tbuckley/cabot-search huggingface dataset:
High dose testosterone in men with metastatic castrate-resistant prostate cancer (mCRPC) and homologous recombination deficiency (HRD).
Authors: Julia Chen, Anthony M. Joshua, Samuel R. Denmeade, Emmanuel S. Antonarakis, Megan Crumbaker
Journal: Journal of Clinical Oncology (2019)

TPS5095 Background: mCRPC progresses via adaptive mechanisms that allow ongoing androgen receptor (AR) signalling despite castrate levels of androgens. Bipolar androgen therapy (BAT), cycling between supraphysiologic and subphysiologic serum testosterone levels, aims to exploit these adaptations to induce tumor regression. Extensive clinical data demonstrate the safety and efficacy of BAT in men with asymptomatic mCRPC. However, de novo resistance is still common and predictive biomarkers to refine patient selection are lacking. Pre-clinical data suggest that the induction of double-stranded DNA (dsDNA) breaks by BAT may be crucial to its mechanism of action. DNA repair defects, such as HRD, are particularly relevant in CRPC patients. We hypothesize that CRPC patients with DNA repair deficits such as HRD, may be particularly responsive to BAT. Methods: This is a phase II prospective single arm interventional trial (NCT03522064). Up to 30 patients will be recruited based on a Simon two-stage design with a power of 90% to detect an increase in response rate from 20% to 40%. Key inclusion criteria include i) asymptomatic or minimally symptomatic mCRPC, ii) rising PSA despite a castrate serum testosterone and iii) HRD on germline, tumor and/or circulating tumor DNA (ctDNA) analysis. Key exclusion criteria include i) ADT &lt; 1 year, ii) disease extent/sites that would cause significant risk if tumor flare occurs (e.g.: brain) and iii) significant cardiac disease. Previous PARP inhibitor therapy will be permitted in a subset. Participants will receive IM testosterone enanthate 500mg q4w in combination with ongoing LHRH antagonist/agonist or orchidectomy. The primary endpoint is PSA response rate defined as PSA reduction ≥50% from baseline. Secondary endpoints include time to PSA progression, quality of life, radiologic response and safety and tolerability. Exploratory endpoints include changes in ctDNA and tumoral DNA alterations from baseline to progression. Accrual is ongoing. Clinical trial information: NCT03522064.
CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer
Authors: J. L. Hu, W. Wang, X. L. Lan, Z. C. Zeng, Y. S. Liang, Y. R. Yan, F. Y. Song, F. F. Wang, X. H. Zhu, W. J. Liao, W. T. Liao, Y. Q. Ding, L. Liang
Journal: Molecular Cancer (2019)

Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) metastasis and chemoresistance have not been fully characterized. CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1. CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients. CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC.
Aberrant miRNA expression in glioma.
Authors: Anton Pushkin, Oleg I. Kit, Eduard Evgenevich Rostorguev, David H. Porksheyan, Natalya S. Kuznetsova, Sergey E. Kavitskiy
Journal: Journal of Clinical Oncology (2019)

e13506 Background: Gliomas are the most common type of primary brain tumors, with a high level of recurrence and mortality. The purpose of the study was to determine the expression profile of micro-RNA targeting components of the Hedgehog, Notch, Wnt, EGFR, TGFβ, HIF1α signaling pathways according to MirTarBase, miRDB, TargetScan. Methods: The study included 30 patients (15 women and 15 men) aged 27 to 76 years with histologically verified glial brain tumors. The RT2-qPCR method in operational biopsy specimens determined the relative expression of 12 micro-RNAs: hsa-miR-17-3p, hsa-miR-20a-3p, hsa-miR-326, hsa-miR-330-3p, hsa-miR- 107, hsa-miR-143-3p, hsa-let-7a-5p, hsa-miR-146a-5p, hsa-miR-29a-3p, hsa-miR-92a-1-5p, hsa-miR-26b-3p, hsa-miR-96-5p. Hsa-miR-7-5p and hsa-miR-126-3p were used as reference micro-RNA. Results: A statistically significant increase in the expression of hsa-miR-143-3p, hsa-miR-146a-5p and hsa-miR-92a-1-5p by 2, 2.2 and 2.9 times, respectively, was found, as well as a decrease in the expression of hsa-miR-330- 3p by 4.1 times in tumor tissue of the brain relative to normal tissue (p &lt; 0.05). Reduced expression of micro-RNA hsa-miR-330-3p may increase the activity of the VEGFA gene, which leads to intensive vascularization of the tumor. In addition, hsa-miR-330-3p is a validated negative regulator of the E2F1 gene known as a regulator of the cell cycle and tumor suppressor proteins. The TRAF6 gene is the direct validated target of hsa-miR-146a-5p, and its overexpression is associated with the patient's chemoresistance to temozolomide. Increased hsa-miR-143-3p micro-RNA expression can reduce the activity of the EGLN1 gene that also mediates the adaptation of tumor cells to hypoxic conditions. Hsa-miR-92a-1-5p micro-RNA is a negative regulator of PTEN gene expression. Conclusions: A significant decrease in hsa-miR-330-3p expression and an increase in hsa-miR-146a-5p, hsa-miR-143-3p, and hsa-miR-92a-1-5p, which was found in gliomas, can potentially be used to develop prognostic markers and therapeutic targets for targeted therapy.
A phase 2 study of nivolumab (NIVO) alone or plus ipilimumab (IPI) for patients with locally advanced unresectable (laBCC) or metastatic basal cell carcinoma (mBCC).
Authors: Julie E. Stein, Patricia Brothers, Katie Applebaum, Angela Gaskin, Hao Wang, Janis M. Taube, Evan J. Lipson
Journal: Journal of Clinical Oncology (2019)

TPS9595 Background: Basal cell carcinoma (BCC) is the most common human cancer. Although laBCC and mBCC are rare (&lt;10,000 cases per year in the US), tumors are typically locally invasive and often destroy skin and surrounding structures, leading to substantial morbidity. Standard-of-care therapies include hedgehog pathway inhibitors (HhPi) (e.g., vismodegib, sonidegib), but these medications may be poorly tolerated due to side effects (e.g., muscle spasms, alopecia, dysgeusia), and anti-tumor responses often lack durability. Several published reports have described patients with advanced HhPi-refractory BCC who experienced durable, objective tumor regressions after administration of anti-PD-1, which may be better tolerated than HhPi. The purpose of this study is to evaluate the efficacy of NIVO (anti-PD-1) alone and in combination with IPI (anti-CTLA-4) in patients with laBCC or mBCC, either in the first-line setting or after HhPi therapy. Methods: NCT03521830 is an open-label, phase 2 study of NIVO alone (cohort A) and plus IPI (cohort B) for patients with laBCC or mBCC. Subjects enrolled to cohort A (treatment-naïve or after HhPi therapy) will receive NIVO 480mg IV q4 weeks for up to 48 weeks. Subjects with progressive BCC after anti-PD-1 +/- HhPi will enroll to cohort B and receive NIVO 240mg + IPI 1mg/kg IV q3 weeks x 4 doses followed by NIVO 480mg IV q4 weeks x 7 doses. The primary endpoint is objective response rate (ORR) per RECIST v1.1. Secondary endpoints are duration of response, progression-free and overall survival, and disease control rate (i.e., % of patients with stable disease lasting ≥26 weeks or complete or partial response). Exploratory studies will include assessment of changes in immune cell subsets and immune checkpoint expression in pre- and on-treatment tumor biopsies, correlated with clinical outcomes. A Simon’s two stage design is planned for each cohort, testing for 15% null vs. 40% alternative ORR for cohort A, and 5% null vs. 20% alternative ORR for cohort B. The study will enroll up to 19 patients on cohort A and 21 patients on cohort B. Subject accrual began in November 2018. Clinical trial information: NCT03521830.
Prognostic significance of CD73 expression in localized renal cell carcinoma (RCC).
Authors: Abhishek Tripathi, Wanling Xie, Abdallah Flaifel, John A. Steinharter, Emily Stern Gatof, Rebecca B Jennings, Gabrielle Bouchard, Justin Fleischer, Nieves M. Chanza, Connor Gray, Charlene Mantia, Xiao X. Wei, Marios Giannakis, Bradley Alexander McGregor, Toni K. Choueiri, David F. McDermott, Sabina Signoretti, Lauren Christine Harshman
Journal: Journal of Clinical Oncology (2019)

4582 Background: CD73 or ecto-5'-nucleotidase mediates the de-phosphorylation of adenosine monophosphate to adenosine which promotes immunosuppression in the tumor microenvironment. Its prognostic significance in localized RCC has not been well characterized. Methods: We assessed CD73 protein expression using immunohistochemistry (Cell Signaling Technology, D7F9A, 1:25) on tissue microarrays (TMAs) containing tumor tissue from patients with pT1-4,N0-1, M0 RCC who underwent nephrectomy.CD73 expression was quantified using a combined score (CS: intensity x percentage of cells staining positive). CD73 positivity was defined as any CD73 expression on tumor cells (CS &gt; 0). Patients were categorized into CD73 negative (CS = 0), low ( &lt; median CS) and high (≥ median CS) groups. Clinical data was collected retrospectively.Baseline patient characteristics were compared between CD73 negative and positive (high + low) groups using the Cochran-Armitage trend test. Multivariable Cox regression evaluated associations of CD73 expression with disease-free and overall survival (DFS, OS) after adjusting for other baseline prognostic variables. Results: Of the 112 patients included, clear cell was the most common histology (70%) followed by chromophobe (12.5%), and papillary (12%) RCC. CD73 expression (CS &gt; 0) was noted in 22% (n = 25) of tumors and was associated with more advanced stage (T3-4/N+: 37.5% vs. 25%; p = 0.02) and a trend towards higher nuclear grade (≥3: 48% vs. 35%; p = 0.07). Median follow-up from nephrectomy was 9.7 yrs. In multivariable analysis adjusting for nuclear grade ( &lt; 3 vs. ≥3) and stage (T1-2, N0 vs. T3-4/N+), tumors with high CD73 expression had significantly worse DFS and OS (Table). Conclusions: CD73 expression was found in 22% of RCC patients and was associated with adverse pathologic features and poor prognosis independent of tumor stage and histologic grade. Our results provide strong rationale for further investigation of the CD73/adenosine pathway as a therapeutic target in RCC. [Table: see text]
The impact of method of recurrence detection on esophageal/gastroesophageal junction (EGJ) cancer outcomes.
Authors: Jubin Eghbali Matloubieh, Alexandra Pilar Licona-Freudensten, Andrea M Baran, Richard Francis Dunne, Aram F Hezel, Marcus Smith Noel, Michal J Lada, Christian G Peyre, Carolyn E Jones, Mohamedtaki Abdulaziz Tejani
Journal: Journal of Clinical Oncology (2019)

e15580 Background: Trimodality treatment (tx) with neoadjuvant chemoradiation (CRT) followed by esophagectomy is standard tx for locally advanced EGJ cancer. Post-operatively, there is no strong consensus about role of routine surveillance imaging. At the University of Rochester, patients (pts) have surveillance CT scans every 4-6 months (mos) for the first 2 years post-esophagectomy and every 6-12 mos for the next 3 years. Methods: Pts were identified who underwent esophagectomy for T1-T3 EGJ cancer between January 2011 and December 2015 at our institution. Objectives were to describe the impact of timing and methods of recurrence detection (MoRD) on patient outcomes. Recurrence-free (RFS) and overall survival (OS) were graphed via the Kaplan-Meier method. Results: 138 pts underwent esophagectomy for EGJ cancer: 107 (77.5%) were male, median age was 64, and 116 patients (84.1%) had adenocarcinoma. 112 pts (81.2%) had neoadjuvant CRT. The entire cohort’s median OS was 38.4 mos. 68 pts (49.3%) relapsed with a median RFS of 20.0 mos. Recurrence was detected by routine imaging in 36 pts (52.9%), imaging triggered by symptoms in 27 pts (39.7%), and symptoms alone in 5 pts (7.4%). Post-relapse median OS was 2.3 mos when detected based on symptoms alone, 5.0 mos when detected by imaging triggered by symptoms, and 13.7 mos when detected by routine scans (log-rank p = 0.041). There was no significant association between baseline patient/tumor characteristics or pathologic response and MoRD . 53 patients (77.9%) received salvage/palliative tx with a median of 2 tx (IQR = 1). There was no significant association between MoRD and number of salvage/palliative tx. Conclusions: 49.3% of pts relapsed after esophagectomy for EGJ cancer, consistent with current literature. Almost half of relapses were detected based on symptoms despite routine imaging. Increased OS for pts with relapse detected by routine scans is likely related to lead time bias, but may also be related to increased tx intensity or less aggressive tumors. MoRD did not have a measurable impact on number of lines of post-relapse tx. Prospective randomized trials are needed to determine real benefit of regular surveillance scans among EGJ cancer survivors.
Disruption of the Myc-PDE4B regulatory circuitry impairs B-cell lymphoma survival
Authors: Jehyun Nam, Dong Uk Kim, Eungyoung Kim, Bomi Kwak, Min Ji Ko, Ah-Young Oh, Bum-Joon Park, Yea Woon Kim, AeRi Kim, Hokeun Sun, Youngmi Jung, Jae-Hoon Lee, Ho-Jin Shin, Inmyoung Park, Dae-Kyu Song, Jee-Yeong Jeong, Yun-Han Lee, Sang-Woo Kim
Journal: Leukemia (2019)
Targeted next-generation sequencing (tNGS) of metastatic castrate-sensitive prostate cancer (M1 CSPC): A pilot molecular analysis in the STAMPEDE multi-center clinical trial.
Authors: Clare Gilson, Fiona Ingleby, Duncan C Gilbert, Marina Parry, Nafisah B Atako, Malcolm David Mason, Zafar Malik, Ruth E Langley, Andrew Simmons, Andrea Loehr, Noel Clarke, Nicholas James, Mahesh K B Parmar, Matthew Robert Sydes, Gerhardt Attard, Simon Chowdhury
Journal: Journal of Clinical Oncology (2019)

5019 Background: The STAMPEDE trial recruits men with high risk prostate cancer commencing first line systemic therapy. In a pilot study to ascertain the feasibility of tNGS and the prevalence of common genomic aberrations, we tested a commercial clinically-accredited assay on tumor blocks and present data obtained in the largest cohort of treatment-naïve M1 CSPC to date. Methods: Archival FFPE blocks were retrieved from trial participants and a single block submitted for sequencing by a Foundation Medicine. Inc. tNGS assay that includes 395 genes. Results: We successfully obtained tNGS data on 115 (62%) of 186 patients enrolled between Nov-2011 and April-2017 at 15 UK participating centers. The median age was 70 years (IQR 44-85); 97% had de novo M1 disease and 83% Gleason score ≥8. We observed PTEN deficiency (34%) due to copy-number loss (25%) or mutation (9%); TP53 mutation or loss (33%) and aberrations in PI3K signaling (16%), genes involved in DNA repair (14%), Wnt signaling (14%) and cell cycle control (6%). In total, these aberrations were observed in 76% of patients, with 35% harboring two or more. No androgen receptor ( AR) mutations were detected. Conclusions: The prevalence of PTEN deficiency is comparable with that observed in mCRPC consistent with this being a feature of metastatic disease. In contrast, AR mutations are not observed in this treatment-naïve group. The prevalence of DNA repair deficiency is less than observed in mCRPC but more than reported in prostatectomy cohorts. Although it is possible to use FFPE biopsies for tNGS, the test failure-rate poises challenges to evaluating treatments in low prevalence biomarker-defined groups. These data will inform the design and conduct of biomarker-directed trials.
Renal cell carcinoma epidemiology in the era of widespread imaging.
Authors: Ido Orlin, Barbara G Silverman, Yoram Dekel, Avi Stein, Boris Friedman, Maya Ben-Lasson
Journal: Journal of Clinical Oncology (2019)

e13083 Background: Cancers of the kidney and renal pelvis are the third most commonly diagnosed urological cancers. Renal Cell Carcinoma (RCC) is the most common histological type. The age-standardized rate (ASR) of RCC world-wide is 4.4/100,000 with higher rates in higher income countries. One third of diagnosed RCC patients have metastatic disease at presentation, although recent reports indicate smaller proportions. It has been suggested that the widespread use of imaging performed for various reasons has led to a rise of incidentally diagnosed RCC. We conducted a retrospective analysis of trends in cancers of the kidney and renal pelvis in Israel. Methods: We selected all cases of renal cell carcinoma of the kidney and renal pelvis neoplasms reported to the Israel National Cancer Registry (INCR) for the years 2000-2015. Demographic and clinical variables extracted from the registry included gender, population group, dates of birth/death, tumor size, stage at presentation (according to the Surveillance, Epidemiology and End Results (SEER) summary staging manual 2000). We calculated the overall and population group age-standardized incidence, using the direct method and the Segi World Standard population. Results: A total of 9,595 cases of RCC were identified. The average ASR was 7.7/100,000. RCC incidence was highest in the seventh decade of life with a male/female ratio of 1.7:1. Incidence was higher in the Jewish population than in the Arab population. The proportion of cases with metastatic disease at time of diagnosis was 10%; this figure was unchanged during the study period. Masses smaller than 4 cm. comprised almost two thirds of localized tumors with a significant increase in trend during the period of the study (p &lt; 0.001). Five-year overall survival for localized and metastatic disease was 86% and 12%, respectively. Survival was similar in the Arab and Jewish populations (p = 0.06). Conclusions: RCC incidence and survival in Israel mirror those of other western countries. The proportion of cases with distant spread at diagnosis is smaller than elsewhere reported. Small incidental renal masses (less than 4 cm) are increasingly diagnosed in the localized stages, possibly due to increased using of imaging.
Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer
Authors: Ian D. Davis, Andrew J. Martin, Martin R. Stockler, Stephen Begbie, Kim N. Chi, Simon Chowdhury, Xanthi Coskinas, Mark Frydenberg, Wendy E. Hague, Lisa G. Horvath, Anthony M. Joshua, Nicola J. Lawrence, Gavin Marx, John McCaffrey, Ray McDermott, Margaret McJannett, Scott A. North, Francis Parnis, Wendy Parulekar, David W. Pook, M. Neil Reaume, Shahneen K. Sandhu, Alvin Tan, T. Hsiang Tan, Alastair Thomson, Emily Tu, Francisco Vera-Badillo, Scott G. Williams, Sonia Yip, Alison Y. Zhang, Robert R. Zielinski, Christopher J. Sweeney
Journal: New England Journal of Medicine (2019)

Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer.In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events.A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group.Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).