Combined Longitudinal Clinical and Autopsy Phenomic Assessment in Lethal Metastatic Prostate Cancer: Recommendations for Advancing Precision Medicine

Juho Jasu; Teemu Tolonen; Emmanuel S. Antonarakis; Himisha Beltran; Susan Halabi; Mario A. Eisenberger; Michael A. Carducci; Yohann Loriot; Kim Van der Eecken; Martijn Lolkema; Charles J. Ryan; Sinja Taavitsainen; Silke Gillessen; Gunilla Högnäs; Timo Talvitie; Robert J. Taylor; Antti Koskenalho; Piet Ost; Teemu J. Murtola; Irina Rinta-Kiikka; Teuvo Tammela; Anssi Auvinen; Paula Kujala; Thomas J. Smith; Pirkko Liisa Kellokumpu-Lehtinen; William B. Isaacs; Matti Nykter; Juha Kesseli; G. Steven Bova

doi:10.1016/j.euros.2021.05.011

Combined Longitudinal Clinical and Autopsy Phenomic Assessment in Lethal Metastatic Prostate Cancer: Recommendations for Advancing Precision Medicine

Juho Jasu, Teemu Tolonen, Emmanuel S. Antonarakis, Himisha Beltran, Susan Halabi, Mario A. Eisenberger, Michael A. Carducci, Yohann Loriot, Kim Van der Eecken, Martijn Lolkema, Charles J. Ryan, Sinja Taavitsainen, Silke Gillessen, Gunilla Högnäs, Timo Talvitie, Robert J. Taylor, Antti Koskenalho, Piet Ost, Teemu J. Murtola, Irina Rinta-KiikkaTeuvo Tammela, Anssi Auvinen, Paula Kujala, Thomas J. Smith, Pirkko Liisa Kellokumpu-Lehtinen, William B. Isaacs, Matti Nykter, Juha Kesseli, G. Steven Bova

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Background: Systematic identification of data essential for outcome prediction in metastatic prostate cancer (mPC) would accelerate development of precision oncology.

Objective: To identify novel phenotypes and features associated with mPC outcome, and to identify biomarker and data requirements to be tested in future precision oncology trials.

Design setting and participants: We analyzed deep longitudinal clinical, neuroendocrine expression, and autopsy data of 33 men who died from mPC between 1995 and 2004 (PELICAN33), and related findings to mPC biomarkers reported in the literature.

Intervention: Thirty-three men prospectively consented to participate in an integrated clinical-molecular rapid autopsy study of mPC.

Outcome measurements and statistical analysis: Data exploration with correction for multiple testing and survival analysis from the time of diagnosis to time to death and time to first occurrence of severe pain as outcomes were carried out. The effect of seven complications on the modeled probability of dying within 2 yr after presenting with the complication was evaluated using logistic regression.

Results and limitations: Feature exploration revealed novel phenotypes related to mPC outcome. Four complications (pleural effusion, severe anemia, severe or controlled pain, and bone fracture) predict the likelihood of death within 2 yr. Men with Gleason grade group 5 cancers developed severe pain sooner than those with lower-grade tumors. Surprisingly, neuroendocrine (NE) differentiation was frequently observed in the setting of high serum prostate-specific antigen (PSA) levels (≥30 ng/ml). In 4/33 patients, no controlled (requiring analgesics) or severe pain was detected, and strikingly, 14/15 metastatic sites studied in these men did not express NE markers, suggesting an inverse relationship between NE differentiation and pain in mPC. Intracranial subdural metastasis is common (36%) and is usually clinically undetected. Categorization of "skeletal-related events" complications used in recent studies likely obscures the understanding of spinal cord compression and fracture. Early death from prostate cancer was identified in a subgroup of men with a low longitudinal PSA bandwidth. Cachexia is common (body mass index <0.89 in 24/31 patients) but limited to the last year of life. Biomarker review identified 30 categories of mPC biomarkers in need of winnowing in future trials. All findings require validation in larger cohorts, preferably alongside data from this study.

Conclusions: The study identified novel outcome subgroups for future validation and provides "vision for mPC precision oncology 2020-2050" draft recommendations for future data collection and biomarker studies.

Patient summary: To better understand variation in metastatic prostate cancer behavior, we assembled and analyzed longitudinal clinical and autopsy records in 33 men. We identified novel outcomes, phenotypes, and aspects of disease burden to be tested and refined in future trials.

Original language	English (US)
Pages (from-to)	47-62
Number of pages	16
Journal	European Urology Open Science
Volume	30
DOIs	https://doi.org/10.1016/j.euros.2021.05.011
State	Published - Aug 2021

Bibliographical note

Funding Information:
Funding/Support and role of the sponsor: Financial support to G. Steven Bova for the PELICAN33 study includes the following: the Academy of Finland (2011 to present), Cancer Society of Finland (2013 to present), Sigrid Juselius Foundation (2016 to present), C.J. Heilig Foundation (2010), PELICAN Autopsy Study family members and friends (1998–2004), John and Kathe Dyson (2000), US National Cancer Institute CA92234 (2000–2005), American Cancer Society (1998–2000), Millenium Pharmaceuticals (1998–2002), Johns Hopkins University Department of Pathology (1997–2011), Johns Hopkins Oncology Center (1994–2004), Women’s Board of Johns Hopkins Hospital (1998), the Grove Foundation (1998), Schering-Plough (1998), Nycomed Amersham (1998), Association for the Cure of Cancer of the Prostate (1994–1998), Brady Urological Institute (1994–1997), and American Foundation for Urologic Disease (1991–1994). Financial support to Thomas J. Smith includes US NCI grants P30 006973 and CA177562 , PCORI IHS 1609-36518 , the Harry J. Duffey Family Fund for Palliative Care , and The Lerner Foundation, Washington DC .

Funding Information:
Financial disclosures: G. Steven Bova certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Juho Jasu, Susan Halabi, Mario A. Eisenberger, Kim Van der Eecken, Sinja Taavitsainen, Gunilla Högnäs, Timo Talvitie, Robert J. Taylor, Antti Koskenalho, Paula Kujala, Thomas J. Smith, William B. Isaacs, Matti Nykter, and Juha Kesseli have no conflict of interest disclosures. Teemu Tolonen has received honoraria from Roche and Objective Imaging, and travel and accommodation expenses from Roche and Pfizer. Emmanuel S. Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, Lilly, Bayer, AstraZeneca, Bristol-Myers Squibb, Clovis, and Merck; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis, and Merck; and is the coinventor of an AR-V7 biomarker technology that has been licensed to Qiagen. Himisha Beltran has served as a consultant/advisory board member for Janssen, Sanofi Genzyme, Astellas, Astra Zeneca, Merck, Pfizer, and Blue Earth, and has received research funding from Janssen Oncology (Inst), AbbVie/Stemcentrx (Inst), Eli Lilly (Inst), and Millennium Pharmaceuticals (Inst). Michael A. Carducci reports past consultation for Pfizer, Astellas, and Exelexis, and current research funding from Arcus, Pfizer, and Merck. Yohann Loriot has received personal fees from Immunomedics; personal fees and nonfinancial support from Roche, AstraZeneca, BMS, Pfizer, Astellas, and Seattle Genetics; and grant support, personal fees, and nonfinancial support from MSD and Janssen. Martijn Lolkema has received personal fees from Incyte, Amgen, Bayer, Servier, Roche, INCa, Pfizer, AstraZeneca, Novartis, and Julius Clinical, and grants and personal fees from JnJ, Sanofi, Astellas, and MSD. Charles J. Ryan has received consulting fees from Bayer, Janssen, and Sanofi Genzyme; has received funds for research support from Clovis Oncology and the Prostate Cancer Foundation; has received fees for non-CME/CE services from Janssen; and has served in a study leadership position for Clovis Oncology. Silke Gillessen: has received (last 3 yr) honoraria from Janssen Cilag; received consulting fees from or had an advisory role (including IDMC) at Astellas Pharma, Amgen, Roche, Pfizer, AAA International, Janssen, Innocrin Pharma Inst, Sanofi, Bayer, Orion Pharma GmbH, Clovis Oncology, Menarini Silicon Biosystems, Tolero Pharmaceuticals, and MSD; reports patents, royalties, other intellectual property for Method for biomarker WO2009138392; has received travel grant from ProteoMediX; and has other relationship with Aranda. Piet Ost reports a consulting/scientific advisory role at Bayer, Janssen, Curium, and Ferring, and has received grants for clinical research from Ferring, Merck, Varian, and Bayer. Teemu J. Murtola has received honoraria from Astellas, Janssen, Novartis, and Sanofi; has received travel and accommodation expenses from Sanofi and Pfizer; reports patents, royalties, and other intellectual property from Arocell; reports stock and other ownership interests in Arocell; and has received research funding from Arocell. Teuvo Tammela has received research funding from Finnish Cancer Society and Sigrid Juselius Foundation, and has been an investigator in studies sponsored by Bayer, Astellas, Orion Pharma, and Pfizer. Anssi Auvinen has received lecture fees from Amgen and Janssen. Pirkko-Liisa Kellokumpu-Lehtinen has been a consultant/advisor to Bristol Myers Squibb and MSD; has received research funding for her institution from Eli Lilly, Roche, Sanofi and Merck; and has received travelling expenses from Sanofi. G. Steven Bova reports speaker’s fees from Brupbacher Foundation, Sanofi Aventis, and Astellas Pharma.

Funding Information:
Funding/Support and role of the sponsor: Financial support to G. Steven Bova for the PELICAN33 study includes the following: the Academy of Finland (2011 to present), Cancer Society of Finland (2013 to present), Sigrid Juselius Foundation (2016 to present), C.J. Heilig Foundation (2010), PELICAN Autopsy Study family members and friends (1998?2004), John and Kathe Dyson (2000), US National Cancer Institute CA92234 (2000?2005), American Cancer Society (1998?2000), Millenium Pharmaceuticals (1998?2002), Johns Hopkins University Department of Pathology (1997?2011), Johns Hopkins Oncology Center (1994?2004), Women's Board of Johns Hopkins Hospital (1998), the Grove Foundation (1998), Schering-Plough (1998), Nycomed Amersham (1998), Association for the Cure of Cancer of the Prostate (1994?1998), Brady Urological Institute (1994?1997), and American Foundation for Urologic Disease (1991?1994). Financial support to Thomas J. Smith includes US NCI grants P30 006973 and CA177562, PCORI IHS 1609-36518, the Harry J. Duffey Family Fund for Palliative Care, and The Lerner Foundation, Washington DC.

Publisher Copyright:
© 2021 The Author(s)

Keywords

Autopsy
Complications
Electronic medical records
Metastasis
Outcome
Phenotyping
Precision medicine
Prostate cancer
Text mining

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.euros.2021.05.011

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Jasu, J., Tolonen, T., Antonarakis, E. S., Beltran, H., Halabi, S., Eisenberger, M. A., Carducci, M. A., Loriot, Y., Van der Eecken, K., Lolkema, M., Ryan, C. J., Taavitsainen, S., Gillessen, S., Högnäs, G., Talvitie, T., Taylor, R. J., Koskenalho, A., Ost, P., Murtola, T. J., ... Bova, G. S. (2021). Combined Longitudinal Clinical and Autopsy Phenomic Assessment in Lethal Metastatic Prostate Cancer: Recommendations for Advancing Precision Medicine. European Urology Open Science, 30, 47-62. https://doi.org/10.1016/j.euros.2021.05.011

Jasu, J, Tolonen, T, Antonarakis, ES, Beltran, H, Halabi, S, Eisenberger, MA, Carducci, MA, Loriot, Y, Van der Eecken, K, Lolkema, M, Ryan, CJ, Taavitsainen, S, Gillessen, S, Högnäs, G, Talvitie, T, Taylor, RJ, Koskenalho, A, Ost, P, Murtola, TJ, Rinta-Kiikka, I, Tammela, T, Auvinen, A, Kujala, P, Smith, TJ, Kellokumpu-Lehtinen, PL, Isaacs, WB, Nykter, M, Kesseli, J & Bova, GS 2021, 'Combined Longitudinal Clinical and Autopsy Phenomic Assessment in Lethal Metastatic Prostate Cancer: Recommendations for Advancing Precision Medicine', European Urology Open Science, vol. 30, pp. 47-62. https://doi.org/10.1016/j.euros.2021.05.011

@article{cb70973340d5405297ca5ea68a0dd020,

title = "Combined Longitudinal Clinical and Autopsy Phenomic Assessment in Lethal Metastatic Prostate Cancer: Recommendations for Advancing Precision Medicine",

abstract = "Background: Systematic identification of data essential for outcome prediction in metastatic prostate cancer (mPC) would accelerate development of precision oncology.Objective: To identify novel phenotypes and features associated with mPC outcome, and to identify biomarker and data requirements to be tested in future precision oncology trials.Design setting and participants: We analyzed deep longitudinal clinical, neuroendocrine expression, and autopsy data of 33 men who died from mPC between 1995 and 2004 (PELICAN33), and related findings to mPC biomarkers reported in the literature.Intervention: Thirty-three men prospectively consented to participate in an integrated clinical-molecular rapid autopsy study of mPC.Outcome measurements and statistical analysis: Data exploration with correction for multiple testing and survival analysis from the time of diagnosis to time to death and time to first occurrence of severe pain as outcomes were carried out. The effect of seven complications on the modeled probability of dying within 2 yr after presenting with the complication was evaluated using logistic regression.Results and limitations: Feature exploration revealed novel phenotypes related to mPC outcome. Four complications (pleural effusion, severe anemia, severe or controlled pain, and bone fracture) predict the likelihood of death within 2 yr. Men with Gleason grade group 5 cancers developed severe pain sooner than those with lower-grade tumors. Surprisingly, neuroendocrine (NE) differentiation was frequently observed in the setting of high serum prostate-specific antigen (PSA) levels (≥30 ng/ml). In 4/33 patients, no controlled (requiring analgesics) or severe pain was detected, and strikingly, 14/15 metastatic sites studied in these men did not express NE markers, suggesting an inverse relationship between NE differentiation and pain in mPC. Intracranial subdural metastasis is common (36%) and is usually clinically undetected. Categorization of {"}skeletal-related events{"} complications used in recent studies likely obscures the understanding of spinal cord compression and fracture. Early death from prostate cancer was identified in a subgroup of men with a low longitudinal PSA bandwidth. Cachexia is common (body mass index <0.89 in 24/31 patients) but limited to the last year of life. Biomarker review identified 30 categories of mPC biomarkers in need of winnowing in future trials. All findings require validation in larger cohorts, preferably alongside data from this study.Conclusions: The study identified novel outcome subgroups for future validation and provides {"}vision for mPC precision oncology 2020-2050{"} draft recommendations for future data collection and biomarker studies.Patient summary: To better understand variation in metastatic prostate cancer behavior, we assembled and analyzed longitudinal clinical and autopsy records in 33 men. We identified novel outcomes, phenotypes, and aspects of disease burden to be tested and refined in future trials.",

keywords = "Autopsy, Complications, Electronic medical records, Metastasis, Outcome, Phenotyping, Precision medicine, Prostate cancer, Text mining",

author = "Juho Jasu and Teemu Tolonen and Antonarakis, {Emmanuel S.} and Himisha Beltran and Susan Halabi and Eisenberger, {Mario A.} and Carducci, {Michael A.} and Yohann Loriot and {Van der Eecken}, Kim and Martijn Lolkema and Ryan, {Charles J.} and Sinja Taavitsainen and Silke Gillessen and Gunilla H{\"o}gn{\"a}s and Timo Talvitie and Taylor, {Robert J.} and Antti Koskenalho and Piet Ost and Murtola, {Teemu J.} and Irina Rinta-Kiikka and Teuvo Tammela and Anssi Auvinen and Paula Kujala and Smith, {Thomas J.} and Kellokumpu-Lehtinen, {Pirkko Liisa} and Isaacs, {William B.} and Matti Nykter and Juha Kesseli and Bova, {G. Steven}",

note = "Funding Information: Funding/Support and role of the sponsor: Financial support to G. Steven Bova for the PELICAN33 study includes the following: the Academy of Finland (2011 to present), Cancer Society of Finland (2013 to present), Sigrid Juselius Foundation (2016 to present), C.J. Heilig Foundation (2010), PELICAN Autopsy Study family members and friends (1998–2004), John and Kathe Dyson (2000), US National Cancer Institute CA92234 (2000–2005), American Cancer Society (1998–2000), Millenium Pharmaceuticals (1998–2002), Johns Hopkins University Department of Pathology (1997–2011), Johns Hopkins Oncology Center (1994–2004), Women{\textquoteright}s Board of Johns Hopkins Hospital (1998), the Grove Foundation (1998), Schering-Plough (1998), Nycomed Amersham (1998), Association for the Cure of Cancer of the Prostate (1994–1998), Brady Urological Institute (1994–1997), and American Foundation for Urologic Disease (1991–1994). Financial support to Thomas J. Smith includes US NCI grants P30 006973 and CA177562 , PCORI IHS 1609-36518 , the Harry J. Duffey Family Fund for Palliative Care , and The Lerner Foundation, Washington DC . Funding Information: Financial disclosures: G. Steven Bova certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Juho Jasu, Susan Halabi, Mario A. Eisenberger, Kim Van der Eecken, Sinja Taavitsainen, Gunilla H{\"o}gn{\"a}s, Timo Talvitie, Robert J. Taylor, Antti Koskenalho, Paula Kujala, Thomas J. Smith, William B. Isaacs, Matti Nykter, and Juha Kesseli have no conflict of interest disclosures. Teemu Tolonen has received honoraria from Roche and Objective Imaging, and travel and accommodation expenses from Roche and Pfizer. Emmanuel S. Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, Lilly, Bayer, AstraZeneca, Bristol-Myers Squibb, Clovis, and Merck; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis, and Merck; and is the coinventor of an AR-V7 biomarker technology that has been licensed to Qiagen. Himisha Beltran has served as a consultant/advisory board member for Janssen, Sanofi Genzyme, Astellas, Astra Zeneca, Merck, Pfizer, and Blue Earth, and has received research funding from Janssen Oncology (Inst), AbbVie/Stemcentrx (Inst), Eli Lilly (Inst), and Millennium Pharmaceuticals (Inst). Michael A. Carducci reports past consultation for Pfizer, Astellas, and Exelexis, and current research funding from Arcus, Pfizer, and Merck. Yohann Loriot has received personal fees from Immunomedics; personal fees and nonfinancial support from Roche, AstraZeneca, BMS, Pfizer, Astellas, and Seattle Genetics; and grant support, personal fees, and nonfinancial support from MSD and Janssen. Martijn Lolkema has received personal fees from Incyte, Amgen, Bayer, Servier, Roche, INCa, Pfizer, AstraZeneca, Novartis, and Julius Clinical, and grants and personal fees from JnJ, Sanofi, Astellas, and MSD. Charles J. Ryan has received consulting fees from Bayer, Janssen, and Sanofi Genzyme; has received funds for research support from Clovis Oncology and the Prostate Cancer Foundation; has received fees for non-CME/CE services from Janssen; and has served in a study leadership position for Clovis Oncology. Silke Gillessen: has received (last 3 yr) honoraria from Janssen Cilag; received consulting fees from or had an advisory role (including IDMC) at Astellas Pharma, Amgen, Roche, Pfizer, AAA International, Janssen, Innocrin Pharma Inst, Sanofi, Bayer, Orion Pharma GmbH, Clovis Oncology, Menarini Silicon Biosystems, Tolero Pharmaceuticals, and MSD; reports patents, royalties, other intellectual property for Method for biomarker WO2009138392; has received travel grant from ProteoMediX; and has other relationship with Aranda. Piet Ost reports a consulting/scientific advisory role at Bayer, Janssen, Curium, and Ferring, and has received grants for clinical research from Ferring, Merck, Varian, and Bayer. Teemu J. Murtola has received honoraria from Astellas, Janssen, Novartis, and Sanofi; has received travel and accommodation expenses from Sanofi and Pfizer; reports patents, royalties, and other intellectual property from Arocell; reports stock and other ownership interests in Arocell; and has received research funding from Arocell. Teuvo Tammela has received research funding from Finnish Cancer Society and Sigrid Juselius Foundation, and has been an investigator in studies sponsored by Bayer, Astellas, Orion Pharma, and Pfizer. Anssi Auvinen has received lecture fees from Amgen and Janssen. Pirkko-Liisa Kellokumpu-Lehtinen has been a consultant/advisor to Bristol Myers Squibb and MSD; has received research funding for her institution from Eli Lilly, Roche, Sanofi and Merck; and has received travelling expenses from Sanofi. G. Steven Bova reports speaker{\textquoteright}s fees from Brupbacher Foundation, Sanofi Aventis, and Astellas Pharma. Funding Information: Funding/Support and role of the sponsor: Financial support to G. Steven Bova for the PELICAN33 study includes the following: the Academy of Finland (2011 to present), Cancer Society of Finland (2013 to present), Sigrid Juselius Foundation (2016 to present), C.J. Heilig Foundation (2010), PELICAN Autopsy Study family members and friends (1998?2004), John and Kathe Dyson (2000), US National Cancer Institute CA92234 (2000?2005), American Cancer Society (1998?2000), Millenium Pharmaceuticals (1998?2002), Johns Hopkins University Department of Pathology (1997?2011), Johns Hopkins Oncology Center (1994?2004), Women's Board of Johns Hopkins Hospital (1998), the Grove Foundation (1998), Schering-Plough (1998), Nycomed Amersham (1998), Association for the Cure of Cancer of the Prostate (1994?1998), Brady Urological Institute (1994?1997), and American Foundation for Urologic Disease (1991?1994). Financial support to Thomas J. Smith includes US NCI grants P30 006973 and CA177562, PCORI IHS 1609-36518, the Harry J. Duffey Family Fund for Palliative Care, and The Lerner Foundation, Washington DC. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = aug,

doi = "10.1016/j.euros.2021.05.011",

language = "English (US)",

volume = "30",

pages = "47--62",

journal = "European Urology Open Science",

issn = "2666-1691",

publisher = "Elsevier B.V.",

}

TY - JOUR

T1 - Combined Longitudinal Clinical and Autopsy Phenomic Assessment in Lethal Metastatic Prostate Cancer

T2 - Recommendations for Advancing Precision Medicine

AU - Jasu, Juho

AU - Tolonen, Teemu

AU - Antonarakis, Emmanuel S.

AU - Beltran, Himisha

AU - Halabi, Susan

AU - Eisenberger, Mario A.

AU - Carducci, Michael A.

AU - Loriot, Yohann

AU - Van der Eecken, Kim

AU - Lolkema, Martijn

AU - Ryan, Charles J.

AU - Taavitsainen, Sinja

AU - Gillessen, Silke

AU - Högnäs, Gunilla

AU - Talvitie, Timo

AU - Taylor, Robert J.

AU - Koskenalho, Antti

AU - Ost, Piet

AU - Murtola, Teemu J.

AU - Rinta-Kiikka, Irina

AU - Tammela, Teuvo

AU - Auvinen, Anssi

AU - Kujala, Paula

AU - Smith, Thomas J.

AU - Kellokumpu-Lehtinen, Pirkko Liisa

AU - Isaacs, William B.

AU - Nykter, Matti

AU - Kesseli, Juha

AU - Bova, G. Steven

N1 - Funding Information: Funding/Support and role of the sponsor: Financial support to G. Steven Bova for the PELICAN33 study includes the following: the Academy of Finland (2011 to present), Cancer Society of Finland (2013 to present), Sigrid Juselius Foundation (2016 to present), C.J. Heilig Foundation (2010), PELICAN Autopsy Study family members and friends (1998–2004), John and Kathe Dyson (2000), US National Cancer Institute CA92234 (2000–2005), American Cancer Society (1998–2000), Millenium Pharmaceuticals (1998–2002), Johns Hopkins University Department of Pathology (1997–2011), Johns Hopkins Oncology Center (1994–2004), Women’s Board of Johns Hopkins Hospital (1998), the Grove Foundation (1998), Schering-Plough (1998), Nycomed Amersham (1998), Association for the Cure of Cancer of the Prostate (1994–1998), Brady Urological Institute (1994–1997), and American Foundation for Urologic Disease (1991–1994). Financial support to Thomas J. Smith includes US NCI grants P30 006973 and CA177562 , PCORI IHS 1609-36518 , the Harry J. Duffey Family Fund for Palliative Care , and The Lerner Foundation, Washington DC . Funding Information: Financial disclosures: G. Steven Bova certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Juho Jasu, Susan Halabi, Mario A. Eisenberger, Kim Van der Eecken, Sinja Taavitsainen, Gunilla Högnäs, Timo Talvitie, Robert J. Taylor, Antti Koskenalho, Paula Kujala, Thomas J. Smith, William B. Isaacs, Matti Nykter, and Juha Kesseli have no conflict of interest disclosures. Teemu Tolonen has received honoraria from Roche and Objective Imaging, and travel and accommodation expenses from Roche and Pfizer. Emmanuel S. Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, Lilly, Bayer, AstraZeneca, Bristol-Myers Squibb, Clovis, and Merck; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis, and Merck; and is the coinventor of an AR-V7 biomarker technology that has been licensed to Qiagen. Himisha Beltran has served as a consultant/advisory board member for Janssen, Sanofi Genzyme, Astellas, Astra Zeneca, Merck, Pfizer, and Blue Earth, and has received research funding from Janssen Oncology (Inst), AbbVie/Stemcentrx (Inst), Eli Lilly (Inst), and Millennium Pharmaceuticals (Inst). Michael A. Carducci reports past consultation for Pfizer, Astellas, and Exelexis, and current research funding from Arcus, Pfizer, and Merck. Yohann Loriot has received personal fees from Immunomedics; personal fees and nonfinancial support from Roche, AstraZeneca, BMS, Pfizer, Astellas, and Seattle Genetics; and grant support, personal fees, and nonfinancial support from MSD and Janssen. Martijn Lolkema has received personal fees from Incyte, Amgen, Bayer, Servier, Roche, INCa, Pfizer, AstraZeneca, Novartis, and Julius Clinical, and grants and personal fees from JnJ, Sanofi, Astellas, and MSD. Charles J. Ryan has received consulting fees from Bayer, Janssen, and Sanofi Genzyme; has received funds for research support from Clovis Oncology and the Prostate Cancer Foundation; has received fees for non-CME/CE services from Janssen; and has served in a study leadership position for Clovis Oncology. Silke Gillessen: has received (last 3 yr) honoraria from Janssen Cilag; received consulting fees from or had an advisory role (including IDMC) at Astellas Pharma, Amgen, Roche, Pfizer, AAA International, Janssen, Innocrin Pharma Inst, Sanofi, Bayer, Orion Pharma GmbH, Clovis Oncology, Menarini Silicon Biosystems, Tolero Pharmaceuticals, and MSD; reports patents, royalties, other intellectual property for Method for biomarker WO2009138392; has received travel grant from ProteoMediX; and has other relationship with Aranda. Piet Ost reports a consulting/scientific advisory role at Bayer, Janssen, Curium, and Ferring, and has received grants for clinical research from Ferring, Merck, Varian, and Bayer. Teemu J. Murtola has received honoraria from Astellas, Janssen, Novartis, and Sanofi; has received travel and accommodation expenses from Sanofi and Pfizer; reports patents, royalties, and other intellectual property from Arocell; reports stock and other ownership interests in Arocell; and has received research funding from Arocell. Teuvo Tammela has received research funding from Finnish Cancer Society and Sigrid Juselius Foundation, and has been an investigator in studies sponsored by Bayer, Astellas, Orion Pharma, and Pfizer. Anssi Auvinen has received lecture fees from Amgen and Janssen. Pirkko-Liisa Kellokumpu-Lehtinen has been a consultant/advisor to Bristol Myers Squibb and MSD; has received research funding for her institution from Eli Lilly, Roche, Sanofi and Merck; and has received travelling expenses from Sanofi. G. Steven Bova reports speaker’s fees from Brupbacher Foundation, Sanofi Aventis, and Astellas Pharma. Funding Information: Funding/Support and role of the sponsor: Financial support to G. Steven Bova for the PELICAN33 study includes the following: the Academy of Finland (2011 to present), Cancer Society of Finland (2013 to present), Sigrid Juselius Foundation (2016 to present), C.J. Heilig Foundation (2010), PELICAN Autopsy Study family members and friends (1998?2004), John and Kathe Dyson (2000), US National Cancer Institute CA92234 (2000?2005), American Cancer Society (1998?2000), Millenium Pharmaceuticals (1998?2002), Johns Hopkins University Department of Pathology (1997?2011), Johns Hopkins Oncology Center (1994?2004), Women's Board of Johns Hopkins Hospital (1998), the Grove Foundation (1998), Schering-Plough (1998), Nycomed Amersham (1998), Association for the Cure of Cancer of the Prostate (1994?1998), Brady Urological Institute (1994?1997), and American Foundation for Urologic Disease (1991?1994). Financial support to Thomas J. Smith includes US NCI grants P30 006973 and CA177562, PCORI IHS 1609-36518, the Harry J. Duffey Family Fund for Palliative Care, and The Lerner Foundation, Washington DC. Publisher Copyright: © 2021 The Author(s)

PY - 2021/8

Y1 - 2021/8

N2 - Background: Systematic identification of data essential for outcome prediction in metastatic prostate cancer (mPC) would accelerate development of precision oncology.Objective: To identify novel phenotypes and features associated with mPC outcome, and to identify biomarker and data requirements to be tested in future precision oncology trials.Design setting and participants: We analyzed deep longitudinal clinical, neuroendocrine expression, and autopsy data of 33 men who died from mPC between 1995 and 2004 (PELICAN33), and related findings to mPC biomarkers reported in the literature.Intervention: Thirty-three men prospectively consented to participate in an integrated clinical-molecular rapid autopsy study of mPC.Outcome measurements and statistical analysis: Data exploration with correction for multiple testing and survival analysis from the time of diagnosis to time to death and time to first occurrence of severe pain as outcomes were carried out. The effect of seven complications on the modeled probability of dying within 2 yr after presenting with the complication was evaluated using logistic regression.Results and limitations: Feature exploration revealed novel phenotypes related to mPC outcome. Four complications (pleural effusion, severe anemia, severe or controlled pain, and bone fracture) predict the likelihood of death within 2 yr. Men with Gleason grade group 5 cancers developed severe pain sooner than those with lower-grade tumors. Surprisingly, neuroendocrine (NE) differentiation was frequently observed in the setting of high serum prostate-specific antigen (PSA) levels (≥30 ng/ml). In 4/33 patients, no controlled (requiring analgesics) or severe pain was detected, and strikingly, 14/15 metastatic sites studied in these men did not express NE markers, suggesting an inverse relationship between NE differentiation and pain in mPC. Intracranial subdural metastasis is common (36%) and is usually clinically undetected. Categorization of "skeletal-related events" complications used in recent studies likely obscures the understanding of spinal cord compression and fracture. Early death from prostate cancer was identified in a subgroup of men with a low longitudinal PSA bandwidth. Cachexia is common (body mass index <0.89 in 24/31 patients) but limited to the last year of life. Biomarker review identified 30 categories of mPC biomarkers in need of winnowing in future trials. All findings require validation in larger cohorts, preferably alongside data from this study.Conclusions: The study identified novel outcome subgroups for future validation and provides "vision for mPC precision oncology 2020-2050" draft recommendations for future data collection and biomarker studies.Patient summary: To better understand variation in metastatic prostate cancer behavior, we assembled and analyzed longitudinal clinical and autopsy records in 33 men. We identified novel outcomes, phenotypes, and aspects of disease burden to be tested and refined in future trials.

AB - Background: Systematic identification of data essential for outcome prediction in metastatic prostate cancer (mPC) would accelerate development of precision oncology.Objective: To identify novel phenotypes and features associated with mPC outcome, and to identify biomarker and data requirements to be tested in future precision oncology trials.Design setting and participants: We analyzed deep longitudinal clinical, neuroendocrine expression, and autopsy data of 33 men who died from mPC between 1995 and 2004 (PELICAN33), and related findings to mPC biomarkers reported in the literature.Intervention: Thirty-three men prospectively consented to participate in an integrated clinical-molecular rapid autopsy study of mPC.Outcome measurements and statistical analysis: Data exploration with correction for multiple testing and survival analysis from the time of diagnosis to time to death and time to first occurrence of severe pain as outcomes were carried out. The effect of seven complications on the modeled probability of dying within 2 yr after presenting with the complication was evaluated using logistic regression.Results and limitations: Feature exploration revealed novel phenotypes related to mPC outcome. Four complications (pleural effusion, severe anemia, severe or controlled pain, and bone fracture) predict the likelihood of death within 2 yr. Men with Gleason grade group 5 cancers developed severe pain sooner than those with lower-grade tumors. Surprisingly, neuroendocrine (NE) differentiation was frequently observed in the setting of high serum prostate-specific antigen (PSA) levels (≥30 ng/ml). In 4/33 patients, no controlled (requiring analgesics) or severe pain was detected, and strikingly, 14/15 metastatic sites studied in these men did not express NE markers, suggesting an inverse relationship between NE differentiation and pain in mPC. Intracranial subdural metastasis is common (36%) and is usually clinically undetected. Categorization of "skeletal-related events" complications used in recent studies likely obscures the understanding of spinal cord compression and fracture. Early death from prostate cancer was identified in a subgroup of men with a low longitudinal PSA bandwidth. Cachexia is common (body mass index <0.89 in 24/31 patients) but limited to the last year of life. Biomarker review identified 30 categories of mPC biomarkers in need of winnowing in future trials. All findings require validation in larger cohorts, preferably alongside data from this study.Conclusions: The study identified novel outcome subgroups for future validation and provides "vision for mPC precision oncology 2020-2050" draft recommendations for future data collection and biomarker studies.Patient summary: To better understand variation in metastatic prostate cancer behavior, we assembled and analyzed longitudinal clinical and autopsy records in 33 men. We identified novel outcomes, phenotypes, and aspects of disease burden to be tested and refined in future trials.

KW - Autopsy

KW - Complications

KW - Electronic medical records

KW - Metastasis

KW - Outcome

KW - Phenotyping

KW - Precision medicine

KW - Prostate cancer

KW - Text mining

UR - http://www.scopus.com/inward/record.url?scp=85110176750&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85110176750&partnerID=8YFLogxK

U2 - 10.1016/j.euros.2021.05.011

DO - 10.1016/j.euros.2021.05.011

M3 - Article

C2 - 34337548

AN - SCOPUS:85110176750

SN - 2666-1691

VL - 30

SP - 47

EP - 62

JO - European Urology Open Science

JF - European Urology Open Science

ER -

Combined Longitudinal Clinical and Autopsy Phenomic Assessment in Lethal Metastatic Prostate Cancer: Recommendations for Advancing Precision Medicine

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