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1. What Experts Think About Prostate Cancer Management During the COVID-19 Pandemic: Report from the Advanced Prostate Cancer Consensus Conference 2021

Author: Turco, F, Armstrong, A, Attard, G, Beer, TM, Beltran, H, Bjartell, A, Bossi, A, Briganti, A, Bristow, RG, Bulbul, M, Caffo, O, Chi, KN, Clarke, C, Clarke, N, Davis, ID, de Bono, J, Duran, I, Eeles, R, Efstathiou, E, Efstathiou, J, Evans, CP, Fanti, S, Feng, FY, Fizazi, K, Frydenberg, M, George, D, Gleave, M, Halabi, S, Heinrich, D, Higano, C, Hofman, MS, Hussain, M, James, N, Jones, R, Kanesvaran, R, Khauli, RB, Klotz, L, Leibowitz, R, Logothetis, C, Maluf, F, Millman, R, Morgans, AK, Morris, MJ, Mottet, N, Mrabti, H, Murphy, DG, Murthy, V, Oh, WK, Onyeanunam, NE, Ost, P, O'Sullivan, JM, Padhani, AR, Parker, C, Poon, DMC, Pritchard, CC, Rabah, DM, Rathkopf, D, Reiter, RE, Rubin, M, Ryan, CJ, Saad, F, Pablo Sade, J, Sartor, O, Scher, H, Shore, N, Skoneczna, I, Small, E, Smith, M, Soule, H, Spratt, D, Sternberg, CN, Suzuki, H, Sweeney, C, Sydes, M, Taplin, M-E, Tilki, D, Tombal, B, Turkeri, L, Uemura, H, van Oort, I, Yamoah, K, Ye, D, Zapatero, A, Gillessen, S, Omlin, A, Turco, F, Armstrong, A, Attard, G, Beer, TM, Beltran, H, Bjartell, A, Bossi, A, Briganti, A, Bristow, RG, Bulbul, M, Caffo, O, Chi, KN, Clarke, C, Clarke, N, Davis, ID, de Bono, J, Duran, I, Eeles, R, Efstathiou, E, Efstathiou, J, Evans, CP, Fanti, S, Feng, FY, Fizazi, K, Frydenberg, M, George, D, Gleave, M, Halabi, S, Heinrich, D, Higano, C, Hofman, MS, Hussain, M, James, N, Jones, R, Kanesvaran, R, Khauli, RB, Klotz, L, Leibowitz, R, Logothetis, C, Maluf, F, Millman, R, Morgans, AK, Morris, MJ, Mottet, N, Mrabti, H, Murphy, DG, Murthy, V, Oh, WK, Onyeanunam, NE, Ost, P, O'Sullivan, JM, Padhani, AR, Parker, C, Poon, DMC, Pritchard, CC, Rabah, DM, Rathkopf, D, Reiter, RE, Rubin, M, Ryan, CJ, Saad, F, Pablo Sade, J, Sartor, O, Scher, H, Shore, N, Skoneczna, I, Small, E, Smith, M, Soule, H, Spratt, D, Sternberg, CN, Suzuki, H, Sweeney, C, Sydes, M, Taplin, M-E, Tilki, D, Tombal, B, Turkeri, L, Uemura, H, van Oort, I, Yamoah, K, Ye, D, Zapatero, A, Gillessen, S, and Omlin, A
Abstract: Patients with advanced prostate cancer (APC) may be at greater risk for severe illness, hospitalisation, or death from coronavirus disease 2019 (COVID-19) due to male gender, older age, potential immunosuppressive treatments, or comorbidities. Thus, the optimal management of APC patients during the COVID-19 pandemic is complex. In October 2021, during the Advanced Prostate Cancer Consensus Conference (APCCC) 2021, the 73 voting members of the panel members discussed and voted on 13 questions on this topic that could help clinicians make treatment choices during the pandemic. There was a consensus for full COVID-19 vaccination and booster injection in APC patients. Furthermore, the voting results indicate that the expert's treatment recommendations are influenced by the vaccination status: the COVID-19 pandemic altered management of APC patients for 70% of the panellists before the vaccination was available but only for 25% of panellists for fully vaccinated patients. Most experts (71%) were less likely to use docetaxel and abiraterone in unvaccinated patients with metastatic hormone-sensitive prostate cancer. For fully vaccinated patients with high-risk localised prostate cancer, there was a consensus (77%) to follow the usual treatment schedule, whereas in unvaccinated patients, 55% of the panel members voted for deferring radiation therapy. Finally, there was a strong consensus for the use of telemedicine for monitoring APC patients. PATIENT SUMMARY: In the Advanced Prostate Cancer Consensus Conference 2021, the panellists reached a consensus regarding the recommendation of the COVID-19 vaccine in prostate cancer patients and use of telemedicine for monitoring these patients.
Published: 2022

2. Management of Patients with Advanced Prostate Cancer: Report from the Advanced Prostate Cancer Consensus Conference 2021

Author: Gillessen, S, Armstrong, A, Attard, G, Beer, TM, Beltran, H, Bjartell, A, Bossi, A, Briganti, A, Bristow, RG, Bulbul, M, Caffo, O, Chi, KN, Clarke, CS, Clarke, N, Davis, ID, de Bono, JS, Duran, I, Eeles, R, Efstathiou, E, Efstathiou, J, Ekeke, ON, Evans, CP, Fanti, S, Feng, FY, Fizazi, K, Frydenberg, M, George, D, Gleave, M, Halabi, S, Heinrich, D, Higano, C, Hofman, MS, Hussain, M, James, N, Jones, R, Kanesvaran, R, Khauli, RB, Klotz, L, Leibowitz, R, Logothetis, C, Maluf, F, Millman, R, Morgans, AK, Morris, MJ, Mottet, N, Mrabti, H, Murphy, DG, Murthy, V, Oh, WK, Ost, P, O'Sullivan, JM, Padhani, AR, Parker, C, Poon, DMC, Pritchard, CC, Rabah, DM, Rathkopf, D, Reiter, RE, Rubin, M, Ryan, CJ, Saad, F, Sade, JP, Sartor, O, Scher, H, Shore, N, Skoneczna, I, Small, E, Smith, M, Soule, H, Spratt, DE, Sternberg, CN, Suzuki, H, Sweeney, C, Sydes, MR, Taplin, M-E, Tilki, D, Tombal, B, Turkeri, L, Uemura, H, van Oort, I, Yamoah, K, Ye, D, Zapatero, A, Omlin, A, Gillessen, S, Armstrong, A, Attard, G, Beer, TM, Beltran, H, Bjartell, A, Bossi, A, Briganti, A, Bristow, RG, Bulbul, M, Caffo, O, Chi, KN, Clarke, CS, Clarke, N, Davis, ID, de Bono, JS, Duran, I, Eeles, R, Efstathiou, E, Efstathiou, J, Ekeke, ON, Evans, CP, Fanti, S, Feng, FY, Fizazi, K, Frydenberg, M, George, D, Gleave, M, Halabi, S, Heinrich, D, Higano, C, Hofman, MS, Hussain, M, James, N, Jones, R, Kanesvaran, R, Khauli, RB, Klotz, L, Leibowitz, R, Logothetis, C, Maluf, F, Millman, R, Morgans, AK, Morris, MJ, Mottet, N, Mrabti, H, Murphy, DG, Murthy, V, Oh, WK, Ost, P, O'Sullivan, JM, Padhani, AR, Parker, C, Poon, DMC, Pritchard, CC, Rabah, DM, Rathkopf, D, Reiter, RE, Rubin, M, Ryan, CJ, Saad, F, Sade, JP, Sartor, O, Scher, H, Shore, N, Skoneczna, I, Small, E, Smith, M, Soule, H, Spratt, DE, Sternberg, CN, Suzuki, H, Sweeney, C, Sydes, MR, Taplin, M-E, Tilki, D, Tombal, B, Turkeri, L, Uemura, H, van Oort, I, Yamoah, K, Ye, D, Zapatero, A, and Omlin, A
Abstract: BACKGROUND: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence. OBJECTIVE: To present the voting results from APCCC 2021. DESIGN, SETTING, AND PARTICIPANTS: The experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process. RESULTS AND LIMITATIONS: The voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material. CONCLUSIONS: These voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical eviden
Published: 2022

3. What Experts Think About Prostate Cancer Management During the COVID-19 Pandemic: Report from the Advanced Prostate Cancer Consensus Conference 2021 (vol 82, pg 6, 2022)

Author: Turco, F, Armstrong, A, Attard, G, Beer, TM, Beltran, H, Bjartell, A, Bossi, A, Briganti, A, Bristow, RG, Bulbul, M, Caffo, O, Chi, KN, Clarke, C, Clarke, N, Davis, ID, de Bono, J, Duran, I, Eeles, R, Efstathiou, E, Efstathiou, J, Evans, CP, Fanti, S, Feng, FY, Fizazi, K, Frydenberg, M, George, D, Gleave, M, Halabi, S, Heinrich, D, Higano, C, Hofman, MS, Hussain, M, James, N, Jones, R, Kanesvaran, R, Khauli, RB, Klotz, L, Leibowitz, R, Logothetis, C, Maluf, F, Millman, R, Morgans, AK, Morris, MJ, Mottet, N, Mrabti, H, Murphy, DG, Murthy, V, Oh, WK, Ekeke, ON, Ost, P, O'Sullivan, JM, Padhani, AR, Parker, C, Poon, DMC, Pritchard, CC, Rabah, DM, Rathkopf, D, Reiter, RE, Rubin, M, Ryan, CJ, Saad, F, Sade, JP, Sartor, O, Scher, HI, Shore, N, Skoneczna, I, Small, E, Smith, M, Soule, H, Spratt, D, Sternberg, CN, Suzuki, H, Sweeney, C, Sydes, M, Taplin, M-E, Tilki, D, Tombal, B, Turkeri, L, Uemura, H, van Oort, I, Yamoah, K, Ye, D, Zapatero, A, Gillessen, S, Omlin, A, Turco, F, Armstrong, A, Attard, G, Beer, TM, Beltran, H, Bjartell, A, Bossi, A, Briganti, A, Bristow, RG, Bulbul, M, Caffo, O, Chi, KN, Clarke, C, Clarke, N, Davis, ID, de Bono, J, Duran, I, Eeles, R, Efstathiou, E, Efstathiou, J, Evans, CP, Fanti, S, Feng, FY, Fizazi, K, Frydenberg, M, George, D, Gleave, M, Halabi, S, Heinrich, D, Higano, C, Hofman, MS, Hussain, M, James, N, Jones, R, Kanesvaran, R, Khauli, RB, Klotz, L, Leibowitz, R, Logothetis, C, Maluf, F, Millman, R, Morgans, AK, Morris, MJ, Mottet, N, Mrabti, H, Murphy, DG, Murthy, V, Oh, WK, Ekeke, ON, Ost, P, O'Sullivan, JM, Padhani, AR, Parker, C, Poon, DMC, Pritchard, CC, Rabah, DM, Rathkopf, D, Reiter, RE, Rubin, M, Ryan, CJ, Saad, F, Sade, JP, Sartor, O, Scher, HI, Shore, N, Skoneczna, I, Small, E, Smith, M, Soule, H, Spratt, D, Sternberg, CN, Suzuki, H, Sweeney, C, Sydes, M, Taplin, M-E, Tilki, D, Tombal, B, Turkeri, L, Uemura, H, van Oort, I, Yamoah, K, Ye, D, Zapatero, A, Gillessen, S, and Omlin, A
Published: 2022

4. Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations

Author: Böttcher, René, Kweldam, Charlotte, Livingstone, J, Lalonde, E, Yamaguchi, TN, Huang, V, Yousif, F, Fraser, M, Bristow, RG, van der Kwast, T, Boutros, PC, Jenster, Guido, van Leenders, Arno, Böttcher, René, Kweldam, Charlotte, Livingstone, J, Lalonde, E, Yamaguchi, TN, Huang, V, Yousif, F, Fraser, M, Bristow, RG, van der Kwast, T, Boutros, PC, Jenster, Guido, and van Leenders, Arno
Published: 2018

5. Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

Author: Taylor, RA, Fraser, M, Livingstone, J, Espiritu, SMG, Thorne, H, Huang, V, Lo, W, Shiah, Y-J, Yamaguchi, TN, Sliwinski, A, Horsburgh, S, Meng, A, Heisler, LE, Yu, N, Yousif, F, Papargiris, M, Lawrence, MG, Timms, L, Murphy, DG, Frydenberg, M, Hopkins, JF, Bolton, D, Clouston, D, McPherson, JD, van der Kwast, T, Boutros, PC, Risbridger, GP, Bristow, RG, Taylor, RA, Fraser, M, Livingstone, J, Espiritu, SMG, Thorne, H, Huang, V, Lo, W, Shiah, Y-J, Yamaguchi, TN, Sliwinski, A, Horsburgh, S, Meng, A, Heisler, LE, Yu, N, Yousif, F, Papargiris, M, Lawrence, MG, Timms, L, Murphy, DG, Frydenberg, M, Hopkins, JF, Bolton, D, Clouston, D, McPherson, JD, van der Kwast, T, Boutros, PC, Risbridger, GP, and Bristow, RG
Abstract: Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.
Published: 2017

6. RAD51: A DNA repair target for increasing the therapeutic potential in bladder cancer

Author: Choudhury, A, Jalali, F, Kiltie, AE, and Bristow, RG
Published: 2016

7. DNA Double-Strand Break Repair Pathway Choice Is Directed by Distinct MRE11 Nuclease Activities (vol 53, pg 7, 2014)

Author: Shibata, A, Moiani, D (Davide), Arvai, AS, Perry, J, Harding, SM, Genois, MM, Maity, R, Van Rossum - Fikkert, Sari, Kertokalio, Aryandi, Romoli, F, Ismail, A, Ismalaj, E, Petricci, E, Neale, MJ, Bristow, RG, Masson, JY, Wyman, C.L., Jeggo, PA, Tainer, JA, Molecular Genetics, and Radiation Oncology
Published: 2014

8. WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

Author: Zhukova, N, Ramaswamy, V, Remke, M, Martin, DC, Castelo-Branco, P, Zhang, CH, Fraser, M, Tse, K, Poon, R, Shih, DJH, Baskin, B, Ray, PN, Bouffet, E, Dirks, P, von Bueren, AO, Pfaff, E, Korshunov, A, Jones, DTW, Northcott, PA, Kool, M, Pugh, TJ, Pomeroy, SL, Cho, YJ, Pietsch, T, Gessi, M, Rutkowski, S, Bognár, L, Cho, BK, Eberhart, CG, Conter, CF, Fouladi, M, French, PJ, Grajkowska, WA, Gupta, N, Hauser, P, Jabado, N, Vasiljevic, A, Jung, S, Kim, SK, Klekner, A, Kumabe, T, Lach, B, Leonard, JR, Liau, LM, Massimi, L, Pollack, IF, Ra, YS, Rubin, JB, Van Meir, EG, Wang, KC, Weiss, WA, Zitterbart, K, Bristow, RG, Alman, B, Hawkins, CE, Malkin, D, Clifford, SC, Pfister, SM, Taylor, MD, Tabori, U, Zhukova, N, Ramaswamy, V, Remke, M, Martin, DC, Castelo-Branco, P, Zhang, CH, Fraser, M, Tse, K, Poon, R, Shih, DJH, Baskin, B, Ray, PN, Bouffet, E, Dirks, P, von Bueren, AO, Pfaff, E, Korshunov, A, Jones, DTW, Northcott, PA, Kool, M, Pugh, TJ, Pomeroy, SL, Cho, YJ, Pietsch, T, Gessi, M, Rutkowski, S, Bognár, L, Cho, BK, Eberhart, CG, Conter, CF, Fouladi, M, French, PJ, Grajkowska, WA, Gupta, N, Hauser, P, Jabado, N, Vasiljevic, A, Jung, S, Kim, SK, Klekner, A, Kumabe, T, Lach, B, Leonard, JR, Liau, LM, Massimi, L, Pollack, IF, Ra, YS, Rubin, JB, Van Meir, EG, Wang, KC, Weiss, WA, Zitterbart, K, Bristow, RG, Alman, B, Hawkins, CE, Malkin, D, Clifford, SC, Pfister, SM, Taylor, MD, and Tabori, U
Abstract: TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% ± 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% ± 2% vs. 57.4% ± 1.8% (p < 0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% ± 1.5% in lithium treated cells vs. 56.6 ± 3% (p < 0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% ± 8% for lithium treated cells vs. 27% ± 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
Published: 2014

9. Erratum: Corrigendum: Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue

Author: Cooper, CS, Eeles, R, Wedge, DC, Van Loo, P, Gundem, G, Alexandrov, LB, Kremeyer, B, Butler, A, Lynch, AG, Camacho, N, Massie, CE, Kay, J, Luxton, HJ, Edwards, S, Kote-Jarai, Z, Dennis, N, Merson, S, Leongamornlert, D, Zamora, J, Corbishley, C, Thomas, S, Nik-Zainal, S, Ramakrishna, M, O'Meara, S, Matthews, L, Clark, J, Hurst, R, Mithen, R, Bristow, RG, Boutros, PC, Fraser, M, Cooke, S, Raine, K, Jones, D, Menzies, A, Stebbings, L, Hinton, J, Teague, J, McLaren, S, Mudie, L, Hardy, C, Anderson, E, Joseph, O, Goody, V, Robinson, B, Maddison, M, Gamble, S, Greenman, C, Berney, D, Hazell, S, Livni, N, ICGC Prostate Group, Fisher, C, Ogden, C, Kumar, P, Thompson, A, Woodhouse, C, Nicol, D, Mayer, E, Dudderidge, T, Shah, NC, Gnanapragasam, V, Voet, T, Campbell, P, Futreal, A, Easton, D, Warren, AY, Foster, CS, Stratton, MR, Whitaker, HC, McDermott, U, Brewer, DS, and Neal, DE
Subjects: Genetics, Prostate cancer, medicine.anatomical_structure, Phylogenetics, Prostate, ICGC Prostate Group, medicine, 11 Medical And Health Sciences, 06 Biological Sciences, Biology, medicine.disease, Developmental Biology
Published: 2015

10. An arranged marriage for precision medicine: hypoxia and genomic assays in localized prostate cancer radiotherapy

Author: Bristow, RG, primary, Berlin, A, additional, and Dal Pra, A, additional
Published: 2014
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11. ATM and DNA-PK: the sensing, signalling, and repair of DNA damage

Author: Bristow, RG (Robert), Bluyssen, JAR (Hans), de Klein, Annelies, van Gent, Dik, Woodgett, J., and Molecular Genetics
Published: 2000

12. DISCUSSION: RAILWAY UNDERLINE BRIDGES: DEVELOPMENTS WITHIN CONSTRAINTS OF LIMITED POSSESSION.

Author: EDEY, N, KITCHING, I, NICHOLSON, T, CLEMENTS, J, MITCHELL, DE, BRISTOW, RG, WIGLEY, PJG, COLE, D, HAYWARD, ACG, BROWN, RH, HUMPHRIES, EF, and ATKINS, FE
Published: 1989
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13. Radiosensitivity of cancer-initiating cells and normal stem cells (or what the Heisenberg uncertainly principle has to do with biology)

Author: Woodward WA and Bristow RG
Abstract: Mounting evidence suggests that parallels between normal stem cell biology and cancer biology may provide new targets for cancer therapy. Prospective identification and isolation of cancer-initiating cells from solid tumors has promoted the descriptive and functional identification of these cells allowing for characterization of their response to contemporary cancer therapies, including chemotherapy and radiation. In clinical radiation therapy, the failure to clinically eradicate all tumor cells (eg, a lack of response, partial response, or nonpermanent complete response by imaging) is considered a treatment failure. As such, biologists have explored the characteristics of the small population of clonogenic cancer cells that can survive and are capable of repopulating the tumor after subcurative therapy. Herein, we discuss the convergence of these clonogenic studies with contemporary radiosensitivity studies that use cell surface markers to identify cancer-initiating cells. Implications for and uncertainties regarding incorporation of these concepts into the practice of modern radiation oncology are discussed. Copyright © 2009 by Elsevier Inc. [ABSTRACT FROM AUTHOR]
Published: 2009
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14. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue

Author: Cooper, CS, Eeles, R, Wedge, DC, Van Loo, P, Gundem, G, Alexandrov, LB, Kremeyer, B, Butler, A, Lynch, AG, Camacho, N, Massie, CE, Kay, J, Lmcton, HJ, Edwards, S, Kote-Jarai, Z, Dennis, N, Merson, S, Leongamornlert, D, Zamora, J, Corbishley, C, Thomas, S, Nik-Zainal, S, Ramakrishna, M, O'Meara, S, Matthews, L, Clark, J, Hurst, R, Mithen, R, Bristow, RG, Boutros, PC, Fraser, M, Cooke, S, Raine, K, Jones, D, Menzies, A, Stebbings, L, Hinton, J, Teague, J, McLaren, S, Mudie, L, Hardy, C, Anderson, E, Joseph, O, Goody, V, Robinson, B, Maddison, M, Gamble, S, Greenman, C, Berney, D, Hazell, S, Livni, N, Fisher, C, Ogden, C, Kumar, P, Thompson, A, Woodhouse, C, Nicol, D, Mayer, E, Dudderidge, T, Shah, NC, Gnanapragasam, V, Voet, T, Campbell, P, Futreal, A, Easton, D, Warren, AY, Foster, CS, Stratton, MR, Whitaker, HC, McDermott, U, Brewer, DS, Neal, DE, and Grp, ICGCP
Subjects: DNA sequencing, prostate cancer, 3. Good health
Abstract: Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases., This work was funded by Cancer Research UK (grant C5047/A14835), the Dallaglio Foundation and the Wellcome Trust. We also acknowledge support from the Bob Champion Cancer Trust, the Orchid Cancer Appeal, the RoseTrees Trust, the North West Cancer Research Fund, Big C, the King family, the Grand Charity of Freemasons, and the Research Foundation Flanders (FWO). We thank D. Holland from the Infrastructure Management Team and P. Clapham from the Informatics Systems Group at the Wellcome Trust Sanger Institute. We acknowledge the Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, supported by the National Institute for Health Research. We acknowledge support from the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative (grant G0500966/75466). We thank the National Institute for Health Research, Hutchison Whampoa Limited and the Human Research Tissue Bank (Addenbrooke's Hospital), the Cancer Research UK Cambridge Research Institute Histopathology, the In-situ Hybridisation Core Facility, the Genomics Core Facility Cambridge and the Cambridge University Hospitals Media Studio.

15. Excellent translational research in oncology: A journey towards novel and more effective anti-cancer therapies

Author: Rajan, A, Berns, A, Ringborg, U, Celis, J, Ponder, B, Caldas, C, Livingston, D, Bristow, RG, Hecht, TT, Tursz, T, Van Luenen, H, Bono, P, Helander, T, Seamon, K, Smyth, JF, Louvard, D, Eggermont, A, and Van Harten, WH
Subjects: Europe, Translational Research, Biomedical, Performance assessment, Neoplasms, Excellence, Humans, Quality improvement, Translational research, Cancer Care Facilities, 3. Good health, Quality of Health Care
Abstract: Comprehensive Cancer Centres (CCCs) serve as critical drivers for improving cancer survival. In Europe, we have developed an Excellence Designation System (EDS) consisting of criteria to assess "excellence" of CCCs in translational research (bench to bedside and back), with the expectation that many European CCCs will aspire to this status.

16. DISCUSSION: RAILWAY UNDERLINE BRIDGES: DEVELOPMENTS WITHIN CONSTRAINTS OF LIMITED POSSESSION.

Author: ATKINS, FE, primary, HAYWARD, ACG, additional, BROWN, RH, additional, CLEMENTS, J, additional, WIGLEY, PJG, additional, KITCHING, I, additional, NICHOLSON, T, additional, HUMPHRIES, EF, additional, MITCHELL, DE, additional, BRISTOW, RG, additional, EDEY, N, additional, and COLE, D, additional
Published: 1989
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17. Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019

Author: Charles G. Drake, Matthew R. Smith, Almudena Zapatero, Charles J. Ryan, Philip W. Kantoff, Piet Ost, Inge M. van Oort, Ian D. Davis, Nicolas James, Matthew R. Sydes, Vedang Murthy, Martin E. Gleave, Maha Hussain, Michael S Hofman, Susan Halabi, Ignacio Duran, Oliver Sartor, Raya Leibowitz, Christopher P. Evans, Anders Bjartell, Ros Eeles, Mack Roach, Hiroyoshi Suzuki, Colin C. Pritchard, Levent Türkeri, Daniel Heinrich, Fred Saad, William Oh, Karim Fizazi, Himisha Beltran, Declan G. Murphy, Joe M. O'Sullivan, Thomas Steuber, Raja B. Khauli, Axel Heidenreich, Silke Gillessen, Eric J. Small, Robert E. Reiter, Juan Pablo Sade, Chris Logothetis, Tomasz M. Beer, Alberto Briganti, Mary-Ellen Taplin, Johann S. de Bono, Howard I. Scher, Eleni Efstathiou, Stefano Fanti, Darren M.C. Poon, Felix Y. Feng, Aurelius Omlin, Hind Mrabti, Chris Parker, Anwar R. Padhani, Kim N. Chi, Mark A. Rubin, Neal D. Shore, Nicolas Mottet, Alicia K. Morgans, Christopher Sweeney, Mark Frydenberg, Robert G. Bristow, Fernando C. Maluf, Robin Millman, Cora N. Sternberg, Ravindran Kanesvaran, Michael J. Morris, Noel W. Clarke, Gerhardt Attard, Alberto Bossi, Bertrand Tombal, Celestia S. Higano, Howard R. Soule, Acibadem University Dspace, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - (SLuc) Service d'urologie, and Gillessen S, Attard G, Beer TM, Beltran H, Bjartell A, Bossi A, Briganti A, Bristow RG, Chi KN, Clarke N, Davis ID, de Bono J, Drake CG, Duran I, Eeles R, Efstathiou E, Evans CP, Fanti S, Feng FY, Fizazi K, Frydenberg M, Gleave M, Halabi S, Heidenreich A, Heinrich D, Higano CTS, Hofman MS, Hussain M, James N, Kanesvaran R, Kantoff P, Khauli RB, Leibowitz R, Logothetis C, Maluf F, Millman R, Morgans AK, Morris MJ, Mottet N, Mrabti H, Murphy DG, Murthy V, Oh WK, Ost P, O'Sullivan JM, Padhani AR, Parker C, Poon DMC, Pritchard CC, Reiter RE, Roach M, Rubin M, Ryan CJ, Saad F, Sade JP, Sartor O, Scher HI, Shore N, Small E, Smith M, Soule H, Sternberg CN, Steuber T, Suzuki H, Sweeney C, Sydes MR, Taplin ME, Tombal B, Türkeri L, van Oort I, Zapatero A, Omlin A.
Subjects: Male, Oncology, Aging, Advanced prostate cance, Hormone-sensitive prostate cancer, Imaging, SALVAGE RADIATION-THERAPY, Prostate cancer, QUALITY-OF-LIFE, Medicine and Health Sciences, Overall survival, Neoplasm Metastasis, DISSECTION, Cancer, Castration-resistant prostate cancer, Tumour genomic profiling, Advanced prostate cancer, Prostate Cancer, RADICAL PROSTATECTOMY, Consensus conference, Progression-free survival, TESTOSTERONE MEASUREMENTS, Urology & Nephrology, High-risk localised prostate cancer, Prostate cancer treatment, Local, Practice Guidelines as Topic, PHASE-II, Overall, profiling, CLINICAL-TRIALS, Urologic Diseases, medicine.medical_specialty, Urology, Clinical Sciences, Bone Neoplasms, HOT FLASHES, survival, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15], Castration-naïve prostate cancer, Genetics, medicine, Humans, LYMPH-NODE, Neoplasm Staging, business.industry, Tumour genomic, Prostatic Neoplasms, Prostate-Specific Antigen, medicine.disease, Oligometastatic prostate cancer, LYMPH-NODE DISSECTION, Hormone sensitive prostate cancer, Neoplasm Recurrence, Good Health and Well Being, ANDROGEN-DEPRIVATION THERAPY, Neoplasm Recurrence, Local, FREE SURVIVAL, business
Abstract: Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence. Objective: To present the results from the APCCC 2019. Design, setting, and participants: Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naive prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions. Outcome measurements and statistical analysis: The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process. Results and limitations: Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material. Conclusions: These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials. Patient summary: The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.
Published: 2020

18. Hypoxia, Androgen Deprivation and Systemic Metastases in Prostate Cancer (In Response to 'Antivascular Effects of Neoadjuvant Androgen Deprivation for Prostate Cancer: An In Vivo Human Study Using Susceptibility and Relaxitivity Dynamic MRI': In Regard to Alonzi R et al. (Int J Radiat Oncol Biol Phys 2011;80(3):721-727)

Author: Dal Pra A, Milosevic M, Hill R, Wouters B, Warde P, and Bristow RG
Published: 2012
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19. Correction to: Up-regulation of autophagy is a mechanism of resistance to chemotherapy and can be inhibited by pantoprazole to increase drug sensitivity.

Author: Tan Q, Joshua AM, Wang M, Bristow RG, Wouters BG, Allen CJ, and Tannock IF
Published: 2024
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20. Characterizing replisome disassembly in human cells.

Author: Jones RM, Ruiz JH, Scaramuzza S, Nath S, Liu C, Henklewska M, Natsume T, Bristow RG, Romero F, Kanemaki MT, and Gambus A
Abstract: To ensure timely duplication of the entire eukaryotic genome, thousands of replication machineries (replisomes) act on genomic DNA at any time during S phase. In the final stages of this process, replisomes are unloaded from chromatin. Unloading is driven by polyubiquitylation of MCM7, a subunit of the terminated replicative helicase, and processed by p97/VCP segregase. Most of our knowledge of replication termination comes from model organisms, and little is known about how this process is executed and regulated in human somatic cells. Here we show that replisome disassembly in this system requires CUL2 LRR1 -driven MCM7 ubiquitylation, p97, and UBXN7 for unloading and provide evidence for "backup" mitotic replisome disassembly, demonstrating conservation of such mechanisms. Finally, we find that small-molecule inhibitors against Cullin ubiquitin ligases (CULi) and p97 (p97i) affect replisome unloading but also lead to induction of replication stress in cells, which limits their usefulness to specifically target replisome disassembly processes., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)
Published: 2024
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21. AmplificationTimeR: an R package for timing sequential amplification events.

Author: Jakobsdottir GM, Dentro SC, Bristow RG, and Wedge DC
Subjects: Genomics methods, Algorithms, Humans, DNA Copy Number Variations, Software
Abstract: Motivation: Few methods exist for timing individual amplification events in regions of focal amplification. Current methods are also limited in the copy number states that they are able to time. Here we introduce AmplificationTimeR, a method for timing higher level copy number gains and inferring the most parsimonious order of events for regions that have undergone both single gains and whole genome duplication. Our method is an extension of established approaches for timing genomic gains., Results: We can time more copy number states, and in states covered by other methods our results are comparable to previously published methods., Availability and Implementation: AmplificationTimer is freely available as an R package hosted at https://github.com/Wedge-lab/AmplificationTimeR., (© The Author(s) 2024. Published by Oxford University Press.)
Published: 2024
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22. Retraction notice to "Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors" [Neoplasia 18 (2016) 347- 355/201].

Author: Tan Q, Wang M, Yu M, Zhang J, Bristow RG, Hill RP, and Tannock IF
Published: 2024
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23. Genomic evolution shapes prostate cancer disease type.

Author: Woodcock DJ, Sahli A, Teslo R, Bhandari V, Gruber AJ, Ziubroniewicz A, Gundem G, Xu Y, Butler A, Anokian E, Pope BJ, Jung CH, Tarabichi M, Dentro SC, Farmery JHR, Van Loo P, Warren AY, Gnanapragasam V, Hamdy FC, Bova GS, Foster CS, Neal DE, Lu YJ, Kote-Jarai Z, Fraser M, Bristow RG, Boutros PC, Costello AJ, Corcoran NM, Hovens CM, Massie CE, Lynch AG, Brewer DS, Eeles RA, Cooper CS, and Wedge DC
Subjects: Male, Humans, Prostate metabolism, Mutation, Genomics, Evolution, Molecular, Prostatic Neoplasms genetics
Abstract: The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression., Competing Interests: Declaration of interests An international patent related to this work has been published under international publication no. WO 2023/047140 A1. R.A.E. has the following conflicts of interest to declare: she has received honoraria from GU-ASCO, Janssen, The University of Chicago, and Dana-Farber Cancer Institute USA as a speaker and educational honorarium from Bayer and Ipsen and is a member of the external expert committee to Astra Zeneca UK. She undertakes private practice as a sole trader at The Royal Marsden NHS Foundation Trust and 90 Sloane Street SW1X 9PQ and 280 Kings Road SW3 4NX, London, UK., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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24. First-in-human technique translation of oxygen-enhanced MRI to an MR Linac system in patients with head and neck cancer.

Author: Dubec MJ, Buckley DL, Berks M, Clough A, Gaffney J, Datta A, McHugh DJ, Porta N, Little RA, Cheung S, Hague C, Eccles CL, Hoskin PJ, Bristow RG, Matthews JC, van Herk M, Choudhury A, Parker GJM, McPartlin A, and O'Connor JPB
Subjects: Humans, Magnetic Resonance Imaging methods, Hypoxia, Prognosis, Particle Accelerators, Oxygen, Head and Neck Neoplasms diagnostic imaging
Abstract: Background and Purpose: Tumour hypoxia is prognostic in head and neck cancer (HNC), associated with poor loco-regional control, poor survival and treatment resistance. The advent of hybrid MRI - radiotherapy linear accelerator or 'MR Linac' systems - could permit imaging for treatment adaptation based on hypoxic status. We sought to develop oxygen-enhanced MRI (OE-MRI) in HNC and translate the technique onto an MR Linac system., Materials and Methods: MRI sequences were developed in phantoms and 15 healthy participants. Next, 14 HNC patients (with 21 primary or local nodal tumours) were evaluated. Baseline tissue longitudinal relaxation time (T 1 ) was measured alongside the change in 1/T 1 (termed ΔR 1 ) between air and oxygen gas breathing phases. We compared results from 1.5 T diagnostic MR and MR Linac systems., Results: Baseline T 1 had excellent repeatability in phantoms, healthy participants and patients on both systems. Cohort nasal concha oxygen-induced ΔR 1 significantly increased (p < 0.0001) in healthy participants demonstrating OE-MRI feasibility. ΔR 1 repeatability coefficients (RC) were 0.023-0.040 s -1 across both MR systems. The tumour ΔR 1 RC was 0.013 s -1 and the within-subject coefficient of variation (wCV) was 25% on the diagnostic MR. Tumour ΔR 1 RC was 0.020 s -1 and wCV was 33% on the MR Linac. ΔR 1 magnitude and time-course trends were similar on both systems., Conclusion: We demonstrate first-in-human translation of volumetric, dynamic OE-MRI onto an MR Linac system, yielding repeatable hypoxia biomarkers. Data were equivalent on the diagnostic MR and MR Linac systems. OE-MRI has potential to guide future clinical trials of biology guided adaptive radiotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Published: 2023
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25. Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis.

Author: Zlotta AR, Ballas LK, Niemierko A, Lajkosz K, Kuk C, Miranda G, Drumm M, Mari A, Thio E, Fleshner NE, Kulkarni GS, Jewett MAS, Bristow RG, Catton C, Berlin A, Sridhar SS, Schuckman A, Feldman AS, Wszolek M, Dahl DM, Lee RJ, Saylor PJ, Michaelson MD, Miyamoto DT, Zietman A, Shipley W, Chung P, Daneshmand S, and Efstathiou JA
Subjects: Humans, Male, Female, Aged, Cystectomy adverse effects, Urinary Bladder pathology, Urinary Bladder surgery, Propensity Score, Retrospective Studies, Treatment Outcome, Muscles pathology, Urinary Bladder Neoplasms pathology, Carcinoma, Transitional Cell drug therapy
Abstract: Background: Previous randomised controlled trials comparing bladder preservation with radical cystectomy for muscle-invasive bladder cancer closed due to insufficient accrual. Given that no further trials are foreseen, we aimed to use propensity scores to compare trimodality therapy (maximal transurethral resection of bladder tumour followed by concurrent chemoradiation) with radical cystectomy., Methods: This retrospective analysis included 722 patients with clinical stage T2-T4N0M0 muscle-invasive urothelial carcinoma of the bladder (440 underwent radical cystectomy, 282 received trimodality therapy) who would have been eligible for both approaches, treated at three university centres in the USA and Canada between Jan 1, 2005, and Dec 31, 2017. All patients had solitary tumours less than 7 cm, no or unilateral hydronephrosis, and no extensive or multifocal carcinoma in situ. The 440 cases of radical cystectomy represent 29% of all radical cystectomies performed during the study period at the contributing institutions. The primary endpoint was metastasis-free survival. Secondary endpoints included overall survival, cancer-specific survival, and disease-free survival. Differences in survival outcomes by treatment were analysed using propensity scores incorporated in propensity score matching (PSM) using logistic regression and 3:1 matching with replacement and inverse probability treatment weighting (IPTW)., Findings: In the PSM analysis, the 3:1 matched cohort comprised 1119 patients (837 radical cystectomy, 282 trimodality therapy). After matching, age (71·4 years [IQR 66·0-77·1] for radical cystectomy vs 71·6 years [64·0-78·9] for trimodality therapy), sex (213 [25%] vs 68 [24%] female; 624 [75%] vs 214 [76%] male), cT2 stage (755 [90%] vs 255 [90%]), presence of hydronephrosis (97 [12%] vs 27 [10%]), and receipt of neoadjuvant or adjuvant chemotherapy (492 [59%] vs 159 [56%]) were similar between groups. Median follow-up was 4·38 years (IQR 1·6-6·7) versus 4·88 years (2·8-7·7), respectively. 5-year metastasis-free survival was 74% (95% CI 70-78) for radical cystectomy and 75% (70-80) for trimodality therapy with IPTW and 74% (70-77) and 74% (68-79) with PSM. There was no difference in metastasis-free survival either with IPTW (subdistribution hazard ratio [SHR] 0·89 [95% CI 0·67-1·20]; p=0·40) or PSM (SHR 0·93 [0·71-1·24]; p=0·64). 5-year cancer-specific survival for radical cystectomy versus trimodality therapy was 81% (95% CI 77-85) versus 84% (79-89) with IPTW and 83% (80-86) versus 85% (80-89) with PSM. 5-year disease-free survival was 73% (95% CI 69-77) versus 74% (69-79) with IPTW and 76% (72-80) versus 76% (71-81) with PSM. There were no differences in cancer-specific survival (IPTW: SHR 0·72 [95% CI 0·50-1·04]; p=0·071; PSM: SHR 0·73 [0·52-1·02]; p=0·057) and disease-free survival (IPTW: SHR 0·87 [0·65-1·16]; p=0·35; PSM: SHR 0·88 [0·67-1·16]; p=0·37) between radical cystectomy and trimodality therapy. Overall survival favoured trimodality therapy (IPTW: 66% [95% CI 61-71] vs 73% [68-78]; hazard ratio [HR] 0·70 [95% CI 0·53-0·92]; p=0·010; PSM: 72% [69-75] vs 77% [72-81]; HR 0·75 [0·58-0·97]; p=0·0078). Outcomes for radical cystectomy and trimodality therapy were not statistically different among centres for cancer-specific survival and metastasis-free survival (p=0·22-0·90). Salvage cystectomy was done in 38 (13%) trimodality therapy patients. Pathological stage in the 440 radical cystectomy patients was pT2 in 124 (28%), pT3-4 in 194 (44%), and 114 (26%) node positive. The median number of nodes removed was 39, the soft tissue positive margin rate was 1% (n=5), and the perioperative mortality rate was 2·5% (n=11)., Interpretation: This multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option., Funding: Sinai Health Foundation, Princess Margaret Cancer Foundation, Massachusetts General Hospital., Competing Interests: Declaration of interests ARZ reports participation on a data safety monitoring board or advisory board for Janssen, Verity Pharmaceuticals, Ferring, mIR Scientific, Tolmar, and Theralase; and consulting fees from Janssen, Verity Pharmaceuticals, Ferring, mIR Scientific, Tolmar, and Theralase. NEF reports grants or contracts from Janssen, Sanofi, Astellas, Nucleix, Bayer, and Progenix; consulting fees from Amgen, Sanofi, Janssen, AbbVie, Astellas, Ferring, and Bayer; stock or stock options in Verity Pharmaceuticals and POINT Biopharma; and is Chief Medical Officer for Verity Pharmaceuticals and Chief Medical Officer for POINT Biopharma. GSK reports grants or contracts from Janssen; and participation on a data safety monitoring board or advisory board for BMS, Pfizer, EMD Serono, Theralase, Verity Pharmaceuticals, Merck, Janssen, AstraZeneca, and Ferring. MASJ reports an honorarium from Pfizer; support for attending meetings or travel from the European Association of Urology; and is the Chair of the Board of Directors of the International Kidney Cancer Coalition. SSS reports grants or contracts from Bayer, Janssen, and Seagen; consulting fees from Astellas, AstraZeneca, Bayer, BMS, Eisai, EMD Serona, Hoffmann-LaRoche, Immunomedics, Ipsen, Janssen, Merck, Pfizer, and Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, EMD Serono, Seagen, and Bayer; and support for attending meetings or travel from EMD Serono. MDM reports participation on a data safety monitoring board or advisory board for Merck, Janssen, Eisai, and Exelixis. JAE reports consulting fees from Blue Earth Diagnostics, Boston Scientific, AstraZeneca, and Genentech; and participation on a data safety monitoring board or advisory board for Merck, Roviant Pharma, Myovant Sciences, Janssen, Bayer Healthcare, Progenics Pharmaceuticals, Pfizer, Gilead, and Lantheus. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
Published: 2023
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26. Management of patients with advanced prostate cancer-metastatic and/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022.

Author: Gillessen S, Bossi A, Davis ID, de Bono J, Fizazi K, James ND, Mottet N, Shore N, Small E, Smith M, Sweeney CJ, Tombal B, Antonarakis ES, Aparicio AM, Armstrong AJ, Attard G, Beer TM, Beltran H, Bjartell A, Blanchard P, Briganti A, Bristow RG, Bulbul M, Caffo O, Castellano D, Castro E, Cheng HH, Chi KN, Chowdhury S, Clarke CS, Clarke N, Daugaard G, De Santis M, Duran I, Eeles R, Efstathiou E, Efstathiou J, Ekeke ON, Evans CP, Fanti S, Feng FY, Fonteyne V, Fossati N, Frydenberg M, George D, Gleave M, Gravis G, Halabi S, Heinrich D, Herrmann K, Higano C, Hofman MS, Horvath LG, Hussain M, Jereczek-Fossa BA, Jones R, Kanesvaran R, Kellokumpu-Lehtinen PL, Khauli RB, Klotz L, Kramer G, Leibowitz R, Logothetis C, Mahal B, Maluf F, Mateo J, Matheson D, Mehra N, Merseburger A, Morgans AK, Morris MJ, Mrabti H, Mukherji D, Murphy DG, Murthy V, Nguyen PL, Oh WK, Ost P, O'Sullivan JM, Padhani AR, Pezaro CJ, Poon DMC, Pritchard CC, Rabah DM, Rathkopf D, Reiter RE, Rubin MA, Ryan CJ, Saad F, Sade JP, Sartor O, Scher HI, Sharifi N, Skoneczna I, Soule H, Spratt DE, Srinivas S, Sternberg CN, Steuber T, Suzuki H, Sydes MR, Taplin ME, Tilki D, Türkeri L, Turco F, Uemura H, Uemura H, Ürün Y, Vale CL, van Oort I, Vapiwala N, Walz J, Yamoah K, Ye D, Yu EY, Zapatero A, Zilli T, and Omlin A
Subjects: Male, Humans, Diagnostic Imaging, Hormones, Prostatic Neoplasms, Castration-Resistant pathology, COVID-19
Abstract: Background: Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence., Objective: To present the voting results of the APCCC 2022., Design, Setting, and Participants: The experts voted on controversial questions where high-level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration-resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions., Outcome Measurements and Statistical Analysis: The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration-resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions., Results and Limitations: The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer., Conclusions: These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials., Patient Summary: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer., Twitter Summary: Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer., Take-Home Message: At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration-resistant prostate cancer is summarised here., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aurelis Omlin: Advisory role (compensated, institutional): Astra Zeneca, Astellas, Bayer, Janssen, Molecular Partners, MSD, Pfizer, Roche, Sanofi Aventis. Research support (institutional): TEVA, Janssen. Travel support: Astellas, Bayer, Janssen, Sanofi Aventis. Speakers Bureau (compensated, institutional): Bayer, Astellas, Janssen. Fizazi Karim: Participation to advisory boards or talks for: Amgen, Astellas, Astrazeneca, Bayer, Clovis, Janssen, MSD, Novartis, Pfizer, Sanofi. Honoraria are provided to Gustave Roussy, my institution. Participation to advisory boards with personal honorarium for: CureVac, Orion. Bossi Alberto: Honoraria: Astellas, Ipsen, Janssen, Myovant. Consulting or advisory role: Astellas, Ipsen, Janssen, Myovant. Speakers’ bureau: Astellas, Ipsen, Elketa. Research funding: Astellas, Ipsen, Myovant. Travel, accommodations, expenses: Janssen. Tombal Bertrand: Advisor for Astellas, Amgen, Bayer, Curium, Ferring, Myovant, Janssens, MSD, Novartis (AAA), Pfizer, Sanofi. Gillessen Silke: SG received personal honoraria for participation in advisory boards for Sanofi, Orion, Roche, Amgen, MSD; other honoraria from RSI (Televisione Svizzera Italiana); invited speaker for ESMO, Swiss group for Clinical Cancer Research (SAKK), Swiss Academy of Multidisciplinary oncology (SAMO), Orikata academy research group, China Anti-Cancer Association Genitourinary Oncology Committee (CACA-GU); Speaker’s bureau for Janssen Cilag; travel grant from ProteoMEdiX; institutional honoraria for advisory boards for Bayer, Janssen Cilag, Roche, AAA International including Indipendent Data Monitoring Committee and IDMC and Steering Committee member for Amgen, Menarini Silicon Biosystems, Astellas Pharma, Tolero Pharmaceutcials, MSD, Pfizer, Telixpharma, BMS and Orion; patent royalties and other intellectual property for a research method for biomarker WO2009138392. Ian Davis: Research Funding: Company: Astellas Pharma, Recipient: Your Institution; Company: Pfizer, Recipient: Your Institution; Company: Roche/Genentech, Recipient: Your Institution; Company: MSD Oncology, Recipient: Your Institution; Company: AstraZeneca, Recipient: Your Institution; Company: Janssen Oncology, Recipient: Your Institution; Company: Eisai, Recipient: Your Institution; Company: Bayer, Recipient: Your Institution; Company: Amgen, Recipient: Your Institution; Company: Bristol-Myers Squibb, Recipient: Your Institution; Company: Movember Foundation, Recipient: Your Institution; Company: Exelixis, Recipient: Your Institution; Company: Ipsen, Recipient: Your Institution; Company: Medivation, Recipient: Your Institution; Company: Seagen, Recipient: Your Institution. Patents, Royalties, Other Intellectual Property: Please describe: International Patent Application No: PCT /US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research; Recipient: You. Christopher Sweeney: Receipt of grants/research supports: Astellas, Bayer, Janssen, Pfizer, Sanofi, Dendreon; Receipt of honoraria or consultation fees: Astellas, Bayer, Janssen, Pfizer, Sanofi, Lilly, Genentech. Eric J. Small: Receipt of honoraria or consultation fees: Jannsen, Johnson & Johnson; Participation in a company sponsored speaker’s bureau: Jannsen, Fortis, Teon, Ulgragenyx, Fortis, Harpoon Johann de Bono: Receipt of grants/research supports: Professor De Bono is an employee of The Institute of Cancer Research, which has received funding or other support for his research work from Astellas, Astra Zeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income); Receipt of honoraria or consultation fees: Professor De Bono has served on advisory boards and received fees from Amgen, Astellas, Astra Zeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon. Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Participation in a company sponsored speaker’s bureau: AstraZeneca, MSD. Matthew Smith: Receipt of grants/research supports: Clinical trial funding to my institution from: Amgen, Bayer, ESSA, Janssen, ORIC, Pfizer; Receipt of honoraria or consultation fees: Amgen, Astellas, Astrazeneca, Bayer, Janssen, ORIC, Pfizer. Neal Shore: Receipt of honoraria or consultation fees: Abbvie, Amgen, Astellas, Astrazeneca, Bayer, BMS, Boston Scientific, Clovis Oncology, Cold Genesys, Dendreon, Exact Imaging, Exact Sciences, FerGene, Foundation Medicine, Genesis Care, Invitae, Janssen, MDxhealth, Merck, Myvovant, Myriad, Nymox, Pacific Edge, Pfizer, Phosphorous, Propella, Sanofi, Genzyme, Sesen Bio, Tolmar, Urogen; Partecipation in a company sponsored speaker's bureau: Astellas, Astrazeneca, Bayer, Clovis Oncology, Foundation Medicina, Janssen, Merck, Pfizer, Guardant Health. Nicholas James: Receipt of grants/research supports: • Funding for STAMPEDE trial – Coordinating PI – financial interest, Institutional. Name of commercial company: Astellas. • Funding for RADIO trial bladder cancer – Coordinating. PI – financial interest, Institutional. Name of commercial company: AstraZeneca. • Funding for STAMPEDE trial – Coordinating PI – No. financial interest, Institutional. Name of commercial company: Janssen; Receipt of honoraria or consultation fees: • Advisory Board – Advice around PARP inhibitors, Personal,<€5000. Name of commercial company: AstraZeneca dvisory Board – Prostate cancer therapies, Personal,<€5000. Name of commercial company: Clovis. Expert Testimony – Assisted with submissions. regarding licensing for abiraterone, Institutional>€100,001. Name of commercial company: Janssen. Advisory Board – Prostate cancer therapies, Personal, €5001–€10,000. Name of commercial company: Janssen. Advisory Board – Bladder cancer therapy, Personal,<€5000. Name of commercial company: Merck. Advisory Board – Prostate cancer therapies, Personal,<€5000. Name of commercial company: Novartis Expert Testimony – Providing STAMPEDE trial data to facilitate licence extensions internationally for docetaxel, Institutional,>€100,001. Name of commercial company: Sanofi. Advisory Board - Docetaxel, Personal,<€5000. Name of commercial company: Sanofi. Participation in a company sponsored speaker’s bureau: Bayer, Novartis. Nicolas MOTTET: Receipt of grants/research supports: Astellas, Sanofi Pasteur, Pierre Fabre; Receipt of honoraria or consultation fees: Astellas, Jansen, BMS, Bayer, IPSEN, Ferring, Sanofi, Steba, Astra Zeneca, Carrik, Arquer. diagnostics, GE, Takeda. Thomas ZILLI. AFFILIATION: Geneva University Hospital, Geneva, Switzerland. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Varian Medical Systems International AG; Debiopharm. Receipt of honoraria or consultation fees: Janssen, Astellas, Debiopharm, Ferring, Varian Medical Systems International AG. Participation in a company sponsored speaker’s bureau: Janssen, Astellas, Debiopharm. Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: Geneva 07.02.2022. Christopher Logothetis. AFFILIATION: MD Anderson Cancer Center. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Janssen, ORIC Pharmaceuticals, Novartis, Aragon Pharmaceuticals. Receipt of honoraria or consultation fees: Merck, Sharp & Dohme, Bayer, Amgen. Participation in a company sponsored speakers bureau: None. Stock shareholder: None. Spouse/partner: None. Other support (please specify): None. Signature: Date: February 7, 2022. William Oh. AFFILIATION: Chief Medical Officer at Sema4 and Clinical Professor of Medicine, Div. of Hematology/Medical Oncology at Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Receipt of honoraria or consultation fees: GSK, Janssen, Merck, Pfizer. Participation in a company sponsored speakers bureau: Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 7, 2022. Himisha Beltran. AFFILIATION: Dana Farber Cancer Institute. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Janssen, AbbVie/Stemcentrx, Eli Lilly, Millennium Pharmaceuticals, Bristol Myers Squibb. Receipt of honoraria or consultation fees: Janssen, Astellas, Astra Zeneca, Merck, Pfizer, Foundation Medicine, Blue Earth Diagnostics, Amgen, Oncorus, LOXO. Participation in a company sponsored speaker’s bureau: NONE. Stock shareholder: NONE. Spouse/partner: NONE. Other support (please specify): Signature: Date: Feb 7, 2022. Pirkko-Liisa Kellokumpu-Lehtinen. AFFILIATION: Tampere University and Tampere University Hospital, Tampere, Finland. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Only directly to my hospital; Lilly, Merck and Finnish Cancer Society. Receipt of honoraria or consultation fees: BMS, Merck. Participation in a company sponsored speaker’s bureau: NONE. Stock shareholder: NONE. Spouse/partner: NONE. Other support (please specify):reimbursement of expenses to attend conference; Sanofi. Signature: Date: Feb 7, 2022. Prof. Mark A. Rubin, MD. AFFILIATION: University of Bern, Department for BioMedical Research (DBMR). Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Janssen, Roche, Novartis. Receipt of honoraria or consultation fees: NeoGenomics Labs. Participation in a company sponsored speaker’s bureau: Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: Feb 8, 2022. Prof. Dr. Thomas Steuber. AFFILIATION: Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: NONE. Receipt of honoraria or consultation fees: Astellas, Amgen, Bayer, Janssen, ProteoMedix, Sanofi, Merck, Astra Zeneca. Participation in a company sponsored speaker’s bureau: Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: Feb 8, 2022. Prof. Rob Bristow. AFFILIATION: University of Manchester. I have no potential conflict of interest to report. IGNACIO DURAN. AFFILIATION: HOSPITAL UNIVERSITARIO MARQUES DE VALDECILLA. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Roche and Astra-Zeneca. Receipt of honoraria or consultation fees: Bristol Myers Squibb, MSD, Ipsen, Roche- Genentech, Janssen, Astellas Pharma, EUSA Pharma, Bayer, Novartis. Participation in a company sponsored speaker’s bureau: Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 8th 2022. FERNANDO MALUF. AFFILIATION: ONCOLOGIST. I have no potential conflict of interest to report. Signature: Date: February 8th 2022. Hiroyoshi Suzuki. AFFILIATION: Department of Urology, Toho University Sakura Medical Center. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Takeda, AsahiKasei, Taiho, Ono, Chugai, Sanofi, Daiichi-Sankyo, Nihon, Nippon Shinyaku. Receipt of honoraria or consultation fees: Bayer, Janssen, AstraZeneca, Astellas, Chuga-Roche, MSD. Participation in a company sponsored speaker’s bureau:Takeda, Bayer, Janssen, AstraZeneca, Astellas, Sanofi. Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 8th 2022. Danny M. Rabah. AFFILIATION: King Saud University and king Faisal specialist hospital and research centre. I have no potential conflict of interest to report. Signature: Date: February 8th 2022. LEVENT TÜRKERİ. AFFILIATION: ACIBADEM M.A. AYDINLAR UNIVERSITY, ISTANBUL, TURKEY. I have no potential conflict of interest to report. Signature: Date: February 8th 2022. Mark Frydenberg. AFFILIATION: ACIBADEM M.A. AYDINLAR UNIVERSITY, ISTANBUL, TURKEY. I have no potential conflict of interest to report. Signature: Date: February 8th 2022. Anders Bjartell. AFFILIATION: Dept. Of Urology, Skane University Hospital Malmö, Sweden. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Ferring, Bayer, Astellas. Receipt of honoraria or consultation fees: Astellas, AstraZeneca, Bayer, Janssen, Merck, Recordati, Sandoz. Participation in a company sponsored speaker’s bureau:Astellas, Bayer, IPSEN, Janssen, Recordati, Sandoz. Stock shareholder: LIDDS Pharma, Glactone Pharma, WntResearch. Spouse/partner: NONE. Other support (please specify): Signature: Date: February 9th 2022. Dingwei Ye. AFFILIATION: Fudan University Shanghai Cancer Center. I have no potential conflict of interest to report. Signature: Date: February 9th 2022. Ros Eeles. AFFILIATION: ………………………………………. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: GU-ASCO, The Royal Marsden NHS Foundation Trust, University of Chicago, ESMO, AstraZeneca UK Limited. Receipt of honoraria or consultation fees: Honorarium as speaker. Participation in a company sponsored speaker’s bureau: Stock shareholder: Spouse/partner: Other support (please specify): January 2016. Signature: Date: February 15th 2022. Inge van Oort. AFFILIATION: Urology, Radboudumc, Nijmegen, The Netherlands. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Astellas, Bayer, Janssen. Receipt of honoraria or consultation fees: Astellas, Bayer, MSD-Astra Zeneca, Janssen. Participation in a company sponsored speaker’s bureau: Bayer, Astellas. Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 22nd 2022. Ravindran Kanesvaran. AFFILIATION: Urology, Radboudumc, Nijmegen, The Netherlands. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Sanofi, Eisai. Receipt of honoraria or consultation fees: MSD, BMS, AstraZeneca, Amgen, Astellas, Johnson&Johnson, Novartis, Merck, Pfizer. Participation in a company sponsored speaker’s bureau:MSD, BMS, AstraZeneca, Amgen, Astellas, Johnson&Johnson, Novartis, Merck, Pfizer. Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 22nd 2022. Signature: Date: February 9th 2022. Nicola Fossati. AFFILIATION: Urology, Ente Ospedaliero Cantonale (EOC), Lugano, CH. I have no potential conflict of interest to report. Signature: Date: February 1st March 2022. Hiroji Uemura. AFFILIATION: Department of Urology and Renal Transplantation, Yokohama City University Medical Center. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: none. Receipt of honoraria or consultation fees: Bayer, Janssen, Sanofi, Takeda, Astellas, AstraZeneca, Amgen, Dai-ichi Sankyo, Pfizer, MSD, Chugai. Participation in a company sponsored speaker’s bureau:none. Stock shareholder: none. Spouse/partner: none. Other support (please specify): none. Signature: Date: March 7th 2022. Lisa Horvath. AFFILIATION: Chris O′Brien Lifehouse. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Astellas. Receipt of honoraria or consultation fees: Astellas, Janssen, Bayer, Imagion Biosystems. Participation in a company sponsored speaker’s bureau:Astellas, Janssen, Bayer. Stock shareholder: Imagion Biosystems. Spouse/partner: Connected Medicine Solutions (Employee, stocks). Other support (please specify): none. Signature: Date: March 9th 2022. Robert Reiter. AFFILIATION: UCLA Urology. X I have no potential conflict of interest to report. Signature: Date: March 11th 2022. Daniel Castellano. AFFILIATION: MEDICAL ONCOLOGIST HEAD GU UNIT HOSPITAL UNIVERSITARIO 12 DE OCTUBRE. MADRID-UNIVERSIDAD COMPLUTENSE. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: JANSSEN. Receipt of honoraria or consultation fees:ASTELLAS, ROCHE, MERCK, PFIZER, NOVARTIS, MSD, BMS, IPSEN, GILEAD, JANSSEN, BAYER. Participation in a company sponsored speaker’s bureau:none. Stock shareholder: none. Spouse/partner: none. Other support (please specify): none. Signature: 28th March 2022. Sandy Srinivas. AFFILIATION: Stanford University, CA. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:BAYER, JANSSEN, MERCK, NOVARTIS. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31ST March 2022. Matthew Sydes. AFFILIATION: MRC Clinical Trials Unit at UCL. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:ASTELLAS, CLOVIS ONCOLOGY, JANSSEN, NOVARTIS, PFIZER, SANOFI AVENTIS. Receipt of honoraria or consultation fees:ELI LILLY, JANSSEN. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 3Oth March 2022. Ekeke, Onyanunam Ngozi. AFFILIATION: DEPARTMENT OF SURGERY, UNIVERSITY OF PORT HARCOURT TEACHING HOSPITAL, PORT HARCOUT, NIGERIA. X I have no potential conflict of interest to report. Signature: Date: March 30 h 2022. Susan Halabi, PhD. AFFILIATION: Duke University. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:ASCO TAPUR, Astellas. Receipt of honoraria or consultation fees:Sanofi, Aveo Oncology. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 3Oth March 2022. Cora N. Sternberg, MD, FACP. AFFILIATION: Eeill Cornell Medicine, New York Presbyterian. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Astellas Pharma, Astrazeneca, Bayer, Genzyme, Gilead, Incyte, Medscape, Janssen, Bristol Myers Squibb, Merck, Msd, Pfizer, Roche, Impact Pharma, Sanofi-Genzyme, Urotoday, Cco Clinical, Nci. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 3Oth March 2022. Hirotsugu Uemura. AFFILIATION:. Kindai University Faculty of Medicine. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:AstraZeneca, Janssen, Takeda, Astellas, Sanofi, Taiho, Ono pharm, Kissei. Receipt of honoraria or consultation fees:Bayer, Sanofi, Janssen, MSD, Ono, BMS, Pfizer. Participation in a company sponsored speaker’s bureau:Bayer, Sanofi, Janssen, MSD, Ono, BMS, Pfizer. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Orazio Caffo. AFFILIATION: Santa Chiara Hospital – Trento (Italy). Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:AAA, Astella, Bayer, Janssen, MSD, Pfizer. Participation in a company sponsored speaker’s bureau:Astellas, Bayer, Janssen, Ipsen, MSD. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Valérie Fonteyne. AFFILIATION:Ghent University Hospital. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Ipsen. Receipt of honoraria or consultation fees:Ipsen, Astellas, Janssen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Muhammad Bulbul. AFFILIATION: American University of Beirut. X I have no potential conflict of interest to report. Signature: Date: March 31st 2022. Claire Vale. AFFILIATION: MRC Clinical Trials Unit at UCL. X I have no potential conflict of interest to report. Signature: Date: March 31st 2022. MRABTI Hind. AFFILIATION: Institut National d′oncologie, Mohamed V University. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Astellas, Sanofi, Janssen, AstraZeneca, Ipsen, MSD, Pfizer, Amgen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Deborah Mukherji. AFFILIATION: American University of Beirut. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Astellas. Receipt of honoraria or consultation fees:Astellas, Janssen, MSD, Ipsen, BMS. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Sloan Kettering Cancer Center. AIQ Pharma. Epic Sciences. Janssen. Menarini Silicon Biosystems. ThermoFisher. Howard I. Scher, MD, FASCO. AFFILIATION: Memorial Sloan Kettering Cancer Center. Howard I. Scher, MD, FASCO - Disclosure Form. March 31, 2022. Honoraria. Sidney Kimmel Cancer Center, Jefferson Health. Elsevier, LTD. Arsenal Capital. Consultancy/Advisory Board. Ambry Genetics Corporation, Konica Minolta,Inc. Amgen. Bayer. Janssen Research & Development, LLC. Pfizer Inc. Sun Pharmaceuticals Industries, Inc. WCG Oncology. Research Funding to Memorial Sloan Kettering Cancer Center. AIQ Pharma. Epic Sciences. Janssen. Menarini Silicon Biosystems. ThermoFisher. Evan Y. Yu, M.D. AFFILIATION: Fred Hutchinson Cancer Center and University of Washington. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Bayer, Blue Earth, Daiichi-Sankyo, Dendreon, Lantheus, Merck, Seagen. Receipt of honoraria or consultation fees:Abbvie, Advanced Accelerator Applications, Bayer, Clovis, Exelixis, Janssen, Merck, Sanofi. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Gedske Daugaard. AFFILIATION: Rigshospitalet, Copenhagen. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Bayer, Sanofi, Astellas, MSD, Bristol Myers. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 30th March 2022. Celestia S. Higano, MD, FACP. AFFILIATION: University of Columbia. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:None last 24 months. Receipt of honoraria or consultation fees:AstraZeneca, Astellas, Genentech, Merck Sharp & Dohme, Myovant, Tolmar, Vaccitech, Verity. Participation in a company sponsored speaker’s bureau:none. Stock shareholder: CTI Biopharma. Spouse/partner: none. Other support (please specify): Expert testimony, Ferring. Signature: 31st March 2022. Dr. Vedang Murthy. AFFILIATION: Radiotion Oncology. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Varian Medical Systems. Receipt of honoraria or consultation fees:. Participation in a company sponsored speaker’s bureau: Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 1st April 2022. Gero Kramer. AFFILIATION: Department of Urology, Medical University of Vienna. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:None. Receipt of honoraria or consultation fees:Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen, MSD, Novartis, Sanofi Genzyme, Takeda, Ferring. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Niven Mehra. AFFILIATION: Radboudumc. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Astellas, Astrazeneca, BMS. Receipt of honoraria or consultation fees:Astellas, Astrazeneca, Bayer, Janssen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 1st April 2022. Juan Pablo Sade. AFFILIATION: Instituto Alexnder Fleming, Buenos Aires, Argentina. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Janssen, Astellas, AtraZeneca, MSD, BMS. Receipt of honoraria or consultation fees:Janssen, Bayer, Pfizer, Astellas. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 3rd April 2022. Dr Maria De Santis. AFFILIATION: Charité Universitätsmedizin Berlin, Department of Urology. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:AAA, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, BMS, EISAI, Ferring, Immunomedics, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, SeaGen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 1st April 2022. Iwona Skoneczna. AFFILIATION: Maria Sklodowska-Curie National Research Institute of Oncology, Szpital Grochowski, Warsaw, Poland. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Astellas, Bayer, BMS, Janssen, Roche. Receipt of honoraria or consultation fees:Astellas, Bayer, Janssen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 1st April 2022. Laurence Klotz. AFFILIATION: University of Toronto. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:miR Scientific, Exact Imaging. Receipt of honoraria or consultation fees:miR Scientific, Antev. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 30th March 2022. Yüksel Ürün. AFFILIATION: Ankara University School of Medicine. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Astellas, AtraZeneca, BMS, Janssen Oncology, MSD, Pfizer, Roche. Participation in a company sponsored speaker’s bureau:Astellas, Amgen, AtraZeneca, BMS, Janssen Oncology, Pfizer, Roche. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 01st April 2022. Howard R. Soule. AFFILIATION: Prostate Cancer Foundation. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Compugen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 4th April 2022. Simon Chowdhury. AFFILIATION:. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Janssen Oncology, Beigene, Clovis Oncology, Pfizer,. Receipt of honoraria or consultation fees:. Participation in a company sponsored speaker’s bureau:Janssen Oncology, AstraZeneca, Bayer, Pfizer, Sandoz. Stock shareholder:. Spouse/partner:. Other support (please specify): Janssen Oncology (Advisory board). Novartis (advisory board, consultancy). Bayer (Advisory board). Astellas (advisory board, consultancy). Athenex (advisory board). Beigene (advisory board). Clovis Oncology (Advisory board). Telix (advisory board, consultancy). Curve.Life (founder and stock). Huma (consulting fees and Stock). Remedy Bio: consulting fees, Stock. Signature: 4th April 2022. Daniel Heinrich. AFFILIATION: Innlandet Hospital, Department of Oncology and Radiotherapy, Gjøvik, Norway. X I have no potential conflict of interest to report. Signature: Date: 28th February 2022. Raya Leibowitz. AFFILIATION: Shamir Medical Center, Zerifin, Be’er Yaakov, Israel. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:MSD, BMS, Isotopia, Bayer, AstraZeneca, Astellas, Janssen, Pfizer. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 05th April 2022. Raja Khauli. AFFILIATION: American University of Beirut Medical Ctr Clinical. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify): honoraria: Astellas, Janssen, Algorithm SAL. Signature: 06th April 2022. Axel Merseburger. AFFILIATION: Campus Lübeck, University Hospital Schleswig-Holstein. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Lectures/Speaker/Honoraria:. Astra Zeneca, Bristol-Myers Squibb, Eisai, Ferring, Ipsen, MSD, Merck Serono, Janssen, Takeda, TEVA, Astellas, Novartis, Pfizer, Recordati and Roche. Consultant:. AstraZeneca, Astellas, Bristol-Myers Squibb, Ferring, Ipsen, Janssen, EUSAPharm, MSD, Merck Serono, Novartis, Takeda, Teva, Pfizer, Recordati and Roche. Research and clinical trials:. AstraZeneca, Astellas, Bristol-Myers Squibb, Ipsen, Janssen, EUSAPharm, MSD, Merck Serono, Novartis, Takeda, Teva, Pfizer und Roche. Signature: 06th April 2022. Carmel Pezaro. AFFILIATION: Sheffield Teaching Hospitals NHS Foundation Trust. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Janssen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify): Bayer, Ipsen (travel support). Signature: 06th April 2022. All remaining authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Published: 2023
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27. A polygenic two-hit hypothesis for prostate cancer.

Author: Houlahan KE, Livingstone J, Fox NS, Kurganovs N, Zhu H, Sietsma Penington J, Jung CH, Yamaguchi TN, Heisler LE, Jovelin R, Costello AJ, Pope BJ, Kishan AU, Corcoran NM, Bristow RG, Waszak SM, Weischenfeldt J, He HH, Hung RJ, Hovens CM, and Boutros PC
Subjects: Male, Humans, Risk Factors, Prognosis, Genetic Predisposition to Disease, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
Abstract: Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic "two-hit" model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Published: 2023
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28. Systemic treatment of metastatic hormone-sensitive prostate cancer-upfront triplet versus doublet combination therapy.

Author: Oing C and Bristow RG
Subjects: Male, Humans, Docetaxel, Hormones, Prostatic Neoplasms drug therapy
Abstract: Competing Interests: Disclosure CO: advisory role: secondment as clinical advisor to Astex Pharmaceuticals; speaker’s honoraria and/or advisory board participation: AstraZeneca, Ipsen, Roche, Sandoz; research funding: PharmaMar (non-financial), all outside the submitted work. RGB has declared no conflicts of interest.
Published: 2023
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29. 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 S, Bossi A, Davis ID, de Bono J, Fizazi K, James ND, Mottet N, Shore N, Small E, Smith M, Sweeney C, Tombal B, Antonarakis ES, Aparicio AM, Armstrong AJ, Attard G, Beer TM, Beltran H, Bjartell A, Blanchard P, Briganti A, Bristow RG, Bulbul M, Caffo O, Castellano D, Castro E, Cheng HH, Chi KN, Chowdhury S, Clarke CS, Clarke N, Daugaard G, De Santis M, Duran I, Eeles R, Efstathiou E, Efstathiou J, Ngozi Ekeke O, Evans CP, Fanti S, Feng FY, Fonteyne V, Fossati N, Frydenberg M, George D, Gleave M, Gravis G, Halabi S, Heinrich D, Herrmann K, Higano C, Hofman MS, Horvath LG, Hussain M, Jereczek-Fossa BA, Jones R, Kanesvaran R, Kellokumpu-Lehtinen PL, Khauli RB, Klotz L, Kramer G, Leibowitz R, Logothetis CJ, Mahal BA, Maluf F, Mateo J, Matheson D, Mehra N, Merseburger A, Morgans AK, Morris MJ, Mrabti H, Mukherji D, Murphy DG, Murthy V, Nguyen PL, Oh WK, Ost P, O'Sullivan JM, Padhani AR, Pezaro C, Poon DMC, Pritchard CC, Rabah DM, Rathkopf D, Reiter RE, Rubin MA, Ryan CJ, Saad F, Pablo Sade J, Sartor OA, Scher HI, Sharifi N, Skoneczna I, Soule H, Spratt DE, Srinivas S, Sternberg CN, Steuber T, Suzuki H, Sydes MR, Taplin ME, Tilki D, Türkeri L, Turco F, Uemura H, Uemura H, Ürün Y, Vale CL, van Oort I, Vapiwala N, Walz J, Yamoah K, Ye D, Yu EY, Zapatero A, Zilli T, and Omlin A
Subjects: Humans, Male, Neoplasm Recurrence, Local, Prostatic Neoplasms drug therapy, Prostatic Neoplasms diagnosis, Prostatic Neoplasms, Castration-Resistant pathology
Abstract: Background: Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management., Objective: To present consensus voting results for select questions from APCCC 2022., Design, Setting, and Participants: Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members ("panellists") who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1-3., Outcome Measurements and Statistical Analysis: Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement., Results and Limitations: The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis., Conclusions: These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials., Patient Summary: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)
Published: 2023
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30. Author Correction: Divergent mutational processes distinguish hypoxic and normoxic tumours.

Author: Bhandari V, Li CH, Bristow RG, and Boutros PC
Published: 2022
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31. Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment: A Pan Prostate Cancer Group Study.

Author: Burns D, Anokian E, Saunders EJ, Bristow RG, Fraser M, Reimand J, Schlomm T, Sauter G, Brors B, Korbel J, Weischenfeldt J, Waszak SM, Corcoran NM, Jung CH, Pope BJ, Hovens CM, Cancel-Tassin G, Cussenot O, Loda M, Sander C, Hayes VM, Dalsgaard Sorensen K, Lu YJ, Hamdy FC, Foster CS, Gnanapragasam V, Butler A, Lynch AG, Massie CE, Woodcock DJ, Cooper CS, Wedge DC, Brewer DS, Kote-Jarai Z, and Eeles RA
Subjects: Germ Cells, Germ-Line Mutation, Humans, Male, Neoplasm Recurrence, Local genetics, Prostatectomy, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins p21(ras) genetics, TOR Serine-Threonine Kinases, Phosphatidylinositol 3-Kinases genetics, Prostatic Neoplasms surgery, Prostatic Neoplasms therapy
Abstract: Background: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression., Objective: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa and understand the genetic factors associated with such progression., Design, Setting, and Participants: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG) consortium from the UK, Canada, Germany, Australia, and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA) dataset., Outcome Measurements and Statistical Analysis: A total of 15,822 rare (MAF <1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene sets. Models were tested for robustness using bootstrap resampling., Results and Limitations: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in "Hallmark" gene sets were consistently associated with altered time to BCR. Three gene sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response, and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher-grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB, and Hypoxia, the latter of which was validated in the independent TCGA dataset., Conclusions: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management., Patient Summary: Prostate cancer patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify patients who might need additional treatments earlier., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)
Published: 2022
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32. Management of Patients with Advanced Prostate Cancer: Report from the Advanced Prostate Cancer Consensus Conference 2021.

Author: Gillessen S, Armstrong A, Attard G, Beer TM, Beltran H, Bjartell A, Bossi A, Briganti A, Bristow RG, Bulbul M, Caffo O, Chi KN, Clarke CS, Clarke N, Davis ID, de Bono JS, Duran I, Eeles R, Efstathiou E, Efstathiou J, Ekeke ON, Evans CP, Fanti S, Feng FY, Fizazi K, Frydenberg M, George D, Gleave M, Halabi S, Heinrich D, Higano C, Hofman MS, Hussain M, James N, Jones R, Kanesvaran R, Khauli RB, Klotz L, Leibowitz R, Logothetis C, Maluf F, Millman R, Morgans AK, Morris MJ, Mottet N, Mrabti H, Murphy DG, Murthy V, Oh WK, Ost P, O'Sullivan JM, Padhani AR, Parker C, Poon DMC, Pritchard CC, Rabah DM, Rathkopf D, Reiter RE, Rubin M, Ryan CJ, Saad F, Sade JP, Sartor O, Scher HI, Shore N, Skoneczna I, Small E, Smith M, Soule H, Spratt DE, Sternberg CN, Suzuki H, Sweeney C, Sydes MR, Taplin ME, Tilki D, Tombal B, Türkeri L, Uemura H, Uemura H, van Oort I, Yamoah K, Ye D, Zapatero A, and Omlin A
Subjects: Consensus, Humans, Male, Prostatic Neoplasms diagnosis, Prostatic Neoplasms pathology, Prostatic Neoplasms therapy
Abstract: Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence., Objective: To present the voting results from APCCC 2021., Design, Setting, and Participants: The experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions., Outcome Measurements and Statistical Analysis: The panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process., Results and Limitations: The voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material., Conclusions: These voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical evidence and logistic and economic constraints. Enrolment in clinical trials should be strongly encouraged. Importantly, APCCC 2021 once again identified salient questions that merit evaluation in specifically designed trials., Patient Summary: The Advanced Prostate Cancer Consensus Conference is a forum for discussing current diagnosis and treatment options for patients with advanced prostate cancer. An expert panel votes on predefined questions focused on the most clinically relevant areas for treatment of advanced prostate cancer for which there are gaps in knowledge. The voting results provide a practical guide to help clinicians in discussing treatment options with patients as part of shared decision-making., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)
Published: 2022
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33. What Experts Think About Prostate Cancer Management During the COVID-19 Pandemic: Report from the Advanced Prostate Cancer Consensus Conference 2021.

Author: Turco F, Armstrong A, Attard G, Beer TM, Beltran H, Bjartell A, Bossi A, Briganti A, Bristow RG, Bulbul M, Caffo O, Chi KN, Clarke C, Clarke N, Davis ID, de Bono J, Duran I, Eeles R, Efstathiou E, Efstathiou J, Evans CP, Fanti S, Feng FY, Fizazi K, Frydenberg M, George D, Gleave M, Halabi S, Heinrich D, Higano C, Hofman MS, Hussain M, James N, Jones R, Kanesvaran R, Khauli RB, Klotz L, Leibowitz R, Logothetis C, Maluf F, Millman R, Morgans AK, Morris MJ, Mottet N, Mrabti H, Murphy DG, Murthy V, Oh WK, Ekeke Onyeanunam N, Ost P, O'Sullivan JM, Padhani AR, Parker C, Poon DMC, Pritchard CC, Rabah DM, Rathkopf D, Reiter RE, Rubin M, Ryan CJ, Saad F, Pablo Sade J, Sartor O, Scher HI, Shore N, Skoneczna I, Small E, Smith M, Soule H, Spratt D, Sternberg CN, Suzuki H, Sweeney C, Sydes M, Taplin ME, Tilki D, Tombal B, Türkeri L, Uemura H, Uemura H, van Oort I, Yamoah K, Ye D, Zapatero A, Gillessen S, and Omlin A
Subjects: Androgen Antagonists therapeutic use, COVID-19 Vaccines, Humans, Male, Pandemics prevention & control, COVID-19, Prostatic Neoplasms pathology
Abstract: Patients with advanced prostate cancer (APC) may be at greater risk for severe illness, hospitalisation, or death from coronavirus disease 2019 (COVID-19) due to male gender, older age, potential immunosuppressive treatments, or comorbidities. Thus, the optimal management of APC patients during the COVID-19 pandemic is complex. In October 2021, during the Advanced Prostate Cancer Consensus Conference (APCCC) 2021, the 73 voting members of the panel members discussed and voted on 13 questions on this topic that could help clinicians make treatment choices during the pandemic. There was a consensus for full COVID-19 vaccination and booster injection in APC patients. Furthermore, the voting results indicate that the expert's treatment recommendations are influenced by the vaccination status: the COVID-19 pandemic altered management of APC patients for 70% of the panellists before the vaccination was available but only for 25% of panellists for fully vaccinated patients. Most experts (71%) were less likely to use docetaxel and abiraterone in unvaccinated patients with metastatic hormone-sensitive prostate cancer. For fully vaccinated patients with high-risk localised prostate cancer, there was a consensus (77%) to follow the usual treatment schedule, whereas in unvaccinated patients, 55% of the panel members voted for deferring radiation therapy. Finally, there was a strong consensus for the use of telemedicine for monitoring APC patients. PATIENT SUMMARY: In the Advanced Prostate Cancer Consensus Conference 2021, the panellists reached a consensus regarding the recommendation of the COVID-19 vaccine in prostate cancer patients and use of telemedicine for monitoring these patients., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
Published: 2022
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34. Corrigendum to "What Experts Think About Prostate Cancer Management During the COVID-19 Pandemic: Report from the Advanced Prostate Cancer Consensus Conference 2021" [Eur Urol 82(1):6-11].

Author: Turco F, Armstrong A, Attard G, Beer TM, Beltran H, Bjartell A, Bossi A, Briganti A, Bristow RG, Bulbul M, Caffo O, Chi KN, Clarke C, Clarke N, Davis ID, de Bono J, Duran I, Eeles R, Efstathiou E, Efstathiou J, Evans CP, Fanti S, Feng FY, Fizazi K, Frydenberg M, George D, Gleave M, Halabi S, Heinrich D, Higano C, Hofman MS, Hussain M, James N, Jones R, Kanesvaran R, Khauli RB, Klotz L, Leibowitz R, Logothetis C, Maluf F, Millman R, Morgans AK, Morris MJ, Mottet N, Mrabti H, Murphy DG, Murthy V, Oh WK, Ekeke ON, Ost P, O'Sullivan JM, Padhani AR, Parker C, Poon DMC, Pritchard CC, Rabah DM, Rathkopf D, Reiter RE, Rubin M, Ryan CJ, Saad F, Sade JP, Sartor O, Scher HI, Shore N, Skoneczna I, Small E, Smith M, Soule H, Spratt D, Sternberg CN, Suzuki H, Sweeney C, Sydes M, Taplin ME, Tilki D, Tombal B, Türkeri L, Uemura H, Uemura H, van Oort I, Yamoah K, Ye D, Zapatero A, Gillessen S, and Omlin A
Published: 2022
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35. RadBone: bone toxicity following pelvic radiotherapy - a prospective randomised controlled feasibility study evaluating a musculoskeletal health package in women with gynaecological cancers undergoing pelvic radiotherapy.

Author: Chatzimavridou Grigoriadou V, Barraclough LH, Baricevic-Jones I, Bristow RG, Eden M, Haslett K, Johnson K, Kochhar R, Merchant Z, Moore J, O'Connell S, Taylor S, Westwood T, Whetton AD, Yorke J, and Higham CE
Subjects: Diphosphonates, Feasibility Studies, Female, Humans, Prospective Studies, Research Design, Genital Neoplasms, Female radiotherapy
Abstract: Introduction: Patients receiving radiotherapy are at risk of developing radiotherapy-related insufficiency fractures, which are associated with increased morbidity and pose a significant burden to patients' quality of life and to the health system. Therefore, effective preventive techniques are urgently required. The RadBone randomised controlled trial (RCT) aims to determine the feasibility and acceptability of a musculoskeletal health package (MHP) intervention in women undergoing pelvic radiotherapy for gynaecological malignancies and to preliminary explore clinical effectiveness of the intervention., Methods and Analysis: The RadBone RCT will evaluate the addition to standard care of an MHP consisting of a physical assessment of the musculoskeletal health, a 3-month prehabilitation personalised exercise package, as well as an evaluation of the fracture risk and if required the prescription of appropriate bone treatment including calcium, vitamin D and-for high-risk individuals-bisphosphonates. Forty participants will be randomised in each group (MHP or observation) and will be followed for 18 months. The primary outcome of this RCT will be feasibility, including the eligibility, screening and recruitment rate, intervention fidelity and attrition rates; acceptability and health economics. Clinical effectiveness and bone turnover markers will be evaluated as secondary outcomes., Ethics and Dissemination: This study has been approved by the Greater Manchester East Research Ethics Committee (Reference: 20/NW/0410, November 2020). The results will be published in peer-reviewed journals, will be presented in national and international conferences and will be communicated to relevant stakeholders. Moreover, a plain English report will be shared with the study participants, patients' organisations and media., Trial Registration Number: NCT04555317., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
Published: 2022
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36. Determining the Impact of Spatial Heterogeneity on Genomic Prognostic Biomarkers for Localized Prostate Cancer.

Author: Brastianos HC, Murgic J, Salcedo A, Chua MLK, Meng A, Fraser M, Brundage M, Fleshner NE, van der Kwast T, Bristow RG, Boutros PC, and Berlin A
Subjects: DNA, Genomics, Humans, Male, Prognosis, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Prostatic Neoplasms pathology
Abstract: Localized prostate tumors show remarkably diverse clinical courses, with some being cured by local therapy alone, while others rapidly relapse and have a lethal course despite precision surgery or radiotherapy. Many genomic biomarkers have been developed to predict this clinical behavior, but these are confounded by the extreme spatial heterogeneity of prostate tumors: most are multifocal and harbor multiple subclonal populations. To quantify the influence of spatial heterogeneity on genomic prognostic biomarkers, we developed a case-control high-risk cohort (n = 42) using a prospective registry, risk matched by clinicopathologic prognostic indices. Half of the cohort had early biochemical recurrence (BCR; ie, ≤18 mo), while half remained without evidence of disease for at least 48 mo after radical prostatectomy. We then genomically profiled multiple tumor foci per patient, analyzing 119 total specimens. These data allowed us to validate three published genomic prognostic biomarkers and quantify their sensitivity to tumor spatial heterogeneity. Remarkably, all three biomarkers robustly predicted early BCR, and all three were robust to spatiogenomic variability. These data suggest that DNA-based genomic biomarkers can overcome intratumoral heterogeneity: single biopsies may be sufficient to estimate the risk of early BCR after radical treatment in patients with high-risk disease. PATIENT SUMMARY: We investigated whether heterogeneity between tumor regions within the prostate affects the accuracy of DNA-based biomarkers predicting early relapse after prostatectomy. We observed persistent accuracy in predicting disease relapse, suggesting that spatial heterogeneity may not hinder biomarker performance., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
Published: 2022
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37. Redox-responsive nanoparticles enhance radiation therapy by altering multifaceted radio-resistance mechanisms in human castration-resistant prostate cancer cells and xenografts.

Author: Lip H, Amini MA, Zetrini A, Cai P, Abbasi AZ, Bristow RG, Rauth AM, and Wu XY
Subjects: Animals, Cell Line, Tumor, Heterografts, Humans, Hypoxia, Male, Mice, Mice, SCID, Oxidation-Reduction, Tumor Microenvironment, Nanoparticles, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant metabolism, Prostatic Neoplasms, Castration-Resistant radiotherapy
Abstract: Introduction: Radiation therapy (RT) is a major modality for the treatment of prostate cancer (PCa), especially castration-resistant PCa (CRPC). However, hypoxia, often seen in PCa tumors, leads to radiation-resistance. This work investigates the effect of a novel oxygen-generating polymer-lipid manganese dioxide nanoparticle (PLMDs) on improving RT outcomes in CRPC xenograft models by modulating the tumor microenvironment (TME) both before and after RT., Materials and Methods: Human PC3 and DU145 PCa cells were used to investigate clonogenic inhibition and DNA repair pathways in vitro. Tumor hypoxia and post-RT angiogenesis were evaluated in a PC3-bearing SCID mouse model. PC3 and DU145 xenografts were used to study the efficacy of PLMD in combination with single or fractionated RT., Results: PLMD plus RT significantly inhibited clonogenic potential, increased DNA double-strand breaks, and reduced DNA damage repair in hypoxic PC3 and DU145 cells as compared to RT alone. PLMD significantly reduced hypoxia-positive areas, hypoxia induced factor 1α (HIF-1α) expression, and protein carbonyl levels (a measure of oxidative stress). Application of PLMD with RT decreased RT-induced angiogenic biomarkers by up to 3-fold. Treatment of the human CRPC xenografts with PLMD plus RT (single or fractionated doses) significantly prolonged median survival of the host compared to RT alone resulting in up to a 40% curative rate., Conclusion: PLMD treatment modulated TME and sensitized hypoxic human CRPC cells to RT thus enhancing the efficacy of RT. These results confirmed the potential of PLMD as an adjuvant to RT for the treatment of hypoxic CRPC., (Copyright © 2022 Elsevier B.V. All rights reserved.)
Published: 2022
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38. Conversations with LGBT+ scientists about visibility, leadership and climbing the career ladder.

Author: Bristow RG, Engel J, Jayasinghe I, Kampmann M, James Sansom O, and Bryant DM
Subjects: Career Mobility, Communication, Humans, Leadership, Sexual and Gender Minorities
Abstract: February is LGBT+ history month, and to celebrate, Journal of Cell Science Editorial Advisory Board member David Bryant organised a conversation with a selection of scientists to explore their experiences of being LGBT+ in academia., (© 2022. Published by The Company of Biologists Ltd.)
Published: 2022
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39. Prostate zones and cancer: lost in transition?

Author: Ali A, Du Feu A, Oliveira P, Choudhury A, Bristow RG, and Baena E
Subjects: Biomarkers, Tumor blood, Humans, Male, Organ Size, Prognosis, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Prostate pathology, Prostatic Neoplasms pathology
Abstract: Localized prostate cancer shows great clinical, genetic and environmental heterogeneity; however, prostate cancer treatment is currently guided solely by clinical staging, serum PSA levels and histology. Increasingly, the roles of differential genomics, multifocality and spatial distribution in tumorigenesis are being considered to further personalize treatment. The human prostate is divided into three zones based on its histological features: the peripheral zone (PZ), the transition zone (TZ) and the central zone (CZ). Each zone has variable prostate cancer incidence, prognosis and outcomes, with TZ prostate tumours having better clinical outcomes than PZ and CZ tumours. Molecular and cell biological studies can improve understanding of the unique molecular, genomic and zonal cell type features that underlie the differences in tumour progression and aggression between the zones. The unique biology of each zonal tumour type could help to guide individualized treatment and patient risk stratification., (© 2021. Springer Nature Limited.)
Published: 2022
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40. Subpathologies and genomic classifier for treatment individualization of post-prostatectomy radiotherapy.

Author: Ramotar M, Chua MLK, Truong H, Hosni A, Pintilie M, Davicioni E, Fleshner NE, Dicker AP, Bristow RG, He HH, van der Kwast T, Den RB, and Berlin A
Subjects: Adult, Aged, Cohort Studies, Combined Modality Therapy, Genome, Humans, Male, Middle Aged, Postoperative Period, Prognosis, Prostatic Neoplasms genetics, Prostatic Neoplasms surgery, Prostatectomy, Prostatic Neoplasms classification, Prostatic Neoplasms radiotherapy
Abstract: Purpose/objective: Risk-stratification for post-prostatectomy radiotherapy (PORT) using conventional clinicopathologic indexes leads to substantial over- and under-treatment. Better patient selection could spare unnecessary toxicities and improve outcomes. We investigated the prognostic utility of unfavorable subpathologies intraductal carcinoma and cribriform architecture (IDC/CA), and a 22-gene Decipher genomic classifier (GC) in prostate cancer (PCa) patients receiving PORT., Material/methods: A cohort of 302 men who received PORT at 2 academic institutions was pooled. PORT was predominately delivered as salvage (62% of cases); 20% received HT+PORT. Specimens were centrally reviewed for IDC/CA presence. In 104 cases, GC scores were determined. Endpoints were biochemical relapse-free (bRFR) and metastasis-free (mFR) rates., Results: After a median follow-up of 6.49-years, 135 (45%) and 40 (13%) men experienced biochemical relapse and metastasis, respectively. IDC/CA were identified in 160 (53%) of cases. Men harboring IDC/CA experienced inferior bRFR (HR 2.6, 95%CI 1.8-3.2, P<0.001) and mFR (HR 3.1, 95%CI 1.5-6.4, P = 0.0014). Patients with GC scores, 22 (21%) were stratified low-, 30 (29%) intermediate-, and 52 (50%) high-risk. GC low-risk was associated with superior bRFR (HR 0.25, 95%CI 0.1-0.5, P<0.001) and mFR (HR 0.15, 95%CI 0.03-0.8, P = 0.025). On multivariable analyses, IDC/CA and GC independently predicted for bRFR, corresponding to improved discrimination (C-index = 0.737 (95%CI 0.662-0.813))., Conclusions: IDC/CA subpathologies and GC predict for biochemical relapse and metastasis beyond conventional clinicopathologic indexes in the PORT setting. Patients harboring IDC/CA are at higher risk of relapse after maximal local therapies, thus warranting consideration for treatment intensification strategies. Conversely, for men with absence of IDC/CA and low GC scores, de-intensification strategies could be explored., Competing Interests: Conflict of interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)
Published: 2022
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41. Reorganization of the 3D Genome Pinpoints Noncoding Drivers of Primary Prostate Tumors.

Author: Hawley JR, Zhou S, Arlidge C, Grillo G, Kron KJ, Hugh-White R, van der Kwast TH, Fraser M, Boutros PC, Bristow RG, and Lupien M
Subjects: Carcinogenesis pathology, Gene Rearrangement, Humans, Male, Prostatic Neoplasms pathology, RNA-Seq, Carcinogenesis genetics, Chromatin genetics, Gene Expression Regulation, Neoplastic, Genome, Human, Genomic Instability, Prostatic Neoplasms genetics, RNA, Untranslated genetics
Abstract: Prostate cancer is a heterogeneous disease whose progression is linked to genome instability. However, the impact of this instability on the noncoding genome and its three-dimensional organization to aid progression is unclear. Using primary benign and tumor tissue, we find a high concordance in higher-order three-dimensional genome organization. This concordance argues for constraints to the topology of prostate tumor genomes. Nonetheless, we identified changes in focal chromatin interactions, typical of loops bridging noncoding cis -regulatory elements, and showed how structural variants can induce these changes to guide cis -regulatory element hijacking. Such events resulted in opposing differential expression of genes found at antipodes of rearrangements. Collectively, these results argue that changes to focal chromatin interactions, as opposed to higher-order genome organization, allow for aberrant gene regulation and are repeatedly mediated by structural variants in primary prostate cancer. SIGNIFICANCE: This work showcases how the noncoding genome can be hijacked by focal insults to its three-dimensional organization that contribute to prostate cancer oncogenesis., (©2021 American Association for Cancer Research.)
Published: 2021
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42. The telomere length landscape of prostate cancer.

Author: Livingstone J, Shiah YJ, Yamaguchi TN, Heisler LE, Huang V, Lesurf R, Gebo T, Carlin B, Eng S, Drysdale E, Green J, van der Kwast T, Bristow RG, Fraser M, and Boutros PC
Subjects: DNA Copy Number Variations, Epigenome, Gene Fusion, Genomics, Humans, Male, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Proteome, Telomerase genetics, Telomerase metabolism, Transcriptome, Prostatic Neoplasms genetics, Telomere genetics
Abstract: Replicative immortality is a hallmark of cancer, and can be achieved through telomere lengthening and maintenance. Although the role of telomere length in cancer has been well studied, its association to genomic features is less well known. Here, we report the telomere lengths of 392 localized prostate cancer tumours and characterize their relationship to genomic, transcriptomic and proteomic features. Shorter tumour telomere lengths are associated with elevated genomic instability, including single-nucleotide variants, indels and structural variants. Genes involved in cell proliferation and signaling are correlated with tumour telomere length at all levels of the central dogma. Telomere length is also associated with multiple clinical features of a tumour. Longer telomere lengths in non-tumour samples are associated with a lower rate of biochemical relapse. In summary, we describe the multi-level integration of telomere length, genomics, transcriptomics and proteomics in localized prostate cancer., (© 2021. The Author(s).)
Published: 2021
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43. Dimensional reduction based on peak fitting of Raman micro spectroscopy data improves detection of prostate cancer in tissue specimens.

Author: Plante A, Dallaire F, Grosset AA, Nguyen T, Birlea M, Wong J, Daoust F, Roy N, Kougioumoutzakis A, Azzi F, Aubertin K, Kadoury S, Latour M, Albadine R, Prendeville S, Boutros P, Fraser M, Bristow RG, van der Kwast T, Orain M, Brisson H, Benzerdjeb N, Hovington H, Bergeron A, Fradet Y, Têtu B, Saad F, Trudel D, and Leblond F
Subjects: Area Under Curve, Humans, Machine Learning, Male, Spectrum Analysis, Raman, Carcinoma, Intraductal, Noninfiltrating, Prostatic Neoplasms diagnostic imaging
Abstract: Significance: Prostate cancer is the most common cancer among men. An accurate diagnosis of its severity at detection plays a major role in improving their survival. Recently, machine learning models using biomarkers identified from Raman micro-spectroscopy discriminated intraductal carcinoma of the prostate (IDC-P) from cancer tissue with a ≥85 % detection accuracy and differentiated high-grade prostatic intraepithelial neoplasia (HGPIN) from IDC-P with a ≥97.8 % accuracy., Aim: To improve the classification performance of machine learning models identifying different types of prostate cancer tissue using a new dimensional reduction technique., Approach: A radial basis function (RBF) kernel support vector machine (SVM) model was trained on Raman spectra of prostate tissue from a 272-patient cohort (Centre hospitalier de l'Université de Montréal, CHUM) and tested on two independent cohorts of 76 patients [University Health Network (UHN)] and 135 patients (Centre hospitalier universitaire de Québec-Université Laval, CHUQc-UL). Two types of engineered features were used. Individual intensity features, i.e., Raman signal intensity measured at particular wavelengths and novel Raman spectra fitted peak features consisting of peak heights and widths., Results: Combining engineered features improved classification performance for the three aforementioned classification tasks. The improvements for IDC-P/cancer classification for the UHN and CHUQc-UL testing sets in accuracy, sensitivity, specificity, and area under the curve (AUC) are (numbers in parenthesis are associated with the CHUQc-UL testing set): +4 % (+8 % ), +7 % (+9 % ), +2 % (6%), +9 (+9) with respect to the current best models. Discrimination between HGPIN and IDC-P was also improved in both testing cohorts: +2.2 % (+1.7 % ), +4.5 % (+3.6 % ), +0 % (+0 % ), +2.3 (+0). While no global improvements were obtained for the normal versus cancer classification task [+0 % (-2 % ), +0 % (-3 % ), +2 % (-2 % ), +4 (+3)], the AUC was improved in both testing sets., Conclusions: Combining individual intensity features and novel Raman fitted peak features, improved the classification performance on two independent and multicenter testing sets in comparison to using only individual intensity features.
Published: 2021
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44. Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse.

Author: Fraser M, Livingstone J, Wrana JL, Finelli A, He HH, van der Kwast T, Zlotta AR, Bristow RG, and Boutros PC
Subjects: Cell Cycle genetics, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Gene Expression Regulation, Neoplastic, Humans, Male, Neoplasm Recurrence, Local genetics, Prevalence, Prognosis, Biomarkers, Tumor genetics, Mutation, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Ubiquitin-Protein Ligases genetics
Abstract: Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers. We analyze 1,844 localized (1,289) or mCRPC (555) tumors and quantify the prevalence of 113 somatic driver single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) in each state. One-third are significantly more prevalent in mCRPC than expected while a quarter are less prevalent. Mutations in AR and its enhancer are more prevalent in mCRPC, as are those in TP53, MYC, ZNRF3 and PRKDC. ZNRF3 loss is associated with decreased ZNRF3 mRNA abundance, WNT, cell cycle & PRC1/2 activity, and genomic instability. ZNRF3 loss, RNA downregulation and hypermethylation are prognostic of metastasis and overall survival, independent of clinical and pathologic indices. These data demonstrate a strategy for identifying biomarkers of localized cancer aggression, with ZNRF3 loss as a predictor of metastasis in prostate cancer., (© 2021. The Author(s).)
Published: 2021
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45. Prostate cancer.

Author: Sandhu S, Moore CM, Chiong E, Beltran H, Bristow RG, and Williams SG
Subjects: Humans, Magnetic Resonance Imaging, Male, Neoplasm Grading, Prostatic Neoplasms physiopathology, Androgen Antagonists therapeutic use, Disease Management, Genomics trends, Immunotherapy trends, Prostatic Neoplasms drug therapy
Abstract: The management of prostate cancer continues to evolve rapidly, with substantial advances being made in understanding the genomic landscape and biology underpinning both primary and metastatic prostate cancer. Similarly, the emergence of more sensitive imaging methods has improved diagnostic and staging accuracy and refined surveillance strategies. These advances have introduced personalised therapeutics to clinical practice, with treatments targeting genomic alterations in DNA repair pathways now clinically validated. An important shift in the therapeutic framework for metastatic disease has taken place, with metastatic-directed therapies being evaluated for oligometastatic disease, aggressive management of the primary lesion shown to benefit patients with low-volume metastatic disease, and with several novel androgen pathway inhibitors significantly improving survival when used as a first-line therapy for metastatic disease. Research into the molecular characterisation of localised, recurrent, and progressive disease will undoubtedly have an impact on clinical management. Similarly, emerging research into novel therapeutics, such as targeted radioisotopes and immunotherapy, holds much promise for improving the lives of patients with prostate cancer., Competing Interests: Declarations of interests SGW reports grant support from Bristol-Myers Squibb; consultancy fees and travel support from Astellas Pharma, Janssen, Bayer, Amgen, and Noxopharm paid to institution; and chaired the prostate cancer subcommittee of the Australia and New Zealand Urogenital and Prostate clinical trials group, during which time he received scientific grant support from Bayer and Astellas Pharma. SS reports advisory board fees paid to institution and grant support from AstraZeneca, Merck Sharp & Dohme, Amgen, Endocyte, Bristol-Myers Squibb, and Genentech. EC reports speaker honorarium and advisory board fees from Beckman Coulter Singapore, Janssen, Astellas Pharma, Bayer, Ipsen, AstraZeneca, Ferring, Amgen, and grant support from Janssen and Astellas Pharma. HB reports research support from AbbVie, Janssen, Millennium, Eli Lilly, and Astellas Pharma; and has served as advisor or consultant for Janssen, Astellas Pharma, Sanofi Genzyme, Merck Sharp & Dohme, Pfizer, Amgen, and Blue Earth. CMM reports speaker fees from Astellas Pharma, Janssen, and Steba Biotech; and grant support from SpectraCure. RGB reports no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
Published: 2021
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46. Curative-intent Metastasis-directed Therapies for Molecularly-defined Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis.

Author: Glicksman RM, Metser U, Vines D, Valliant J, Liu Z, Chung PW, Bristow RG, Finelli A, Hamilton R, Fleshner NE, Perlis N, Zlotta AR, Green D, Bayley A, Helou J, Raman S, Kulkarni G, Catton C, Lam T, Chan R, Warde P, Gospodarowicz M, Jaffray DA, and Berlin A
Subjects: Humans, Male, Middle Aged, Prospective Studies, Prostatectomy, Radiotherapy, Adjuvant, Neoplasm Micrometastasis diagnosis, Neoplasm Micrometastasis diagnostic imaging, Neoplasm Micrometastasis genetics, Neoplasm Micrometastasis therapy, Neoplasm Recurrence, Local blood, Neoplasm Recurrence, Local diagnostic imaging, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local therapy, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms genetics, Prostatic Neoplasms therapy
Abstract: Background: The hypothesis of a curable oligometastatic prostate cancer (PCa) state remains to be clinically-proven. Conventional imaging often fails to localize early recurrences, hampering the potential for radical approaches., Objective: We hypothesize that prostate-specific membrane antigen (PSMA)-targeted PET-MR/CT allows for earlier detection and localization of oligorecurrent-PCa, unveiling a molecularly-defined state amenable to curative-intent metastasis-directed treatment (MDT)., Design/setting/participants: Single-institution single-arm phase-two study. Patients with rising PSA (0.4-3.0 ng/mL) after maximal local therapy (radical prostatectomy and post-operative radiotherapy), negative conventional staging, and no prior salvage hormonal therapy (HT) were eligible., Interventions: All patients underwent [ 18 F]DCFPyL PET-MR/CT. Patients with molecularly-defined oligorecurrent-PCa had MDT (stereotactic ablative body radiotherapy [SABR] or surgery) without HT., Outcome Measurements/statistical Analysis: Primary endpoint was biochemical response (complete, i.e. biochemical 'no evidence of disease' [bNED], or partial response [100% or ≥50% PSA decline from baseline, respectively]) after MDT. Simon's two-stage design was employed (null and alternate hypotheses <5% and >20% response rate, respectively), with α and β of 0.1., Results: Seventy-two patients were enrolled (May/2017-July/2019). Thirty-eight (53%) had PSMA-detected oligorecurrent-PCa amenable for MDT. Thirty-seven (51%) agreed to MDT: 10 and 27 underwent surgery and SABR, respectively. Median follow-up was 15.9 months (IQR 9.8-19.1). Of patients receiving MDT, the overall response rate was 60%, including 22% rendered bNED. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed., Conclusions: PSMA-defined oligorecurrent-PCa can be rendered bNED, a necessary step towards cure, in 1 of 5 patients receiving MDT alone. Randomized trials are justified to determine if MDT +/- systemic agents can expand the curative therapeutic armamentarium for PCa., Patient Summary: We studied men treated for prostate cancer with rising PSA. We found PSMA imaging detected recurrent cancer in three-quarters of patients, and targeted treatment to these areas significantly decreased PSA in half of patients., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
Published: 2021
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47. Repurposing FDA approved drugs as radiosensitizers for treating hypoxic prostate cancer.

Author: Bibby BAS, Thiruthaneeswaran N, Yang L, Pereira RR, More E, McArt DG, O'Reilly P, Bristow RG, Williams KJ, Choudhury A, and West CML
Subjects: Cell Line, Tumor, Humans, Hypoxia complications, Male, Prostatic Neoplasms complications, United States, United States Food and Drug Administration, Drug Repositioning, Hypoxia drug therapy, Prostatic Neoplasms drug therapy, Radiation-Sensitizing Agents
Abstract: Background: The presence of hypoxia is a poor prognostic factor in prostate cancer and the hypoxic tumor microenvironment promotes radioresistance. There is potential for drug radiotherapy combinations to improve the therapeutic ratio. We aimed to investigate whether hypoxia-associated genes could be used to identify FDA approved drugs for repurposing for the treatment of hypoxic prostate cancer., Methods: Hypoxia associated genes were identified and used in the connectivity mapping software QUADrATIC to identify FDA approved drugs as candidates for repurposing. Drugs identified were tested in vitro in prostate cancer cell lines (DU145, PC3, LNCAP). Cytotoxicity was investigated using the sulforhodamine B assay and radiosensitization using a clonogenic assay in normoxia and hypoxia., Results: Menadione and gemcitabine had similar cytotoxicity in normoxia and hypoxia in all three cell lines. In DU145 cells, the radiation sensitizer enhancement ratio (SER) of menadione was 1.02 in normoxia and 1.15 in hypoxia. The SER of gemcitabine was 1.27 in normoxia and 1.09 in hypoxia. No radiosensitization was seen in PC3 cells., Conclusion: Connectivity mapping can identify FDA approved drugs for potential repurposing that are linked to a radiobiologically relevant phenotype. Gemcitabine and menadione could be further investigated as potential radiosensitizers in prostate cancer.
Published: 2021
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48. Lost in application: Measuring hypoxia for radiotherapy optimisation.

Author: Thiruthaneeswaran N, Bibby BAS, Yang L, Hoskin PJ, Bristow RG, Choudhury A, and West C
Subjects: Gene Expression Profiling, Humans, Neoplasms genetics, Neoplasms radiotherapy, Prognosis, Biomarkers, Tumor genetics, Neoplasms pathology, Tumor Hypoxia genetics
Abstract: The history of radiotherapy is intertwined with research on hypoxia. There is level 1a evidence that giving hypoxia-targeting treatments with radiotherapy improves locoregional control and survival without compromising late side-effects. Despite coming in and out of vogue over decades, there is now an established role for hypoxia in driving molecular alterations promoting tumour progression and metastases. While tumour genomic complexity and immune profiling offer promise, there is a stronger evidence base for personalising radiotherapy based on hypoxia status. Despite this, there is only one phase III trial targeting hypoxia modification with full transcriptomic data available. There are no biomarkers in routine use for patients undergoing radiotherapy to aid management decisions, and a roadmap is needed to ensure consistency and provide a benchmark for progression to application. Gene expression signatures address past limitations of hypoxia biomarkers and could progress biologically optimised radiotherapy. Here, we review recent developments in generating hypoxia gene expression signatures and highlight progress addressing the challenges that must be overcome to pave the way for their clinical application., Competing Interests: Conflict of interest statement Authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2021
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49. Early Adaptation of Colorectal Cancer Cells to the Peritoneal Cavity Is Associated with Activation of "Stemness" Programs and Local Inflammation.

Author: Barriuso J, Nagaraju RT, Belgamwar S, Chakrabarty B, Burghel GJ, Schlecht H, Foster L, Kilgour E, Wallace AJ, Braun M, Dive C, Evans DG, Bristow RG, Saunders MP, O'Dwyer ST, and Aziz O
Subjects: Adult, Aged, Colorectal Neoplasms immunology, Colorectal Neoplasms mortality, Colorectal Neoplasms therapy, Cytoreduction Surgical Procedures, Disease-Free Survival, Female, Follow-Up Studies, Humans, Hyperthermic Intraperitoneal Chemotherapy, Male, Middle Aged, Neoplasm Recurrence, Local immunology, Neoplasm Recurrence, Local pathology, Peritoneal Neoplasms mortality, Peritoneal Neoplasms secondary, Peritoneal Neoplasms therapy, Risk Assessment methods, Tumor Microenvironment immunology, Colorectal Neoplasms pathology, Neoplasm Recurrence, Local epidemiology, Neoplastic Stem Cells pathology, Peritoneal Cavity pathology, Peritoneal Neoplasms immunology
Abstract: Purpose: At diagnosis, colorectal cancer presents with synchronous peritoneal metastasis in up to 10% of patients. The peritoneum is poorly characterized with respect to its superspecialized microenvironment. Our aim was to describe the differences between peritoneal metastases and their matched primary tumors excised simultaneously at the time of surgery. Also, we tested the hypothesis of these differences being present in primary colorectal tumors and having prognostic capacity., Experimental Design: We report a comprehensive analysis of 30 samples from peritoneal metastasis with their matched colorectal cancer primaries obtained during cytoreductive surgery. We tested and validated the prognostic value of our findings in a pooled series of 660 colorectal cancer primary samples with overall survival (OS) information and 743 samples with disease-free survival (DFS) information from publicly available databases., Results: We identified 20 genes dysregulated in peritoneal metastasis that promote an early increasing role of "stemness" in conjunction with tumor-favorable inflammatory changes. When adjusted for age, gender, and stage, the 20-gene peritoneal signature proved to have prognostic value for both OS [adjusted HR for the high-risk group (vs. low-risk) 2.32 (95% confidence interval, CI, 1.69-3.19; P < 0.0001)] and for DFS [adjusted HR 2.08 (95% CI, 1.50-2.91; P < 0.0001)]., Conclusions: Our findings indicated that the activation of "stemness" pathways and adaptation to the peritoneal-specific environment are key to early stages of peritoneal carcinomatosis. The in silico analysis suggested that this 20-gene peritoneal signature may hold prognostic information with potential for development of new precision medicine strategies in this setting., (©2020 American Association for Cancer Research.)
Published: 2021
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50. Prostate cancer.

Author: Rebello RJ, Oing C, Knudsen KE, Loeb S, Johnson DC, Reiter RE, Gillessen S, Van der Kwast T, and Bristow RG
Subjects: Humans, Male, Neoplasm Recurrence, Local surgery, Neoplasm Recurrence, Local therapy, Prostate-Specific Antigen, Prostatectomy, Androgen Antagonists, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics, Prostatic Neoplasms therapy
Abstract: Prostate cancer is a complex disease that affects millions of men globally, predominantly in high human development index regions. Patients with localized disease at a low to intermediate risk of recurrence generally have a favourable outcome of 99% overall survival for 10 years if the disease is detected and treated at an early stage. Key genetic alterations include fusions of TMPRSS2 with ETS family genes, amplification of the MYC oncogene, deletion and/or mutation of PTEN and TP53 and, in advanced disease, amplification and/or mutation of the androgen receptor (AR). Prostate cancer is usually diagnosed by prostate biopsy prompted by a blood test to measure prostate-specific antigen levels and/or digital rectal examination. Treatment for localized disease includes active surveillance, radical prostatectomy or ablative radiotherapy as curative approaches. Men whose disease relapses after prostatectomy are treated with salvage radiotherapy and/or androgen deprivation therapy (ADT) for local relapse, or with ADT combined with chemotherapy or novel androgen signalling-targeted agents for systemic relapse. Advanced prostate cancer often progresses despite androgen ablation and is then considered castration-resistant and incurable. Current treatment options include AR-targeted agents, chemotherapy, radionuclides and the poly(ADP-ribose) inhibitor olaparib. Current research aims to improve prostate cancer detection, management and outcomes, including understanding the fundamental biology at all stages of the disease.
Published: 2021
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