Predicting time to castration resistance in hormone sensitive prostate cancer by a personalization algorithm based on a mechanistic model integrating patient data

Moran Elishmereni, Yuri Kheifetz, Ilan Shukrun, Graham H. Bevan, Debashis Nandy, Kyle McKenzie, Manish Kohli, Zvia Agur

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

BACKGROUND Prostate cancer (PCa) is a leading cause of cancer death of men worldwide. In hormone-sensitive prostate cancer (HSPC), androgen deprivation therapy (ADT) is widely used, but an eventual failure on ADT heralds the passage to the castration-resistant prostate cancer (CRPC) stage. Because predicting time to failure on ADT would allow improved planning of personal treatment strategy, we aimed to develop a predictive personalization algorithm for ADT efficacy in HSPC patients. METHODS A mathematical mechanistic model for HSPC progression and treatment was developed based on the underlying disease dynamics (represented by prostate-specific antigen; PSA) as affected by ADT. Following fine-tuning by a dataset of ADT-treated HSPC patients, the model was embedded in an algorithm, which predicts the patient's time to biochemical failure (BF) based on clinical metrics obtained before or early in-treatment. RESULTS The mechanistic model, including a tumor growth law with a dynamic power and an elaborate ADT-resistance mechanism, successfully retrieved individual time-courses of PSA (R2 = 0.783). Using the personal Gleason score (GS) and PSA at diagnosis, as well as PSA dynamics from 6 months after ADT onset, and given the full ADT regimen, the personalization algorithm accurately predicted the individual time to BF of ADT in 90% of patients in the retrospective cohort (R2 = 0.98). CONCLUSIONS The algorithm we have developed, predicting biochemical failure based on routine clinical tests, could be especially useful for patients destined for short-lived ADT responses and quick progression to CRPC. Prospective studies must validate the utility of the algorithm for clinical decision-making. Prostate 76:48-57, 2016.

Original languageEnglish (US)
Pages (from-to)48-57
Number of pages10
JournalProstate
Volume76
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • androgen deprivation therapy (ADT)
  • Bayesian estimation
  • biochemical failure (BF)
  • mathematical model
  • non-linear mixed-effect modeling (NLMEM)

ASJC Scopus subject areas

  • Urology
  • Oncology

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