tbuckley/cabot-search huggingface dataset:
Lessons learned from clinical genetic testing for hereditary breast and ovarian cancer (HBOC) syndromes in community and academic oncology centers.
Authors: Laurie M. Connors, W. Sam Yi, Nicoleta Voian
Journal: Journal of Clinical Oncology (2015)

e12501 Background: Evaluate the current methodology in clinical genetic testing for HBOC syndromes. Methods: Retrospective review of results of genetic testing in individuals evaluated for HBOC syndromes at a community or academic oncology practice in the northeast US. Solo provider data from each site with review of the following testing: (1) syndrome-specific genes, (2) next-generation sequencing panels: breast and ovarian cancer specific-high-penetrant genes (with established clinical guidelines) and moderate and high- penetrant genes (some genes lacking established clinical guidelines), and (3) comprehensive cancer risk panels (multiple types of cancer syndromes). Institutional Review Board review obtained. Results: See table below. Conclusions: Majority of patients evaluated for HBOC proceeded with clinical genetic testing through syndrome specific and cancer specific high-penetrant genes at both cancer centers. Mutations in BRCA1 and BRCA2 were the most common findings in individuals tested for HBOC. Academic center had a more conservative approach offering more syndrome specific tests compared to the community. This discrepancy is due to the lack of consensus as to who should be offered panels, gene panels yield a high rate of variants of unknown significance and for carriers of moderate penetrant genes, there is no clear medical management or impact to relatives. Percentage of total genetic tests. Type of genetic testing Community n=195 Academic n=57 Percent of tests Results Percent of tests Results Positive Negative VUS/ other Positive Negative VUS/ other Syndrome Specific BRCA1/2 TP53 34% 18% (6%) BRCA1 BRCA2 82% (28%) 0% (0%) 63% 8% (5%) BRCA2 NF1 92% (58%) 0% (0%) Next Generation Sequencing Panels Cancer-specific High-Penetrant genes 16% 10% (1.5%) BRCA1 BRCA2 87% (14%) 3% (0.5%) TP53 16 % 0% (0%) 78% (12%) 22% (3.5%) BRCA2 Cancer-specific High & moderate-penetrant genes 43% 11% (5%) BRCA1 BRCA2 CHEK2 MLH1 MUTYH PTEN 70% (30%) 19% (8%) ATM BRCA2 BRIP1 CDH1 CHEK2 MSH6 MUTYH NBN PTEN RAD50 RAD51C 5% 0% (0%) 100% (5%) 0% (0%) Comprehensive Cancer Risk Panels 7% 8% (0.5%) PALB2 61% (4%) 31% (2%) BRCA2 MUTYH SMAD4 16% 33%* (5%) BRCA2 MUTYH SDHB *+ & VUS 55% (9%) 44%* (7%) NF1 RAD51C SMAD4 TMEM127 *+ & VUS
Abstract P201: Separation of Postprandial Lipoproteins: Purification of Chylomicrons Using an ApoB100 Immunoaffinity Method
Authors: Grace Marie Jones, Russell Caccavello, Sergiu P Palii, Clive R Pullinger, John Kane, Kathleen Mulligan, Alejandro Gugliucci, Jean-Marc Schwarz
Journal: Circulation (2019)

Introduction: Elevated fasting and postprandial triglyceride-rich lipoproteins (TRL) are associated with increased risk for atherosclerosis. In the postprandial state circulating lipids consist of dietary fat transported from the intestine, by chylomicrons (containing ApoB48) and fat transported from the liver, in very low-density lipoproteins (VLDL, containing ApoB100). Research into the roles of endogenous versus dietary fat has been hindered because current methods are inadequate to fully separate these particles. Specifically, chylomicron fractions have considerable contamination from VLDL. Hypothesis: We hypothesized that the generation of resin crosslinked to specific ApoB100 antibodies unique to VLDL would allow purification of chylomicron particles. Proof-of-principle experiments will determine: 1) individual contributions of newly synthesized fatty acids (de novo lipogenesis (DNL)), to triglycerides found in VLDL and chylomicrons; and 2) the proportion of labeled acetyl-CoA (precursor-pool value (PPV)) used to synthesize new palmitate. A difference in DNL and PPV for the purified VLDL and chylomicron fractions will confirm the successful separation of these particles. Methods: Polyclonal antibodies were produced against the C-terminus of the ApoB100 protein and crosslinked to resin generating ApoB100-specific affinity columns. To yield purified chylomicron and VLDL particles we used this technique in conjunction with stable-isotope tracer methodology in a human feeding study. Two healthy volunteers consumed a standardized diet accompanied by oral dosing of 1- 13 C-acetate every 30 minutes for 8 hours. Plasma collected hourly was used for the isolation of TRL, which was applied to the affinity resin and purified chylomicrons and VLDL collected. Triglycerides were isolated and derivatized. The enrichment of methyl-palmitate was measured by GC/MS and Mass Isotopomer Distribution Analysis was used to calculate DNL and PPV. Results: Western blots confirmed the separation of chylomicrons and VLDL by the described method. From the purified TRL fractions, the DNL-AUC (%DNL x 5 hours) values for subject 1 were chylomicron 4% and VLDL 34%, an 88% difference, and for subject 2 were chylomicron 8% and VLDL 83%, a 90% difference. The PPV calculated for each fraction in subject 1 were chylomicron 10% and VLDL 13% and in subject 2 were chylomicron 10%, VLDL 12%. On average, the PPV in the chylomicron fraction were 18% less than the VLDL fraction. Conclusions: In conclusion, results demonstrate that the immunoaffinity method effectively separated postprandial lipoproteins showing fractionated particles carry unique information regarding tissue of origin . Future applications include investigating the respective contribution of fat and sugar to atherosclerosis risk.
Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors
Authors: Ariella B. Hanker, Virginia Kaklamani, Carlos L. Arteaga
Journal: Cancer Discovery (2019)

The PI3K pathway is mutated and aberrantly activated in many cancers and plays a central role in tumor cell proliferation and survival, making it a rational therapeutic target. Until recently, however, results from clinical trials with PI3K inhibitors in solid tumors have been largely disappointing. Here, we describe several factors that have limited the success of these agents, including the weak driver oncogenic activity of mutant PI3K, suboptimal patient selection in trials, drug-related toxicities, feedback upregulation of compensatory mechanisms when PI3K is blocked, increased insulin production upon PI3Kα inhibition, lack of mutant-specific inhibitors, and a relative scarcity of studies using combinations with PI3K antagonists. We also suggest strategies to improve the impact of these agents in solid tumors. Despite these challenges, we are optimistic that isoform-specific PI3K inhibitors, particularly in combination with other agents, may be valuable in treating appropriately selected patients with PI3K-dependent tumors. SIGNIFICANCE: Despite the modest clinical activity of PI3K inhibitors in solid tumors, there is an increasing understanding of the factors that may have limited their success. Strategies to ameliorate drug-related toxicities, use of rational combinations with PI3K antagonists, development of mutant-selective PI3K inhibitors, and better patient selection should improve the success of these targeted agents against solid tumors.
Muscle invasive bladder cancer (MIBC) demonstrates neoadjuvant cisplatin-based chemotherapy (NAC) related changes in molecular subtype and immune infiltration.
Authors: Samuel Aaron Funt, Alexander Solovyov, Bishoy Morris Faltas, Gopa Iyer, Mariel Elena Boyd, Catharine Kline Cipolla, Ashley Marie Regazzi, Min Yuen Teo, Chung-Han Lee, Hikmat Al-Ahmadie, Jonathan E. Rosenberg, Benjamin Greenbaum, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2019)

443 Background: Defining the role of MIBC molecular subtypes and immune expression in determining clinical outcomes is an area of active investigation. However, changes in these transcriptomic profiles pre- and post-NAC have not been well characterized. Methods: This retrospective study reviewed 53 pts with MIBC treated with NAC, of whom 12 pts without complete pathological response had both pre- and post-NAC samples of sufficient quality. Post-NAC staging was &gt; = pT2 in 11 pts and pT1 in 1 pt. We performed RNA expression analysis of matched pre-NAC transurethral resection of bladder tumor specimens and post-treatment radical cystectomy primary bladder tumor specimens. We used a customized NanoString panel incorporating previously reported immune signatures (Ayers, JCI 2017; O’Donnell, ASCO 2017) and additional genes to assign basal ( CD14, CD44, PDGFC, KRT14, KRT5) and luminal ( GATA3, PPARG, SHH, CD24, FOXA1, WNT7B, ERBB2) molecular subtypes. Results: We first classified the bladder cancer cohort of The Cancer Genome Atlas into basal and luminal subtypes using the BASE47 signature (Damrauer, PNAS 2014) and the NanoString panel and there was good agreement (Rand Index = 0.72). We then assigned subtypes using the NanoString panel on matched pre- and post-NAC samples and found marked subtype shift (Table). We identified two robust clusters of samples according to immune expression with a 3-fold change of immune expression between them (FDR = 0.0008). We found that 4 pts switched from the low to the high cluster, while 2 switched from the high to the low cluster after NAC (Table). Conclusions: MIBC molecular subtype membership is dynamic and is influenced by NAC. NAC can induce both enhanced and suppressed immune activity. These findings have implications on future studies exploring the predictive value of RNA expression patterns for bladder cancer therapies as well as post-NAC immunotherapy. [Table: see text]
Toxicity results from a novel phase I/II trial of VMAT radiotherapy to prostate and pelvic nodes plus six cycles of radium-223 in mCSPC metastatic to bone post ADT and docetaxel.
Authors: Joe O'Sullivan, Philip Geoffrey Turner, Suneil Jain, Alan R. Hounsell, Darren M. Mitchell, Sandra Biggart, Arthur Grey, Aidan Cole
Journal: Journal of Clinical Oncology (2019)

196 Background: Recent data has shown an overall survival (OS) benefit for up front Docetaxel or Abiraterone combined with androgen deprivation therapy (ADT) in metastatic castration sensitive prostate cancer (mCSPC). Data from STAMPEDE also suggests an additional OS benefit for radiotherapy to the prostate in men with low volume metastases. We hypothesised that Radium-223 + Radiotherapy to prostate and pelvic nodes following docetaxel (DOC) would be well tolerated and potentially improve OS in men with mCSPC involving bone. Methods: Men with mCSPC involving bone were treated in a single arm phase 1/2 study in which they received radical dose radiotherapy (74Gy/37) to prostate and pelvic nodes using Volumetric Modulated Arc Therapy (VMAT) radiotherapy and 6 cycles of Radium-223, 55kBq/kg following up front ADT and DOC. The primary endpoint was toxicity with secondary endpoints including time to PSA and ALP progression and radiological response. Results: We report the results of 27 men, median age 67 years treated in the study with a median follow up of 25 months post 1 st ADT. 81% of men had high volume disease. The schedule was well tolerated with grade ≥3 toxicity occurring in 5 patients (18.5%). Most toxicity was short lived thrombocytopenia and leucopenia. No unexpected toxicity was observed. All but 2 patients received all 6 cycles of Radium-223. One patient died of progressive disease before completion of the course of Radium-223. To date, 6 out of 27 patients have died, actuarial survival at 24 months is 83%. To date 9 out of 27 (33%) patients have developed PSA progression. Only 1 patient had a progressive alkaline phosphatase levels during the course of Radium-223 treatment. Conclusions: In men with mCSPC involving bone, a schedule of radical dose radiotherapy to prostate and pelvis + 6 cycles of Radium-223 is well tolerated post ADT + DOC. This treatment schedule will now join as a new arm of the STAMPEDE trial with OS as primary endpoint. Clinical trial information: 2014-000273-39.
A multicenter, open-label, proof of concept phase 1b/2 study to evaluate the safety and efficacy of RX-0201 in combination with everolimus to treat subjects with advanced renal cell carcinoma.
Authors: Christine Peterson, Ely Benaim
Journal: Journal of Clinical Oncology (2015)

TPS4580 Background: RX-0201 is a 20-mer oligonucleotide that is complementary to AKT-1 messenger ribonucleic acid (mRNA). The specificity of RX-0201-mediated effect on AKT-1 mRNA levels was examined in human renal cell carcinoma (von Hippel-Lindau protein-deficient renal cell carcinoma cell line) UMRC2 cells and resulted in a reduction of AKT-1 mRNA levels Methods: The current study is a proof of concept phase 1b/2, multicenter, open label study conducted in 2 stages. Stage 1 is an open-label, dose-escalation phase 1b study of RX-0201 administered in combination with everolimus. RX-0201 will be administered by a 24 hour continuous intravenous infusion for 14 days followed by 7 days of rest. It is expected that 250 mg/m2/day or a lower dose of RX-0201 will be identified as safe and well-tolerated when administered in combination with 10 mg of everolimus. The dose of RX-0201 identified in Stage 1 will be studied further in Stage 2 which is the randomized, open-label, 2-arm study of RX-0201 in combination with 10 mg of everolimus versus 10 mg of everolimus alone. Up to 8 cycles of study treatment will be permitted. Approximately 9 subjects are targeted to receive escalating doses of RX-0201 in combination with everolimus in Stage 1. The initial dose of RX-0201 is 125 mg/m2/day. In Stage 2 approximately 30 subjects are planned to be randomized in a 1:2 ratio (i.e., up to 10 subjects in the everolimus arm and up to 20 subjects in the everolimus/RX-0201 arm). Eligible subjects must have confirmed histologic or cytologic evidence of renal cancer with a clear cell component, measurable or evaluable disease as defined by RECIST, received at least 1 course of therapy with a VEGFR inhibitor and progressed within 6 months of planned first dose of on study treatment and received no more than 3 prior treatments of systemic renal cancer therapy. Radiological imaging for disease assessments will be according to RECIST ver. 1.1 Clinical trial information: NCT02089334.
Characterizing the effects of radiation dermatitis on quality of life: A prospective survey-based study
Authors: Alexandra Rzepecki, Mathew Birnbaum, Nitin Ohri, Johanna Daily, Jana Fox, William Bodner, Rafi Kabarriti, Madhur Garg, Keyur Mehta, Shalom Kalnicki, Beth N. McLellan
Journal: Journal of the American Academy of Dermatology (2019)
Regional variations in online education test performance for prostate cancer care.
Authors: Hamsa Jaganathan, Anne Roc, Wendy Turell, Daniel J. George
Journal: Journal of Clinical Oncology (2019)

317 Background: Regional variations in prostate cancer (PC) care in the US remain an issue with inconsistent clinician adherence to quality measures endorsed by national health services. To assess potential disparities in PC care among US-based healthcare providers (HCPs), we compared test performance of clinician participants in PC continuing medical education (CME) activities across 4 US regions. This would enable targeted education with region-specific strategies to effectively manage PC and promote consistent, high-quality care for all patients. Methods: PlatformQ Health developed and executed 3 online CME activities in PC (live broadcast and on-demand). The 1st 2 activities attracted 448 learners July 2016-2017. The 3rd activity attracted 319 learners to date May-Nov 2018. Self-reported US-based practicing HCPs (294) were included in this study. The percent of correct answers to CME tests pre-activity, post-activity, and at 8-weeks were collected and tested for significance (using 1 and 2 factor ANOVA tests) among 4 US regions: Northeast, Midwest, South, and West. CME test questions included case studies, new data on castration-resistant PC, and managing adverse events. Results: No significant difference was observed among the 4 regions in the pretest scores (p = 0.080, α = 0.05). While there was a significant improvement in performance among learners between pretest and posttest (p = 0.001), no significant regional variations were observed. There was also a significant improvement in performance from pretest to the follow-up test, which validates retention of knowledge 8 weeks after the education (p = 0.0016). However, learners from the South region performed significantly better than learners from the other regions (p &lt; 0.05) when it came to 8-week retention. Conclusions: Education can improve knowledge and competence in PC management among US-based HCPs. Future studies, including post- test surveys regarding practice integration, should identify reasons for regional discrepancies in test performances among providers specializing in PC. A broader understanding towards PC care variations can help tailor CME activities specific to regional issues and identify region-specific best practices and learning gaps.
Hereditary breast-ovarian cancer knowledge and interest in genetic testing among African American women.
Authors: Sheshadri Madhusudhana
Journal: Journal of Clinical Oncology (2015)

e12510 Background: African American (AA) women are diagnosed with breast cancer (BCA) at a young age, have the poorest BCA and ovarian cancer (OC) outcomes. They have a higher prevalence of triple-negative BCA (TNBC), a more aggressive form of BCA associated with BRCA gene mutations carriers. Yet, AA women’s knowledge of hereditary breast-ovarian cancer (HBOC) and uptake of genetic counseling and genetic testing for BRCA1/2 lag behind those for Caucasian women. Methods: Eligibility criteria were: AA woman diagnosed with BCA at age < 50 years (n = 24), or diagnosed with TNBC at any age (n = 5), or diagnosed with OC at any age (n = 3), or unaffected first-degree relative (FDR, n = 8). Potential participants were identified through the cancer registry and recruited by mail or during clinic visits, while FDRs were referred by affected relatives. Participants signed a consent form, completed a demographic questionnaire, and a survey to assess knowledge of HBOC (11-items), perceptions of BCA or OC risk (6-items), and perceived advantages and disadvantages of genetic testing (a 22-items, 4-point likert scale). The same survey was completed before (pre) and after (post) an educational session. Data were analyzed by descriptive and non-parametric statistics. Results: Mean participants’ age was 48.2±9.98 years and 32.5% had FDRs with BCA. Annual household income was < $15,000 for 52.5% of participants, and 62.5% had Medicaid. Participants’ knowledge of HBOC increased significantly following the educational session. However, their perceptions about knowing their BRCA genetic status did not change. Over 90% of participants indicated they would participate in genetic research about BCA and OC in Black women. Over 75% of participants indicated they would seek genetic testing if provided, with 46% indicating they would do so within the next 30 days. Conclusions: Knowledge of HBOC among AA women with personal or family history of BCA or OC increased significantly following a basic one-on-one educational session about HBOC. Participants indicated interest in genetic research and willingness to participate in genetic testing if given the opportunity.
A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets
Authors: Juan Bayo, Esteban J. Fiore, Luciana M. Dominguez, Alejandrina Real, Mariana Malvicini, Manglio Rizzo, Catalina Atorrasagasti, Mariana G. García, Josepmaria Argemi, Elisabeth D. Martinez, Guillermo D. Mazzolini
Journal: Journal of Hepatology (2019)
Efficacy and safety of everolimus in advanced low- to intermediate-grade neuroendocrine tumors.
Authors: Ioannis Gkiozos, Konstantinos N. Syrigos
Journal: Journal of Clinical Oncology (2015)

e15198 Background: Most patients with neuroendocrine tumors (NET) have advanced disease at the time of diagnosis, and 65% die within the first 5 years after diagnosis. The benefits associated with cytotoxic chemotherapy in advanced neuroendocrine tumors appear to be modest. Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors. It has also shown beneficial activity in neuroendocrine tumors of pulmonary or gastrointestinal origin Here it is presented an evaluation of the agent in a retrospective study in patients with low-grade or intermediate-grade neuroendocrine tumours. Methods: This is a retrospective study of the registries of 10 patients diagnosed with neuroendocrine tumors, in whom it was administrated everolimus during the course of their management, as monotherapy or in combination with somatostatin analogues. Everolimus was administrated in a dose of 10 mg once daily. The primary endpoint was the evaluation of the activity through estimation of the progression-free survival, as well as the safety of the drug through identification of the adverse events of all grades. The findings were compared with the recent published data of randomized, double-blind, placebo controlled studies. Results: Median progression-free survival was 10.5 months, a result comparable with recent published data. The benefit from everolimus with respect to progression-free survival was seen primarily in the stabilization of disease or minor tumor shrinkage. It was not recorded a case of partial or complete response. The noted adverse events were usually of grade 1 or 2 and rarely led to drug discontinuation. It was not recorded deadly outcome during the drug administration. Conclusions: Everolimus, offers long term progression free survival, usually by achieving stable disease, in patients with advanced neuroendocrine tumors and it is associated with a low rate of severe adverse events. The findings of this study, although underpowered, were similar with the results of the RADIANT-2 and RADIANT-3 studies.