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2. Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

Author

Huynh-Le, Minh-Phuong, Karunamuni, Roshan, Fan, Chun Chieh, Asona, Lui, Thompson, Wesley K, Martinez, Maria Elena, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth R, Lophatananon, Artitaya, Schleutker, Johanna, Pashayan, Nora, Batra, Jyotsna, Grönberg, Henrik, Neal, David E, Nordestgaard, Børge G, Tangen, Catherine M, MacInnis, Robert J, Wolk, Alicja, Albanes, Demetrius, Haiman, Christopher A, Travis, Ruth C, Blot, William J, Stanford, Janet L, Mucci, Lorelei A, West, Catharine ML, Nielsen, Sune F, Kibel, Adam S, Cussenot, Olivier, Berndt, Sonja I, Koutros, Stella, Sørensen, Karina Dalsgaard, Cybulski, Cezary, Grindedal, Eli Marie, Menegaux, Florence, Park, Jong Y, Ingles, Sue A, Maier, Christiane, Hamilton, Robert J, Rosenstein, Barry S, Lu, Yong-Jie, Watya, Stephen, Vega, Ana, Kogevinas, Manolis, Wiklund, Fredrik, Penney, Kathryn L, Huff, Chad D, Teixeira, Manuel R, Multigner, Luc, Leach, Robin J, Brenner, Hermann, John, Esther M, Kaneva, Radka, Logothetis, Christopher J, Neuhausen, Susan L, De Ruyck, Kim, Ost, Piet, Razack, Azad, Newcomb, Lisa F, Fowke, Jay H, Gamulin, Marija, Abraham, Aswin, Claessens, Frank, Castelao, Jose Esteban, Townsend, Paul A, Crawford, Dana C, Petrovics, Gyorgy, van Schaik, Ron HN, Parent, Marie-Élise, Hu, Jennifer J, Zheng, Wei, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and Seibert, Tyler M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prevention, Cancer, Health Disparities, Prostate Cancer, Aging, Genetics, Precision Medicine, Urologic Diseases, Minority Health, Good Health and Well Being, Male, Humans, Prostate-Specific Antigen, Prostatic Neoplasms, Early Detection of Cancer, Polymorphism, Single Nucleotide, Risk Factors, Risk Assessment, Genetic Predisposition to Disease, UKGPCS collaborators, APCB, NC-LA PCaP Investigators, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium, Urology & Nephrology, Clinical sciences, Oncology and carcinogenesis
Abstract

BackgroundProstate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.MethodsIn total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.ResultsThe final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.ConclusionsWe demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Published
2022

3. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants

Author

Wang, Anqi, Shen, Jiayi, Rodriguez, Alex A., Saunders, Edward J., Chen, Fei, Janivara, Rohini, Darst, Burcu F., Sheng, Xin, Xu, Yili, Chou, Alisha J., Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N., Plym, Anna, Sahimi, Ali, Hoffman, Thomas J., Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Laisk, Triin, Figuerêdo, Jéssica, Muir, Kenneth, Ito, Shuji, Liu, Xiaoxi, Uchio, Yuji, Kubo, Michiaki, Kamatani, Yoichiro, Lophatananon, Artitaya, Wan, Peggy, Andrews, Caroline, Lori, Adriana, Choudhury, Parichoy P., Schleutker, Johanna, Tammela, Teuvo L. J., Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G., Southey, Melissa C., MacInnis, Robert J., Cybulski, Cezary, Wokolorczyk, Dominika, Lubinski, Jan, Rentsch, Christopher T., Cho, Kelly, Mcmahon, Benjamin H., Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Martin, Richard M., Nordestgaard, Borge G., Nielsen, Sune F., Weischer, Maren, Bojesen, Stig E., Røder, Andreas, Stroomberg, Hein V., Batra, Jyotsna, Chambers, Suzanne, Horvath, Lisa, Clements, Judith A., Tilly, Wayne, Risbridger, Gail P., Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordstrom, Tobias, Pashayan, Nora, Dunning, Alison M., Ghoussaini, Maya, Travis, Ruth C., Key, Tim J., Riboli, Elio, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie, Cook, Michael B., Mucci, Lorelei A., Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J., Penney, Kathryn L., Turman, Constance, Tangen, Catherine M., Goodman, Phyllis J., Thompson, Jr., Ian M., Hamilton, Robert J., Fleshner, Neil E., Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L., Ostrander, Elaine A., Koutros, Stella, Beane Freeman, Laura E., Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L., Hoover, Robert N., Machiela, Mitchell J., Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J., Zheng, Wei, Yeboah, Edward D., Mensah, James E., Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Wu, Yudong, Zhao, Shan-Chao, Sun, Zan, Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., West, Catharine M. L., Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S., Drake, Bettina F., Cussenot, Olivier, Cancel-Tassin, Geraldine, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, John, Esther M., Grindedal, Eli Marie, Maehle, Lovise, Khaw, Kay-Tee, Ingles, Sue A., Stern, Mariana C., Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Rosenstein, Barry S., Kerns, Sarah L., Ostrer, Harry, Teixeira, Manuel R., Paulo, Paula, Brandão, Andreia, Watya, Stephen, Lubwama, Alexander, Bensen, Jeannette T., Butler, Ebonee N., Mohler, James L., Taylor, Jack A., Kogevinas, Manolis, Dierssen-Sotos, Trinidad, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C., Huff, Chad D., Pilie, Patrick, Yu, Yao, Bohlender, Ryan J., Gu, Jian, Strom, Sara S., Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J., Brenner, Hermann, Chen, Xuechen, Holleczek, Bernd, Schöttker, Ben, Klein, Eric A., Hsing, Ann W., Kittles, Rick A., Murphy, Adam B., Logothetis, Christopher J., Kim, Jeri, Neuhausen, Susan L., Steele, Linda, Ding, Yuan Chun, Isaacs, William B., Nemesure, Barbara, Hennis, Anselm J. M., Carpten, John, Pandha, Hardev, Michael, Agnieszka, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Xu, Jianfeng, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Newcomb, Lisa F., Lin, Daniel W., Fowke, Jay H., Neslund-Dudas, Christine M., Rybicki, Benjamin A., Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Abraham, Aswin, Singhal, Sandeep, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van den Broeck, Thomas, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Larkin, Samantha, Townsend, Paul A., Aukim-Hastie, Claire, Bush, William S., Aldrich, Melinda C., Crawford, Dana C., Srivastava, Shiv, Cullen, Jennifer, Petrovics, Gyorgy, Casey, Graham, Wang, Ying, Tettey, Yao, Lachance, Joseph, Tang, Wei, Biritwum, Richard B., Adjei, Andrew A., Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Yamoah, Kosj, Govindasami, Koveela, Chokkalingam, Anand P., Keaton, Jacob M., Hellwege, Jacklyn N., Clark, Peter E., Jalloh, Mohamed, Gueye, Serigne M., Niang, Lamine, Ogunbiyi, Olufemi, Shittu, Olayiwola, Amodu, Olukemi, Adebiyi, Akindele O., Aisuodionoe-Shadrach, Oseremen I., Ajibola, Hafees O., Jamda, Mustapha A., Oluwole, Olabode P., Nwegbu, Maxwell, Adusei, Ben, Mante, Sunny, Darkwa-Abrahams, Afua, Diop, Halimatou, Gundell, Susan M., Roobol, Monique J., Jenster, Guido, van Schaik, Ron H. N., Hu, Jennifer J., Sanderson, Maureen, Kachuri, Linda, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Preuss, Michael H., Loos, Ruth J. F., Zawistowski, Matthew, Zöllner, Sebastian, Lu, Zeyun, Van Den Eeden, Stephen K., Easton, Douglas F., Ambs, Stefan, Edwards, Todd L., Mägi, Reedik, Rebbeck, Timothy R., Fritsche, Lars, Chanock, Stephen J., Berndt, Sonja I., Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S., Gaziano, J. Michael, Justice, Amy C., Mancuso, Nick, Terao, Chikashi, Eeles, Rosalind A., Kote-Jarai, Zsofia, Madduri, Ravi K., Conti, David V., and Haiman, Christopher A.

Published
2023
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4. Characterization of prostate cancer adrenal metastases: dependence upon androgen receptor signaling and steroid hormones

Author

Sakellakis, Minas J., Hahn, Andrew W., Ramachandran, Sumankalai, Zhang, Miao, Hoang, Anh, Song, Jian H., Liu, Jingjing, Wang, Feng, Basu, Hirak S., Sheperd, Peter, Wang, Xuemei, Frigo, Daniel E., Lin, Sue-Hwa, Panaretakis, Theocharis, Zhang, Jianhua, Navone, Nora, Troncoso, Patricia, Logothetis, Christopher J., and Titus, Mark A.

Published
2023
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5. Genetic factors associated with prostate cancer conversion from active surveillance to treatment

Author

Jiang, Yu, Meyers, Travis J, Emeka, Adaeze A, Cooley, Lauren Folgosa, Cooper, Phillip R, Lancki, Nicola, Helenowski, Irene, Kachuri, Linda, Lin, Daniel W, Stanford, Janet L, Newcomb, Lisa F, Kolb, Suzanne, Finelli, Antonio, Fleshner, Neil E, Komisarenko, Maria, Eastham, James A, Ehdaie, Behfar, Benfante, Nicole, Logothetis, Christopher J, Gregg, Justin R, Perez, Cherie A, Garza, Sergio, Kim, Jeri, Marks, Leonard S, Delfin, Merdie, Barsa, Danielle, Vesprini, Danny, Klotz, Laurence H, Loblaw, Andrew, Mamedov, Alexandre, Goldenberg, S Larry, Higano, Celestia S, Spillane, Maria, Wu, Eugenia, Carter, H Ballentine, Pavlovich, Christian P, Mamawala, Mufaddal, Landis, Tricia, Carroll, Peter R, Chan, June M, Cooperberg, Matthew R, Cowan, Janet E, Morgan, Todd M, Siddiqui, Javed, Martin, Rabia, Klein, Eric A, Brittain, Karen, Gotwald, Paige, Barocas, Daniel A, Dallmer, Jeremiah R, Gordetsky, Jennifer B, Steele, Pam, Kundu, Shilajit D, Stockdale, Jazmine, Roobol, Monique J, Venderbos, Lionne DF, Sanda, Martin G, Arnold, Rebecca, Patil, Dattatraya, Evans, Christopher P, Dall’Era, Marc A, Vij, Anjali, Costello, Anthony J, Chow, Ken, Corcoran, Niall M, Rais-Bahrami, Soroush, Phares, Courtney, Scherr, Douglas S, Flynn, Thomas, Karnes, R Jeffrey, Koch, Michael, Dhondt, Courtney Rose, Nelson, Joel B, McBride, Dawn, Cookson, Michael S, Stratton, Kelly L, Farriester, Stephen, Hemken, Erin, Stadler, Walter M, Pera, Tuula, Banionyte, Deimante, Bianco, Fernando J, Lopez, Isabel H, Loeb, Stacy, Taneja, Samir S, Byrne, Nataliya, Amling, Christopher L, Martinez, Ann, Boileau, Luc, Gaylis, Franklin D, Petkewicz, Jacqueline, Kirwen, Nicholas, Helfand, Brian T, Xu, Jianfeng, Scholtens, Denise M, Catalona, William J, and Witte, John S

Subjects
Biological Sciences, Genetics, Prostate Cancer, Prevention, Human Genome, Urologic Diseases, Cancer, Aging, Cancer Genomics, 2.1 Biological and endogenous factors, genetics, genome-wide association study, prostate, prostatic neoplasms
Abstract

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

Published
2022

8. A GATA2-CDC6 axis modulates androgen receptor blockade-induced senescence in prostate cancer

Author

Mourkioti, Ioanna, Polyzou, Aikaterini, Veroutis, Dimitris, Theocharous, George, Lagopati, Nefeli, Gentile, Emanuela, Stravokefalou, Vasiliki, Thanos, Dimitris-Foivos, Havaki, Sophia, Kletsas, Dimitris, Panaretakis, Theocharis, Logothetis, Christopher J., Stellas, Dimitris, Petty, Russell, Blandino, Giovanni, Papaspyropoulos, Angelos, and Gorgoulis, Vassilis G.

Published
2023
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9. Factors Associated with Time to Conversion from Active Surveillance to Treatment for Prostate Cancer in a Multi-Institutional Cohort

Author

Cooley, Lauren Folgosa, Emeka, Adaeze A, Meyers, Travis J, Cooper, Phillip R, Lin, Daniel W, Finelli, Antonio, Eastham, James A, Logothetis, Christopher J, Marks, Leonard S, Vesprini, Danny, Goldenberg, S Larry, Higano, Celestia S, Pavlovich, Christian P, Chan, June M, Morgan, Todd M, Klein, Eric A, Barocas, Daniel A, Loeb, Stacy, Helfand, Brian T, Scholtens, Denise M, Witte, John S, and Catalona, William J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Aging, Urologic Diseases, Genetics, Human Genome, Cancer, Prostate Cancer, Cancer Genomics, Aged, Biopsy, Large-Core Needle, Disease Progression, Follow-Up Studies, Humans, Kallikreins, Male, Middle Aged, Neoplasm Grading, Neoplasm Staging, Prostate, Prostate-Specific Antigen, Prostatectomy, Prostatic Neoplasms, Risk Assessment, Risk Factors, Time Factors, Tumor Burden, Watchful Waiting, Collaborators, human genetics, prostatic neoplasms, race factors, watchful waiting
Abstract

PurposeWe examined the demographic and clinicopathological parameters associated with the time to convert from active surveillance to treatment among men with prostate cancer.Materials and methodsA multi-institutional cohort of 7,279 patients managed with active surveillance had data and biospecimens collected for germline genetic analyses.ResultsOf 6,775 men included in the analysis, 2,260 (33.4%) converted to treatment at a median followup of 6.7 years. Earlier conversion was associated with higher Gleason grade groups (GG2 vs GG1 adjusted hazard ratio [aHR] 1.57, 95% CI 1.36-1.82; ≥GG3 vs GG1 aHR 1.77, 95% CI 1.29-2.43), serum prostate specific antigen concentrations (aHR per 5 ng/ml increment 1.18, 95% CI 1.11-1.25), tumor stages (cT2 vs cT1 aHR 1.58, 95% CI 1.41-1.77; ≥cT3 vs cT1 aHR 4.36, 95% CI 3.19-5.96) and number of cancerous biopsy cores (3 vs 1-2 cores aHR 1.59, 95% CI 1.37-1.84; ≥4 vs 1-2 cores aHR 3.29, 95% CI 2.94-3.69), and younger age (age continuous per 5-year increase aHR 0.96, 95% CI 0.93-0.99). Patients with high-volume GG1 tumors had a shorter interval to conversion than those with low-volume GG1 tumors and behaved like the higher-risk patients. We found no significant association between the time to conversion and self-reported race or genetic ancestry.ConclusionsA shorter time to conversion from active surveillance to treatment was associated with higher-risk clinicopathological tumor features. Furthermore, patients with high-volume GG1 tumors behaved similarly to those with intermediate and high-risk tumors. An exploratory analysis of self-reported race and genetic ancestry revealed no association with the time to conversion.

Published
2021

10. Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis

Author

Landi, Maria Teresa, Stevens, Victoria, Wang, Ying, Albanes, Demetrios, Caporaso, Neil, Brennan, Paul, Amos, Christopher I., Shete, Sanjay, Hung, Rayjean J., Bickeböller, Heike, Risch, Angela, Houlston, Richard, Lam, Stephen, Tardon, Adonina, Chen, Chu, Bojesen, Stig E., Johansson, Mattias, Wichmann, H-Erich, Christiani, David, Rennert, Gadi, Arnold, Susanne, Field, John K., Le Marchand, Loic, Melander, Olle, Brunnström, Hans, Liu, Geoffrey, Andrew, Angeline, Kiemeney, Lambertus A., Shen, Hongbing, Zienolddiny, Shan, Grankvist, Kjell, Johansson, Mikael, Teare, M. Dawn, Hong, Yun-Chul, Yuan, Jian-Min, Lazarus, Philip, Schabath, Matthew B., Aldrich, Melinda C., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Benlloch, Sara, Al Olama, Ali Amin, Muir, Kenneth R., Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Tangen, Catherine M., Batra, Jyotsna, Clements, Judith A., Grönberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie J., Wolk, Alicja, West, Catharine M.L., Mucci, Lorelei A., Cancel-Tassin, Géraldine, Koutros, Stella, Sørensen, Karina Dalsgaard, Grindedal, Eli Marie, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry S., Lu, Yong-Jie, Giles, Graham G., MacInnis, Robert J., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L., Park, Jong Y., Stanfrod, Janet L., Cybulski, Cezary, Nordestgaard, Børge G., Nielsen, Sune F., Brenner, Hermann, Maier, Christiane, Logothetis, Christopher J., John, Esther M., Teixeira, Manuel R., Neuhausen, Susan L., De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F., Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A., Castelao, Jose Esteban, Roobol, Monique J., Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albright, Lisa, Pandha, Hardev, Thibodeau, Stephen N., Hunter, David J., Kraft, Peter, Blot, William J., Riboli, Elio, Yarmolinsky, James, Robinson, Jamie W., Mariosa, Daniela, Karhunen, Ville, Huang, Jian, Dimou, Niki, Murphy, Neil, Burrows, Kimberley, Bouras, Emmanouil, Smith-Byrne, Karl, Lewis, Sarah J., Galesloot, Tessel E., Vermeulen, Sita, Martin, Paul, Hou, Lifang, Newcomb, Polly A., White, Emily, Wu, Anna H., Le Marchand, Loïc, Phipps, Amanda I., Buchanan, Daniel D., Zhao, Sizheng Steven, Gill, Dipender, Chanock, Stephen J., Purdue, Mark P., Davey Smith, George, Herzig, Karl-Heinz, Järvelin, Marjo-Riitta, Amos, Chris I., Dehghan, Abbas, Gunter, Marc J., Tsilidis, Kostas K., and Martin, Richard M.

Published
2024
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11. Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Author

Karunamuni, Roshan A, Huynh-Le, Minh-Phuong, Fan, Chun C, Thompson, Wesley, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth, Lophatananon, Artitaya, UKGPCS collaborators, Schleutker, Johanna, Pashayan, Nora, Batra, Jyotsna, APCB BioResource (Australian Prostate Cancer BioResource), Grönberg, Henrik, Walsh, Eleanor I, Turner, Emma L, Lane, Athene, Martin, Richard M, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Nordestgaard, Børge G, Tangen, Catherine M, MacInnis, Robert J, Wolk, Alicja, Albanes, Demetrius, Haiman, Christopher A, Travis, Ruth C, Stanford, Janet L, Mucci, Lorelei A, West, Catharine ML, Nielsen, Sune F, Kibel, Adam S, Wiklund, Fredrik, Cussenot, Olivier, Berndt, Sonja I, Koutros, Stella, Sørensen, Karina Dalsgaard, Cybulski, Cezary, Grindedal, Eli Marie, Park, Jong Y, Ingles, Sue A, Maier, Christiane, Hamilton, Robert J, Rosenstein, Barry S, Vega, Ana, IMPACT Study Steering Committee and Collaborators, Kogevinas, Manolis, Penney, Kathryn L, Teixeira, Manuel R, Brenner, Hermann, John, Esther M, Kaneva, Radka, Logothetis, Christopher J, Neuhausen, Susan L, Razack, Azad, Newcomb, Lisa F, Canary PASS Investigators, Gamulin, Marija, Usmani, Nawaid, Claessens, Frank, Gago-Dominguez, Manuela, Townsend, Paul A, Roobol, Monique J, Zheng, Wei, Profile Study Steering Committee, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, and PRACTICAL Consortium

Subjects
UKGPCS collaborators, APCB BioResource, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium, Prevention, Urologic Diseases, Cancer, Prostate Cancer, Aging, Urology & Nephrology, Oncology and Carcinogenesis
Abstract

BackgroundPolygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).Materials and method180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.Results166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.ConclusionsIncorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

Published
2021

12. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Author

Huynh-Le, Minh-Phuong, Fan, Chun Chieh, Karunamuni, Roshan, Thompson, Wesley K, Martinez, Maria Elena, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth, Schleutker, Johanna, Pashayan, Nora, Batra, Jyotsna, Grönberg, Henrik, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Nielsen, Sune F, Nordestgaard, Børge G, Wiklund, Fredrik, Tangen, Catherine M, Giles, Graham G, Wolk, Alicja, Albanes, Demetrius, Travis, Ruth C, Blot, William J, Zheng, Wei, Sanderson, Maureen, Stanford, Janet L, Mucci, Lorelei A, West, Catharine ML, Kibel, Adam S, Cussenot, Olivier, Berndt, Sonja I, Koutros, Stella, Sørensen, Karina Dalsgaard, Cybulski, Cezary, Grindedal, Eli Marie, Menegaux, Florence, Khaw, Kay-Tee, Park, Jong Y, Ingles, Sue A, Maier, Christiane, Hamilton, Robert J, Thibodeau, Stephen N, Rosenstein, Barry S, Lu, Yong-Jie, Watya, Stephen, Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L, Huff, Chad, Teixeira, Manuel R, Multigner, Luc, Leach, Robin J, Cannon-Albright, Lisa, Brenner, Hermann, John, Esther M, Kaneva, Radka, Logothetis, Christopher J, Neuhausen, Susan L, De Ruyck, Kim, Pandha, Hardev, Razack, Azad, Newcomb, Lisa F, Fowke, Jay H, Gamulin, Marija, Usmani, Nawaid, Claessens, Frank, Gago-Dominguez, Manuela, Townsend, Paul A, Bush, William S, Roobol, Monique J, Parent, Marie-Élise, Hu, Jennifer J, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, UKGPCS collaborators, APCB (Australian Prostate Cancer BioResource), NC-LA PCaP Investigators, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, and PRACTICAL Consortium

Subjects
UKGPCS collaborators, APCB, NC-LA PCaP Investigators, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium, Humans, Prostatic Neoplasms, Neoplasm Invasiveness, Multivariate Analysis, Multifactorial Inheritance, Aged, Middle Aged, Ethnic Groups, Male, Self Report, Aging, Urologic Diseases, Cancer, Prostate Cancer
Abstract

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p

Published
2021

13. Management of Patients with Advanced Prostate Cancer. Part I: Intermediate-/High-risk and Locally Advanced Disease, Biochemical Relapse, and Side Effects of Hormonal Treatment: Report of the Advanced Prostate Cancer Consensus Conference 2022

Author

Gillessen, Silke, Bossi, Alberto, Davis, Ian D., de Bono, Johann, Fizazi, Karim, James, Nicholas D., Mottet, Nicolas, Shore, Neal, Small, Eric, Smith, Matthew, Sweeney, Christopher, Tombal, Bertrand, Antonarakis, Emmanuel S., Aparicio, Ana M., Armstrong, Andrew J., Attard, Gerhardt, Beer, Tomasz M., Beltran, Himisha, Bjartell, Anders, Blanchard, Pierre, Briganti, Alberto, Bristow, Rob G., Bulbul, Muhammad, Caffo, Orazio, Castellano, Daniel, Castro, Elena, Cheng, Heather H., Chi, Kim N., Chowdhury, Simon, Clarke, Caroline S., Clarke, Noel, Daugaard, Gedske, De Santis, Maria, Duran, Ignacio, Eeles, Ros, Efstathiou, Eleni, Efstathiou, Jason, Ngozi Ekeke, Onyeanunam, Evans, Christopher P., Fanti, Stefano, Feng, Felix Y., Fonteyne, Valerie, Fossati, Nicola, Frydenberg, Mark, George, Daniel, Gleave, Martin, Gravis, Gwenaelle, Halabi, Susan, Heinrich, Daniel, Herrmann, Ken, Higano, Celestia, Hofman, Michael S., Horvath, Lisa G., Hussain, Maha, Jereczek-Fossa, Barbara Alicja, Jones, Robert, Kanesvaran, Ravindran, Kellokumpu-Lehtinen, Pirkko-Liisa, Khauli, Raja B., Klotz, Laurence, Kramer, Gero, Leibowitz, Raya, Logothetis, Christopher J., Mahal, Brandon A., Maluf, Fernando, Mateo, Joaquin, Matheson, David, Mehra, Niven, Merseburger, Axel, Morgans, Alicia K., Morris, Michael J., Mrabti, Hind, Mukherji, Deborah, Murphy, Declan G., Murthy, Vedang, Nguyen, Paul L., Oh, William K., Ost, Piet, O'Sullivan, Joe M., Padhani, Anwar R., Pezaro, Carmel, Poon, Darren M.C., Pritchard, Colin C., Rabah, Danny M., Rathkopf, Dana, Reiter, Robert E., Rubin, Mark. A., Ryan, Charles J., Saad, Fred, Pablo Sade, Juan, Sartor, Oliver A., Scher, Howard I., Sharifi, Nima, Skoneczna, Iwona, Soule, Howard, Spratt, Daniel E., Srinivas, Sandy, Sternberg, Cora N., Steuber, Thomas, Suzuki, Hiroyoshi, Sydes, Matthew R., Taplin, Mary-Ellen, Tilki, Derya, Türkeri, Levent, Turco, Fabio, Uemura, Hiroji, Uemura, Hirotsugu, Ürün, Yüksel, Vale, Claire L., van Oort, Inge, Vapiwala, Neha, Walz, Jochen, Yamoah, Kosj, Ye, Dingwei, Yu, Evan Y., Zapatero, Almudena, Zilli, Thomas, and Omlin, Aurelius

Published
2023
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15. Effects of metformin and statins on outcomes in men with castration-resistant metastatic prostate cancer: Secondary analysis of COU-AA-301 and COU-AA-302

Author

Wilson, Brooke E., Armstrong, Andrew J., de Bono, Johann, Sternberg, Cora N., Ryan, Charles J., Scher, Howard I., Smith, Matthew R., Rathkopf, Dana, Logothetis, Christopher J., Chi, Kim N., Jones, Robert J., Saad, Fred, De Porre, Peter, Tran, NamPhuong, Hu, Peter, Gillessen, Silke, Carles, Joan, Fizazi, Karim, and Joshua, Anthony M.

Published
2022
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16. Body composition in recurrent prostate cancer and the role of steroidogenic genotype.

Author

Venkatesh, Neha, Tidwell, Rebecca S., Yao Yu, Aparicio, Ana, Zurita, Amado J., Subudhi, Sumit K., Siddiqui, Bilal A., Mukhida, Sagar S., Gregg, Justin R., Corn, Paul G., Koutroumpakis, Efstratios, McQuade, Jennifer L., Frigo, Daniel E., Pilie, Patrick G., Huff, Chad, Logothetis, Christopher J., and Hahn, Andrew W.

Subjects
BODY composition, WHOLE genome sequencing, ADIPOSE tissues, TYPE 2 diabetes, MUSCLE mass
Abstract

Hormone therapy (HT) to treat prostate cancer is reported to cause adverse changes in body composition. Clinically, interpatient body composition changes are heterogeneous, but the biological and clinical determinants of body composition toxicity are unknown. Herein, we test the hypothesis that inherited polymorphisms in steroidogenic genes are associated with differential changes in body composition after HT. Men with biochemically recurrent prostate cancer (BCR) who received 8 months of LHRH analog (LHRHa) +/- abiraterone acetate (AAP) were eligible if they had: i) CT imaging of L3 prior to and after treatment; and ii) nucleated cells collected. Cardiometabolic co-morbidities were retrospectively extracted. Body composition was measured using an AI-based segmentation tool. Germline DNA whole exome or genome sequencing was performed. In 162 men treated with 8 months of HT, median skeletal muscle mass (SMMi) loss was 6.6% and subcutaneous adipose gain was 12.3%. Men with type 2 diabetes had higher losses of SMMi after treatment (-11.1% vs -6.3%, P = 0.003). For the 150 men with germline NGS, SRD5A2 rs523349 genotype was associated with differential loss in skeletal muscle density after HT, (-1.3% vs -7.1%, P = 0.04). In addition, the HSD3B1 rs104703 genotype was associated with decreased baseline visceral adipose tissue (63.0 cm2/m2 vs 77.9, P = 0.05). In men with BCR, HT induced notable loss of skeletal muscle and increased subcutaneous adipose tissue. An inherited polymorphism in SRD5A2 and T2DM was associated with differential skeletal muscle toxicity. These findings suggest that inherited polymorphisms may contribute to the body composition toxicity observed with HT. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis

Author

Han, Hyunho, Wang, Yan, Curto, Josue, Gurrapu, Sreeharsha, Laudato, Sara, Rumandla, Alekya, Chakraborty, Goutam, Wang, Xiaobo, Chen, Hong, Jiang, Yan, Kumar, Dhiraj, Caggiano, Emily G., Capogiri, Monica, Zhang, Boyu, Ji, Yan, Maity, Sankar N., Hu, Min, Bai, Shanshan, Aparicio, Ana M., Efstathiou, Eleni, Logothetis, Christopher J., Navin, Nicholas, Navone, Nora M., Chen, Yu, and Giancotti, Filippo G.

Published
2022
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18. MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers

Author

Alhalabi, Omar, Chen, Jianfeng, Zhang, Yuxue, Lu, Yang, Wang, Qi, Ramachandran, Sumankalai, Tidwell, Rebecca Slack, Han, Guangchun, Yan, Xinmiao, Meng, Jieru, Wang, Ruiping, Hoang, Anh G., Wang, Wei-Lien, Song, Jian, Lopez, Lidia, Andreev-Drakhlin, Alex, Siefker-Radtke, Arlene, Zhang, Xinqiao, Benedict, William F., Shah, Amishi Y., Wang, Jennifer, Msaouel, Pavlos, Zhang, Miao, Guo, Charles C., Czerniak, Bogdan, Behrens, Carmen, Soto, Luisa, Papadimitrakopoulou, Vassiliki, Lewis, Jeff, Rinsurongkawong, Waree, Rinsurongkawong, Vadeerat, Lee, Jack, Roth, Jack, Swisher, Stephen, Wistuba, Ignacio, Heymach, John, Wang, Jing, Campbell, Matthew T., Efstathiou, Eleni, Titus, Mark, Logothetis, Christopher J., Ho, Thai H., Zhang, Jianjun, Wang, Linghua, and Gao, Jianjun

Published
2022
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19. A phase II trial of apalutamide for intermediate‐risk prostate cancer and molecular correlates

Author

Hahn, Andrew W., primary, Manyam, Ganiraju C., additional, Chapin, Brian F., additional, Zhang, Miao, additional, Yu, Yao, additional, Pettaway, Curtis A., additional, Chery, Lisly, additional, Pisters, Louis L., additional, Ward, John F., additional, Gregg, Justin R., additional, Papadopoulos, John, additional, Kamat, Ashish M., additional, Lozano, Marisa, additional, Hoang, Anh, additional, Broom, Bradley, additional, Wang, Xuemei, additional, Huff, Chad D., additional, Logothetis, Christopher J., additional, Troncoso, Patricia, additional, Pilié, Patrick G., additional, and Davis, John W., additional

Published
2024
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24. A Phase 2 Trial of Abiraterone Followed by Randomization to Addition of Dasatinib or Sunitinib in Men With Metastatic Castration-Resistant Prostate Cancer

Author

Spetsieris, Nicholas, Boukovala, Myrto, Weldon, Justin A., Tsikkinis, Alexandros, Hoang, Anh, Aparicio, Ana, Tu, Shi-Ming, Araujo, John C., Zurita, Amado J., Corn, Paul G., Pagliaro, Lance, Kim, Jeri, Wang, Jennifer, Subudhi, Sumit K., Tannir, Nizar M., Logothetis, Christopher J., Troncoso, Patricia, Wang, Xuemei, Wen, Sijin, and Efstathiou, Eleni

Published
2021
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25. A candidate androgen signalling signature predictive of response to abiraterone acetate in men with metastatic castration-resistant prostate cancer

Author

Boukovala, Myrto, Spetsieris, Nicholas, Weldon, Justin A., Tsikkinis, Alexandros, Hoang, Anh, Aparicio, Ana, Tu, Shi-Ming, Araujo, John C., Zurita, Amado J., Corn, Paul G., Pagliaro, Lance, Kim, Jeri, Wang, Jennifer, Subudhi, Sumit K., Tannir, Nizar M., Logothetis, Christopher J., Troncoso, Patricia, Wen, Sijin, and Efstathiou, Eleni

Published
2020
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26. Supplementary Table S6 from Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series

Author

Anselmino, Nicolas, primary, Labanca, Estefania, primary, Shepherd, Peter D.A., primary, Dong, Jiabin, primary, Yang, Jun, primary, Song, Xiaofei, primary, Nandakumar, Subhiksha, primary, Kundra, Ritika, primary, Lee, Cindy, primary, Schultz, Nikolaus, primary, Zhang, Jianhua, primary, Araujo, John C., primary, Aparicio, Ana M., primary, Subudhi, Sumit K., primary, Corn, Paul G., primary, Pisters, Louis L., primary, Ward, John F., primary, Davis, John W., primary, Vazquez, Elba S., primary, Gueron, Geraldine, primary, Logothetis, Christopher J., primary, Futreal, Andrew, primary, Troncoso, Patricia, primary, Chen, Yu, primary, and Navone, Nora M., primary

Published
2024
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27. Data from Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series

Author

Anselmino, Nicolas, primary, Labanca, Estefania, primary, Shepherd, Peter D.A., primary, Dong, Jiabin, primary, Yang, Jun, primary, Song, Xiaofei, primary, Nandakumar, Subhiksha, primary, Kundra, Ritika, primary, Lee, Cindy, primary, Schultz, Nikolaus, primary, Zhang, Jianhua, primary, Araujo, John C., primary, Aparicio, Ana M., primary, Subudhi, Sumit K., primary, Corn, Paul G., primary, Pisters, Louis L., primary, Ward, John F., primary, Davis, John W., primary, Vazquez, Elba S., primary, Gueron, Geraldine, primary, Logothetis, Christopher J., primary, Futreal, Andrew, primary, Troncoso, Patricia, primary, Chen, Yu, primary, and Navone, Nora M., primary

Published
2024
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28. Supplementary Figure S4 from Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series

Author

Anselmino, Nicolas, primary, Labanca, Estefania, primary, Shepherd, Peter D.A., primary, Dong, Jiabin, primary, Yang, Jun, primary, Song, Xiaofei, primary, Nandakumar, Subhiksha, primary, Kundra, Ritika, primary, Lee, Cindy, primary, Schultz, Nikolaus, primary, Zhang, Jianhua, primary, Araujo, John C., primary, Aparicio, Ana M., primary, Subudhi, Sumit K., primary, Corn, Paul G., primary, Pisters, Louis L., primary, Ward, John F., primary, Davis, John W., primary, Vazquez, Elba S., primary, Gueron, Geraldine, primary, Logothetis, Christopher J., primary, Futreal, Andrew, primary, Troncoso, Patricia, primary, Chen, Yu, primary, and Navone, Nora M., primary

Published
2024
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29. Supplementary Figure S1 from Phase I Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Progressing on Enzalutamide

Author

Abida, Wassim, primary, Hahn, Andrew W., primary, Shore, Neal, primary, Agarwal, Neeraj, primary, Sieber, Paul, primary, Smith, Matthew R., primary, Dorff, Tanya, primary, Monk, Paul, primary, Rettig, Matthew, primary, Patel, Rupal, primary, Page, Anne, primary, Duff, Maureen, primary, Xu, Rongda, primary, Wang, Jian, primary, Barkund, Shravani, primary, Pankov, Aleksandr, primary, Wang, Amber, primary, Junttila, Melissa R., primary, Multani, Pratik S., primary, Daemen, Anneleen, primary, Chow Maneval, Edna, primary, Logothetis, Christopher J., primary, and Morris, Michael J., primary

Published
2024
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30. Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series

Author

Anselmino, Nicolas, primary, Labanca, Estefania, additional, Shepherd, Peter D.A., additional, Dong, Jiabin, additional, Yang, Jun, additional, Song, Xiaofei, additional, Nandakumar, Subhiksha, additional, Kundra, Ritika, additional, Lee, Cindy, additional, Schultz, Nikolaus, additional, Zhang, Jianhua, additional, Araujo, John C., additional, Aparicio, Ana M., additional, Subudhi, Sumit K., additional, Corn, Paul G., additional, Pisters, Louis L., additional, Ward, John F., additional, Davis, John W., additional, Vazquez, Elba S., additional, Gueron, Geraldine, additional, Logothetis, Christopher J., additional, Futreal, Andrew, additional, Troncoso, Patricia, additional, Chen, Yu, additional, and Navone, Nora M., additional

Published
2024
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31. Data from Phase I Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Progressing on Enzalutamide

Author

Abida, Wassim, primary, Hahn, Andrew W., primary, Shore, Neal, primary, Agarwal, Neeraj, primary, Sieber, Paul, primary, Smith, Matthew R., primary, Dorff, Tanya, primary, Monk, Paul, primary, Rettig, Matthew, primary, Patel, Rupal, primary, Page, Anne, primary, Duff, Maureen, primary, Xu, Rongda, primary, Wang, Jian, primary, Barkund, Shravani, primary, Pankov, Aleksandr, primary, Wang, Amber, primary, Junttila, Melissa R., primary, Multani, Pratik S., primary, Daemen, Anneleen, primary, Chow Maneval, Edna, primary, Logothetis, Christopher J., primary, and Morris, Michael J., primary

Published
2024
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32. Supplementary Table S1 from Phase I Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Progressing on Enzalutamide

Author

Abida, Wassim, primary, Hahn, Andrew W., primary, Shore, Neal, primary, Agarwal, Neeraj, primary, Sieber, Paul, primary, Smith, Matthew R., primary, Dorff, Tanya, primary, Monk, Paul, primary, Rettig, Matthew, primary, Patel, Rupal, primary, Page, Anne, primary, Duff, Maureen, primary, Xu, Rongda, primary, Wang, Jian, primary, Barkund, Shravani, primary, Pankov, Aleksandr, primary, Wang, Amber, primary, Junttila, Melissa R., primary, Multani, Pratik S., primary, Daemen, Anneleen, primary, Chow Maneval, Edna, primary, Logothetis, Christopher J., primary, and Morris, Michael J., primary

Published
2024
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33. MORPHOLOGICAL PROGRESSION IN RELAPSING PATIENTS WITH SMALL CELL BLADDER CANCER

Author

Moussa, Mohammad Jad, primary, Radtke, Arlene O. Siefker, additional, Shah, Amishi Y., additional, Gao, Jianjun, additional, Goswami, Sangeeta, additional, Logothetis, Christopher J., additional, Corn, Paul G., additional, Aparicio, Ana, additional, Tannir, Nizar M., additional, Kamat, Ashish M., additional, Navai, Neema, additional, Lee, Byron, additional, Dinney, Colin P.N., additional, Czerniak, Bogdan A., additional, Guo, Charles C., additional, Hansel, Donna E., additional, Campbell, Matthew T., additional, Alhalabi, Omar, additional, and Wilson, Nathaniel R., additional

Published
2024
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35. The combination of serum insulin, osteopontin, and hepatocyte growth factor predicts time to castration-resistant progression in androgen dependent metastatic prostate cancer- an exploratory study

Author

Dayyani, Farshid, Zurita, Amado J, Nogueras-González, Graciela M, Slack, Rebecca, Millikan, Randall E, Araujo, John C, Gallick, Gary E, Logothetis, Christopher J, and Corn, Paul G

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Urologic Diseases, Cancer, Prostate Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Aged, Aged, 80 and over, Biomarkers, Tumor, Follow-Up Studies, Hepatocyte Growth Factor, Humans, Insulin, Male, Middle Aged, Neoplasm Grading, Osteopontin, Prognosis, Prostatic Neoplasms, Castration-Resistant, Retrospective Studies, Survival Rate, Hepatocyte growth factor, Castration resistance, Metastatic prostate cancer, Prognostic marker, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis, Epidemiology
Abstract

BackgroundWe hypothesized that pretreatment serum levels of insulin and other serum markers would predict Progression-free survival (PFS), defined as time to castration-resistant progression or death, in metastatic androgen-dependent prostate cancer (mADPC).MethodsSerum samples from treatment-naïve men participating in a randomized phase 3 trial of ADT +/- chemotherapy were retrospectively analyzed using multiplex assays for insulin and multiple other soluble factors. Cox proportional hazards regression models were used to identify associations between individual factor levels and PFS.ResultsSixty six patients were evaluable (median age = 72 years; median prostate surface antigen [PSA] = 31.5 ng/mL; Caucasian = 86 %; Gleason score ≥8 = 77 %). In the univariable analysis, higher insulin (HR = 0.81 [0.67, 0.98] p = 0.03) and C-peptide (HR = 0.62 [0.39, 1.00]; p = 0.05) levels were associated with a longer PFS, while higher Hepatocyte Growth Factor (HGF; HR = 1.63 [1.06, 2.51] p = 0.03) and Osteopontin (OPN; HR = 1.56 [1.13, 2.15]; p = 0.01) levels were associated with a shorter PFS. In multivariable analysis, insulin below 2.1 (ln scale; HR = 2.55 [1.24, 5.23]; p = 0.011) and HGF above 8.9 (ln scale; HR = 2.67 [1.08, 3.70]; p = 0.027) levels were associated with longer PFS, while adjusted by OPN, C-peptide, trial therapy and metastatic volume. Four distinct risk groups were identified by counting the number of risk factors (RF) including low insulin, high HGF, high OPN levels, and low C-peptide levels (0, 1, 2, and 3). Median PFS was 9.8, 2.0, 1.6, and 0.7 years for each, respectively (p

Published
2016

36. Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer

Author

Kim, Jeri, Davis, John W, Klein, Eric A, Magi-Galluzzi, Cristina, Lotan, Yair, Ward, John F, Pisters, Louis L, Basler, Joseph W, Pettaway, Curtis A, Stephenson, Andrew, Tapia, Elsa M Li Ning, Efstathiou, Eleni, Wang, Xuemei, Do, Kim-Anh, Lee, J Jack, Gorlov, Ivan P, Vornik, Lana A, Hoque, Ashraful M, Prokhorova, Ina N, Parnes, Howard L, Lippman, Scott M, Thompson, Ian M, Brown, Powel H, Logothetis, Christopher J, and Troncoso, Patricia

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Trials and Supportive Activities, Urologic Diseases, Prostate Cancer, Clinical Research, Aging, Cancer, Administration, Oral, Aged, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Double-Blind Method, Finasteride, Humans, Logistic Models, Male, Middle Aged, Neoplasm Grading, Prostatic Neoplasms, Receptors, Androgen, Treatment Outcome, Prostate cancer, alpha-reductase inhibitors, Cancer prevention, Biomarkers, 5α-reductase inhibitors, Public Health and Health Services, Clinical sciences, Epidemiology
Abstract

BackgroundIn the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride.MethodsFrom 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5mg finasteride or placebo daily in a double-blind study during the 4-6weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERβ, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers.FindingsWe found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups.InterpretationWe showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT.

Published
2016

39. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Conti, David V., Darst, Burcu F., Moss, Lilit C., Saunders, Edward J., Sheng, Xin, Chou, Alisha, Schumacher, Fredrick R., Olama, Ali Amin Al, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N., Sahimi, Ali, Hoffmann, Thomas J., Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Muir, Kenneth, Lophatananon, Artitaya, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne R., Stevens, Victoria L., Gapstur, Susan M., Carter, Brian D., Schleutker, Johanna, Tammela, Teuvo L. J., Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G., Southey, Melissa C., MacInnis, Robert J., Cybulski, Cezary, Wokołorczyk, Dominika, Lubiński, Jan, Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Martin, Richard M., Nordestgaard, Børge G., Nielsen, Sune F., Weischer, Maren, Bojesen, Stig E., Røder, Martin Andreas, Iversen, Peter, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Horvath, Lisa, Clements, Judith A., Tilley, Wayne, Risbridger, Gail P., Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordström, Tobias, Pashayan, Nora, Dunning, Alison M., Ghoussaini, Maya, Travis, Ruth C., Key, Tim J., Riboli, Elio, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie J., Mucci, Lorelei A., Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J., Penney, Kathryn L., Turman, Constance, Tangen, Catherine M., Goodman, Phyllis J., Thompson, Jr., Ian M., Hamilton, Robert J., Fleshner, Neil E., Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L., Ostrander, Elaine A., Geybels, Milan S., Koutros, Stella, Freeman, Laura E. Beane, Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L., Hoover, Robert N., Machiela, Mitchell J., Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J., Zheng, Wei, Yeboah, Edward D., Mensah, James E., Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Wu, Yudong, Zhao, Shan-Chao, Sun, Zan, Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., West, Catharine M. L., Burnet, Neil, Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S., Drake, Bettina F., Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, John, Esther M., Grindedal, Eli Marie, Maehle, Lovise, Khaw, Kay-Tee, Ingles, Sue A., Stern, Mariana C., Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Rosenstein, Barry S., Kerns, Sarah L., Ostrer, Harry, Teixeira, Manuel R., Paulo, Paula, Brandão, Andreia, Watya, Stephen, Lubwama, Alexander, Bensen, Jeannette T., Fontham, Elizabeth T. H., Mohler, James, Taylor, Jack A., Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C., Huff, Chad D., Strom, Sara S., Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J., Weaver, Brandi, Brenner, Hermann, Cuk, Katarina, Holleczek, Bernd, Saum, Kai-Uwe, Klein, Eric A., Hsing, Ann W., Kittles, Rick A., Murphy, Adam B., Logothetis, Christopher J., Kim, Jeri, Neuhausen, Susan L., Steele, Linda, Ding, Yuan Chun, Isaacs, William B., Nemesure, Barbara, Hennis, Anselm J. M., Carpten, John, Pandha, Hardev, Michael, Agnieszka, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Xu, Jianfeng, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Newcomb, Lisa F., Lin, Daniel W., Fowke, Jay H., Neslund-Dudas, Christine, Rybicki, Benjamin A., Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Singhal, Sandeep, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van den Broeck, Thomas, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Larkin, Samantha, Townsend, Paul A., Aukim-Hastie, Claire, Bush, William S., Aldrich, Melinda C., Crawford, Dana C., Srivastava, Shiv, Cullen, Jennifer C., Petrovics, Gyorgy, Casey, Graham, Roobol, Monique J., Jenster, Guido, van Schaik, Ron H. N., Hu, Jennifer J., Sanderson, Maureen, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Mancuso, Nicholas, Berndt, Sonja I., Van Den Eeden, Stephen K., Easton, Douglas F., Chanock, Stephen J., Cook, Michael B., Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S., Eeles, Rosalind A., Kote-Jarai, Zsofia, and Haiman, Christopher A.

Published
2021
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40. PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

Author

Salameh, Ahmad, Lee, Alessandro K, Cardó-Vila, Marina, Nunes, Diana N, Efstathiou, Eleni, Staquicini, Fernanda I, Dobroff, Andrey S, Marchiò, Serena, Navone, Nora M, Hosoya, Hitomi, Lauer, Richard C, Wen, Sijin, Salmeron, Carolina C, Hoang, Anh, Newsham, Irene, Lima, Leandro A, Carraro, Dirce M, Oliviero, Salvatore, Kolonin, Mikhail G, Sidman, Richard L, Do, Kim-Anh, Troncoso, Patricia, Logothetis, Christopher J, Brentani, Ricardo R, Calin, George A, Cavenee, Webster K, Dias-Neto, Emmanuel, Pasqualini, Renata, and Arap, Wadih

Subjects
Aging, Genetics, Prostate Cancer, Biotechnology, Cancer, Urologic Diseases, 2.1 Biological and endogenous factors, Aetiology, Adenosine Deaminase, Animals, Antigens, Neoplasm, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, HEK293 Cells, HeLa Cells, Humans, Immunoblotting, Introns, MCF-7 Cells, Male, Mice, SCID, Molecular Sequence Data, Neoplasm Proteins, Prostatic Neoplasms, Protein Binding, RNA Interference, RNA Precursors, RNA, Long Noncoding, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins, Xenograft Model Antitumor Assays, PRUNE2, PCA3, long noncoding RNA, ADAR, prostate cancer, Hela Cells
Abstract

Prostate cancer antigen 3 (PCA3) is the most specific prostate cancer biomarker but its function remains unknown. Here we identify PRUNE2, a target protein-coding gene variant, which harbors the PCA3 locus, thereby classifying PCA3 as an antisense intronic long noncoding (lnc)RNA. We show that PCA3 controls PRUNE2 levels via a unique regulatory mechanism involving formation of a PRUNE2/PCA3 double-stranded RNA that undergoes adenosine deaminase acting on RNA (ADAR)-dependent adenosine-to-inosine RNA editing. PRUNE2 expression or silencing in prostate cancer cells decreased and increased cell proliferation, respectively. Moreover, PRUNE2 and PCA3 elicited opposite effects on tumor growth in immunodeficient tumor-bearing mice. Coregulation and RNA editing of PRUNE2 and PCA3 were confirmed in human prostate cancer specimens, supporting the medical relevance of our findings. These results establish PCA3 as a dominant-negative oncogene and PRUNE2 as an unrecognized tumor suppressor gene in human prostate cancer, and their regulatory axis represents a unique molecular target for diagnostic and therapeutic intervention.

Published
2015

41. Radiographic Progression-Free Survival As a Response Biomarker in Metastatic Castration-Resistant Prostate Cancer: COU-AA-302 Results

Author

Morris, Michael J, Molina, Arturo, Small, Eric J, de Bono, Johann S, Logothetis, Christopher J, Fizazi, Karim, de Souza, Paul, Kantoff, Philip W, Higano, Celestia S, Li, Jinhui, Kheoh, Thian, Larson, Steven M, Matheny, Shannon L, Naini, Vahid, Burzykowski, Tomasz, Griffin, Thomas W, Scher, Howard I, and Ryan, Charles J

Subjects
Urologic Diseases, Clinical Trials and Supportive Activities, Prostate Cancer, Cancer, Clinical Research, Abiraterone Acetate, Androstenes, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Bone Neoplasms, Disease-Free Survival, Double-Blind Method, Humans, Male, Neoplasm Metastasis, Prednisone, Prostatic Neoplasms, Castration-Resistant, Radiography, Survival Rate, Treatment Outcome, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeProgression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) trials has been inconsistently defined and poorly associated with overall survival (OS). A reproducible quantitative definition of radiographic PFS (rPFS) was tested for association with a coprimary end point of OS in a randomized trial of abiraterone in patients with mCRPC.Patients and methodsrPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 12 weeks after random assignment, and/or progression in nodes or viscera on cross-sectional imaging, or death. rPFS was assessed by independent review at 15% of deaths and by investigator review at 15% and 40% of deaths. rPFS and OS association was evaluated by Spearman's correlation.ResultsA total of 1,088 patients were randomly assigned to abiraterone plus prednisone or prednisone alone. At first interim analysis, the hazard ratio (HR) by independent review was 0.43 (95% CI, 0.35 to 0.52; P < .001; abiraterone plus prednisone: median rPFS, not estimable; prednisone: median rPFS, 8.3 months). Similar HRs were obtained by investigator review at the first two interim analyses (HR, 0.49; 95% CI, 0.41 to 0.60; P < .001 and HR, 0.53; 95% CI, 0.45 to 0.62; P < .001, respectively), validating the imaging data assay used. Spearman's correlation coefficient between rPFS and OS was 0.72.ConclusionrPFS was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials.

Published
2015

42. Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1–2 trial

Author

Corn, Paul G, Heath, Elisabeth I, Zurita, Amado, Ramesh, Naveen, Xiao, Lianchun, Sei, Emi, Li-Ning-Tapia, Elsa, Tu, Shi-Ming, Subudhi, Sumit K, Wang, Jennifer, Wang, Xuemei, Efstathiou, Eleni, Thompson, Timothy C, Troncoso, Patricia, Navin, Nicholas, Logothetis, Christopher J, and Aparicio, Ana M

Published
2019
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44. Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis

Author

Yarmolinsky, James, primary, Robinson, Jamie W., additional, Mariosa, Daniela, additional, Karhunen, Ville, additional, Huang, Jian, additional, Dimou, Niki, additional, Murphy, Neil, additional, Burrows, Kimberley, additional, Bouras, Emmanouil, additional, Smith-Byrne, Karl, additional, Lewis, Sarah J., additional, Galesloot, Tessel E., additional, Kiemeney, Lambertus A., additional, Vermeulen, Sita, additional, Martin, Paul, additional, Albanes, Demetrius, additional, Hou, Lifang, additional, Newcomb, Polly A., additional, White, Emily, additional, Wolk, Alicja, additional, Wu, Anna H., additional, Le Marchand, Loïc, additional, Phipps, Amanda I., additional, Buchanan, Daniel D., additional, Zhao, Sizheng Steven, additional, Gill, Dipender, additional, Chanock, Stephen J., additional, Purdue, Mark P., additional, Davey Smith, George, additional, Brennan, Paul, additional, Herzig, Karl-Heinz, additional, Järvelin, Marjo-Riitta, additional, Amos, Chris I., additional, Hung, Rayjean J., additional, Dehghan, Abbas, additional, Johansson, Mattias, additional, Gunter, Marc J., additional, Tsilidis, Kostas K., additional, Martin, Richard M., additional, Landi, Maria Teresa, additional, Stevens, Victoria, additional, Wang, Ying, additional, Albanes, Demetrios, additional, Caporaso, Neil, additional, Amos, Christopher I., additional, Shete, Sanjay, additional, Bickeböller, Heike, additional, Risch, Angela, additional, Houlston, Richard, additional, Lam, Stephen, additional, Tardon, Adonina, additional, Chen, Chu, additional, Bojesen, Stig E., additional, Wichmann, H-Erich, additional, Christiani, David, additional, Rennert, Gadi, additional, Arnold, Susanne, additional, Field, John K., additional, Le Marchand, Loic, additional, Melander, Olle, additional, Brunnström, Hans, additional, Liu, Geoffrey, additional, Andrew, Angeline, additional, Shen, Hongbing, additional, Zienolddiny, Shan, additional, Grankvist, Kjell, additional, Johansson, Mikael, additional, Teare, M. Dawn, additional, Hong, Yun-Chul, additional, Yuan, Jian-Min, additional, Lazarus, Philip, additional, Schabath, Matthew B., additional, Aldrich, Melinda C., additional, Eeles, Rosalind A., additional, Haiman, Christopher A., additional, Kote-Jarai, Zsofia, additional, Schumacher, Fredrick R., additional, Benlloch, Sara, additional, Al Olama, Ali Amin, additional, Muir, Kenneth R., additional, Berndt, Sonja I., additional, Conti, David V., additional, Wiklund, Fredrik, additional, Chanock, Stephen, additional, Tangen, Catherine M., additional, Batra, Jyotsna, additional, Clements, Judith A., additional, Grönberg, Henrik, additional, Pashayan, Nora, additional, Schleutker, Johanna, additional, Weinstein, Stephanie J., additional, West, Catharine M.L., additional, Mucci, Lorelei A., additional, Cancel-Tassin, Géraldine, additional, Koutros, Stella, additional, Sørensen, Karina Dalsgaard, additional, Grindedal, Eli Marie, additional, Neal, David E., additional, Hamdy, Freddie C., additional, Donovan, Jenny L., additional, Travis, Ruth C., additional, Hamilton, Robert J., additional, Ingles, Sue Ann, additional, Rosenstein, Barry S., additional, Lu, Yong-Jie, additional, Giles, Graham G., additional, MacInnis, Robert J., additional, Kibel, Adam S., additional, Vega, Ana, additional, Kogevinas, Manolis, additional, Penney, Kathryn L., additional, Park, Jong Y., additional, Stanfrod, Janet L., additional, Cybulski, Cezary, additional, Nordestgaard, Børge G., additional, Nielsen, Sune F., additional, Brenner, Hermann, additional, Maier, Christiane, additional, Logothetis, Christopher J., additional, John, Esther M., additional, Teixeira, Manuel R., additional, Neuhausen, Susan L., additional, De Ruyck, Kim, additional, Razack, Azad, additional, Newcomb, Lisa F., additional, Lessel, Davor, additional, Kaneva, Radka, additional, Usmani, Nawaid, additional, Claessens, Frank, additional, Townsend, Paul A., additional, Castelao, Jose Esteban, additional, Roobol, Monique J., additional, Menegaux, Florence, additional, Khaw, Kay-Tee, additional, Cannon-Albright, Lisa, additional, Pandha, Hardev, additional, Thibodeau, Stephen N., additional, Hunter, David J., additional, Kraft, Peter, additional, Blot, William J., additional, and Riboli, Elio, additional

Published
2024
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45. Phase I Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Progressing on Enzalutamide

Author

Abida, Wassim, primary, Hahn, Andrew W., additional, Shore, Neal, additional, Agarwal, Neeraj, additional, Sieber, Paul, additional, Smith, Matthew R., additional, Dorff, Tanya, additional, Monk, Paul, additional, Rettig, Matthew, additional, Patel, Rupal, additional, Page, Anne, additional, Duff, Maureen, additional, Xu, Rongda, additional, Wang, Jian, additional, Barkund, Shravani, additional, Pankov, Aleksandr, additional, Wang, Amber, additional, Junttila, Melissa R., additional, Multani, Pratik S., additional, Daemen, Anneleen, additional, Chow Maneval, Edna, additional, Logothetis, Christopher J., additional, and Morris, Michael J., additional

Published
2024
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46. Updated Interim Efficacy Analysis and Long-term Safety of Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer Patients Without Prior Chemotherapy (COU-AA-302)

Author

Rathkopf, Dana E, Smith, Matthew R, de Bono, Johann S, Logothetis, Christopher J, Shore, Neal D, de Souza, Paul, Fizazi, Karim, Mulders, Peter FA, Mainwaring, Paul, Hainsworth, John D, Beer, Tomasz M, North, Scott, Fradet, Yves, Van Poppel, Hendrik, Carles, Joan, Flaig, Thomas W, Efstathiou, Eleni, Yu, Evan Y, Higano, Celestia S, Taplin, Mary-Ellen, Griffin, Thomas W, Todd, Mary B, Yu, Margaret K, Park, Youn C, Kheoh, Thian, Small, Eric J, Scher, Howard I, Molina, Arturo, Ryan, Charles J, and Saad, Fred

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Prostate Cancer, Urologic Diseases, Rehabilitation, Aging, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Abiraterone Acetate, Aged, Androstenes, Antineoplastic Agents, Hormonal, Antineoplastic Combined Chemotherapy Protocols, Cytochrome P-450 Enzyme Inhibitors, Disease Progression, Disease-Free Survival, Double-Blind Method, Drug Administration Schedule, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Metastasis, Neoplasms, Hormone-Dependent, Prednisone, Proportional Hazards Models, Prostatic Neoplasms, Castration-Resistant, Risk Factors, Steroid 17-alpha-Hydroxylase, Time Factors, Treatment Outcome, Abiraterone acetate, Chemotherapy-naive, Efficacy, Metastatic castration-resistant, prostate cancer, Safety, Metastatic castration-resistant prostate cancer, Urology & Nephrology, Clinical sciences
Abstract

BackgroundAbiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy.ObjectiveReport the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302.Design, setting, and participantsStudy COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1).InterventionPatients were randomised 1:1 to abiraterone 1000mg plus prednisone 5mg twice daily by mouth versus prednisone.Outcome measurements and statistical analysisCo-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets α-spending function was used for OS. Adverse events were summarised descriptively.Results and limitationsWith a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; p2 yr.

Published
2014

47. PCAT-1, a Long Noncoding RNA, Regulates BRCA2 and Controls Homologous Recombination in Cancer

Author

Prensner, John R, Chen, Wei, Iyer, Matthew K, Cao, Qi, Ma, Teng, Han, Sumin, Sahu, Anirban, Malik, Rohit, Wilder-Romans, Kari, Navone, Nora, Logothetis, Christopher J, Araujo, John C, Pisters, Louis L, Tewari, Ashutosh K, Canman, Christine E, Knudsen, Karen E, Kitabayashi, Naoki, Rubin, Mark A, Demichelis, Francesca, Lawrence, Theodore S, Chinnaiyan, Arul M, and Feng, Felix Y

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Urologic Diseases, Prostate Cancer, Cancer, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, 3' Untranslated Regions, Animals, Antineoplastic Agents, BRCA2 Protein, Cell Death, Cell Line, Tumor, DNA Damage, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, SCID, Phthalazines, Piperazines, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Prostatic Neoplasms, RNA Interference, RNA, Long Noncoding, Recombinational DNA Repair, Xenograft Model Antitumor Assays, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) in DSB repair in prostate cancer. We identify PCAT-1, a prostate cancer outlier lncRNA, which regulates cell response to genotoxic stress. PCAT-1 expression produces a functional deficiency in homologous recombination through its repression of the BRCA2 tumor suppressor, which, in turn, imparts a high sensitivity to small-molecule inhibitors of PARP1. These effects reflected a posttranscriptional repression of the BRCA2 3'UTR by PCAT-1. Our observations thus offer a novel mechanism of "BRCAness" in sporadic cancers.

Published
2014

48. Prostate cancer-induced endothelial-cell-to-osteoblast transition drives immunosuppression in the bone-tumor microenvironment through Wnt pathway-induced M2 macrophage polarization.

Author

Guoyu Yu, Corn, Paul G., Sze Ling Mak, Celia, Xin Liang, Miao Zhang, Troncoso, Patricia, Song, Jian H., Song-Chang Lin, Xingzhi Song, Jingjing Liu, Jianhua Zhang, Logothetis, Christopher J., Melancon, Marites P., Panaretakis, Theocharis, Guocan Wang, and Sue-Hwa Lin

Subjects
CASTRATION-resistant prostate cancer, LYSYL oxidase, BONE metastasis, IMMUNE checkpoint proteins, LYMPHATIC metastasis, PROSTATE cancer patients
Abstract

Immune checkpoint therapy has limited efficacy for patients with bone-metastatic castration-resistant prostate cancer (bmCRPC). To improve immunotherapy for bmCRPC, we aimed to identify the mechanism of bmCRPC-induced changes in the immune microenvironment. Among bmCRPC patients, higher levels of a 32-gene M2-like macrophage signature in bone metastasis samples correlated with shorter overall survival. Immunohistochemistry showed that CD206-positive (CD206+) macrophages were enriched in bmCRPC bone biopsy specimens compared with primary tumors or lymph node metastases. In preclinical osteogenic prostate cancer (Pca) xenograft models, CD206+ macrophages were recruited to areas with tumor-induced bone. RNA sequencing (RNAseq) analysis showed higher expression of an M2-like gene signature, with activated canonical and noncanonical Wnt pathways, in tumor-associated macrophages isolated from osteogenic tumors (bone-TAMs) than in TAMs isolated from nonosteogenic tumors (ctrl-TAMs). Mechanistic studies showed that endothelial cells (ECs) that had undergone EC-to-osteoblast (EC-to-OSB) transition, the precursors of tumor-induced OSBs, produced paracrine factors, including Wnts, CXCL14, and lysyl oxidase, which induced M2 polarization and recruited M2-like TAMs to the bone-tumor microenvironment (bone-TME). Bone-TAMs suppressed CD8+ T cells' proliferation and cytolytic activity, and these effects were partially reversed by treating bone-TAMs with Wnt inhibitors. Genetic or pharmacological inhibition of Pca-induced EC-to-OSB transition reduced the levels of M2-like macrophages in osteogenic tumors. Our study demonstrates that Pca-induced EC-to-OSB transition drives immunosuppression in the bone-TME, suggesting that therapies that reduce Pca-induced bone formation may improve immunotherapeutic outcomes for bmCRPC. [ABSTRACT FROM AUTHOR]

Published
2024
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49. Radium-223 Treatment Produces Prolonged Suppression of Resident Osteoblasts and Decreased Bone Mineral Density in Trabecular Bone in Osteoblast Reporter Mice.

Author

Lin, Song-Chang, Yu, Guoyu, Corn, Paul G., Damasco, Jossana, Lee, Yu-Chen, Song, Jian H., Navone, Nora M., Logothetis, Christopher J., Melancon, Marites P., Panaretakis, Theocharis, and Lin, Sue-Hwa

Subjects
OSTEOBLASTS, BONE density, RADIOTHERAPY, RESEARCH funding, T-test (Statistics), TRABECULECTOMY, COMPUTED tomography, PROSTATE tumors, DESCRIPTIVE statistics, MICE, ANIMAL experimentation, DATA analysis software
Abstract

Simple Summary: Radium 223 (Ra-223) is a radiopharmaceutical that targets tumor-induced osteoblasts (bone-forming cells). Ra-223 reduces bone pain and prolongs overall survival in men with bone-metastatic, castrate-resistant prostate cancer. However, increased fracture risk in skeletal sites with no bone metastasis has been observed in patients treated with Ra-223. The aim of this study was to examine the effects of Ra-223 on resident osteoblasts and normal bone structure in mouse models. Upon Ra-223 treatment, 70% of resident osteoblasts were reduced within 2 days, and the reduction lasted for at least 18 weeks. Ra-223 reduced the osteoblasts mainly localized in trabecular bone areas. Ra-223 also reduced bone mineral density and altered bone microstructure in the trabecular area of femurs. Furthermore, Ra-223 treatment also significantly reduced tumor-induced osteoblasts. These studies show that Ra-223 affects the structure of bones that are not involved in bone metastasis. Strategies that improve bone health may reduce fracture risk in patients receiving Ra-223. Radium 223 (Ra-223) is an α-emitting bone-homing radiopharmaceutical that targets tumor-induced osteoblasts and is used to reduce bone pain and prolong overall survival in men with bone-metastatic, castrate-resistant prostate cancer. However, increased fracture risk in skeletal sites with no bone metastasis has been observed in patients treated with Ra-223. Both luciferase- or green fluorescence protein (GFP)-labeled osteoblast reporter mice were used to monitor the effect of Ra-223 on resident osteoblasts and normal bone structure. Upon Ra-223 treatment, 70% of resident osteoblasts were reduced within 2 days, and the osteoblast reduction lasted for at least 18 weeks without detectable recovery, as measured by in vivo bioluminescent imaging. In GFP-labeled osteoblast reporter mice, Ra-223 mainly reduced osteoblasts localized in the trabecular bone areas; the osteoblasts in the growth plates were less affected. Micro-computed tomography analyses showed that Ra-223 significantly reduced bone mineral density and bone microstructure in the trabecular area of femurs but not in the cortical bone. Tumor-induced bone was generated by inoculating osteogenic TRAMP-BMP4 prostate cancer cells into the mouse femurs; Ra-223 treatment significantly reduced tumor-induced osteoblasts. Our study shows that Ra-223 affects bone structures that are not involved in bone metastasis. Strategies that improve bone health may reduce fracture risk in patients receiving Ra-223. [ABSTRACT FROM AUTHOR]

Published
2024
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