tbuckley/cabot-search huggingface dataset:
Inferences About Drug Safety in Phase III Trials in Oncology: Examples From Advanced Prostate Cancer
Authors: Joshua Z Drago, Mithat Gönen, Gita Thanarajasingam, Chana A Sacks, Michael J Morris, Philip W Kantoff, Konrad H Stopsack
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background Safety is a central consideration when choosing between multiple medications with similar efficacy. We aimed to evaluate whether adverse event (AE) profiles of 3 such drugs in advanced prostate cancer could be distinguished based on published literature. Methods We assessed consistency in AE reporting, AE risk in placebo arms, and methodology used for risk estimates and quantification of statistical uncertainty in randomized placebo-controlled phase III trials of apalutamide, enzalutamide, and darolutamide in advanced prostate cancer. Results Seven included clinical trials enrolled a total of 9215 participants (range = 1051-1715 per trial) across 3 prostate cancer disease states. Within disease states, baseline patient characteristics appeared similar between trials. Of 54 distinct AE types in total, only 3 (fatigue, hypertension, and seizure) were reported by all 7 trials. Absolute risks of AEs in the placebo arms differed systematically and more than twofold between trials, which was associated with visit frequency and resulted in different degrees of uncertainty in AE profiles between trials. No trial used inferential methodology to quantify statistical uncertainty in AE risks, but 6 of 7 trials drew overall conclusions. Two trials concluded that there was no elevated AE risk because of the intervention, including the trial of darolutamide, which had the greatest statistical uncertainty. Conclusions Rigorous comparison of drug safety was precluded by heterogeneity in AE reporting, variation in AE risks in the placebo arms, and lack of inferential statistical methodology, underscoring considerable opportunities to improve how AE data are collected, analyzed, and interpreted in oncology trials.
Abstract B27: Cellular retinoic acid binding protein 2 (CRABP2) is a novel biomarker and potential therapeutic target for high-grade serous ovarian carcinomas
Authors: Yi Feng, Michael Gillette, Eric Kuhn, David Klinkebiel, Marilyn A. Mitchell, Kai Doberstein, Daniele Chaves-Moreira, Sho Sato, Haineng Xu, Brett Bomwell, Michelle S. Hirsch, Carolina Reyes, Adam R. Karpf, Michael J. Birrer, Steven J. Skates, Steven A. Carr, Ronny Drapkin
Journal: Clinical Cancer Research (2020)

Abstract Ovarian cancer ranks fifth in cancer deaths among women in the United States, accounting for more deaths than any other gynecologic cancer. There is an unmet medical need for biomarkers that can detect high-grade serous ovarian carcinoma (HGSOC) at an early stage. Our laboratory evaluated the biomarker potential of cellular retinoic acid binding protein 2 (CRABP2). Using Western blots (WB) and immunohistochemistry (IHC), we show that CRABP2 is expressed and secreted by HGSOC cells and tissues and is absent in normal fallopian tube (FT) epithelium. CRABP2 expression was associated with poor overall survival in patients with HGSOC. Proteomic analyses quantified specific secretion of CRABP2 in conditioned media from HGSOC cell lines, primary ascites-derived tumor cells, and serum from HGSOC patients. Expression of CRABP2 was positively associated with CRABP2 copy number amplifications by mining The Cancer Genome Atlas database. In addition, DNA methylation studies identified a putative enhancer downstream of CRABP2 that is hyper-methylated in fallopian tube epithelia (FTE) tissue and hypomethylated in HGSOC cells and tissues that expressed CRABP2. Inhibition of DNA methylation with DNA methytransferase (DNMT) inhibitors resulted in robust expression of CRABP2 protein in FT cell lines. Finally, a finding supported by CRABP2 knockdown experiments showed that CRABP2 loss triggers cell death in HGSOC cell lines. In conclusion, CRABP2 may serve as a novel biomarker for HGSOC with clinical potential as a therapeutic target. Citation Format: Yi Feng, Michael Gillette, Eric Kuhn, David Klinkebiel, Marilyn A. Mitchell, Kai Doberstein, Daniele Chaves-Moreira, Sho Sato, Haineng Xu, Brett Bomwell, Michelle S. Hirsch, Carolina Reyes, Adam R. Karpf, Michael J. Birrer, Steven J. Skates, Steven A. Carr, Ronny Drapkin. Cellular retinoic acid binding protein 2 (CRABP2) is a novel biomarker and potential therapeutic target for high-grade serous ovarian carcinomas [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B27.
Abstract 185: Longitudinal aqueous humor sampling reflects treatment response in retinoblastoma patients
Authors: Ashley Polski, Liya Xu, Rishvanth K. Prabakar, Jonathan W. Kim, Peter Kuhn, David Cobrinik, James Hicks, Jesse L. Berry
Journal: Cancer Research (2020)

Abstract Purpose: The aqueous humor (AH) liquid biopsy for retinoblastoma (RB) facilitates in vivo sampling of tumor-derived cell-free DNA (cfDNA). We previously demonstrated that tumor-derived somatic copy number alterations (SCNAs) in AH predict poor ocular salvage. However, whether AH sampling can be used to monitor clinical response throughout therapy remains unknown. In this retrospective study, we hypothesize that SCNA amplitude (amp) and tumor fraction (TFx) of RB cfDNA in the AH correspond to treatment response over time. Methods: Eyes that required intravitreal chemotherapy (IVM) for tumor seeding and had ≥3 sequential AH samples extracted during active IVM therapy and/or at secondary enucleation between 2015-2019 were included. Shallow whole-genome sequencing of AH cfDNA was performed to assess RB SCNA amp, and ichorCNA software estimated cfDNA TFx based on SCNAs present. Eyes without SCNAs in any sample were removed from final analysis. For each eye, clinical treatment response (regression vs progression) at each sample timepoint relative to the initial sample timepoint was determined from clinical records. Mann-Whitney U test was used for statistical analyses. Results: Twenty eyes of 20 patients had ≥3 AH extractions during the study period; 6 eyes had no SCNAs and were excluded from final analysis. Disease progression at any timepoint was associated with significantly higher SCNA amp (1.65±0.34) and TFx (0.57±0.36) than disease regression (SCNA amp 1.22±0.34, P=0.0002; TFx 0.29±0.34, P=0.01). Relative increases in SCNA amp (Δamp 1.19±0.35) and TFx (ΔTFx 3.68±5.27) from start to end of longitudinal AH sampling were associated with overall disease progression, whereas relative decreases in SCNA amp (Δamp 0.78±0.08; P=0.005) and TFx (ΔTFx 0.55±0.52; P=0.006) were associated with overall disease regression. Conclusions: We demonstrate that increases and decreases in AH-derived SCNA amp and TFx during therapy tend to correspond to clinical progression and regression of disease, respectively. Our findings suggest that longitudinal AH evaluation throughout active RB therapy may provide a novel quantitative method of monitoring RB treatment response. Citation Format: Ashley Polski, Liya Xu, Rishvanth K. Prabakar, Jonathan W. Kim, Peter Kuhn, David Cobrinik, James Hicks, Jesse L. Berry. Longitudinal aqueous humor sampling reflects treatment response in retinoblastoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 185.
SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19
Authors: Si Zhang, Yangyang Liu, Xiaofang Wang, Li Yang, Haishan Li, Yuyan Wang, Mengduan Liu, Xiaoyan Zhao, Youhua Xie, Yan Yang, Shenghui Zhang, Zhichao Fan, Jianzeng Dong, Zhenghong Yuan, Zhongren Ding, Yi Zhang, Liang Hu
Journal: Journal of Hematology & Oncology (2020)

Critically ill patients diagnosed with COVID-19 may develop a pro-thrombotic state that places them at a dramatically increased lethal risk. Although platelet activation is critical for thrombosis and is responsible for the thrombotic events and cardiovascular complications, the role of platelets in the pathogenesis of COVID-19 remains unclear.
Abstract 3093: Quantifying the confounders of panel-based tumor mutational burden (TMB) measurement
Authors: Jan Budczies, Daniel Kazdal, Michael Allgäuer, Petros Christopoulos, Eugen Rempel, Nicole Pfarr, Wilko Weichert, Stefan Fröhling, Michael Thomas, Solange Peters, Volker Endris, Peter Schirmacher, Albrecht Stenzinger
Journal: Cancer Research (2020)

Abstract Retrospective data including subgroup analyses in clinical studies have sparked strong interest in developing tumor mutational burden (TMB) as a predictive biomarker for immune checkpoint blockade. While individual factors interfering with panel sequencing based measurement of TMB (psTMB) have been discussed in recent studies, an integrative study quantifying, comparing and combining all potential confounders is still missing. We separated different potential confounders of psTMB measurement including “panel size”, “germline mutation filtering”, “biological variance” and “technical variance” and developed a specific error model for each of these factors. Published experimental psTMB data were fitted to the error models to quantify the contribution of each of the confounders. The total psTMB variance was obtained as sum over the different variance contributions. Using a typical large panel (size 1 to 1.5 Mbp) total errors of 57%, 42%, 34% and 28% were observed for tumors with psTMB of 5, 10, 20 and 40 muts/Mbp. Even for large panels, the stochastic error connected to the panel size represented the largest of all contributions to the total psTMB variance, especially for tumors with TMB up to 20 muts/Mbp. Other sources of psTMB variability could be kept under control, but rigorous quality control, best practice laboratory workflows and optimized bioinformatics pipelines are essential. We developed an integrated framework for the analysis of psTMB variability and provide a set of recommendations for implementation of psTMB as a laboratory developed test. Our approach highlights the stochastic portion of psTMB variability. The stochastic error connected inherently with psTMB could in part explain the suboptimal performance of the biomarker in some of the recent lung cancer studies. Citation Format: Jan Budczies, Daniel Kazdal, Michael Allgäuer, Petros Christopoulos, Eugen Rempel, Nicole Pfarr, Wilko Weichert, Stefan Fröhling, Michael Thomas, Solange Peters, Volker Endris, Peter Schirmacher, Albrecht Stenzinger. Quantifying the confounders of panel-based tumor mutational burden (TMB) measurement [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3093.
Diversity in Medical Faculty and Students
Authors: Said A. Ibrahim
Journal: JAMA Network Open (2020)

Simply put, diversity in academic medicine makes us better at delivering on our core missions of clinical care, research, and education.Diversity makes our institutions reflective of the communities we serve.Patients will trust us more. 1 A diverse research workforce also makes for more scientifically innovative teams and helps us attract students and faculty from diverse communities.We should value diversity and inclusion, which is why leading health care organizations recommend diversifying the health care profession as an important strategy to address inequalities in medical care.The disproportionate effect of the ongoing coronavirus disease 2019 pandemic on communities of color and socioeconomically disenfranchised communities and the past several weeks of unrest in response to tragic social injustices are also strong reminders of the need for diversity in academic medicine. [2][4][5] Within this context comes the report by Ogunwole et al 6 in this issue of JAMA Network Open.The authors used data from the Association of American Medical Colleges on full-time faculty and medical school matriculant from 1980 to 2018 and data from the US Census Bureau to examine trends by sex and race/ethnicity and implications for the future.The authors focused their analysis on faculty in internal medicine (IM), in part because IM is the largest specialty in medicine and a significant source of teachers and role models for future generations of physicians.
Abstract 3430: The protein phosphatase 4 complex is a tumor suppressor in prostate cancer
Authors: Philip A. Watson, Kayla E. Lawrence, Tejasveeta V. Nadkarni, Taslima F. Ishmael, Eugine Lee, Aura C. Agudelo Rivera, Jillian R. Love, John Wongvipat, Ling Cai, Abbas Nazir, Phillip J. Iaquinta, Kenneth Chang, Yupu Liang, Greg J. Hannon, Charles L. Sawyers
Journal: Cancer Research (2020)

Abstract Regions of recurring chromosomal deletions have been annotated in clinical prostate cancer (PCa), but for many of them there is an incomplete understanding of their contributions to disease progression. From an in vivo shRNA enrichment screen of the PCa deletome, we identified the serine threonine protein phosphatase 4 (PP4) regulatory subunit 2 (PPP4R2) as a candidate tumor suppressor, which undergoes copy number loss in 16% of primary PCa. Knockdown or CRISPR-Cas9 mediated knockout of PPP4R2 increased the growth rate of PCa xenograft tumors. Along with the catalytic subunit PP4C and an additional regulatory subunit (either PP4R3A or PP4R3B), PP4R2 forms two distinct heterotrimeric phosphatase holoenzymes. PP4R2 was critical for holoenzyme stability, as its deletion resulted in rapid, moderate downregulation of the other PP4 subunit proteins. The increased tumor growth rate and downregulation of PP4C resulting from loss of PP4R2 could be replicated by combined deletion of PPP4R3A and PPP4R3B, or by directly targeting PPP4C itself. Collectively, these findings implicated PP4C as the likely direct mediator of tumor suppression through the PP4 complex. This was confirmed in both PPP4R2 and PPP4R3A/PPP4R3B knockout cells in vivo by restoring PP4C to its normal physiological level through a dox-inducible cDNA, which reversed the accelerated tumor growth rate conferred by the deletion of the regulatory subunits. Phosphatase activity of PP4C was critical, as add-back of a catalytically dead PP4C mutant (D82A) was unable to reverse the growth rate of PPP4C knockout tumors. Interestingly, we found that the androgen receptor (AR), which is the principal therapeutic target for PCa, was co-immunoprecipitated by PP4C and its regulatory subunits. This suggests that AR could be a substrate for PP4C and is potentially present in a hyperphosphorylated and hyperactivated state in PCa that have decreased PP4 phosphatase activity. Our findings highlight a previously unappreciated tumor suppressor role for the PP4 complex in PCa, with the regulatory subunit PP4R2 providing a key function in stabilizing PP4C and thereby preserving its phosphatase activity. Citation Format: Philip A. Watson, Kayla E. Lawrence, Tejasveeta V. Nadkarni, Taslima F. Ishmael, Eugine Lee, Aura C. Agudelo Rivera, Jillian R. Love, John Wongvipat, Ling Cai, Abbas Nazir, Phillip J. Iaquinta, Kenneth Chang, Yupu Liang, Greg J. Hannon, Charles L. Sawyers. The protein phosphatase 4 complex is a tumor suppressor in prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3430.
Abstract 2677: Sequential same slide multiplex immunofluorescence and H&amp;E staining for combined phenotypic and morphologic characterization of formalin-fixed paraffin-embedded tissue sections
Authors: Katir K. Patel, Amanda Bares, Mael Manesse, Mark Burton, Bonnie Phillips, Kate Lillard, Anne Hellebust, Melinda Duplessis, Kyla Teplitz, Tad George
Journal: Cancer Research (2020)

Abstract Multiplex immunofluorescence (mIF) has become an established method for characterizing the tumor immune microenvironment. Currently, hematoxylin and eosin (H&amp;E) staining is typically performed on a serial tissue section to provide morphologic context for the mIF data. Serial sections do not represent identical cell populations, however, and are not always possible to obtain when the amount of available tissue is limited. Consequently, a method to examine the same tissue section by both fluorescence and brightfield imaging would be advantageous. Here we present a streamlined method and system for serial mIF and H&amp;E staining on a single tissue slide for a comprehensive analysis to support high-throughput tissue immunophenotyping. The UltiMapper I/O PD-L1 kit was used for multiplex immunofluorescence staining of CD8, CD68, PD-L1, and pan-Cytokeratin in formalin-fixed, paraffin-embedded (FFPE) samples from human tonsil and primary tumor biopsies using the Leica Biosystems BOND RX autostainer. Stained tissues were imaged in five spectrally distinct fluorescence channels (DAPI, FITC, TRITC, Cy5, Cy7) on the RareCyte CyteFinder II HT Instrument. Slides were de-coverslipped and stained with H&amp;E, then imaged with brightfield using the CyteFinder II HT instrument. To segment the tumor and stroma tissue regions, a HALO AI classifier was created. Fluorescence images were analyzed using the HALO Highplex FL module to identify CD8+ cytotoxic T-cells, CD68+ macrophages, CD68+/PD-L1+ immuno-suppressive macrophages, pan-CK+ tumor cells, and pan-CK+/PD-L1+ immune-evading tumor cells within the tumor and stromal regions identified by the H&amp;E stain. This novel combination of fluorescence and brightfield analysis enables deep phenotyping of immune cells as well as assessment of cellular morphology and tumor architecture in the same tissue section. Citation Format: Katir K. Patel, Amanda Bares, Mael Manesse, Mark Burton, Bonnie Phillips, Kate Lillard, Anne Hellebust, Melinda Duplessis, Kyla Teplitz, Tad George. Sequential same slide multiplex immunofluorescence and H&amp;E staining for combined phenotypic and morphologic characterization of formalin-fixed paraffin-embedded tissue sections [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2677.
Capmatinib in<i>MET</i>Exon 14–Mutated or<i>MET</i>-Amplified Non–Small-Cell Lung Cancer
Authors: Jürgen Wolf, Takashi Seto, Ji-Youn Han, Noemi Reguart, Edward B. Garon, Harry J.M. Groen, Daniel S.W. Tan, Toyoaki Hida, Maja de Jonge, Sergey V. Orlov, Egbert F. Smit, Pierre-Jean Souquet, Johan Vansteenkiste, Maximilian Hochmair, Enriqueta Felip, Makoto Nishio, Michael Thomas, Kadoaki Ohashi, Ryo Toyozawa, Tobias R. Overbeck, Filippo de Marinis, Tae-Min Kim, Eckart Laack, Anna Robeva, Sylvie Le Mouhaer, Maeve Waldron-Lynch, Banu Sankaran, O. Alejandro Balbin, Xiaoming Cui, Monica Giovannini, Mikhail Akimov, Rebecca S. Heist
Journal: New England Journal of Medicine (2020)

Among patients with non–small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation.
Abstract 1986: Mutation analysis in cell-free DNA upon development of resistance to afatinib
Authors: Nanao Terada, Hideharu Kimura, Mako Miyakawa, Hayato Koba, Taro Yoneda, Takayuki Takeda, Hiroki Shirasaki, Kazuhiko Shibata, Koichi Nishi, Koichi Takayama, Kazuo Kasahara
Journal: Cancer Research (2020)

Abstract Introduction: EGFR-mutant lung cancers are genomically heterogeneous in terms of compound EGFR mutations and mutations in other genes. The purpose of this study was to explore gene mutations in circulating cell-free DNA that are related to resistance to afatinib. Patients and methods: Patients with EGFR-mutant non-small cell lung cancer who received afatinib monotherapy were enrolled in this trial. Plasma samples were longitudinally collected before afatinib treatment, during treatment, and at the time of development of afatinib resistance. Written informed consent was obtained from all patients. Cell-free DNA was extracted from plasma using the QIAamp Circulating Nucleic Acid Kit (QIAGEN). Mutation profiles were determined by next-generation sequencing and analyzed using a human lung cancer panel (QIAGEN). Results: A total of 71 patients were enrolled in this study. Plasma samples both before treatment and at the time of resistance to afatinib were collected from 21 patients. Although currently under analysis, the mutation profiles determined by next-generation sequencing revealed the following changes. 1) The number of gene mutations per patient that newly appeared at resistance development ranged from 0 to 7. 2) The allele frequency of the T790M EGFR mutation, a mutation responsible for resistance to EGFR tyrosine kinase inhibitors, was increased after development of afatinib resistance in approximately half of the patients. Conclusions: The T790M allele frequency tended to increase after the development of resistance to afatinib. Some mutations were detected after resistance to afatinib. The role of this mutation needs to be investigated in a further study. Citation Format: Nanao Terada, Hideharu Kimura, Mako Miyakawa, Hayato Koba, Taro Yoneda, Takayuki Takeda, Hiroki Shirasaki, Kazuhiko Shibata, Koichi Nishi, Koichi Takayama, Kazuo Kasahara. Mutation analysis in cell-free DNA upon development of resistance to afatinib [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1986.
Abstract 4721: Arid1a suppresses Akt/NRas-driven hepatocarcinogenesis in mice
Authors: Shanshan Zhang, Yufeng Zhou, Di Cao, Qiannan Ren, Meiyin Zhang, Shijuan Mai, Huiyun Wang
Journal: Cancer Research (2020)

Abstract The SWI/SNF chromatin remodeling complexes are increasingly appreciated for their roles in carcinogenesis. Recent progress in human cancer genomic sequencing revealed that chromatin remodeling complexes are frequently targeted by cancer mutations, particularly in hepatocellular carcinomas (HCC). However, their precise role in HCC remains controversial and incompletely understood. AKT and NRAS are two major liver oncogenes that promote aberrant growth, metabolism and proliferation of hepatocytes, leading to initiation and development of HCC. Here, we investigated the role of Arid1a, one of the most mutated subunits of the SWI/SNF chromatin-remodeling complex across all human cancers, in hepatocarcinogenesis. To this end, we used Akt/NRas-driven mouse liver cancer model generated by hydrodynamic transfection (HDT). We found that overexpression of Arid1a strongly attenuated Akt/NRas-driven liver tumorigenesis and prolonged survival of animals. Conversely, knockdown of Arid1a accelerated Akt/NRas-driven liver cancer development and shortened survival in mice. We further showed that Arid1a antagonized activation of multiple molecular pathways downstream of Akt/NRas. Conclusion: Arid1a acts as a tumor suppressor in the Akt/NRas mouse HCC model. These new findings provide in vivo evidence for a tumor suppressive role of Arid1a-dependent chromatin remodeling in Akt/NRas-driven hepatocarinogenesis. Citation Format: Shanshan Zhang, Yufeng Zhou, Di Cao, Qiannan Ren, Meiyin Zhang, Shijuan Mai, Huiyun Wang. Arid1a suppresses Akt/NRas-driven hepatocarcinogenesis in mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4721.