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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. Management of patients with advanced prostate cancer: report from the Advanced Prostate Cancer Consensus Conference 2021

Author

Tilki, Derya, Gillessen, S.; Armstron, A.; Attard, G.; Beer, T.M.; Beltran, H.; Bjartell, A.; Bossi, A.; Briganti, A.; Bristow, R.G.; Bulbul, M.; Caffo, O.; Chi, K.N.; Clarke, C.S.; Clarke, N.; Davis, I.D.; de Bono, J.S.; Duran, I.; Eeles, R.; Efstathiou, E.; Efstathiou, J.; Ekeke, O.N.; Evans, C.P.; Fanti, S.; Feng, F.Y.; Fizazi, K.; Frydenberg, M.; George, D.; Gleave, M.; Halabi, S.; Heinrich, D.; Higano, C.; Hofman, M.S.; Hussain, M.; James, N.; Jones, R.; Kanesvaran, R.; Khauli, R.B.; Klotz, L.; Leibowitz, R.; Logothetis, C.; Maluf, F.; Millman, R.; Morgans, A.K.; Morris, M.J.; Mottet, N.; Mrabti, H.; Murphy, D.G.; Murthy, V.; Oh, W.K.; Ost, P.; O'Sullivan, J.M.; Padhani, A.R.; Parker, C.; Poon, D.M.C.; Pritchard, C.C.; Rabah, D.M.; Rathkopf, D.; Reiter, R.E.; Rubin, M.; Ryan, C.J.; Saad, F.; Sade, J.P.; Sartor, O.; Scher, H.I.; Shore, N.; Skoneczna, I.; Small, E.; Smith, M.; Soule, H.; Spratt, D.E.; Sternberg, C.N.; Suzuki, H.; Sweeney, C.; Sydes, M.R.; Taplin, M.E.; Tombal, B.; Türkeri, L.; Uemura, H.; Uemura, H.; van Oort, I., Yamoah, K.; Ye, D.; Zapatero, A.; Omlin, A., Koç University Hospital, School of Medicine, Tilki, Derya, Gillessen, S.; Armstron, A.; Attard, G.; Beer, T.M.; Beltran, H.; Bjartell, A.; Bossi, A.; Briganti, A.; Bristow, R.G.; Bulbul, M.; Caffo, O.; Chi, K.N.; Clarke, C.S.; Clarke, N.; Davis, I.D.; de Bono, J.S.; Duran, I.; Eeles, R.; Efstathiou, E.; Efstathiou, J.; Ekeke, O.N.; Evans, C.P.; Fanti, S.; Feng, F.Y.; Fizazi, K.; Frydenberg, M.; George, D.; Gleave, M.; Halabi, S.; Heinrich, D.; Higano, C.; Hofman, M.S.; Hussain, M.; James, N.; Jones, R.; Kanesvaran, R.; Khauli, R.B.; Klotz, L.; Leibowitz, R.; Logothetis, C.; Maluf, F.; Millman, R.; Morgans, A.K.; Morris, M.J.; Mottet, N.; Mrabti, H.; Murphy, D.G.; Murthy, V.; Oh, W.K.; Ost, P.; O'Sullivan, J.M.; Padhani, A.R.; Parker, C.; Poon, D.M.C.; Pritchard, C.C.; Rabah, D.M.; Rathkopf, D.; Reiter, R.E.; Rubin, M.; Ryan, C.J.; Saad, F.; Sade, J.P.; Sartor, O.; Scher, H.I.; Shore, N.; Skoneczna, I.; Small, E.; Smith, M.; Soule, H.; Spratt, D.E.; Sternberg, C.N.; Suzuki, H.; Sweeney, C.; Sydes, M.R.; Taplin, M.E.; Tombal, B.; Türkeri, L.; Uemura, H.; Uemura, H.; van Oort, I., Yamoah, K.; Ye, D.; Zapatero, A.; Omlin, A., Koç University Hospital, and School of Medicine

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, National Health and Medical Research Council (NHMRC) Practitioner Fellowship; Prostate Cancer Foundation; Peter MacCallum Foundation; NHMRC Investigator Grant

Published
2022

5. What experts think about prostate cancer management during the COVID-19 pandemic: report from The Advanced Prostate Cancer Consensus Conference 2021

Author

Tilki, Derya, Turco, F.; Armstrong, A.; Attard, G.; Beer, T.M.; Beltran, H.; Bjartell, A.; Bossi, A.; Briganti, A.; Bristow, R.G.; Bulbul, M.; Caffo, O.; Chi, K.N.; Clarke, C.S.; Clarke, N.; Davis, I.D.; de Bono, J.; Duran, I.; Eeles, R.; Efstathiou, E.; Efstathiou, J.; Evans, C.P.; Fanti, S.; Feng, F.Y.; Fizazi, K.; Frydenberg, M.; George, D.; Gleave, M.; Halabi, S.; Heinrich, D.; Higano, C.; Hofman, M.S.; Hussain, M.; James, N.; Jones, R.; Kanesvaran, R.; Khauli, R.B.; Klotz, L.; Leibowitz, R.; Logothetis, C.; Maluf, F.; Millman, R.; Morgans, A.K.; Morris, M.J.; Mottet, N.; Mrabti, H.; Murphy, D.G.; Murthy, V.; Oh, W.K.; Ekeke, O.N.; Ost, P.; O'Sullivan, J.M.; Padhani, A.R.; Parker, C.; Poon, D.M.C.; Pritchard, C.C.; Rabah, D.M.; Rathkopf, D.; Reiter, R.E.; Rubin, M.; Ryan, C.J.; Saad, F.; Sade, J.P.; Sartor, O.; Scher, H.I.; Shore, N.; Skoneczna, I.; Small, E.; Smith, M.; Soule, H.; Spratt, D.E.; Sternberg, C.N.; Suzuki, H.; Sweeney, C.; Sydes, M.R.; Taplin, M.-E.; Tombal, B.; Türkeri, L.; Uemura, H.; Uemura, H.; van Oort, I.; Yamoah, K.; Ye, D.; Zapatero, A.; Gillessen, S.; Omlin, A., Koç University Hospital, School of Medicine, Tilki, Derya, Turco, F.; Armstrong, A.; Attard, G.; Beer, T.M.; Beltran, H.; Bjartell, A.; Bossi, A.; Briganti, A.; Bristow, R.G.; Bulbul, M.; Caffo, O.; Chi, K.N.; Clarke, C.S.; Clarke, N.; Davis, I.D.; de Bono, J.; Duran, I.; Eeles, R.; Efstathiou, E.; Efstathiou, J.; Evans, C.P.; Fanti, S.; Feng, F.Y.; Fizazi, K.; Frydenberg, M.; George, D.; Gleave, M.; Halabi, S.; Heinrich, D.; Higano, C.; Hofman, M.S.; Hussain, M.; James, N.; Jones, R.; Kanesvaran, R.; Khauli, R.B.; Klotz, L.; Leibowitz, R.; Logothetis, C.; Maluf, F.; Millman, R.; Morgans, A.K.; Morris, M.J.; Mottet, N.; Mrabti, H.; Murphy, D.G.; Murthy, V.; Oh, W.K.; Ekeke, O.N.; Ost, P.; O'Sullivan, J.M.; Padhani, A.R.; Parker, C.; Poon, D.M.C.; Pritchard, C.C.; Rabah, D.M.; Rathkopf, D.; Reiter, R.E.; Rubin, M.; Ryan, C.J.; Saad, F.; Sade, J.P.; Sartor, O.; Scher, H.I.; Shore, N.; Skoneczna, I.; Small, E.; Smith, M.; Soule, H.; Spratt, D.E.; Sternberg, C.N.; Suzuki, H.; Sweeney, C.; Sydes, M.R.; Taplin, M.-E.; Tombal, B.; Türkeri, L.; Uemura, H.; Uemura, H.; van Oort, I.; Yamoah, K.; Ye, D.; Zapatero, A.; Gillessen, S.; Omlin, A., Koç University Hospital, and School of Medicine

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., NA

Published
2022

6. What experts think about prostate cancer management during the COVID-19 pandemic: report from The Advanced Prostate Cancer Consensus Conference 2021

Author

Fabio Turco, Andrew Armstrong, Gerhardt Attard, Tomasz M. Beer, Himisha Beltran, Anders Bjartell, Alberto Bossi, Alberto Briganti, Rob G. Bristow, Muhammad Bulbul, Orazio Caffo, Kim N. Chi, Caroline Clarke, Noel Clarke, Ian D. Davis, Johann de Bono, Ignacio Duran, Ros Eeles, Eleni Efstathiou, Jason Efstathiou, Christopher P. Evans, Stefano Fanti, Felix Y. Feng, Karim Fizazi, Mark Frydenberg, Dan George, Martin Gleave, Susan Halabi, Daniel Heinrich, Celestia Higano, Michael S. Hofman, Maha Hussain, Nicholas James, Rob Jones, Ravindran Kanesvaran, Raja B. Khauli, Laurence Klotz, Raya Leibowitz, Christopher Logothetis, Fernando Maluf, Robin Millman, Alicia K. Morgans, Michael J. Morris, Nicolas Mottet, Hind Mrabti, Declan G. Murphy, Vedang Murthy, William K. Oh, Ngozi Ekeke Onyeanunam, Piet Ost, Joe M. O'Sullivan, Anwar R. Padhani, Christopher Parker, Darren M.C. Poon, Colin C. Pritchard, Danny M. Rabah, Dana Rathkopf, Robert E. Reiter, Mark Rubin, Charles J. Ryan, Fred Saad, Juan Pablo Sade, Oliver Sartor, Howard I. Scher, Neal Shore, Iwona Skoneczna, Eric Small, Matthew Smith, Howard Soule, Daniel Spratt, Cora N. Sternberg, Hiroyoshi Suzuki, Christopher Sweeney, Matthew Sydes, Mary-Ellen Taplin, Derya Tilki, Bertrand Tombal, Levent Türkeri, Hiroji Uemura, Hirotsugu Uemura, Inge van Oort, Kosj Yamoah, Dingwei Ye, Almudena Zapatero, Silke Gillessen, Aurelius Omlin, Tilki, Derya, Turco, F., Armstrong, A., Attard, G., Beer, T.M., Beltran, H., Bjartell, A., Bossi, A., Briganti, A., Bristow, R.G., Bulbul, M., Caffo, O., Chi, K.N., Clarke, C.S., Clarke, N., Davis, I.D., de Bono, J., Duran, I., Eeles, R., Efstathiou, E., Efstathiou, J., Evans, C.P., Fanti, S., Feng, F.Y., Fizazi, K., Frydenberg, M., George, D., Gleave, M., Halabi, S., Heinrich, D., Higano, C., Hofman, M.S., Hussain, M., James, N., Jones, R., Kanesvaran, R., Khauli, R.B., Klotz, L., Leibowitz, R., Logothetis, C., Maluf, F., Millman, R., Morgans, A.K., Morris, M.J., Mottet, N., Mrabti, H., Murphy, D.G., Murthy, V., Oh, W.K., Ekeke, O.N., Ost, P., O'Sullivan, J.M., Padhani, A.R., Parker, C., Poon, D.M.C., Pritchard, C.C., Rabah, D.M., Rathkopf, D., Reiter, R.E., Rubin, M., Ryan, C.J., Saad, F., Sade, J.P., Sartor, O., Scher, H.I., Shore, N., Skoneczna, I., Small, E., Smith, M., Soule, H., Spratt, D.E., Sternberg, C.N., Suzuki, H., Sweeney, C., Sydes, M.R., Taplin, M.-E., Tombal, B., Türkeri, L., Uemura, H., van Oort, I., Yamoah, K., Ye, D., Zapatero, A., Gillessen, S., Omlin, A., Koç University Hospital, School of Medicine, Acibadem University Dspace, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, and UCL - (SLuc) Service d'urologie

Subjects
Male, COVID-19 Vaccines, Prostate cancer, Urology, COVID-19 boost injection, COVID-19 pandemic, COVID-19 vaccine, Prostate cancer management, Telemedicine, COVID-19, Prostatic Neoplasms, Androgen Antagonists, 610 Medicine & health, Urology and nephrology, SDG 3 - Good Health and Well-being, Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15], Humans, Pandemics
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., NA

Published
2022

7. Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas

Author

Gregory P. Way, Francisco Sanchez-Vega, Konnor La, Joshua Armenia, Walid K. Chatila, Augustin Luna, Chris Sander, Andrew D. Cherniack, Marco Mina, Giovanni Ciriello, Nikolaus Schultz, Yolanda Sanchez, Casey S. Greene, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Debyani Chakravarty, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Marc Ladanyi, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, Armaz Mariamidze, Cancer Genome Atlas Research Network, Caesar-Johnson, S.J., Demchok, J.A., Felau, I., Kasapi, M., Ferguson, M.L., Hutter, C.M., Sofia, H.J., Tarnuzzer, R., Wang, Z., Yang, L., Zenklusen, J.C., Zhang, J.J., Chudamani, S., Liu, J., Lolla, L., Naresh, R., Pihl, T., Sun, Q., Wan, Y., Wu, Y., Cho, J., DeFreitas, T., Frazer, S., Gehlenborg, N., Getz, G., Heiman, D.I., Kim, J., Lawrence, M.S., Lin, P., Meier, S., Noble, M.S., Saksena, G., Voet, D., Zhang, H., Bernard, B., Chambwe, N., Dhankani, V., Knijnenburg, T., Kramer, R., Leinonen, K., Liu, Y., Miller, M., Reynolds, S., Shmulevich, I., Thorsson, V., Zhang, W., Akbani, R., Broom, B.M., Hegde, A.M., Ju, Z., Kanchi, R.S., Korkut, A., Li, J., Liang, H., Ling, S., Liu, W., Lu, Y., Mills, G.B., Ng, K.S., Rao, A., Ryan, M., Wang, J., Weinstein, J.N., Zhang, J., Abeshouse, A., Armenia, J., Chakravarty, D., Chatila, W.K., de Bruijn, I., Gao, J., Gross, B.E., Heins, Z.J., Kundra, R., La, K., Ladanyi, M., Luna, A., Nissan, M.G., Ochoa, A., Phillips, S.M., Reznik, E., Sanchez-Vega, F., Sander, C., Schultz, N., Sheridan, R., Sumer, S.O., Sun, Y., Taylor, B.S., Anur, P., Peto, M., Spellman, P., Benz, C., Stuart, J.M., Wong, C.K., Yau, C., Hayes, D.N., Parker, J.S., Wilkerson, M.D., Ally, A., Balasundaram, M., Bowlby, R., Brooks, D., Carlsen, R., Chuah, E., Dhalla, N., Holt, R., Jones, SJM, Kasaian, K., Lee, D., Ma, Y., Marra, M.A., Mayo, M., Moore, R.A., Mungall, A.J., Mungall, K., Robertson, A.G., Sadeghi, S., Schein, J.E., Sipahimalani, P., Tam, A., Thiessen, N., Tse, K., Wong, T., Berger, A.C., Beroukhim, R., Cherniack, A.D., Cibulskis, C., Gabriel, S.B., Gao, G.F., Ha, G., Meyerson, M., Schumacher, S.E., Shih, J., Kucherlapati, M.H., Kucherlapati, R.S., Baylin, S., Cope, L., Danilova, L., Bootwalla, M.S., Lai, P.H., Maglinte, D.T., Van Den Berg, D.J., Weisenberger, D.J., Auman, J.T., Balu, S., Bodenheimer, T., Fan, C., Hoadley, K.A., Hoyle, A.P., Jefferys, S.R., Jones, C.D., Meng, S., Mieczkowski, P.A., 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Chabot, J., Hibshoosh, H., Sepulveda, A., Su, T., Wang, T., Potapova, O., Voronina, O., Desjardins, L., Mariani, O., Roman-Roman, S., Sastre, X., Stern, M.H., Cheng, F., Signoretti, S., Berchuck, A., Bigner, D., Lipp, E., Marks, J., McCall, S., McLendon, R., Secord, A., Sharp, A., Behera, M., Brat, D.J., Chen, A., Delman, K., Force, S., Khuri, F., Magliocca, K., Maithel, S., Olson, J.J., Owonikoko, T., Pickens, A., Ramalingam, S., Shin, D.M., Sica, G., Van Meir, E.G., Eijckenboom, W., Gillis, A., Korpershoek, E., Looijenga, L., Oosterhuis, W., Stoop, H., van Kessel, K.E., Zwarthoff, E.C., Calatozzolo, C., Cuppini, L., Cuzzubbo, S., DiMeco, F., Finocchiaro, G., Mattei, L., Perin, A., Pollo, B., Chen, C., Houck, J., Lohavanichbutr, P., Hartmann, A., Stoehr, C., Stoehr, R., Taubert, H., Wach, S., Wullich, B., Kycler, W., Murawa, D., Wiznerowicz, M., Chung, K., Edenfield, W.J., Martin, J., Baudin, E., Bubley, G., Bueno, R., De Rienzo, A., Richards, W.G., Kalkanis, S., Mikkelsen, T., Noushmehr, H., Scarpace, L., Girard, N., Aymerich, M., Campo, E., Giné, E., Guillermo, A.L., Van Bang, N., Hanh, P.T., Phu, B.D., Tang, Y., Colman, H., Evason, K., Dottino, P.R., Martignetti, J.A., Gabra, H., Juhl, H., Akeredolu, T., Stepa, S., Hoon, D., Ahn, K., Kang, K.J., Beuschlein, F., Breggia, A., Birrer, M., Bell, D., Borad, M., Bryce, A.H., Castle, E., Chandan, V., Cheville, J., Copland, J.A., Farnell, M., Flotte, T., Giama, N., Ho, T., Kendrick, M., Kocher, J.P., Kopp, K., Moser, C., Nagorney, D., O'Brien, D., O'Neill, B.P., Patel, T., Petersen, G., Que, F., Rivera, M., Roberts, L., Smallridge, R., Smyrk, T., Stanton, M., Thompson, R.H., Torbenson, M., Yang, J.D., Zhang, L., Brimo, F., Ajani, J.A., Gonzalez, AMA, Behrens, C., Bondaruk, J., Broaddus, R., Czerniak, B., Esmaeli, B., Fujimoto, J., Gershenwald, J., Guo, C., Lazar, A.J., Logothetis, C., Meric-Bernstam, F., Moran, C., Ramondetta, L., Rice, D., Sood, A., Tamboli, P., Thompson, T., Troncoso, P., Tsao, A., Wistuba, I., 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Antenucci, A., Facciolo, F., Grazi, G., Marino, M., Merola, R., de Krijger, R., Gimenez-Roqueplo, A.P., Piché, A., Chevalier, S., McKercher, G., Birsoy, K., Barnett, G., Brewer, C., Farver, C., Naska, T., Pennell, N.A., Raymond, D., Schilero, C., Smolenski, K., Williams, F., Morrison, C., Borgia, J.A., Liptay, M.J., Pool, M., Seder, C.W., Junker, K., Omberg, L., Dinkin, M., Manikhas, G., Alvaro, D., Bragazzi, M.C., Cardinale, V., Carpino, G., Gaudio, E., Chesla, D., Cottingham, S., Dubina, M., Moiseenko, F., Dhanasekaran, R., Becker, K.F., Janssen, K.P., Slotta-Huspenina, J., Abdel-Rahman, M.H., Aziz, D., Bell, S., Cebulla, C.M., Davis, A., Duell, R., Elder, J.B., Hilty, J., Kumar, B., Lang, J., Lehman, N.L., Mandt, R., Nguyen, P., Pilarski, R., Rai, K., Schoenfield, L., Senecal, K., Wakely, P., Hansen, P., Lechan, R., Powers, J., Tischler, A., Grizzle, W.E., Sexton, K.C., Kastl, A., Henderson, J., Porten, S., Waldmann, J., Fassnacht, M., Asa, S.L., Schadendorf, D., Couce, M., Graefen, M., Huland, H., Sauter, G., Schlomm, T., Simon, R., Tennstedt, P., Olabode, O., Nelson, M., Bathe, O., Carroll, P.R., Chan, J.M., Disaia, P., Glenn, P., Kelley, R.K., Landen, C.N., Phillips, J., Prados, M., Simko, J., Smith-McCune, K., VandenBerg, S., Roggin, K., Fehrenbach, A., Kendler, A., Sifri, S., Steele, R., Jimeno, A., Carey, F., Forgie, I., Mannelli, M., Carney, M., Hernandez, B., Campos, B., Herold-Mende, C., Jungk, C., Unterberg, A., von Deimling, A., Bossler, A., Galbraith, J., Jacobus, L., Knudson, M., Knutson, T., Ma, D., Milhem, M., Sigmund, R., Godwin, A.K., Madan, R., Rosenthal, H.G., Adebamowo, C., Adebamowo, S.N., Boussioutas, A., Beer, D., Giordano, T., Mes-Masson, A.M., Saad, F., Bocklage, T., Landrum, L., Mannel, R., Moore, K., Moxley, K., Postier, R., Walker, J., Zuna, R., Feldman, M., Valdivieso, F., Dhir, R., Luketich, J., Pinero, EMM, Quintero-Aguilo, M., Carlotti, C.G., Dos Santos, J.S., Kemp, R., Sankarankuty, A., Tirapelli, D., Catto, J., Agnew, K., Swisher, E., Creaney, J., Robinson, B., Shelley, C.S., Godwin, E.M., Kendall, S., Shipman, C., Bradford, C., Carey, T., Haddad, A., Moyer, J., Peterson, L., Prince, M., Rozek, L., Wolf, G., Bowman, R., Fong, K.M., Yang, I., Korst, R., Rathmell, W.K., Fantacone-Campbell, J.L., Hooke, J.A., Kovatich, A.J., Shriver, C.D., DiPersio, J., Drake, B., Govindan, R., Heath, S., Ley, T., Van Tine, B., Westervelt, P., Rubin, M.A., Lee, J.I., Aredes, N.D., Mariamidze, A., SAIC-F-Frederick, Inc, and Leidos Biomedical Research, Inc.

Subjects
0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Genetics and Molecular Biology (all), PATHOGENESIS, pan-cancer, PROTEIN, Cancer Genome Atlas Research Network, medicine.disease_cause, computer.software_genre, Genome, Biochemistry, Transcriptome, Gene expression, HRAS, KRAS, NF1, NRAS, Ras, TCGA, drug sensitivity, machine learning, Neoplasms, PRECISION ONCOLOGY, lcsh:QH301-705.5, Regulation of gene expression, PREVIOUSLY TREATED PATIENTS, 3. Good health, Gene Expression Regulation, Neoplastic, PHASE-II, Life Sciences & Biomedicine, Signal Transduction, Biology, Machine learning, General Biochemistry, Genetics and Molecular Biology, Article, BRAF, 03 medical and health sciences, Cell Line, Tumor, medicine, Biochemistry, Genetics and Molecular Biology (all), Humans, Gene, SIGNATURES, Science & Technology, business.industry, Genome, Human, MUTATIONS, EXPRESSÃO GÊNICA, Cell Biology, SELUMETINIB, GENE, 030104 developmental biology, lcsh:Biology (General), Selumetinib, ras Proteins, Artificial intelligence, business, computer
Abstract

SUMMARY Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these “hidden responders” may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders., In Brief Way et al. develop a machine-learning approach using PanCanAtlas data to detect Ras activation in cancer. Integrating mutation, copy number, and expression data, the authors show that their method detects Ras-activating variants in tumors and sensitivity to MEK inhibitors in cell lines.

Published
2018

8. Genomic and functional approaches to understanding cancer aneuploidy

Author

Alison M. Taylor, Juliann Shih, Gavin Ha, Galen F. Gao, Xiaoyang Zhang, Ashton C. Berger, Steven E. Schumacher, Chen Wang, Hai Hu, Jianfang Liu, Alexander J. Lazar, Andrew D. Cherniack, Rameen Beroukhim, Matthew Meyerson, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Carrie Cibulskis, Stacey B. Gabriel, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, Armaz Mariamidze, SAIC-F-Frederick, Inc, Leidos Biomedical Research, Inc., Taylor A.M., Shih J., Ha G., Gao G.F., Zhang X., Berger A.C., Schumacher S.E., Wang C., Hu H., Liu J., Lazar A.J., Caesar-Johnson S.J., Demchok J.A., Felau I., Kasapi M., Ferguson M.L., Hutter C.M., Sofia H.J., Tarnuzzer R., Wang Z., Yang L., Zenklusen J.C., Zhang J.J., Chudamani S., Lolla L., Naresh R., Pihl T., Sun Q., Wan Y., Wu Y., Cho J., DeFreitas T., Frazer S., Gehlenborg N., Getz G., Heiman D.I., Kim J., Lawrence M.S., Lin P., Meier S., Noble M.S., Saksena G., Voet D., Zhang H., Bernard B., Chambwe N., Dhankani V., Knijnenburg T., Kramer R., Leinonen K., Liu Y., Miller M., Reynolds S., Shmulevich I., Thorsson V., Zhang W., Akbani R., Broom B.M., Hegde A.M., Ju Z., Kanchi R.S., Korkut A., Li J., Liang H., Ling S., Liu W., Lu Y., Mills G.B., Ng K.-S., Rao A., Ryan M., Wang J., Weinstein J.N., Zhang J., Abeshouse A., Armenia J., Chakravarty D., Chatila W.K., de Bruijn I., Gao J., Gross B.E., Heins Z.J., Kundra R., La K., Ladanyi M., Luna A., Nissan M.G., Ochoa A., Phillips S.M., Reznik E., Sanchez-Vega F., Sander C., Schultz N., Sheridan R., Sumer S.O., Sun Y., Taylor B.S., Anur P., Peto M., Spellman P., Benz C., Stuart J.M., Wong C.K., Yau C., Hayes D.N., Parker J.S., Wilkerson M.D., Ally A., Balasundaram M., Bowlby R., Brooks D., Carlsen R., Chuah E., Dhalla N., Holt R., Jones S.J.M., Kasaian K., Lee D., Ma Y., Marra M.A., Mayo M., Moore R.A., Mungall A.J., Mungall K., Robertson A.G., Sadeghi S., Schein J.E., Sipahimalani P., Tam A., Thiessen N., Tse K., Wong T., Beroukhim R., Cherniack A.D., Cibulskis C., Gabriel S.B., Meyerson M., Kucherlapati M.H., Kucherlapati R.S., Baylin S., Cope L., Danilova L., Bootwalla M.S., Lai P.H., Maglinte D.T., Van Den Berg D.J., Weisenberger D.J., Auman J.T., Balu S., Bodenheimer T., Fan C., Hoadley K.A., Hoyle A.P., Jefferys S.R., Jones C.D., Meng S., Mieczkowski P.A., Mose L.E., Perou A.H., Perou C.M., Roach J., Shi Y., Simons J.V., Skelly T., Soloway M.G., Tan D., Veluvolu U., Fan H., Hinoue T., Laird P.W., Shen H., Zhou W., Bellair M., Chang K., Covington K., Creighton C.J., Dinh H., Doddapaneni H., Donehower L.A., Drummond J., Gibbs R.A., Glenn R., Hale W., Han Y., Hu J., Korchina V., Lee S., Lewis L., Li W., Liu X., Morgan M., Morton D., Muzny D., Santibanez J., Sheth M., Shinbrot E., Wang L., Wang M., Wheeler D.A., Xi L., Zhao F., Hess J., Appelbaum E.L., Bailey M., Cordes M.G., Ding L., Fronick C.C., Fulton L.A., Fulton R.S., Kandoth C., Mardis E.R., McLellan M.D., Miller C.A., Schmidt H.K., Wilson R.K., Crain D., Curley E., Gardner J., Lau K., Mallery D., Morris S., Paulauskis J., Penny R., Shelton C., Shelton T., Sherman M., Thompson E., Yena P., Bowen J., Gastier-Foster J.M., Gerken M., Leraas K.M., Lichtenberg T.M., Ramirez N.C., Wise L., Zmuda E., Corcoran N., Costello T., Hovens C., Carvalho A.L., de Carvalho A.C., Fregnani J.H., Longatto-Filho A., Reis R.M., Scapulatempo-Neto C., Silveira H.C.S., Vidal D.O., Burnette A., Eschbacher J., Hermes B., Noss A., Singh R., Anderson M.L., Castro P.D., Ittmann M., Huntsman D., Kohl B., Le X., Thorp R., Andry C., Duffy E.R., Lyadov V., Paklina O., Setdikova G., Shabunin A., Tavobilov M., McPherson C., Warnick R., Berkowitz R., Cramer D., Feltmate C., Horowitz N., Kibel A., Muto M., Raut C.P., Malykh A., Barnholtz-Sloan J.S., Barrett W., Devine K., Fulop J., Ostrom Q.T., Shimmel K., Wolinsky Y., Sloan A.E., De Rose A., Giuliante F., Goodman M., Karlan B.Y., Hagedorn C.H., Eckman J., Harr J., Myers J., Tucker K., Zach L.A., Deyarmin B., Kvecher L., Larson C., Mural R.J., Somiari S., Vicha A., Zelinka T., Bennett J., Iacocca M., Rabeno B., Swanson P., Latour M., Lacombe L., Tetu B., Bergeron A., McGraw M., Staugaitis S.M., Chabot J., Hibshoosh H., Sepulveda A., Su T., Wang T., Potapova O., Voronina O., Desjardins L., Mariani O., Roman-Roman S., Sastre X., Stern M.-H., Cheng F., Signoretti S., Berchuck A., Bigner D., Lipp E., Marks J., McCall S., McLendon R., Secord A., Sharp A., Behera M., Brat D.J., Chen A., Delman K., Force S., Khuri F., Magliocca K., Maithel S., Olson J.J., Owonikoko T., Pickens A., Ramalingam S., Shin D.M., Sica G., Van Meir E.G., Eijckenboom W., Gillis A., Korpershoek E., Looijenga L., Oosterhuis W., Stoop H., van Kessel K.E., Zwarthoff E.C., Calatozzolo C., Cuppini L., Cuzzubbo S., DiMeco F., Finocchiaro G., Mattei L., Perin A., Pollo B., Chen C., Houck J., Lohavanichbutr P., Hartmann A., Stoehr C., Stoehr R., Taubert H., Wach S., Wullich B., Kycler W., Murawa D., Wiznerowicz M., Chung K., Edenfield W.J., Martin J., Baudin E., Bubley G., Bueno R., De Rienzo A., Richards W.G., Kalkanis S., Mikkelsen T., Noushmehr H., Scarpace L., Girard N., Aymerich M., Campo E., Gine E., Guillermo A.L., Van Bang N., Hanh P.T., Phu B.D., Tang Y., Colman H., Evason K., Dottino P.R., Martignetti J.A., Gabra H., Juhl H., Akeredolu T., Stepa S., Hoon D., Ahn K., Kang K.J., Beuschlein F., Breggia A., Birrer M., Bell D., Borad M., Bryce A.H., Castle E., Chandan V., Cheville J., Copland J.A., Farnell M., Flotte T., Giama N., Ho T., Kendrick M., Kocher J.-P., Kopp K., Moser C., Nagorney D., O'Brien D., O'Neill B.P., Patel T., Petersen G., Que F., Rivera M., Roberts L., Smallridge R., Smyrk T., Stanton M., Thompson R.H., Torbenson M., Yang J.D., Zhang L., Brimo F., Ajani J.A., Angulo Gonzalez A.M., Behrens C., Bondaruk J., Broaddus R., Czerniak B., Esmaeli B., Fujimoto J., Gershenwald J., Guo C., Logothetis C., Meric-Bernstam F., Moran C., Ramondetta L., Rice D., Sood A., Tamboli P., Thompson T., Troncoso P., Tsao A., Wistuba I., Carter C., Haydu L., Hersey P., Jakrot V., Kakavand H., Kefford R., Lee K., Long G., Mann G., Quinn M., Saw R., Scolyer R., Shannon K., Spillane A., Stretch J., Synott M., Thompson J., Wilmott J., Al-Ahmadie H., Chan T.A., Ghossein R., Gopalan A., Levine D.A., Reuter V., Singer S., Singh B., Tien N.V., Broudy T., Mirsaidi C., Nair P., Drwiega P., Miller J., Smith J., Zaren H., Park J.-W., Hung N.P., Kebebew E., Linehan W.M., Metwalli A.R., Pacak K., Pinto P.A., Schiffman M., Schmidt L.S., Vocke C.D., Wentzensen N., Worrell R., Yang H., Moncrieff M., Goparaju C., Melamed J., Pass H., Botnariuc N., Caraman I., Cernat M., Chemencedji I., Clipca A., Doruc S., Gorincioi G., Mura S., Pirtac M., Stancul I., Tcaciuc D., Albert M., Alexopoulou I., Arnaout A., Bartlett J., Engel J., Gilbert S., Parfitt J., Sekhon H., Thomas G., Rassl D.M., Rintoul R.C., Bifulco C., Tamakawa R., Urba W., Hayward N., Timmers H., Antenucci A., Facciolo F., Grazi G., Marino M., Merola R., de Krijger R., Gimenez-Roqueplo A.-P., Piche A., Chevalier S., McKercher G., Birsoy K., Barnett G., Brewer C., Farver C., Naska T., Pennell N.A., Raymond D., Schilero C., Smolenski K., Williams F., Morrison C., Borgia J.A., Liptay M.J., Pool M., Seder C.W., Junker K., Omberg L., Dinkin M., Manikhas G., Alvaro D., Bragazzi M.C., Cardinale V., Carpino G., Gaudio E., Chesla D., Cottingham S., Dubina M., Moiseenko F., Dhanasekaran R., Becker K.-F., Janssen K.-P., Slotta-Huspenina J., Abdel-Rahman M.H., Aziz D., Bell S., Cebulla C.M., Davis A., Duell R., Elder J.B., Hilty J., Kumar B., Lang J., Lehman N.L., Mandt R., Nguyen P., Pilarski R., Rai K., Schoenfield L., Senecal K., Wakely P., Hansen P., Lechan R., Powers J., Tischler A., Grizzle W.E., Sexton K.C., Kastl A., Henderson J., Porten S., Waldmann J., Fassnacht M., Asa S.L., Schadendorf D., Couce M., Graefen M., Huland H., Sauter G., Schlomm T., Simon R., Tennstedt P., Olabode O., Nelson M., Bathe O., Carroll P.R., Chan J.M., Disaia P., Glenn P., Kelley R.K., Landen C.N., Phillips J., Prados M., Simko J., Smith-McCune K., VandenBerg S., Roggin K., Fehrenbach A., Kendler A., Sifri S., Steele R., Jimeno A., Carey F., Forgie I., Mannelli M., Carney M., Hernandez B., Campos B., Herold-Mende C., Jungk C., Unterberg A., von Deimling A., Bossler A., Galbraith J., Jacobus L., Knudson M., Knutson T., Ma D., Milhem M., Sigmund R., Godwin A.K., Madan R., Rosenthal H.G., Adebamowo C., Adebamowo S.N., Boussioutas A., Beer D., Giordano T., Mes-Masson A.-M., Saad F., Bocklage T., Landrum L., Mannel R., Moore K., Moxley K., Postier R., Walker J., Zuna R., Feldman M., Valdivieso F., Dhir R., Luketich J., Mora Pinero E.M., Quintero-Aguilo M., Carlotti C.G., Dos Santos J.S., Kemp R., Sankarankuty A., Tirapelli D., Catto J., Agnew K., Swisher E., Creaney J., Robinson B., Shelley C.S., Godwin E.M., Kendall S., Shipman C., Bradford C., Carey T., Haddad A., Moyer J., Peterson L., Prince M., Rozek L., Wolf G., Bowman R., Fong K.M., Yang I., Korst R., Rathmell W.K., Fantacone-Campbell J.L., Hooke J.A., Kovatich A.J., Shriver C.D., DiPersio J., Drake B., Govindan R., Heath S., Ley T., Van Tine B., Westervelt P., Rubin M.A., Lee J.I., Aredes N.D., and Mariamidze A.

Subjects
0301 basic medicine, Cancer Research, Aneuploidy, Cancer Genome Atlas Research Network, CHROMOSOMAL INSTABILITY, Genome, EXPRESSION PROFILES, Mutation Rate, Chromosome instability, Gene duplication, MULTIPLE, Databases, Genetic, LS2_1, lung squamous cell carcinoma, LS4_6, 610 Medicine & health, Genetics, Cell Cycle, PROLIFERATION, cancer genomic, Genomics, PROLIFERAÇÃO CELULAR, SQUAMOUS-CELL CARCINOMAS, Oncology, Chromosome Arm, Carcinoma, Squamous Cell, Chromosomes, Human, Pair 3, Chromosome Deletion, aneuploidy, cancer genomics, genome engineering, Life Sciences & Biomedicine, Human, COPY-NUMBER ALTERATION, Biology, Chromosome Aberration, Article, NO, 03 medical and health sciences, Germline mutation, LUNG-CANCER, REVEALS, medicine, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Cell Proliferation, Chromosome Aberrations, Science & Technology, LANDSCAPE, Chromosome, Cell Biology, medicine.disease, DELETIONS, 030104 developmental biology, Chromosome 3, Genomic, Tumor Suppressor Protein p53, 1109 Neurosciences
Abstract

Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy. Analyzing >10,000 human cancers, Taylor et al. show that aneuploidy is correlated with somatic mutation rate, expression of proliferation genes, and decreased leukocyte infiltration. Loss of chromosome arm 3p is common in squamous cancers, but deletion of chromosome 3p reduces cell proliferation in vitro.

Published
2018

9. Clinical outcomes in men of diverse ethnic backgrounds with metastatic castration-resistant prostate cancer.

Author

Halabi S, Dutta S, Tangen CM, Rosenthal M, Petrylak DP, Thompson IM Jr, Chi KN, De Bono JS, Araujo JC, Logothetis C, Eisenberger MA, Quinn DI, Fizazi K, Morris MJ, Higano CS, Tannock IF, Small EJ, and Kelly WK

Subjects
Antineoplastic Combined Chemotherapy Protocols therapeutic use, Disease-Free Survival, Docetaxel therapeutic use, Ethnicity, Humans, Male, Prednisone therapeutic use, Prostate-Specific Antigen, Retrospective Studies, Treatment Outcome, Prostatic Neoplasms, Castration-Resistant drug therapy
Abstract

Background: We have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen., Patients and Methods: Individual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors., Results: Of 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively., Conclusions: We observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP., Competing Interests: Disclosure SH reports other from Bayer, Eisai and Ferring; outside the submitted work. DPP consultant fees: Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics (added January 2020), Boehringer Ingelheim, Bristol Myer Squibb, Clovis, Eli Lilly, Exelixis, Incyte, Janssen, Pfizer, Pharmacyclics, Roche Laboratories, Seattle Genetics, Urogen. Grant support: Ada Cap (Advanced Accelerator Applications), Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis, Eli Lilly, Endocyte, Genentech, Innocrin, MedImmune, Merck, Novartis, Pfizer, Progenics, Roche Laboratories, Sanofi Aventis, Seattle Genetics; Ownership interest/investment: Bellicum, Tyme (sold October 2019). KC reports grants and personal fees from Janssen, Astellas, Sanofi, Bayer, Roche and AstraZeneca, outside the submitted work. JDB has served on advisory boards and received fees from many companies including AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Cellcentric, Daiichi, Genentech/Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals. He is an employee of the Institute of Cancer Research, which have received funding or other support for his research work from AstraZeneca, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GlaxoSmithKline, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, Vertex, and which has a commercial interest in abiraterone, poly (ADP-ribose) polymerase inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income). He was named as an inventor, with no financial interest, for patent 8,822,438. He has been the CI/PI of many industry sponsored clinical trials. JDB is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. CL reports honoraria and consultant fees from Sanofi, Bayer, Janssen, Astellas Pharma. In addition, he reports research grants from Sanofi, Bayer, Janssen, Astellas Pharma and Pfizer. DIQ reports compensated consultant: Astellas, Bayer, BMS, Advanced Accelerator Applications, Roche/Genentech, Janssen, Merck, Novartis, Pfizer. Travel: Astellas, Bayer, Bristol Myers Squibb, Genentech, Merck, Pfizer. Research to institution: Bayer, Bristol Myers Squibb, Roche/Genentech, Merck, Pfizer. KF: participation to advisory boards/honorarium for: Astellas, Bayer, Curevac, Janssen, MSD, Orion, Sanofi. MJM reports consultant fees from Bayer, Endocyte, Advanced Accelerator Applications, Blue Earth Diagnostics, Tokai Pharmaceuticals, Tolmar Pharmaceuticals, ORIC Pharmaceutical. Travel: Bayer, Endocyte. In addition he reports research funding to the institution from Bayer, Sanofi, Endocyte, Progenics, Corcept Therapeutics, Roche/Genentech. CSH reports other from Aptevo, Aragon Pharma, Astellas, AstraZeneca, Bayer, Clovis, Dendreon, eFFECTOR Therapeutics, Emergent, Ferring, Genentech, Hoffman-La Roche, Medivation and Pfizer. She reports personal fees from Aptevo, Asana, Astellas, Bayer, Blue Earth Diagnostics, Pharma, fees from Clovis, Dendreon, Endocyte, Ferring, Hinova, Janssen, Merck, Myriad, Orion, Pfizer, Tolmar, Carrick Therapeutics, Novartis, outside the submitted work. IFT reports other from Sanofi, during the conduct of the study; other from Janssen, Bayer, Roche-Genentech, outside the submitted work. EJS reports consultant fees and honoraria from Fortis, Janssen Oncology, Beigene, Tolero Pharmaceuticals. Travel from Janssen. In addition, he reports research grants to institution from Janssen, Merck. The remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. All rights reserved.)

Published
2020
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10. Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

Author

Gillessen S, Omlin A, Attard G, de Bono JS, Efstathiou E, Fizazi K, Halabi S, Nelson PS, Sartor O, Smith MR, Soule HR, Akaza H, Beer TM, Beltran H, Chinnaiyan AM, Daugaard G, Davis ID, De Santis M, Drake CG, Eeles RA, Fanti S, Gleave ME, Heidenreich A, Hussain M, James ND, Lecouvet FE, Logothetis CJ, Mastris K, Nilsson S, Oh WK, Olmos D, Padhani AR, Parker C, Rubin MA, Schalken JA, Scher HI, Sella A, Shore ND, Small EJ, Sternberg CN, Suzuki H, Sweeney CJ, Tannock IF, and Tombal B

Published
2019
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12. Precision, complexity and stigma in advanced prostate cancer terminology: it is time to move away from 'castration-resistant' prostate cancer.

Author

Pezaro CJ, Omlin A, Mastris K, Attard G, Beer TM, Chi KN, Chowdhury S, Davis ID, Drake CG, de Bono JS, Efstathiou E, Gravis G, Higano CS, Hussain M, James N, Logothetis CJ, Morgans A, Parker C, Ryan CJ, Saad F, Sartor O, Small EJ, Sternberg CN, Sweeney CJ, Tannock I, Tombal B, and Gillessen S

Subjects
Humans, Male, Prostatic Neoplasms, Castration-Resistant diagnosis, Prostatic Neoplasms, Castration-Resistant therapy, Terminology as Topic, Prostatic Neoplasms, Castration-Resistant classification
Published
2017
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13. Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer.

Author

Qiao Y, Feng FY, Wang Y, Cao X, Han S, Wilder-Romans K, Navone NM, Logothetis C, Taichman RS, Keller ET, Palapattu GS, Alva AS, Smith DC, Tomlins SA, Chinnaiyan AM, and Morgan TM

Subjects
Anilides pharmacology, Animals, Benzamides, Cell Line, Tumor, Cell Survival drug effects, Cluster Analysis, Disease Models, Animal, Gene Expression Profiling, Gene Knockdown Techniques, Humans, Male, Mice, Nitriles, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin pharmacology, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Proto-Oncogene Proteins c-met genetics, Pyridines pharmacology, Receptors, Androgen metabolism, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Androgen Receptor Antagonists pharmacology, Antineoplastic Agents pharmacology, Prostatic Neoplasms, Castration-Resistant metabolism, Prostatic Neoplasms, Castration-Resistant pathology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met antagonists & inhibitors
Abstract

A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status ((+) or (-)), which identified MET expression as markedly increased in AR(-) samples. In vitro, AR signaling inhibition in AR(+) CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR(+) CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR(-) disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR(-) prostate cancer., (Copyright © 2015 Institut National de la Santé Et de la Recherche Médicale. Published by Elsevier Inc. All rights reserved.)

Published
2016
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14. Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

Author

Gillessen S, Omlin A, Attard G, de Bono JS, Efstathiou E, Fizazi K, Halabi S, Nelson PS, Sartor O, Smith MR, Soule HR, Akaza H, Beer TM, Beltran H, Chinnaiyan AM, Daugaard G, Davis ID, De Santis M, Drake CG, Eeles RA, Fanti S, Gleave ME, Heidenreich A, Hussain M, James ND, Lecouvet FE, Logothetis CJ, Mastris K, Nilsson S, Oh WK, Olmos D, Padhani AR, Parker C, Rubin MA, Schalken JA, Scher HI, Sella A, Shore ND, Small EJ, Sternberg CN, Suzuki H, Sweeney CJ, Tannock IF, and Tombal B

Subjects
Adenocarcinoma pathology, Antineoplastic Agents therapeutic use, Docetaxel, Humans, Male, Orchiectomy, Practice Guidelines as Topic, Prostatectomy, Prostatic Neoplasms pathology, Prostatic Neoplasms, Castration-Resistant pathology, Radiotherapy, Adjuvant, Adenocarcinoma therapy, Androgen Antagonists therapeutic use, Antineoplastic Agents, Hormonal therapeutic use, Bone Density Conservation Agents therapeutic use, Prostatic Neoplasms therapy, Prostatic Neoplasms, Castration-Resistant therapy, Taxoids therapeutic use
Abstract

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Published
2015
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15. Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial.

Author

Zurita AJ, George DJ, Shore ND, Liu G, Wilding G, Hutson TE, Kozloff M, Mathew P, Harmon CS, Wang SL, Chen I, Chow Maneval E, and Logothetis CJ

Subjects
Aged, Aged, 80 and over, Disease-Free Survival, Docetaxel, Drug Resistance, Neoplasm drug effects, Humans, Indoles administration & dosage, Indoles adverse effects, Kaplan-Meier Estimate, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Metastasis drug therapy, Neoplasm Recurrence, Local mortality, Neoplasm Recurrence, Local pathology, Prednisone administration & dosage, Prednisone adverse effects, Prostate-Specific Antigen blood, Prostatic Neoplasms mortality, Prostatic Neoplasms pathology, Pyrroles administration & dosage, Pyrroles adverse effects, Sunitinib, Taxoids administration & dosage, Taxoids adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasm Recurrence, Local drug therapy, Prostatic Neoplasms drug therapy
Abstract

Background: This phase 1/2 study assessed sunitinib combined with docetaxel (Taxotere) and prednisone in chemotherapy-naive metastatic, castration-resistant prostate cancer (mCRPC) patients., Patients and Methods: To determine the recommended phase 2 dose (RP2D), 25 patients in four dose escalation cohorts received 3-week cycles of sunitinib (2 weeks on, 1 week off), docetaxel and prednisone, preceded by a 4-week sunitinib 50 mg/day lead in. RP2D was evaluated in 55 additional patients. The primary end point was prostate-specific antigen (PSA) response rate., Results: One phase 1 dose-limiting toxicity occurred (grade 3 hyponatremia). The RP2D was sunitinib 37.5 mg/day, docetaxel 75 mg/m(2) and prednisone 5 mg b.i.d. During phase 2, confirmed PSA responses occurred in 31 patients [56.4% (95% confidence interval 42.3-69.7)]. Median time to PSA progression was 9.8 months. Forty-one patients (75%) were treated >3 months, 12 (22%) completed the study (16 cycles) and 43 (78%) discontinued (36% for disease progression and 27% adverse events). The most frequent treatment-related grade 3/4 adverse events were neutropenia (53%; 15% febrile) and fatigue/asthenia (16%). Among 33 assessable patients, 14 (42.4%) had confirmed partial response. Median progression-free and overall survivals were 12.6 and 21.7 months, respectively., Conclusion: This combination was moderately well tolerated, with promising response rate and survival benefit, justifying further investigation in mCRPC.

Published
2012
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16. A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma.

Author

Zurita AJ, Jonasch E, Wang X, Khajavi M, Yan S, Du DZ, Xu L, Herynk MH, McKee KS, Tran HT, Logothetis CJ, Tannir NM, and Heymach JV

Subjects
Antineoplastic Agents therapeutic use, Benzenesulfonates therapeutic use, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell mortality, Cluster Analysis, Disease-Free Survival, Enzyme-Linked Immunosorbent Assay, Humans, Interferon-alpha administration & dosage, Kaplan-Meier Estimate, Kidney Neoplasms drug therapy, Kidney Neoplasms mortality, Niacinamide analogs & derivatives, Phenylurea Compounds, Pyridines therapeutic use, Sorafenib, Biomarkers, Tumor blood, Carcinoma, Renal Cell blood, Cytokines blood, Kidney Neoplasms blood, Vascular Endothelial Growth Factor A blood
Abstract

Background: We investigated cytokines and angiogenic factors (CAFs) in patients with metastatic renal cell carcinoma (mRCC) treated in a randomized phase II clinical trial of sorafenib versus sorafenib+ interferon-α (IFN-α) that yielded no differences in progression-free survival (PFS). We aimed to link the CAF profile to PFS and select candidate predictive and prognostic markers for further study., Methods: The concentrations of 52 plasma CAFs were measured pretreatment (n = 69), day 28, and day 56 using multiplex bead arrays and enzyme-linked immunosorbent assay. We investigated the association between baseline levels of CAFs with PFS and posttreatment changes., Results: Unsupervised CAF clustering analysis revealed two distinct mRCC patient groups with elevated proangiogenic or proinflammatory mediators. A six-marker baseline CAF signature [osteopontin, vascular endothelial growth factor (VEGF), carbonic anhydrase 9, collagen IV, VEGF receptor-2, and tumor necrosis factor-related apoptosis-inducing ligand] correlated with PFS benefit (hazard ratio 0.20 versus 2.25, signature negative versus positive, respectively; P = 0.0002). While changes in angiogenic factors were frequently attenuated by the sorafenib+ IFN combination, most key immunomodulatory mediators increased., Conclusions: Using CAF profiling, we identified two mRCC patient groups, a candidate plasma signature for predicting PFS benefit, and distinct marker changes occurring with each treatment. This platform may provide valuable insights into renal cell carcinoma biology and the molecular consequences of targeted therapies.

Published
2012
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17. Dasatinib: a potent SRC inhibitor in clinical development for the treatment of solid tumors.

Author

Araujo J and Logothetis C

Subjects
Animals, Clinical Trials as Topic, Dasatinib, Humans, Protein Kinase Inhibitors pharmacology, src-Family Kinases drug effects, Antineoplastic Agents pharmacology, Neoplasms drug therapy, Pyrimidines pharmacology, Thiazoles pharmacology, src-Family Kinases antagonists & inhibitors
Abstract

SRC is a tyrosine kinase that plays a role in oncogenic, invasive and bone-metastatic processes. It has therefore been prioritized as a candidate therapeutic target in patients with solid tumors. Several SRC inhibitors are now in development, of which dasatinib has been most explored. Preclinical studies in a wide variety of solid tumor cell lines, including prostate, breast and glioma, have shown that that dasatinib acts as a cytostatic agent, inhibiting the processes of cell proliferation, invasion and metastasis. Dasatinib also inhibits the activity of osteoclasts, which have a major role in the development of metastatic bone lesions. Dasatinib has additive or synergistic activity in combination with a number of other agents, including cytotoxic agents and targeted therapies, providing a rationale for combination treatment in a clinical setting. Emerging clinical data with dasatinib support experimental observations, with preliminary phase 1 and 2 data demonstrating activity, both as a single agent and as combination therapy, in a range of solid tumors. Future clinical trials will further assess the clinical value of SRC inhibition with dasatinib., (2010. Published by Elsevier Ltd.)

Published
2010
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18. Department of Defense prostate cancer clinical trials consortium: a new instrument for prostate cancer clinical research.

Author

Morris MJ, Basch EM, Wilding G, Hussain M, Carducci MA, Higano C, Kantoff P, Oh WK, Small EJ, George D, Mathew P, Beer TM, Slovin SF, Ryan C, Logothetis C, and Scher HI

Subjects
Biomedical Research economics, Government Agencies, Humans, Male, Military Personnel, United States, Biomedical Research trends, Clinical Trials as Topic, Neoplasms therapy, Prostatic Neoplasms prevention & control, Research Support as Topic
Abstract

Background: In 2005, the US Department of Defense, through the US Army Medical Research and Materiel Command, Office of the Congressionally Directed Medical Research Programs, created a funding mechanism to form a clinical trials consortium to conduct phase I and II studies in prostate cancer. This is the first report of the Prostate Cancer Clinical Trials Consortium (PCCTC)., Patients and Methods: The Department of Defense award supports a consortium of 10 prostate cancer research centers. Memorial Sloan-Kettering Cancer Center was awarded the Coordinating Center grant for the consortium and charged with creating an infrastructure to conduct early-phase multicenter clinical trials. Each participating center was required to introduce >or=1 clinical trial per year and maintain accrual of a minimum of 35 patients per year., Results: The PCCTC was launched in 2006 and now encompasses 10 leading prostate cancer research centers. Fifty-one trials have been opened, and 1386 patients have been accrued at member sites. Members share an online clinical trial management system for protocol tracking, electronic data capture, and data storage. A legal framework has been instituted, and standard operating procedures, an administrative structure, editorial support, centralized budgeting, and mechanisms for scientific review are established., Conclusion: The PCCTC fulfills a congressional directive to create a clinical trials instrument dedicated to early-phase prostate cancer studies. The member institutions have built an administrative, informatics, legal, financial, statistical, and scientific infrastructure to support this endeavor. Clinical trials are open and accruing in excess of federally mandated goals.

Published
2009
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19. Prognostic factors for survival among Caucasian, African-American and Hispanic men with androgen-independent prostate cancer.

Author

Wyatt RB, Sánchez-Ortiz RF, Wood CG, Ramirez E, Logothetis C, and Pettaway CA

Subjects
Black or African American statistics & numerical data, Aged, Hispanic or Latino statistics & numerical data, Humans, Male, Prognosis, Regression Analysis, Retrospective Studies, White People statistics & numerical data, Prostatic Neoplasms ethnology, Prostatic Neoplasms mortality
Abstract

Background: African-American men suffer disproportionately with respect to the incidence and mortality from prostate cancer. The objective of the current study was to define if race was an independent prognostic factor among other variables assessed for survival among men treated for androgen independent prostate cancer., Methods: Between 1988 and 1995, 379 patients with AIPC and clinical progression were referred for novel protocol therapies. Measured variables included: 1) patient age, 2) race or ethnicity, 3) hemoglobin, 4) alkaline phosphatase, 5) serum prostate-specific antigen (PSA) level, 6) time from hormonal ablation to AIPC, 7) number of metastases on bone scan, 8) osseous stage, 9) number of organ systems with metastases and 10) type of treatment for AIPC., Results: Median survival for the cohort was not significantly affected by race, on uni- or multivariate analysis. Multivariate analysis demonstrated that increasing hemoglobin (HR = 0.87 per g, 95% CI [0.81-0.94]) and time to AIPC (HR = 0.994, 95% CI [0.990-0.998]) were associated with increased survival while higher osseous stage (HR = 1.49, stage I versus II, 95% CI [1.11-1.99]), treatment group (HR = 1.68, treatment group I versus II, 95% CI [1.33-2.12]), metastases to three or more organ systems (HR = 1.31 versus less than three organs, 95% CI [1.15-1.49]), and advanced age (HR = 1.51 for age > 70 versus < or = 70, 95% CI [1.18-1.94]) were associated with a decrease in survival among patients with AIPC., Conclusion: Independent prognostic variables for survival among patients with AIPC included patient age, serum hemoglobin level, time to androgen-independent disease, treatment group and the extent of metastatic disease. Ethnicity did not adversely affect outcome.

Published
2004

20. Germ-cell tumor survivors: the price for cure.

Author

Fizazi K, Chen I, and Logothetis CJ

Subjects
Antineoplastic Combined Chemotherapy Protocols adverse effects, Germinoma mortality, Humans, Kidney drug effects, Male, Survivors, Testicular Neoplasms mortality, Germinoma therapy, Testicular Neoplasms therapy
Published
2002
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21. A 20% dose reduction of the original CISCA/VB regimen allows better tolerance and similar survival rate in disseminated testicular non-seminomatous germ-cell tumors: final results of a phase III randomized trial.

Author

Fizazi K, Do KA, Wang X, Finn L, Logothetis CJ, and Amato RJ

Subjects
Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bleomycin adverse effects, Cisplatin adverse effects, Cyclophosphamide adverse effects, Dose-Response Relationship, Drug, Doxorubicin adverse effects, Humans, Male, Middle Aged, Neoplasm Staging, Neoplasms, Germ Cell and Embryonal pathology, Survival Analysis, Testicular Neoplasms pathology, Time Factors, Vinblastine adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bleomycin administration & dosage, Bleomycin therapeutic use, Cisplatin administration & dosage, Cisplatin therapeutic use, Cyclophosphamide administration & dosage, Cyclophosphamide therapeutic use, Doxorubicin administration & dosage, Doxorubicin therapeutic use, Neoplasms, Germ Cell and Embryonal drug therapy, Testicular Neoplasms drug therapy, Vinblastine administration & dosage, Vinblastine therapeutic use
Abstract

Background: This prospective randomized clinical trial was designed to compare the efficacy of a low-dose regimen of cisplatin, doxorubicin and cyclophosphamide alternated with vinblastine and bleomycin (CISCA/VB) with the original CISCA/VB regimen in patients with disseminated nonseminomatous germ-cell tumors (NSGCT) and a predicted favorable outcome., Patients and Methods: One hundred and twenty-five patients with disseminated NSGCT and a predicted favorable outcome according to the M.D. Anderson Cancer Center classification [testicular primary and human chorionic gonadotropin (hCG) serum level <50000 mIU/ml] were randomized to receive the original CISCA/VB regimen (100% dose) or a low-dose CISCA/VB regimen (80% dose)., Results: Among the 124 eligible patients, there was no significant difference in the number of patients in the two treatment arms who achieved a complete response to therapy: 53 of 65 patients (82%) on the original CISCA/VB regimen and 53 of 59 patients (90%) on the low-dose CISCA/VB regimen (P = 0.29). Overall, the original CISCA/VB regimen resulted in a significantly higher relative dose intensity (P <0.0001). After a median follow-up of 6.8 years (range 0.37 to 12.94 years), there was no significant difference in disease-free survival (P = 0.87) or in overall survival (P = 0.88) between the two treatment arms. The 5-year overall survival rate was 93.7% [95% confidence interval (CI) 88% to 100%] and 94.1% (95% CI 84% to 100%) in the original CISCA/VB arm and the low-dose CISCA/VB arm, respectively. The 5-year overall survival rate for the entire study population was 98% (95% CI 94% to 100%) and 88% (95% CI 76% to 100%) in the good- and intermediate-prognosis groups, respectively, as defined by the International Germ Cell Consensus Classification Group (IGCCCG). The low-dose CISCA/VB regimen resulted in significantly less neutropenic fever (P <0.001), grade 4 thrombocytopenia (P <0.03) and severe mucositis (P <0.01) than the original CISCA/VB regimen., Conclusions: CISCA/VB is highly efficient in patients with good or intermediate prognosis NSGCT according to the IGCCCG criteria. Although equivalent antitumor efficacy cannot be claimed, the low-dose CISCA/VB regimen appears to be a better mode of delivery than the original CISCA/VB regimen with respect to toxicity, since survival is comparable.

Published
2002
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22. Randomized phase 2 trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate cancer.

Author

Millikan R, Baez L, Banerjee T, Wade J, Edwards K, Winn R, Smith TL, and Logothetis C

Abstract

Eighty-nine patients with progressive prostate cancer despite suppression of testosterone and withdrawal of anti-androgens were studied. This was a relatively advanced population, with 63 of 89 having either osseous metastases (mets) beyond the axial skeleton or visceral mets. Patients were randomly assigned to receive either ketoconazole alone, or ketoconazole with weekly doxorubicin. All patients received replacement hydrocortisone. The primary endpoints were response and survival. Based on PSA reduction criteria (>/= 80% maintained for at least 8 weeks), 14 of 45 patients (31%) in the single-agent ketoconazole arm responded. Sixteen of 44 patients (36%) in the combination ketoconazole/doxorubicin arm responded. There were no important differences between the two treatments in any outcome measure. The median overall survival for all patients was 12.5 months; median time to progression was 3.3 months. Toxicity was significant with both regimens, and more severe in the doxorubicin arm. Fully 20% of patients in each arm discontinued therapy due to intolerable side effects.Each of these regimens is toxic, and produced responses in fewer than half of treated patients. Although the observed median survival does compare favorably with reports from similar cohorts treated in the community, the potential benefit is only modest. In our view, neither of these regimens is sufficiently promising to justify phase 3 evaluation.

Published
2001
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23. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial.

Author

Tu SM, Millikan RE, Mengistu B, Delpassand ES, Amato RJ, Pagliaro LC, Daliani D, Papandreou CN, Smith TL, Kim J, Podoloff DA, and Logothetis CJ

Subjects
Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Bone Neoplasms mortality, Carcinoma mortality, Doxorubicin administration & dosage, Humans, Male, Middle Aged, Prostate-Specific Antigen blood, Prostatic Neoplasms mortality, Survival Analysis, Texas epidemiology, Bone Neoplasms prevention & control, Bone Neoplasms secondary, Carcinoma drug therapy, Prostatic Neoplasms drug therapy, Strontium Radioisotopes therapeutic use
Abstract

Background: Prostate carcinoma is linked to osteoblastic metastasis. We therefore investigated the value of bone-targeted consolidation therapy in selected patients with advanced androgen-independent carcinoma of the prostate., Methods: 103 patients received induction chemotherapy, consisting of ketoconazole and doxorubicin alternating with estramustine and vinblastine. After two or three cycles of induction chemotherapy, we randomly assigned 72 patients who were clinically stable or responders to receive doxorubicin with or without strontium-89 (Sr-89) every week for 6 weeks., Findings: Overall 62 of the 103 (60%, 95% CI 50-70) patients had a 50% or greater reduction in serum prostate-specific antigen concentration that was maintained for at least 8 weeks, and 43 (42%, 32-52) had an 80% or greater reduction. 49 (52%) patients with bone pain at registration had complete resolution of pain. After follow-up of 67 patients until death, the estimated median survival for all 103 patients was 17.5 months (range 0.5-37.7). For the 36 patients randomly assigned to receive Sr-89 and doxorubicin, the median survival time was 27.7 months (4.9-37.7), and for the 36 who received doxorubicin alone it was 16.8 months (4.4-34.2) (p=0.0014). The hazard ratio was 2.76 (95% CI 1.44-5.29)., Interpretation: Bone-targeted consolidation therapy consisting of one dose of Sr-89 plus doxorubicin once a week for 6 weeks, when given to patients with stable or responding advanced androgen-independent carcinoma of the prostate after induction chemotherapy, improved overall survival.

Published
2001
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24. The pattern of serum markers in patients with androgen-independent adenocarcinoma of the prostate.

Author

Kim J, Palmer JL, Finn L, Hodges S, Bowes V V, Deftos L, Murphy G, and Logothetis C

Abstract

In this exploratory study, our objectives were to correlate the serum and bone marrow concentrations of putative markers of prostate cancer progression in patients with advanced androgen-independent prostate cancer (AIPC), to assess the frequency and quantity of relative expression of these markers, and to correlate the expression of the markers with extent of disease (EOD) and overall survival. In a cohort of 50 patients with AIPC with bone metastases, we obtained serum and bone marrow samples and measured prostate specific antigen (PSA), serum interleukin-6 (sIL-6), bone marrow interleukin-6, serum chromogranin A (sCgA), bone marrow chromogranin A, and prostate specific membrane antigen (PSMA) by immunoassays. EOD was determined by quantifying identifiable bone lesions on radionuclide bone scans. Each variable was categorized into two groups (low and high) based on the median found in this cohort or on the cutoff based on normal limits when available. Analyses were performed in two subsets of patients with EOD either <20 or >/=20. Results showed that: (1) PSA is associated with EOD but not with outcome; (2) sIL-6 and sCgA may be intermediate markers of early progression in AIPC, because they are predictive of outcome only in patients with EOD <20; (3) elevated PSMA is associated with elevated sIL-6 but not with PSA, suggesting that PSMA may be a useful marker in AIPC; and (4) the ratio of PSA to putative markers of progression may reflect the complex clonal progression of prostate cancer. We conclude that patients with advanced AIPC exhibit one of two patterns of serologic marker expression: in some patients the disease status is reflected by PSA, and in others it is reflected by other markers. If these data are prospectively confirmed, this would help group patients with advanced AIPC into clinically relevant categories.

Published
2000
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25. Calcium signals in prostate cancer cells: specific activation by bone-matrix proteins.

Author

Lecrone V, Li W, Devoll RE, Logothetis C, and Farach-Carson MC

Subjects
Adenosine Triphosphate metabolism, Adenosine Triphosphate pharmacology, Animals, Bone Morphogenetic Proteins analysis, Bone Morphogenetic Proteins chemistry, Bone Neoplasms drug therapy, Bone Neoplasms metabolism, Brain Neoplasms drug therapy, Brain Neoplasms metabolism, Chemical Fractionation, Fluorescent Dyes analysis, Fura-2 analysis, Humans, Lymphatic Metastasis, Male, Osteonectin pharmacology, Osteopontin, Prostatic Neoplasms drug therapy, Prostatic Neoplasms secondary, Prothrombin pharmacology, Rats, Receptors, Vitronectin metabolism, Sialoglycoproteins chemistry, Sialoglycoproteins pharmacology, Thrombin pharmacology, Tissue Extracts chemistry, Tissue Extracts pharmacology, Tumor Cells, Cultured, Bone Morphogenetic Proteins pharmacology, Calcium Signaling, Prostatic Neoplasms metabolism
Abstract

Cancer of the prostate commonly metastasizes to bony sites where cells acquire an aggressive, rapidly proliferating, androgen-independent phenotype. The interaction between bone and prostate, thus, becomes a key factor in disease progression. Fluctuations in intracellular ionized Ca2+ [Ca2+]i are rapid, regulated signal transduction events often associated with cell proliferation. Hence, Ca2+ signals provide a convenient measure of early events in cancer cell growth. This study developed single cell fluorescent imaging techniques to visualize Ca2+ signals in Fura-2 loaded prostatic cancer cell lines of various metastatic phenotypes. Solubilized bone fractions containing extracellular matrix and associated proteins were tested for the ability to trigger Ca2+ signals in prostate cancer cell lines. Fractions representing the complete repertoire of non-collagenous proteins present in mineralized bone were tested. Results demonstrated that two bone fractions termed D3b- and D4a-triggered Ca2+ signals in prostate cancer cells derived from bone (PC-3), but not brain (DU-145) metastases of prostate cancer. Lymph-node derived LNCaP cells also did not produce a Ca2+ signal in response to addition of soluble bone matrix. No other bone fractions produced a Ca2+ signal in PC-3 cells. It is of interest that bone fractions D3b and D4a contain a number of non-collagenous matrix proteins including osteonectin (SPARC) and osteopontin (OPN), as well as prothrombin. Moreover, antibody LM609 that recognizes the alpha v beta 3 integrin, blocks the ability of OPN to trigger a Ca2+ transient in PC-3 cells. These studies support a conclusion that bone-matrix proteins play a role in the growth and progression of metastatic prostate cancer, and that prior growth in bone may be associated with development of a bone-matrix-responsive phenotype.

Published
2000
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26. Strontium-89 combined with doxorubicin in the treatment of patients with androgen-independent prostate cancer.

Author

Tu SM, Delpassand ES, Jones D, Amato RJ, Ellerhorst J, and Logothetis CJ

Abstract

We investigated the activity of a bone-targeting regimen consisting of strontium-89 and doxorubicin in the treatment of patients with androgen-independent prostate cancer. Three and 22 patients with androgen-independent prostate cancer and bone metastasis received doxorubicin at 15 mg/m(2) and 20 mg/m(2), respectively (intravenously by continuous infusion over 24 hours, once per week). All patients received strontium-89 55 μCi/kg, intravenously, every 3 months. Antitumor activity (a prostate specific antigen decrease of ≥75% from baseline) was seen in 32% of evaluable patients. Clinical benefit based on pain relief and performance improvement was achieved in 76% and 40% of patients, respectively. Strontium-89 combined with doxorubicin can be delivered with acceptable toxicities. Strontium-89 combined with doxorubicin is active in the treatment of androgen-independent prostate cancer and may be useful in future studies designed to optimize organ (bone)-specific therapies.

Published
1996
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27. Absence of antitumor activity with prednisone in patients with progressive androgen-independent prostate carcinoma.

Author

Amato RJ, Ellerhorst J, Finn L, and Logothetis CJ

Abstract

Corticosteroids are reported to have antitumor activity in patients with androgen-independent prostate carcinoma (AIPCa). This trial, a phase II trial of daily oral prednisone 10 mg four times per day for 56 consecutive days, was designed to confirm this finding. From November 1989 to September 1992 16 patients were enrolled in the study. Baseline tumor measurements were taken upon enrollment and re-evaluated at completion of 56 days. If the patient was responding or stable, a maintenance schedule of 5 mg four times per day was resumed until unacceptable toxicity was reached or tumor growth progressed. Antitumor activity was assessed by the decline in the serum level of prostate specific antigen. Entry criteria included strict evidence for progressive AIPCa, tumor growth associated with castrate testosterone level below 50 ng/dl, and adrenal cortical function tests. Patients continued hormone therapy that induced castrate testosterone level. Two patients required early cessation of therapy secondary to symptomatic tumor progression. Of the remaining 14 patients, no responses were seen,. Four (29%) of 16 patients had transient improvement in performance status. No hematologic toxicity was observed. Nonhematologic toxicity was mild and manageable, consisting of fluid retention and metabolic laboratory abnormalities. Suppressive effect of adrenal cortical function was demonstrated in patients, measured by a decrease in serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate. Our results show that corticosteroids have no significant antitumor activity in patients with true progressive AIPCa.

Published
1996
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28. A phase I trial of intermittent high-dose alpha-interferon and dexamethasone in metastatic renal cell carcinoma.

Author

Amato R, Meyers C, Ellerhorst J, Finn L, Kilbourn R, Sella A, and Logothetis C

Subjects
Administration, Oral, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Carcinoma, Renal Cell secondary, Central Nervous System drug effects, Dexamethasone administration & dosage, Dose-Response Relationship, Drug, Drug Interactions, Female, Humans, Injections, Subcutaneous, Interferon-alpha administration & dosage, Interferon-alpha adverse effects, Kidney Neoplasms pathology, Male, Middle Aged, Neuropsychological Tests, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Renal Cell drug therapy, Dexamethasone therapeutic use, Interferon-alpha therapeutic use, Kidney Neoplasms drug therapy
Abstract

Background: Evidence exists that the toxic of alpha-interferon can be ameliorated by co-administration of dexamethasone without compromise of therapeutic efficacy. We therefore conducted a phase I trial to determine the maximum tolerated dose of intermittent interferon when combined with oral dexamethasone., Patients and Methods: Thirty patients with metastatic renal cell carcinoma were enrolled. The starting dose of interferon was 20 million IU/m2/day given as a subcutaneous injection days 1 to 4 of each 14 day cycle. Dose levels were escalated at increments of 5 million IU/m2. Dexamethasone 4 mg was administered orally every 6 hours during administration of high-dose interferon. Low-dose maintenance interferon, 3 million IU/m2/day, was administered without dose escalation on days 5 to 14 of each cycle., Results: The maximum tolerated dose of intermittent high-dose interferon was 40 million IU/m2/day. The dose limiting toxicity was fatigue. EEG abnormalities developed in five patients and neuropsychiatric parameters deteriorated significantly in seventeen., Conclusions: We conclude that co-administration of dexamethasone improves the tolerance of intermittent high-dose interferon. The results of this trial may be useful in designing high-dose interferon regimens for renal cell carcinoma and other interferon-sensitive diseases.

Published
1995
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29. Clinical significance of elevation in neuroendocrine factors and interleukin-6 in metastatic prostate cancer.

Author

Hoosein N, Abdul M, McCabe R, Gero E, Deftos L, Banks M, Hodges S, Finn L, and Logothetis C

Abstract

Serum biomarkers that reflect the complex pathways of cancer progression have contributed to the clinical understanding of many malignancies. Recent studies have suggested that certain neuroendocrine (NE) elements participate in prostate cancer (PCa) progression. Interleukin-6 (IL-6) may serve as a useful marker of and contribute to PCa morbidity. The purpose of this study was to assess the frequency of elevation of two NE factors, chromogranin A (CGA) and bombesin-like immunoreactivity (BLI), in patients with advanced PCa and to determine their relationship to serum prostate-specific antigen PSA) and IL-6 levels, as well as known prognostic indicators (hormonal state, stage). Serum CGA determined by radioimmunoassay was elevated in I (7%) of 15 androgen-dependent (AD) patients and II (52%) of 21 androgen-independent (AI) patients; and urine BLI determined by radioimmunoassay was elevated in 2 (13%) of 16 AD patients and 10 (39%) of 21 AI patients. Frequency of elevation was higher in patients with distant metastasis (bone, visceral) compared with those with local/regional extensions of the disease. Levels of the NE factors correlated well with serum and bone marrow aspirate IL-6 concentrations but not with serum PSA levels. Elevation in either NE factor predicted for shortened survival. Measurement of NE factors in PCa identifies a subset of patients with advanced disease likely to express high levels of IL-6 and have a shorter survival. If confirmed, these findings will support the existence of a clinically relevant subset of patients in whom NE factors are involved in AI PCA progression.

Published
1995
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30. Paclitaxel in extensively pretreated nonseminomatous germ cell tumors.

Author

Nazario A, Amato RJ, Hutchinson L, Bui C, Ellerhorst J, and Logothetis CJ

Abstract

Paclitaxel was given as a single agent to previously treated, cisplatin-refractory, and relapsed patients with metastatic nonseminomatous germ cell tumors (GCT). Fifteen patients received paclitaxel at 250 mg/m(2) as a 24-hour continuous intravenous infusion, repeated every 21 days. The regimen was premedicated to prevent hypersensitivity reactions. Patients were supported with granulocyte-colony stimulating factor until resolution of the neutropenia. Of 15 patients, I I patients had received at least three previous chemotherapy regimens; 80% of the patients were cisplatin-refractory at study entry. A total of 34 courses of paclitaxel were delivered. A serologic partial response and a partial remission for an overall response rate of 13.3% (95% C.I. 2-39%), with a median duration of 9.5 weeks, were achieved. Thirteen (86.6%) patients developed progressive disease. The toxicity of the regimen consisted of grade 3 4 neutropenia, with only one infectious complication and no life-threatening events. Nonhematologic toxicity was significant for progressive peripheral neuropathy in 8 patients. No hypersensitivity reactions or symptomatic cardiac toxicity occurred. In conclusion, paclitaxel in the dose and schedule given has minimal activity in this extensively treated, cisplatin-refractory group of patients with nonseminomatous GCT. Further investigation is warranted to find the role of paclitaxel in GCT by either selecting a better patient population and/or combining it with cisplatin, which would use the synergistic cytotoxicity that has been reported.

Published
1995
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31. Estramustine and vinblastine for patients with progressive androgen-independent adenocarcinoma of the prostate.

Author

Amato RJ, Ellerhorst J, Bui C, and Logothetis CJ

Abstract

A phase II trial was performed to assess antitumor activity and toxicity of estramustine and vinblastine in 31 consecutive patients with androgen-independent prostate cancer. All patients presented with disease progression following castrate serum testosterone levels of less than 50 ng/dl and were treated for 6 consecutive weeks with three daily 140-mg doses of oral estramustine and vinblastine at 6 mg/m(2) weekly by intravenous bolus. Prostate specific antigen (PSA) levels decreased by greater than 50% from baseline in 13 (46%; 95% confidence intervals, 27%-66%) of 28 evaluable patients. Patients who demonstrated a greater than 50% reduction in PSA had a longer delay in time to disease progression. Nonhematologic toxicity was mild, predominantly gastrointestinal. Hematologic toxicity was apparent in 13 patients with grade III granulocytopenia and in 7 patients with grade IV granulocytopenia. No patient was admitted to the hospital for neutropenic fever. Estramustine and vinblastine is a well-tolerated combination. This combination and the clinical significance of this decline in PSA warrants further investigation.

Published
1995
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32. A phase I study of FAP (5-Fluorouracil, α-interferon and cisplatin) combined with methotrexate for the treatment of advanced urothelial malignancies.

Author

Tu SM, Robinson ED, Amato RJ, Ellerhorst JA, Kilbourn RG, and Logothetis CJ

Abstract

Combination chemotherapy using 5-fluorouracil and α-interferon is active against advanced urothelial cancers. Its toxcity profile appears favorable such that addition of other active agents (i.e., cisplatin and methotrexate) may improve its therapeutic window. Our goal was to identify the starting dose of FAP (5-fluorouracil-α-interferon-cisplatin) that will permit delivery of methotrexate in patients with advanced chemotherapy-refractory urothelial cancers. This is a phase 1 study in which the dose level of FAP that permitted delivery of two doses of methotrexate in 28 days will be considered the maximum tolerated dose (MTD). This is based on experiences with MVAC chemotherapy in which only half of the patients received two doses of methotrexate in a 28 days cycle. The dose level identified as the MTD is as follows: 5-FU 500 mg/m(2) by intravenous continuous infusion daily for 5 days in weeks 1 and 4; α-interferon 5 MU/m(2) subcutaneously daily for 5 days simultaneously with 5-FU infusion in weeks 1 and 4 and thrice weekly during weeks 2 and 3; and cisplatin 25 mg/m(2) plus methotrexate 30 mg/m(2) intravenously once weekly for 4 weeks. The treatment will be repeated every 6 weeks. Most of the significant toxic effects, including mucositis, neutropenia, and thrombocytopenia, are encountered during weeks 3 and 4. This study showed that the MTD for FAP combined with methotrexate has been determined for phase II studies. Exploration of alterative regimen such as FAP in the treatment of advanced urothelial cancer is warranted. FAP has a unique mechanism of action and acceptable toxicity profile that may allow novel drug combinations and improved therapeutic efficacy.

Published
1995
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33. Evidence for the existence of an organ specific, androgen-independent pathway of progression in patients with metastatic prostate cancer.

Author

Hsieh JT, Wu HC, Wang Y, Song WT, Li W, Finn L, and Logothetis CJ

Abstract

Ample clinical and preclinical data support the central role of bone-epithelial interaction in the progression of prostate cancer. The clinical progression of prostate cancer has been partially attributed to a cascade of interactions between the cancer compartment and microenvironment compartments. The expression of prostate specific antigen (PSA) parallels the activity of the epithelial compartment of prostate cancer. However, the clinical study of the bone-epithelial interaction has been limited by the lack of accessible relevant human tissue for study. This study was designed (1) to assess the value of human bone marrow as a source of tissue to study the bone-epithelial interaction and (2) to determine whether bone marrow supernatant regulates the expression of PSA in a human prostate cancer cell line (LNCaP) in vitro. The acellular bone marrow supernatant derived from patients with prostate cancer with different degrees of tumor spread, hormonal status, and histology were assayed for their ability to induce PSA expression in a human LNCaP. The bone marrow supernatants were derived from 53 patients with prostate cancer (49 with adenocarcinoma and 4 with small cell carcinoma) and eight control patients, who had cancers in other sites. In addition, the match serum specimens derived from 25 of the study patients also had been assayed for its PSA inductivity. In addition to the comparison with "static" serum and BM concentration of PSA, the rate of significant PSA induction by clinical stage and hormonal status was assessed. Patients with androgen-independent disease had the highest rate of PSA-inducing ability. Only two patients (8%) had weak PSA-inducing ability from their serum (both with high volume disease) and none of the bone marrow supernatants derived from patients without prostate cancer or small cell carcinoma had inducing ability. No correlation between the static BM or serum PSA concentrations and the inducing ability was seen. These results indicate that PSA expression can be regulated by androgen-independent factors. The bone marrow supernatant of patients with prostate cancer has unique properties and is a valuable source of tissue for clinical study of the progression of prostate cancer. These preliminary data suggest that induction of PSA by bone marrow supernatant should be studied for its clinical utility as an assay for the interaction between the epithelial and bone compartments, and it supports the existence of androgen-independent pathways of PSA regulation by the bone marrow supernatant of patients with advanced prostate cancer. If confirmed, these findings would support the use of bone marrow supernatant to study the osseous specific progression of prostate cancer.

Published
1995
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34. Secretion of prostate-specific antigen-suppressing activity by two human prostate carcinoma cell lines.

Author

Abdul M, Hsieh JT, Logothetis CJ, and Hoosein NM

Abstract

The well-differentiated human prostatic carcinoma cell line LNCaP has often been used as a model to study the modulation of prostate-specific antigen (PSA) expression. In this study, we examined the effect of conditioned medium from two androgen-unresponsive, PSA-negative human prostatic carcinoma cell lines, PC-3 and DU-145, on PSA expression by the LNCaP cells. Our results show, for the first time, that the undifferentiated PC-3 and DU-145 cells secrete a factor that lowers PSA mRNA and protein levels in LNCaP cells. Further characterization of the PSA-suppressing activity indicated that it was trypsin as well as acid sensitive, heat-stable, and ammonium sulfate precipitable. The activity was present in the 30-100-kd fraction of PC-3 and DU-145 conditioned media. This PSA-suppression factor could act in an autocrine manner to render undifferentiated prostatic carcinoma cells PSA negative. It may also be responsible for the lack of increase in serum PSA levels observed in a subset of patients with hormone-resistant prostatic carcinoma.

Published
1995
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35. Endodermal sinus tumors.

Author

Logothetis CJ

Subjects
Adult, Combined Modality Therapy, Female, Humans, Infant, Infant, Newborn, Male, Mediastinal Neoplasms drug therapy, Mediastinal Neoplasms metabolism, Mesonephroma drug therapy, Mesonephroma metabolism, Middle Aged, alpha-Fetoproteins metabolism, Mediastinal Neoplasms surgery, Mesonephroma surgery
Published
1985
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36. Surgery in the management of stage III germinal cell tumors. Observations on the M.D. Anderson Hospital experience, 1971-1979.

Author

Logothetis CJ and Samuels ML

Subjects
Adolescent, Adult, Bleomycin therapeutic use, Chorionic Gonadotropin blood, Chorionic Gonadotropin, beta Subunit, Human, Cisplatin therapeutic use, Combined Modality Therapy, Dysgerminoma pathology, Dysgerminoma surgery, Humans, Male, Middle Aged, Neoplasm Staging, Peptide Fragments blood, Retrospective Studies, Teratoma pathology, Teratoma surgery, Testicular Neoplasms pathology, Tomography, X-Ray Computed, Vinblastine therapeutic use, alpha-Fetoproteins analysis, Testicular Neoplasms surgery
Abstract

Sixty patients with initial stage III germinal tumors treated with conventional vinblastine, bleomycin and cisplatin chemotherapy (VB + P) were surgically explored. Twenty-two patients not treated with an initial retroperitoneal node dissection were surgically explored to pathologically confirm a complete remission following chemotherapy. Thirty-eight patients had a persistent mass in the absence of elevated serum markers. Seventeen (28%) patients had viable carcinoma at surgery. Eight (47%) of the 17 patients with viable carcinoma at surgery died of recurrent tumor. All but three patients with persistent viable carcinoma at surgery were treated with surgery followed by chemotherapy. Fourteen patients were found to have mature teratoma and one (7%) developed recurrent carcinomatosis. Two (8%) of the 25 patients found to have scar died. One patient died of recurrent carcinomatosis and one of postoperative complications. Ten additional patients with a suboptimal response to chemotherapy were surgically explored for attempted salvage. All ten died of recurrent tumor, with a median postoperative survival of 7 months. We believe optimal individualized chemotherapy is required for the management of stage III testis cancer. Therapeutic benefit for surgery can be demonstrated only in unusual circumstances. Attempted surgical excision of a clinically active germinal tumor is futile; hence patients with elevated serum biomarkers should not be explored. Patients with non-seminomatous germinal tumors and a residual postchemotherapy mass must be explored. The excision of mature teratoma is mandatory, as is documentation of the absence of viable carcinoma prior to cessation of therapy.

Published
1984
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37. Carcinoma-in-situ of the testis.

Author

Logothetis CJ

Subjects
Humans, Male, Neoplasms, Germ Cell and Embryonal classification, Carcinoma in Situ classification, Testicular Neoplasms classification
Published
1987
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38. Endodermal sinus tumor of the mediastinum. Report of apparent cure in two patients with extensive disease.

Author

Rusch VW, Logothetis C, and Samuels M

Subjects
Adult, Bleomycin administration & dosage, Cisplatin administration & dosage, Combined Modality Therapy, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Humans, Male, Mediastinal Neoplasms drug therapy, Mediastinal Neoplasms surgery, Mesonephroma drug therapy, Mesonephroma surgery, Vinblastine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Mediastinal Neoplasms therapy, Mesonephroma therapy
Abstract

Primary endodermal sinus tumor (EST) of the mediastinum has been regarded as a rare and rapidly fatal germ cell neoplasm. We describe two cases of extensive EST treated with a new high-dose sequential combination chemotherapy regimen (CISCA-VB) followed by radical surgical excision. They are alive at 11 and 20 months, respectively, postoperatively. These cases stand in marked contrast to previously reported series. A new approach to the management of this tumor is proposed.

Published
1984
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