDKN2A gene alteration was 66.7. It was slightly more predominant in male than female (53.1% versus 46.9%) and more in smoker than never-smoker (65.3% versus 34.7%). Among patients with CDKN2A gene alteration, 83.7% (41/49) were found in lung adenocarcinoma, 10.2% were found in lung squamous cell carcinoma and 6.1% were found in other histology. The most common coexisting gene alterations associated with CDKN2A are CDKN2B (61%) followed by TP53 (51%), KRAS (35%), EGFR (14.2%), STK11 (12.2%), MET (10%), PI3KCA (10%), HER-2 (8%), ALK (4%), BRAF (2%). Interestingly, 65% of patients with CDKN2A gene alteration were found to have expression of PD-L1 (defined by > 1% PD-L1). Among them, 61.5% patients have high expression of PD-L1 (defined by > 50% PD-L1). Patients with CDKN2A gene alteration are also associated with high tumor mutation burden (8.77mutation/mb). Conclusions: CDKN2A gene alteration is commonly seen in NSCLC. Co-existing driver mutations such as EGFR, MET, HER-2, ALK, BRAF are found. Immunotherapy related biomarkers such as high expression level of PD-L1 and tumor mutation burden are found common in patients with CDKN2A gene alteration, indicating the likelihood of clinical benefit to immunotherapy and warrant further investigation in a larger, prospective study.
ATOMIC-Meso: A randomized phase 2/3 trial of ADI-PEG20 or placebo with pemetrexed and cisplatin in patients with argininosuccinate synthetase 1-deficient non-epithelioid mesothelioma.
Authors: Peter Wojciech Szlosarek, Paul Baas, Giovanni Luca Ceresoli, Dean Anthony Fennell, David Gilligan, Amanda Johnston, Phuong Lee, Aaron Scott Mansfield, Luke Nolan, Anna K. Nowak, Jeremy P. C. Steele, Paul Taylor, Anne S. Tsao, Marjorie Glass Zauderer, John S. Bomalaski
Journal: Journal of Clinical Oncology (2017)

TPS8582 Background: Argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM) is sensitive to arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20), which also enhances the cytotoxicity of pemetrexed. The TRAP Phase 1 trial (NCT02029690) of ADI-PEG 20 combined with 1st-line pemetrexed (PEM) and cisplatin (CDDP) chemotherapy revealed a 94% disease control rate in non-epithelioid (biphasic and sarcomatoid) MPM subtypes characterized by a 75% rate of ASS1 loss. Thus, we plan to assess the efficacy of ADI-PEG20 or placebo combined with PEM and CDDP in patients (pts) with poor prognosis MPM in a randomized, placebo-controlled, double-blind phase 2/3 global trial. Methods: Up to 386 good performance (ECOG 0-1) pts with non-epithelioid malignant pleural mesothelioma will be enrolled in a phase 2/3 adaptive, biomarker-driven study design. Biopsies will be required prior to randomization: ASS1-agnostic pts will be enrolled initially (phase 2 stage) with an option to restrict enrolment to ASS1-deficient MPM (phase 3 stage). Pts will be randomized to receive weekly ADI-PEG20 (36 mg/m2 IM) or placebo with standard doses of PEM and CDDP for a maximum of 18 weeks (6 cycles) of treatment. Pts who develop CDDP toxicity may be switched to carboplatin. Pts will be assessed every 6 weeks using modified RECIST (RECIST 1.1 allowed for pts with significant extrathoracic disease). The primary endpoint for the phase 2 stage will be overall response rate (ORR) with secondary endpoints of overall survival (OS), safety and toxicity. The phase 2 will test ORR proportions with the placebo triplet set at 15% vs. 35% for the ADI-PEG 20 triplet, with a 1:1 randomization, 80% power. After recruitment of 176 pts, the phase 2 will convert to a phase 3 study with the primary endpoint of OS. In summary, ATOMIC-Meso is the first triplet chemotherapy study to assess the role of targeted arginine deprivation in aggressive subtypes of mesothelioma. Pt accrual has commenced across the US and Asia, with enrolment due in Europe and Australia by 2nd quarter of 2017. [Trial sponsored by Polaris Group]. Clinical trial information: NCT02709512.