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1. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study

Author

Dimitrios Farmakiotis, Susie Owenby, Arturo Loaiza-Bonilla, Mansi R. Shah, Matthew Puc, Vadim S. Koshkin, Ahmad Daher, Prakash Peddi, Cameron Rink, Heloisa P. Soares, Eneida R. Nemecek, Mehmet Asim Bilen, Sanjay Mishra, Lidia Schapira, Amit Verma, Ali Raza Khaki, Chih-Yuan Hsu, Sandy DiLullo, Mark Bonnen, Jeanna Knoble, Carla Casulo, Umit Topaloglu, Jorge A. Garcia, Geoffrey Shouse, Praveen Vikas, Clarke A. Low, Archana Ajmera, George D. Demetri, Leyre Zubiri, Grace Glace, Shannon K. McWeeney, Susan Yackzan, Pamela C Egan, Rachel P. Rosovsky, Salvatore Del Prete, Anthony P. Gulati, Lane R. Rosen, Andy Futreal, Merry Jennifer Markham, Sabitha Prabhakaran, Alicia K. Morgans, Sarah Nagle, Lisa Weissmann, Albert C. Yeh, Ziad Bakouny, Stephanie Berg, David Gill, Marcus Messmer, Ryan Nguyen, Terence Duane Rhodes, Vikram M. Narayan, Matthew D. Galsky, Arielle Elkrief, Lori J. Rosenstein, Roy S. Herbst, Justin Shaya, Thorvardur R. Halfdanarson, Douglas B. Johnson, Orestis A. Panagiotou, Sanjay G. Revankar, Toni K. Choueiri, Yu Shyr, Fiona Busser, Kaitlin M. Kelleher, Nicole M. Kuderer, Paul L. Weinstein, Anup Kasi, Grace Shaw, Adam J. Olszewski, Catherine Curran, Samuel M. Rubinstein, Angelo Cabal, Michael H. Bar, John F. Deeken, Vivek Subbiah, Abdul Hai Mansoor, Hina Khan, Rana R. McKay, Catherine Stratton, Saurabh Dahiya, Marc A. Rovito, John Philip, Sanjay Shete, Oscar K. Serrano, Julie Fu, Daniel W. Bowles, Candice Schwartz, Tian Zhang, Pier Vitale Nuzzo, Eric H. Bernicker, Wenxin Xu, Genevieve M. Boland, Sarah Wall, Babar Bashir, Solange Peters, Neeta K. Venepalli, Sandeep H. Mashru, William A. Wood, Anne H. Angevine, Mary F. Mulcahy, Gilberto Lopes, Justin F. Gainor, Jessica Hawley, Monika Joshi, Christopher R. Friese, Navid Hafez, Heather H. Nelson, Gregory J. Riely, Jordan Kharofa, Nilo Azad, Chintan Shah, Gerald Batist, Mary Salazar, Rosemary Zacks, Alice Zhou, Lawrence E. Feldman, Paul Fu, Gary H. Lyman, Nathaniel Bouganim, John A. Steinharter, Shilpa Gupta, Matthias Weiss, Peter Paul Yu, Susan Van Loon, Jamie Stratton, Karen Vega-Luna, Tyler Masters, Christopher Lemmon, Aakash Desai, Bryan A. Faller, Jessica M. Clement, Zhuoer Xie, Keith Stockerl-Goldstein, Corrie A. Painter, Gabrielle Bouchard, Rulla M. Tamimi, Daruka Mahadevan, Rimma Belenkaya, Jill S. Barnholtz-Sloan, Jarushka Naidoo, Amelie G. Ramirez, Philip E. Lammers, Elizabeth A. Griffiths, Michael J. Gurley, X. Li, Jonathan Riess, Syed A. Ahmad, Daniel Blake Flora, Salma K. Jabbour, Jared D. Acoba, Neeraj Agarwal, Ang Li, Sarah Mushtaq, Firas Wehbe, Tanios Bekaii-Saab, Donald C. Vinh, Emily Hsu, Ryan Monahan, Petros Grivas, Harry Menon, John M. Nakayama, Janice M. Mehnert, Elizabeth Marie Wulff-Burchfield, Sara Matar, Paul E. Oberstein, Mary M. Pasquinelli, Axel Grothey, Jack West, John C. Leighton, Dawn L. Hershman, Leslie A. Fecher, Aditya Bardia, Sumit A. Shah, Barbara Logan, Kerry L. Reynolds, Michael A. Thompson, Robert L. Rice, Erin Cook, Trisha Wise-Draper, Christine Bestvina, Daniel Castellano, Paolo Caimi, K. M.Steve Lo, Ruben A. Mesa, Maheen Z. Abidi, Alvaro G. Menendez, Daniel G. Stover, Colleen Lewis, Bertrand Routy, Deborah B. Doroshow, Carmen C. Solorzano, M. Wasif Saif, Rohit Bishnoi, Michael Glover, David D. Chism, Briana Barrow, Christopher McNair, Dimpy P. Shah, Erin A. Gillaspie, Andrea J. Zimmer, Andrew Schmidt, Jessica K. Altman, Michelle Marcum, Rawad Elias, Balazs Halmos, Karen Stauffer, Gayathri Nagaraj, Ardaman Shergill, Mark E. Dailey, Catherine Handy Marshall, Pramod K. Srivastava, Shuchi Gulati, Alokkumar Jha, Mateo Bover Larroya, Mark A. Lewis, Young Soo Rho, James L. Chen, Eli Van Allen, Julie Tsu Yu Wu, Antonio Giordano, Amit Kulkarni, Joerg Rathmann, Donna R. Rivera, Narjust Duma, Maryam B. Lustberg, Theresa M. Carducci, Jeremy L. Warner, Elizabeth Robilotti, Patricia LoRusso, Rohit Jain, Amit Sanyal, Nizar M. Tannir, Kent Hoskins, Nathan A. Pennell, Brian I. Rini, Suki Subbiah, COVID-19 and Cancer Consortium, Abidi, M., Acoba, J.D., Agarwal, N., Ahmad, S., Ajmera, A., Altman, J., Angevine, A.H., Azad, N., Bar, M.H., Bardia, A., Barnholtz-Sloan, J., Barrow, B., Bashir, B., Belenkaya, R., Berg, S., Bernicker, E.H., Bestvina, C., Bishnoi, R., Boland, G., Bonnen, M., Bouchard, G., Bowles, D.W., Busser, F., Cabal, A., Caimi, P., Carducci, T., Casulo, C., Chen, J.L., Clement, J.M., Chism, D., Cook, E., Curran, C., Daher, A., Dailey, M., Dahiya, S., Deeken, J., Demetri, G.D., DiLullo, S., Duma, N., Elias, R., Faller, B., Fecher, L.A., Feldman, L.E., Friese, C.R., Fu, P., Fu, J., Futreal, A., Gainor, J., Garcia, J., Gill, D.M., Gillaspie, E.A., Giordano, A., Glace, M.G., Grothey, A., Gulati, S., Gurley, M., Halmos, B., Herbst, R., Hershman, D., Hoskins, K., Jain, R.K., Jabbour, S., Jha, A., Johnson, D.B., Joshi, M., Kelleher, K., Kharofa, J., Khan, H., Knoble, J., Koshkin, V.S., Kulkarni, A.A., Lammers, P.E., Leighton, J.C., Lewis, M.A., Li, X., Li, A., Lo, KMS, Loaiza-Bonilla, A., LoRusso, P., Low, C.A., Lustberg, M.B., Mahadevan, D., Mansoor, A.H., Marcum, M., Markham, M.J., Handy Marshall, C., Mashru, S.H., Matar, S., McNair, C., McWeeney, S., Mehnert, J.M., Menendez, A., Menon, H., Messmer, M., Monahan, R., Mushtaq, S., Nagaraj, G., Nagle, S., Naidoo, J., Nakayama, J.M., Narayan, V., Nelson, H.H., Nemecek, E.R., Nguyen, R., Nuzzo, P.V., Oberstein, P.E., Olszewski, A.J., Owenby, S., Pasquinelli, M.M., Philip, J., Prabhakaran, S., Puc, M., Ramirez, A., Rathmann, J., Revankar, S.G., Rho, Y.S., Rhodes, T.D., Rice, R.L., Riely, G.J., Riess, J., Rink, C., Robilotti, E.V., Rosenstein, L., Routy, B., Rovito, M.A., Saif, M.W., Sanyal, A., Schapira, L., Schwartz, C., Serrano, O., Shah, M., Shah, C., Shaw, G., Shergill, A., Shouse, G., Soares, H.P., Solorzano, C.C., Srivastava, P.K., Stauffer, K., Stover, D.G., Stratton, J., Stratton, C., Subbiah, V., Tamimi, R., Tannir, N.M., Topaloglu, U., Van Allen, E., Van Loon, S., Vega-Luna, K., Venepalli, N., Verma, A.K., Vikas, P., Wall, S., Weinstein, P.L., Weiss, M., Wise-Draper, T., Wood, W.A., Xu, W.V., Yackzan, S., Zacks, R., Zhang, T., Zimmer, A.J., and West, J.

Subjects
Prognostic variable, medicine.medical_specialty, business.industry, Cancer, General Medicine, Odds ratio, Aged, Antiviral Agents/therapeutic use, Azithromycin/therapeutic use, Betacoronavirus, Cause of Death, Comorbidity, Coronavirus Infections/drug therapy, Coronavirus Infections/epidemiology, Coronavirus Infections/mortality, Databases, Factual, Female, Humans, Hydroxychloroquine/therapeutic use, Male, Middle Aged, Neoplasms/epidemiology, Neoplasms/mortality, Neoplasms/therapy, Pandemics, Pneumonia, Viral/drug therapy, Pneumonia, Viral/epidemiology, Pneumonia, Viral/mortality, Prognosis, Risk Factors, 030204 cardiovascular system & hematology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Cohort, Clinical endpoint, Medicine, 030212 general & internal medicine, business, Cause of death, Cohort study
Abstract

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Published
2020

2. Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma

Author

Xin Gao, Maxine Sun, Sabina Signoretti, Michael B. Atkins, Catherine J. Wu, Shaan Dudani, Thai H. Ho, Michelle S. Hirsch, Bradley Alexander McGregor, Ziad Bakouny, John A. Steinharter, Daniel Y.C. Heng, Miriam Sant'Angelo, Sylvan C. Baca, Eliezer M. Van Allen, David A. Braun, Lauren C. Harshman, Stephen Tang, Alice Bosma-Moody, Ronan Flippot, Pier Vitale Nuzzo, Kevin Bi, Amin Nassar, Yue Hou, Sarah Abou Alaiwi, Mark Pomerantz, Natalie I. Vokes, W. Marston Linehan, Megan Wind-Rotolo, Laure Hirsch, Giannicola Genovese, David F. McDermott, Jackson Nyman, Juliet Forman, Wanling Xie, Toni K. Choueiri, Jacob E. Berchuck, Jihye Park, Wenting Pan, Sabrina Y. Camp, Meng Xiao He, Gabrielle Bouchard, Xiao X. Wei, Matthew L. Freedman, Gwo-Shu Mary Lee, Petra Ross-Macdonald, Maura Sticco-Ivins, Sachet A. Shukla, Steven L. Chang, Leigh Ellis, Abdallah Flaifel, Srinivas R. Viswanathan, and Miriam Ficial

Subjects
0301 basic medicine, Transcription, Genetic, Programmed Cell Death 1 Receptor, General Physics and Astronomy, medicine.disease_cause, B7-H1 Antigen, Antineoplastic Agents, Immunological, 0302 clinical medicine, Renal cell carcinoma, CDKN2A, Cancer genomics, CTLA-4 Antigen, Immune Checkpoint Inhibitors, BAP1, Mutation, Multidisciplinary, High-Throughput Nucleotide Sequencing, Phenotype, Kidney Neoplasms, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Tumour immunology, Ubiquitin Thiolesterase, Signal Transduction, Science, Tumour heterogeneity, Antigen presentation, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, medicine, Carcinoma, Biomarkers, Tumor, Humans, Carcinoma, Renal Cell, Cyclin-Dependent Kinase Inhibitor p16, Rhabdoid Tumor, Retrospective Studies, Gene Expression Profiling, Tumor Suppressor Proteins, General Chemistry, Immune Checkpoint Proteins, medicine.disease, Survival Analysis, Gene expression profiling, 030104 developmental biology, Cancer research, Immunization
Abstract

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC., Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

Published
2021

3. A Systematic Framework to Rapidly Obtain Data on Patients with Cancer and COVID-19: CCC19 Governance, Protocol, and Quality Assurance

Author

Sarah Wall, Babar Bashir, Toni K. Choueiri, Salvatore Del Prete, Grace Shaw, Solange Peters, Catherine Curran, Navid Hafez, Nathaniel Bouganim, Sarah Nagle, Julie Tsu-Yu Wu, Jared D. Acoba, Vaibhav Kumar, Gabrielle Bouchard, Lisa Weissmann, Hagen F. Kennecke, Tian Zhang, Manmeet Ahluwalia, Sanjay Goel, Samuel M. Rubinstein, Daruka Mahadevan, Elizabeth A. Griffiths, Destry J. Elms, Michael J. Gurley, Arturo Loaiza-Bonilla, Suki Subbiah, Gilberto Lopes, Lisa Tachiki, David M. Aboulafia, Kent Hoskins, Daniel W. Bowles, Sandeep H. Mashru, Matthew Puc, Prakash Peddi, Nathan A. Pennell, Stephen V. Liu, Justin F. Gainor, Ali Raza Khaki, Rebecca L. Zon, Matthew D Tucker, Amanda Nizam, Bryan A. Faller, Deborah B. Doroshow, Nitin Ohri, Brian I. Rini, Abdul-Hai Mansoor, Sachin R. Jhawar, George D. Demetri, Catherine Stratton, Eliezer M. Van Allen, Praveen Vikas, Alvaro G. Menendez, Amelie G. Ramirez, Jonathan M. Loree, Divaya Bhutani, Clarke A. Low, Anju Nohria, Melissa K. Accordino, Rohit Bishnoi, Pamela C Egan, Rachel P. Rosovsky, Julie C. Fu, Fiona Busser, Orestis A. Panagiotou, Aditya Bardia, Peter Paul Yu, Susan Van Loon, Genevieve M. Boland, Douglas B. Johnson, Anup Kasi, Barbara Logan, Alice Zhou, Matthew D. Galsky, Arielle Elkrief, Mary Salazar, Rosemary Zacks, Carmen C. Solorzano, Andrew Schmidt, Paolo Caimi, Zhuoer Xie, Michael T. Schweizer, Briana Barrow McCollough, Jessica K. Altman, Christopher McNair, Cassandra Hennessy, Angelo Cabal, Qamar Ul Zaman, Alex Cheng, Keith Stockerl-Goldstein, John C. Leighton, Joshua D. Palmer, Scott J. Dawsey, Deepak Ravindranathan, Jonathan Riess, Miriam Santos Dutra, Daniel Blake Flora, Aakash Desai, Rana R. McKay, Ruben A. Mesa, Maheen Z. Abidi, Cathleen Park, Jill S. Barnholtz-Sloan, Erin Cook, Trisha Wise-Draper, Shannon K. McWeeney, Donald C. Vinh, Clara Hwang, Stephanie Berg, Leyre Zubiri, Daniel G. Stover, Michelle Marcum, Sarah Mushtaq, Wilhelmina D. Cabalona, Eyob Tadesse, Kanishka G. Patel, Ryan Monahan, Ziad Bakouny, Pankil Shah, David Gill, Terence Duane Rhodes, Marc A. Rovito, Chih-Yuan Hsu, Elizabeth T. Loggers, Shilpa Gupta, Susie Owenby, Benjamin A. Gartrell, David D. Chism, Neeta K. Venepalli, Punita Grover, Adam J. Olszewski, Sonya A. Reid, Firas Wehbe, Omar Butt, Emily Hsu, Poorva Bindal, Paul L. Weinstein, Jessica Hawley, Tanya M. Wildes, Subha Madhavan, Claire Hoppenot, Margaret E. Gatti-Mays, Huili Zhu, Michael Glover, Rawad Elias, Elizabeth S. Nakasone, Heather H. Nelson, Gerald Batist, Gary H. Lyman, John F. Deeken, Michael H. Bar, Pamela Bohachek, Benjamin French, Mark A. Lewis, Daniel J. Hausrath, Mary F. Mulcahy, X. Li, David A. Slosky, Michael J. Wagner, Nicole Williams, Hina Khan, Grace Glace, Jessica M. Clement, Pier Vitale Nuzzo, Petros Grivas, Brett A. Schroeder, Tanios Bekaii-Saab, John M. Nakayama, Vasil Mico, Young Soo Rho, Chaim Miller, Amit Verma, Kaitlin M. Kelleher, Elwyn C. Cabebe, William A. Wood, Elizabeth J. Davis, Anne H. Angevine, Cristiano Ferrario, Shaveta Vinayak, Jerome J. Graber, Monika Joshi, Danielle A. Shafer, Mary M. Pasquinelli, Mark Bonnen, Shirish M. Gadgeel, Balazs Halmos, Lucy L. Wang, Dawn L. Hershman, Sana Z. Mahmood, Dimpy P. Shah, Maryam B. Lustberg, Albert C. Yeh, Eric H. Bernicker, Mitrianna Streckfuss, Leslie A. Fecher, Clement Pillainayagam, Karen Stauffer, Gayathri Nagaraj, Dimitrios Farmakiotis, Elizabeth Marie Wulff-Burchfield, Chintan Shah, Sibel Blau, Ryan H. Nguyen, Lane R. Rosen, Robert L. Rice, Mark E. Dailey, Melanie J. Clark, Goetz Kloecker, Alicia K. Morgans, Cameron Rink, Umit Topaloglu, Mark A. Fiala, Saif I. Alimohamed, Gary K. Schwartz, Jessica Yasmine Islam, Bertrand Routy, James L. Chen, Oscar K. Serrano, Chinmay Jani, Shuchi Gulati, K.M. Lo, Alokkumar Jha, Anthony P. Gulati, Lori J. Rosenstein, Roy S. Herbst, Matthias Weiss, Justin Shaya, Philip E. Lammers, Irene S. Yu, Syed A. Ahmad, Salma K. Jabbour, Erin A. Gillaspie, Irma Hoyo-Ulloa, Jordan Kharofa, Jean M. Connors, Daniel Mundt, Christopher R. Friese, Ryan C. Lynch, Mansi R. Shah, Howard Zaren, M. Wasif Saif, Gerald Gantt, Lawrence E. Feldman, Jian Campian, Daniel Y. Reuben, Sanjay G. Revankar, Merry Jennifer Markham, Melissa Smits, Patricia LoRusso, Thorvardur R. Halfdanarson, Christine Pilar, Eric B. Durbin, Blanche Mavromatis, Yu Shyr, Jaymin M. Patel, Candice Schwartz, Ang Li, Antonio Giordano, Amit Kulkarni, Joerg Rathmann, Harry Menon, Amro Elshoury, Mahir Khan, Theresa M. Carducci, Susan Halabi, Sumit A. Shah, Jeremy L. Warner, Mehmet Asim Bilen, Kerry L. Reynolds, Michael A. Thompson, Ahmad Daher, Lidia Schapira, Eneida R. Nemecek, Sanjay Mishra, Jamie Stratton, Karen Vega-Luna, Tyler Masters, Corrie A. Painter, Archana Ajmera, Jorge A. Garcia, Wenxin Xu, Christopher Lemmon, and Jeanna Knoble

Subjects
0301 basic medicine, Cancer Research, Quality management, MEDLINE, 03 medical and health sciences, COVID-19 Testing, 0302 clinical medicine, Neoplasms, Pandemic, medicine, Electronic Health Records, Humans, Protocol (science), SARS-CoV-2, business.industry, Corporate governance, COVID-19, Cancer, Cell Biology, medicine.disease, Quality Improvement, Data Accuracy, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Scale (social sciences), Commentary, Business, Medical emergency, Quality assurance
Abstract

When the COVID-19 pandemic began, formal frameworks to collect data about affected patients were lacking. The COVID-19 and Cancer Consortium (CCC19) was formed to collect granular data on patients with cancer and COVID-19 at scale and as rapidly as possible. CCC19 has grown from five initial institutions to 125 institutions with >400 collaborators. More than 5,000 cases with complete baseline data have been accrued. Future directions include increased electronic health record integration for direct data ingestion, expansion to additional domestic and international sites, more intentional patient involvement, and granular analyses of still-unanswered questions related to cancer subtypes and treatments.

Published
2020
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4. Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma

Author

Gabrielle Bouchard, Sabina Signoretti, Neeraj Agarwal, Nieves Martinez-Chanza, Abdallah Flaifel, Emily Stern Gatof, David F. McDermott, Xiao X. Wei, Justin H. Fleischer, Bradley Alexander McGregor, Abhishek Tripathi, Wanling Xie, Connor Gray, Marios Giannakis, John A. Steinharter, Lauren C. Harshman, Edwin Lin, Charlene Mantia, Linda F. Thompson, and Toni K. Choueiri

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, tumor, Angiogenesis, medicine.medical_treatment, Immunology, GPI-Linked Proteins, 03 medical and health sciences, NT5E, 0302 clinical medicine, Renal cell carcinoma, Internal medicine, medicine, Immunology and Allergy, Humans, 5'-Nucleotidase, Carcinoma, Renal Cell, RC254-282, Pharmacology, Clinical/Translational Cancer Immunotherapy, Tumor microenvironment, business.industry, Gene Expression Profiling, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, biomarkers, Immunotherapy, medicine.disease, Prognosis, Primary tumor, Nephrectomy, Kidney Neoplasms, 030104 developmental biology, adenosine, 030220 oncology & carcinogenesis, Molecular Medicine, Immunohistochemistry, Female, immunotherapy, business
Abstract

BackgroundCD73–adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5′-nucleotidase (NT5E), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)) and A2 adenosine receptor (A2AR;ADORA2A) transcript levels with markers of angiogenesis and antitumor immune response.MethodsPatients with RCC with available archived nephrectomy samples were eligible for inclusion. Tumor CD73 protein expression was assessed by immunohistochemistry and quantified using a combined score (CS: % positive cells×intensity). Samples were categorized as CD73negative(CS=0), CD73lowor CD73high(< and ≥median CS, respectively). Multivariable Cox regression analysis compared disease-free survival (DFS) and overall survival (OS) between CD73 expression groups. In the TCGA dataset, samples were categorized as low, intermediate and highNT5E,ENTPD1andADORA2Agene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared betweenNT5E,ENTPD1andADORA2Aexpression groups.ResultsAmong the 138 patients eligible for inclusion, ‘any’ CD73 expression was observed in 30% of primary tumor samples. High CD73 expression was more frequent in patients with M1 RCC (29% vs 12% M0), grade 4 tumors (27% vs 13% grade 3 vs 15% grades 1 and 2), advanced T-stage (≥T3: 22% vs T2: 19% vs T1: 12%) and tumors with sarcomatoid histology (50% vs 12%). In the M0 cohort (n=107), patients with CD73hightumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73negativegroup (DFS: 75%, adjusted HR: 2.7, 95% CI 1.3 to 5.9, p=0.01; OS: 64%, adjusted HR: 2.6, 95% CI 1.2 to 5.8, p=0.02) independent of tumor stage and grade. In the TCGA analysis, highNT5Eexpression was associated with significantly worse 5-year OS (p=0.008).NT5EandENTPD1expression correlated with higher regulatory T cell (Treg) signature, whileADORA2Aexpression was associated with increased Treg and angiogenesis signatures.ConclusionsHigh CD73 expression portends significantly worse survival outcomes independent of stage and grade. Our findings provide compelling support for targeting the immunosuppressive and proangiogenic CD73–adenosine pathway in RCC.

Published
2020

5. Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma

Author

Sébastien Vigneau, Bradley Alexander McGregor, Ziad Bakouny, John A. Steinharter, Toni K. Choueiri, Orit Rozenblatt-Rosen, Eliezer M. Van Allen, Grace Grimaldi, Erin Shannon, Sabina Signoretti, Alok K. Tewari, Aviv Regev, Abhay Kanodia, Gabrielle Bouchard, Jihye Park, Thomas Denize, Rizwan Haq, Michael S. Cuoco, Angie Mayorga, Meng Xiao He, Jingyi Wu, Asaf Rotem, Maxine Sun, David A. Braun, Kevin Bi, Laura DelloStritto, Jennifer L. Guerriero, Natalie I. Vokes, Steven L. Chang, and Sara Napolitano

Subjects
0301 basic medicine, kidney, Cancer Research, medicine.medical_treatment, Cell, Article, resistance, 03 medical and health sciences, 0302 clinical medicine, Immune system, Renal cell carcinoma, medicine, Tumor Microenvironment, cancer, Cytotoxic T cell, Humans, Immunologic Factors, Carcinoma, Renal Cell, business.industry, Cancer, Immunotherapy, medicine.disease, Immune checkpoint, Kidney Neoplasms, single cell, DNA-Binding Proteins, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, business, Transcription Factors
Abstract

Summary Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB., Graphical abstract, Highlights • Distinct CD8+ T cell phenotypes are enriched after immune checkpoint blockade (ICB) • Immune checkpoint ligands are upregulated in macrophages and tumor cells after ICB • Two cancer cell subpopulations are conserved across heterogeneous RCC tumors • Cancer cell programs drive distinct immune interactions and predict patient outcomes, Bi et al. dissect the cancer cell and immune microenvironmental transcriptional programs in immune checkpoint blockade-exposed metastatic renal cell carcinoma, revealing immune subpopulation reprogramming and interactions with distinct cancer cell populations in the context of clinical resistance.

Published
2020

6. Detection of renal cell carcinoma using plasma and urine cell-free DNA methylomes

Author

Catherine Curran, Amin Nassar, Mark Pomerantz, Shu Yi Shen, Toni K. Choueiri, Jacob E. Berchuck, Guru Sonpavde, Daniel D. De Carvalho, John A. Steinharter, Sylvan C. Baca, Gabrielle Bouchard, Pier Vitale Nuzzo, Keegan Korthauer, Sushrut S. Waikar, M. Dror Michaelson, Sándor Spisák, Rafael A. Irizarry, Steven L. Chang, Ji-Heui Seo, Matthew L. Freedman, Francesco Boccardo, Ziad Bakouny, Gwo-Shu Mary Lee, Ankur Chakravarthy, Wenting Pan, and Sarah Abou Alaiwi

Subjects
0301 basic medicine, Urine, urologic and male genital diseases, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, chemistry.chemical_compound, Epigenome, 0302 clinical medicine, Text mining, Renal cell carcinoma, medicine, Carcinoma, Biomarkers, Tumor, Humans, Methylated DNA immunoprecipitation, Carcinoma, Renal Cell, Early Detection of Cancer, Receiver operating characteristic, business.industry, High-Throughput Nucleotide Sequencing, General Medicine, DNA Methylation, medicine.disease, 030104 developmental biology, Cell-free fetal DNA, chemistry, 030220 oncology & carcinogenesis, Cancer research, business, Cell-Free Nucleic Acids, DNA
Abstract

Improving early cancer detection has the potential to substantially reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a highly sensitive assay capable of detecting early-stage tumors. We report accurate classification of patients across all stages of renal cell carcinoma (RCC) in plasma (area under the receiver operating characteristic (AUROC) curve of 0.99) and demonstrate the validity of this assay to identify patients with RCC using urine cell-free DNA (cfDNA; AUROC of 0.86).

Published
2019

7. Progressive immune dysfunction with advancing disease stage in renal cell carcinoma

Author

Gabrielle Bouchard, Wenxin Xu, David L. Cookmeyer, Bradley Alexander McGregor, Kelly Street, Ziad Bakouny, Arlene H. Sharpe, Christina B. Pedersen, Lucas Pomerance, Nicholas Schindler, Sachet A. Shukla, Erica Maria Pimenta, Rafael A. Irizarry, Kathleen M. Mahoney, John A. Steinharter, Ang Cui, Kelly P. Burke, Juliet Forman, Steven L. Chang, Michelle S. Hirsch, Maxine Sun, Catherine J. Wu, Lars Rønn Olsen, Sabina Signoretti, David A. Braun, Derin B. Keskin, Toni K. Choueiri, Kenneth J. Livak, Shuqiang Li, Yue Hou, David F. McDermott, Satyen H. Gohil, Teddy Huang, Laure Hirsch, and Thomas Denize

Subjects
0301 basic medicine, Cancer Research, Myeloid, medicine.medical_treatment, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cell–cell interaction, Cancer immunotherapy, medicine, Humans, Carcinoma, Renal Cell, business.industry, Cancer, Immunotherapy, medicine.disease, Kidney Neoplasms, Clear cell renal cell carcinoma, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, business, CD8
Abstract

The tumor immune microenvironment plays a critical role in cancer progression and response to immunotherapy in clear cell renal cell carcinoma (ccRCC), yet the composition and phenotypic states of immune cells in this tumor are incompletely characterized. We performed single-cell RNA and T cell receptor sequencing (scRNA-seq/scTCR-seq) on 164,722 individual cells from tumor and adjacent non-tumor tissue in patients with ccRCC across disease stages – early, locally advanced, and advanced/metastatic. Terminally exhausted CD8(+) T cells were enriched in metastatic disease and were restricted in TCR diversity. Within the myeloid compartment, pro-inflammatory macrophages were decreased, and suppressive M2-like macrophages were increased in advanced disease. Terminally exhausted CD8(+) T cells and M2-like macrophages co-occurred in advanced disease and expressed ligands and receptors that support T cell dysfunction and M2-like polarization. This immune dysfunction circuit is associated with a worse prognosis in external cohorts and identifies potentially targetable immune inhibitory pathways in ccRCC.

Published
2021

8. LBA74 Disparities in cancer during the COVID-19 pandemic: COVID-19 and cancer outcomes study (CCOS)

Author

Deborah B. Doroshow, John A. Steinharter, Catherine Curran, Michelle Evans, Robert I. Haddad, Alaina J. Kessler, Andrew Schmidt, Qian Qin, Ziad Bakouny, Mark M. Awad, Fiona Busser, Gabrielle Bouchard, Pier Vitale Nuzzo, Jonathan Feld, Sheena Bhalla, Matthew D. Galsky, Tomi Jun, Toni K. Choueiri, Brittney S Zimmerman, and Douglas Tremblay

Subjects
0301 basic medicine, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Stock options, Hematology, BioMotiv, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, medicine, Clinical care, business, Bristol-Myers
Abstract

Background: The COVID-19 pandemic has rapidly altered cancer care However, the ways in which it has done so and the associated impact at the individual and societal levels remains poorly defined Methods: CCOS is a multicenter prospective cohort study designed to define the impact of the pandemic on cancer care delivery and outcomes The CCOS cohort comprised consecutive outpatients with cancer seen at two US cancer centers from March 2 to March 6, 2020 (index visit) Data was collected at baseline, retrospectively from the preceding 3 months, and prospectively at 3-month follow up Per patient changes in numbers of visits were compared using Wilcoxon signed rank tests Correlates of increases in telehealth visits and decreases in in-person visits were evaluated using multivariable logistic regression models Adjusted Odds ratios [aOR] and 95% confidence intervals (CI) were reported Results: Of 2365 included patients, 1219 (51 6%) had a decrease in in-person visit frequency during the pandemic period relative to the preceding 3 months Conversely, 760 (32 2%) had an increased frequency of telehealth visits (decrease in in-person and increase in telehealth visits;both p

Published
2020

9. Efficacy of immune checkpoint inhibitors (ICI) and genomic characterization of sarcomatoid and/or rhabdoid (S/R) metastatic renal cell carcinoma (mRCC)

Author

Ronan Flippot, John A. Steinharter, Ziad Bakouny, Sarah Abou Alaiwi, Sabina Signoretti, Amin Nassar, Pier Vitale Nuzzo, Wenting Pan, Natalie I. Vokes, Gabrielle Bouchard, Xin Gao, Eliezer M. Van Allen, Xiao X. Wei, Gwo-Shu Mary Lee, Toni K. Choueiri, David A. Braun, Abdallah Flaifel, Bradley Alexander McGregor, and Lauren C. Harshman

Subjects
Cancer Research, Poor prognosis, business.industry, Immune checkpoint inhibitors, urologic and male genital diseases, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Oncology, Renal cell carcinoma, 030220 oncology & carcinogenesis, Cancer research, Medicine, business, 030215 immunology
Abstract

4514 Background: S/R mRCC are poorly characterized rapidly progressing tumors associated with poor prognosis. Although conventional therapies are less effective for these tumors, emerging data suggests that ICIs may be especially effective. Our aim was to characterize the genomic alterations (GA) in S/R mRCC tumors and evaluate their response to ICIs. Methods: We retrospectively compared the activity of first-line ICIs to non-ICI-based therapies for S/R mRCC patients (pts) treated at DFCI and analyzed sequencing data from an NGS panel (275-447 genes) on a subset of these patients (matched by histology to non-S/R mRCC). For S/R mRCC pts treated with ICI vs non-ICI therapies, overall survival (OS) and time to treatment failure (TTF) were compared by Cox regression and objective response rate (ORR) by logistic regression. GA frequencies were compared by Fisher’s test and tumor mutational burden (TMB) by Mann Whitney U between S/R and non-S/R mRCC. Results were considered statistically significant if p < 0.05 or q < 0.10. Results: 125 S/R mRCC pts were included (88 S, 23 R, 14 S&R) among which 103 were clear cell and 48 had sequencing data. GA in BAP1 were significantly more frequent in S/R vs non-S/R (25% vs 4.3%; q = 0.096) while other GA had similar frequencies and TMB (median [IQR]) was similar (7.2 [5.2-8.4] vs 6.8 [5.3-9.1] mut/Mb; p = 0.98). Median follow-up was 35.4 (95% CI = 24.9 – 46.0) months (m). On multivariable analysis, S/R mRCC pts treated with ICI had significantly better clinical outcomes (Table). Conclusions: Pts with S/R mRCC have a higher frequency of BAP1 GA and better outcomes on ICIs compared to non-ICI-based therapies. Future studies should determine the molecular mechanisms underlying the improved response to ICIs in S/R mRCC. [Table: see text]

Published
2019

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