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 journalArticleScientificpeer-review

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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 languageEnglish
Pages (from-to)47-62
Number of pages16
JournalEuropean Urology Open Science
Publication statusPublished - Aug 2021
Publication typeA1 Journal article-refereed


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

Publication forum classification

  • Publication forum level 1

ASJC Scopus subject areas

  • Urology


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