tbuckley/cabot-search huggingface dataset:
CANTATA: A randomized phase 2 study of CB-839 in combination with cabozantinib vs. placebo with cabozantinib in patients with advanced/metastatic renal cell carcinoma.
Authors: Nizar M. Tannir, Robert J. Motzer, Neeraj Agarwal, Ping-Yu Liu, Samuel H. Whiting, Bridget O'Keeffe, Xuan Tran, Gayle P. Fiji, Bernard Escudier
Journal: Journal of Clinical Oncology (2018)

TPS4601 Background: Glutamine utilization is a metabolic pathway upregulated in renal cell carcinoma (RCC) and important for RCC tumor cell proliferation and survival. CB-839 is a first-in-class, potent, oral inhibitor of the mitochondrial enzyme glutaminase (GLS) that controls a critical step in tumor cell utilization of glutamine. In preclinical RCC models, CB-839 demonstrated synergistic anti-tumor activity when combined with cabozantinib, a VEGFR/MET inhibitor. A phase 1 study cohort of CB-839 plus cabozantinib as 2L+ therapy showed encouraging safety and efficacy results, with 40% overall response rate (ORR; RECIST v1.1) and 100% disease control rate in patients with clear cell advanced/metastatic RCC (mRCC). These findings prompted the initiation of a randomized phase 2 study comparing CB-839 plus cabozantinib vs. placebo plus cabozantinib in patients with clear cell mRCC. Methods: This international, randomized, double-blind, placebo-controlled, multi-center study (NCT03428217) will enroll ~300 patients with clear cell mRCC. Eligible patients will have received 1-2 prior lines of systemic therapy for mRCC including ≥1 anti-angiogenic therapy or the combination of nivolumab + ipilimumab. Other eligibility criteria include KPS ≥70%, measurable disease (RECIST v1.1), and no prior cabozantinib (or other MET inhibitor). Patients will be randomized 1:1 to receive CB-839 (800 mg twice daily per oral [PO] route) or placebo in combination with cabozantinib (60 mg daily PO) in 28-day cycles until disease progression or unacceptable toxicity. Patients will be stratified by prior PD-1/PD-L1 inhibitor therapy (Y/N) and IMDC prognostic risk group (favorable vs intermediate vs poor). The primary endpoint is progression-free survival (PFS; RECIST v1.1) by blinded independent radiology review; secondary endpoints are investigator-assessed PFS and overall survival. Safety, disease responses per RECIST, and quality of life will also be assessed. This important study will contribute to understanding the efficacy and safety profile of CB-839, a first-in-class metabolic inhibitor, in combination with cabozantinib in patients with mRCC. Clinical trial information: NCT03428217.
Outcomes of concurrent chemoradiotherapy for anal cancer in Brazil.
Authors: Andressa Cardoso Azeredo, Bruna Castilhos Silva
Journal: Journal of Clinical Oncology (2017)

e15073 Background: The incidence of anal cancer has increased in the last 30 years and concurrent chemoradiotherapy has been the standard treatment for anal cancer for many decades, since it is a curative treatment in most cases. Although, data from real life outcomes in brazilian patients is lacking. Methods: From October 2001 to November 2016, all the pacientes who were treated with concomitant 5-FU and mitomycin or more recently cisplatin plus radiation at Hospital de Clínicas de Porto Alegre, an academic hospital from South Brazil were identified by electronic database. Medical records were reviewed and demographic data, tumor and treatment characteristics were collected. OS and PFS were estimated by Kaplan-Meier curves. Statistical analysis was performed with SPSS 22. Results: Fifty one patients were analysed for this review. Patient characteristics revealed a mean age of 53 ± 9.03 years, 69% female, with predominantly histology being squamous cell carcinoma (90%). 92% (47) received chemoradiotherapy as a definitive treatment. The chemoterapy regimen used was 5-FU and mitomycin in 69% (35) of the patients and 5-FU plus cisplatin was used in 16 patients (31%). The standard chemoterapy regimen was changed because of lack of supply of mitomycin in our country. Approximately 66% of the patients achieved a complete response while 4 patients (7%) had persistent disease after treatment and 7% had disease progression during treatment. On multivariable analysis, the lymph node status and the size of the tumor were independently associated with worst results. The estimated median PFS was 78 months and the median OS was 92 months. Conclusions: To our knowledge, this is the first report of patients from Brazil treated with concurrent chemoradiation for anal canal cancer. Although we have a delay in the diagnosis and many patients present with locally advanced disease, the CR rate and prognosis are consistent with data from previous studies. We need a longer follow-up to confirm these data and also verify if there will be different outcomes because of the change in the chemoterapy regimen.
Influence of socioeconomic status and religious belief on palliative care in terminally ill cancer patient in a private hospital of central Nepal.
Authors: Shristi Tiwari
Journal: Journal of Clinical Oncology (2016)

e21513 Background: Palliative care for cancer patients in Nepal is in infancy. Various factors like literacy, economical status, accessibility to health care facility and religious belief play a huge role in accepting it. In a developing country like Nepal, not only variety in socio-economic demographics but also variety in religious beliefs comprise of strong factors determining treatment options. As cancer facilities are very few within the country and only few have options of palliative care and most do not have awareness regarding palliative care. Through this study we wanted to explore the level of awareness of terminally ill cancer patients and find common factors influencing decision making in accepting palliative care. Methods: Diagnosed cases of cancer patients , visiting Nepal cancer hospital and Research centre, Lalitpur, Nepal from 2015 April to 2015 December were included. Total of 20 pre formed multiple choice questions were asked verbally for illiterate or asked to tick the appropriate answer for the literate patients after taking the written consent. Those who gave answers to all the questions were included in this study. Results: Total of 188 cancer patients were approached. 42 (22.34%) patients declined to participate. Answers from total 146 patients were analyzed. Out of 146, 77% of patients let their family member to decide for them on treatment options, 13% of patients wished doctors to take decision for them and 10% wished to take their own decision .74% patients had never heard about palliative care before .Among 26 % who knew about palliative care, only 10 % chose palliative care while remaining 16 % wished for traditional religious rituals at home. Conclusions: Most of the decisions of critically ill cancer patients were taken by their immediate family members. It is different from the western world, as in our society people depend on families to care for them during life and wish for religious cremation in hope their souls get to heaven after death. In our study very few patients were aware of palliative care. Among very few who know about it, most refuse hospital based palliative care option due to their religious or socio-economic constraints.
Response by Overvad et al to Letter Regarding Article, “Female Sex Is a Risk Modifier Rather Than a Risk Factor for Stroke in Atrial Fibrillation: Should We Use a CHA <sub>2</sub> DS <sub>2</sub> -VA Score Rather Than CHA <sub>2</sub> DS <sub>2</sub> -VASc?”
Authors: Thure Filskov Overvad, Torben Bjerregaard Larsen, Peter Brønnum Nielsen
Journal: Circulation (2018)
TCT-355 Stroke After Transcatheter vs. Surgical Aortic Valve Replacement; A Meta-Analysis of Randomized Trials and Propensity Matched Observational Studies
Authors: Kuldeep Shah, Zakeih Chaker, Tatiana Busu, Fahad Alqahtani, Vinay Badhwar, Muhammad Alvi, Amelia Adcock, Mohamad Adnan Alkhouli
Journal: Journal of the American College of Cardiology (2018)
Retrospective analysis of AML patients to identifiy a higher risk of anthracycline-associated cardiac toxicity in Hispanic patients.
Authors: Geoffrey Patrick Shouse, Kiwon Park, Lawrence Liu, Aldane Hoilett, Salman Otoukesh, Seema Mukadam, Muhammad Omair Kamal
Journal: Journal of Clinical Oncology (2018)

e19012 Retrospective analysis of AML patients identifies a higher risk of anthracycline associated cardiac toxicity in Hispanic patients. Background: Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults. The development of AML is characterized by maturation arrest of hematopoietic precursors in the bone marrow. The standard treatment for AML includes cytarabine and an anthracycline in a 7+3 regimen. Toxicities associated with remission induction include myelosuppression, rash, and cardiac toxicity associated with anthracycline chemotherapy. Several studies have identified risk factors associated with cardiac toxicity including young age and coronary artery disease risk factors such as hypertension, obesity, diabetes mellitus, and high cholesterol. In the present retrospective review, we investigated factors associated with development of cardiac toxicity associated with anthracycline chemotherapy for AML induction. Methods: Individual health records of consecutive patients diagnosed with AML at Loma Linda University Medical Center between January 2012 and December 2017 were analyzed retrospectively. Approval was obtained from the Institutional Review Board prior to initiating the study. Data was analyzed using Chi Squared analysis, multivariate analysis, and the Kaplan Meier method. Results: A total of 53 adult patients were identified. The median age was 59 years, 47% of patients were female, 28% of patients were Hispanic, 64% were Caucasian, and 8% were other ethnicities. Of these patients, 59% received standard induction with 7+3. Interestingly, Hispanics were 7 times more likely to experience anthracycline-associated cardiomyopathy after than Caucasians (95% CI 1.18 - 41.36). After adjusting for comorbidities, the risk remained statistically significant. Conclusions: In the present study we identified Hispanic ethnicity as a risk factor for the development of anthracycline-associated cardiomyopathy. This ethnic predisposition is of significant clinical interest and warrants further prospective validation and further analysis as to the possible underlying genetic mechanisms responsible for this observation.
Abstract IA06: Molecular mechanisms of lung cancer development: Between metabolic reprogramming and genomic instability in the field of cancerization
Authors: Jamshed Rahman, Xiangming Ji, Chirayu Patel, Jamey Young, Pierre P. Massion
Journal: Clinical Cancer Research (2018)

Abstract Airway epithelial cells are prone to assault by risk factors and considered to be the primary cell type involved in the field of cancerization. To investigate risk-associated changes in the bronchial epithelium proteome that may offer new insights into molecular pathogenesis of lung cancer, proteins were identified in the airway epithelial cells of bronchial brushings specimens from risk-stratified individuals by shotgun proteomics. Differential expression of selected proteins was validated by parallel reaction monitoring mass spectrometry in an independent set of individual bronchial brushings. We identified over 300 proteins with a significant trend in expression. Pathway analysis revealed enrichment of carbohydrate metabolic enzymes in high-risk individuals. Glucose consumption and lactate production were increased in human bronchial epithelial BEAS2B cells treated with cigarette smoke condensate for seven months. Increased lipid biosynthetic capacity and net reductive carboxylation were revealed by metabolic flux analyses of [U-13C5] glutamine in this in vitro model, suggesting profound metabolic reprogramming in the airway epithelium of high-risk individuals. These results also pointed towards a fundamental role of glutamine and cysteine metabolism in lung cancer progression. Two amino acid transporters, specifically SLC1A5 and SLC7A11, captured our attention for their high level of expression in lung cancer. These transporters are associated with worse survival in lung cancer. A small-molecular inhibitor of SLC1A5 prevents tumor progression in nude mice, and a glutaminase inhibitor CB-839 exhibits radiosensitization to lung cancer cells, an effect that may be mediated by decreased GSH production. Taken together, these studies provide a rationale for new chemopreventive strategies, selection of patients for surveillance programs, and determining how metabolic reprogramming may contribute genomic instability a requirement to cancer development. Further investigation into how glutamine and cystine metabolism contribute to lung cancer development and progression may lead to novel early-interception strategies in lung cancer. This work is supported by NCI CA186145, CA152662, and DoD W81XWH-11-2-0161. Citation Format: Jamshed Rahman, Xiangming Ji, Chirayu Patel, Jamey Young, Pierre P. Massion. Molecular mechanisms of lung cancer development: Between metabolic reprogramming and genomic instability in the field of cancerization [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA06.
Prognostic factors for pancreatic metastases in renal cell cancer.
Authors: Alfred Chung, Shufeng Li, Sumit Shah, Alice C. Fan, Sandy Srinivas
Journal: Journal of Clinical Oncology (2016)

e16106 Background: The prognostic significance and optimal management of pancreatic metastases in renal cell carcinoma (RCC) remains unknown. This study aims to identify factors associated with improved survival after the development of pancreatic metastases, including the role of pancreatectomy (PT) and use of tyrosine kinase inhibitors (TKI). Methods: We performed a retrospective study on all patients with renal cell cancer and pancreatic metastasis seen at Stanford Hospital and Clinics from 1997 to 2015. RCC was confirmed via pathologic diagnosis and pancreatic metastasis was determined via imaging or through pathology. Factors investigated included age, gender, Fuhrman grade, stage, time to pancreatic metastasis, use of TKI, and PT status. Hazard ratios were determined using a univariate Cox proportional hazard model and survival estimates were made using Kaplan-Meier method. Results: Thirty-six patients met inclusion criteria. Mean age at the time of diagnosis was 60 years and 70% were male. Median overall survival (OS) from time of initial RCC diagnosis was 9 years with median OS of 3 years from time of pancreatic metastasis. Fuhrman grade was distributed between Grade I (3%), Grade II (31%), Grade III (33%) and Grade IV (8%). 72% of patients underwent treatment with TKIs and 36% of patients underwent PT. The use of TKIs was associated with a hazard ratio of 1.14 (p = 0.84) while PT was associated with a hazard ratio of 0.43 (p = 0.144), neither of which was statistically significant. The duration of time elapsed between initial RCC diagnosis and subsequent diagnosis of pancreatic metastasis was the only factor found to have statistically significant effect on survival after pancreatic metastasis with a hazard ratio of 0.89 (p = 0.0497). Kaplan-Meier curves also revealed a trend toward improved survival with lower grade disease (p = 0.053). Conclusions: Patients with increased length of time between initial RCC diagnosis and subsequent pancreatic metastasis correlated with increased survival after diagnosis of pancreatic metastasis. PT was not found to have a statistically significant survival advantage in this retrospective study, and larger randomized studies would be warranted to determine the utility of PT in the targeted therapy era.
Expanding <i>BRCA1/2</i> testing criteria to include other confirmed breast and ovarian cancer susceptibility genes.
Authors: Fergus Couch, Hermela Shimelis, Jill S. Dolinsky, Eric Polley, Carolyn Horton, Amal Yussuf, Lily Hoang, Jenna Lilyquist, Virginia Speare, Chunling Hu, Steven Hart, Holly LaDuca
Journal: Journal of Clinical Oncology (2018)

1524 Background: The National Comprehensive Cancer Network (NCCN) has expanded its breast and ovarian cancer (BC and OC) genetic testing and management recommendations to address the broader spectrum of cancer predisposition genes. However, management recommendations are pending for some candidate BC genes (e.g. BARD1, RAD51D) and OC genes (e.g. ATM, NBN) due to insufficient evidence of increased cancer risk, and indications for multi-gene panel testing (MGPT) remain vague overall. We aimed to further characterize BC and OC risks for 21 candidate susceptibility genes and explore the potential utility of BRCA1/2 testing criteria as an indication for MGPT. Methods: Gene-specific pathogenic variant (PV) frequencies among Caucasian BC and OC patients (unadjusted for other personal/family cancer history) ascertained from a cohort of > 175,000 patients referred for MGPT were compared to non-Finnish European reference controls from the genome aggregate database (gnomAD). Clinical histories of BC and OC patients were also reviewed to assess whether NCCN BRCA1/2 testing criteria were met (version 2.2017). Results: We confirmed the association of 15 genes with increased risk ( > 2.0-fold) of BC (ATM, BARD1, BRCA1/2, CDH1, CDKN2A, CHEK2 (excluding p.I157T), MLH1, MSH2, MSH6, NF1, PALB2, PTEN, RAD51D, TP53). The pooled frequency of PVs in these genes was 9.2% among BC patients of all ethnicities (3.5% in BRCA1/2 and 5.7% in other genes) and 8.6% among BC patients meeting BRCA1/2 testing criteria (3.4% in BRCA1/2 and 5.2% in other genes). Eleven genes were associated with increased risk of OC ( > 2.0-fold, ATM, BRCA1/2, BRIP1, MSH2, MSH6, NBN, PMS2, RAD51C, RAD51D, TP53). PVs in these genes were detected among 13.0% of OC patients of all ethnicities (8.0% for BRCA1/2 and 5.0% for other genes combined). Therefore, inclusion of additional risk genes increases detection rate for BC and OC patients meeting BRCA1/2 testing criteria by 152.9% and 62.5%, respectively. Conclusions: These results further characterize gene-specific BC and OC risks, which can be used to refine management recommendations for at-risk patients. Current testing criteria fail to capture a substantial proportion of women with increased risk of BC and OC.
TCT-543 Residual ischemia is Frequent in the Vessel Undergoing Percutaneous Coronary Intervention: Results of a Prospective Registry
Authors: Barry Uretsky, Abdul Hakeem, Malek Al-Hawwas, Srikanth Vallurupalli, Kristin Miller, Shiv Kumar Agarwal
Journal: Journal of the American College of Cardiology (2018)
Human endogenous retroviruses and their implication for immunotherapeutics of cancer
Authors: A.S. Attermann, A -M Bjerregaard, S.K. Saini, K. Grønbæk, S.R. Hadrup
Journal: Annals of Oncology (2018)

Human endogenous retroviruses (HERVs) have recently caught increased attention as a potential internal trigger to sensitize tumor cells to immunotherapies. HERVs are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny. Today, HERVs constitute ∼8% of the human genome, but most elements are highly degenerated, under strict epigenetic regulation, and rarely expressed in healthy tissues. However, cancer cells are specifically prone to reactivate the expression of HERV elements due to epigenetic dysregulation that accumulate during malignant transformation and when using epigenetic therapies. HERV expression can induce an interferon response due to induction of the viral defense pathway, so-called 'viral mimicry'. By mimicking viral infections, HERVs could function as an 'intrinsic adjuvant', possibly sensitizing cancer cells to immunological recognition. Furthermore, translated HERV elements may in themselves form a valuable pool of tumor-associated antigens. Epitopes derived from HERVs have been recognized by cytotoxic CD8+ T cells, leading to cancer cell recognition. The combination of 'viral mimicry' and T-cell recognition could provide a powerful combination with existing immune stimulatory therapies, such as checkpoint inhibition. This combination is currently being evaluated in clinical trials in a large number of cancers.
A single cell genomic signature to detect homologous recombination deficiency (HRD) and PARP inhibitors sensitivity using patient's circulating tumor cells (CTCs).
Authors: Gordon Vansant, Angel E Dago, Jerry Lee, Stephanie Greene, Laura Lietz, Yipeng Wang, Mark Andrew Landers, Ryan Vance Dittamore
Journal: Journal of Clinical Oncology (2016)

e23015 Background: PARPi have been successfully exploited as therapeutic agents in breast and ovarian tumors with HRD associated with germline BRCA mutations, and recently in metastatic castration resistance prostate cancer (mCRPC). Stratification of patients sensitive to PARPi is often based on the detection of HRD inactivating mutations and/or genomic scarring conducted in tumor tissue biopsies. These methods lack sensitivity due to their intrinsic limitation to resolve intra-tumor heterogeneity. To circumvent this, we developed a single cell HRD genomic signature aim to predict PARPi response in patients. Methods: 3 breast cancer cell lines (2 PARP sensitive BRCA mutant, MDA-MB-436 and HCC1395, and 1 BRCA wild type MDA-MB-231), and 3 BRCA wild type PARP resistant prostate cancer cell lines (VCaP, LnCaP and PC3) were identified and analyzed using Epic’s proprietary technology. Single cell DNA sequencing libraries were constructed to detect genome-wide Large Scale Transitions (LSTs) while target enrichment was performed to simultaneously assess for HRD inactivating mutations and loss of heterozygosity (LOH). Results: The highest median LSTs were observed in the BRCA mutant cell lines (50 ± 1; 58 ± 4, in HCC1395 and MDA-MB-436, respectively). Among BRCA wild type, the LSTs were highest in VCaP (33 ± 3) and PC3 (33 ± 4), both harboring p53 and/or PTEN alterations. The lowest LSTs were detected in VCaP (12 ± 1) and MDA-MBA-231 (21 ± 4). All detected LSTs were validated in comparison to gDNA. Concordantly, the highest number of LOHs were detected in BRCA mutant cell lines. All known point mutations (TP53, PTEN, BRCA) were recapitulated. Conclusions: We consistently detect genomic scars and inactivating HRD mutations at single cell resolution. Overall, our data indicates that high genomic instability as measured by the numbers of LSTs and LOHs may help to select for PARP sensitive patients.