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Area of Science:

  • Genomics and Precision Medicine
  • Oncology
  • Molecular Diagnostics

Background:

  • Metastatic castration-resistant prostate cancer (mCRPC) treatment faces challenges due to therapeutic resistance.
  • Circulating tumor DNA (ctDNA) next-generation sequencing (NGS) offers valuable insights into prognosis, treatment selection, and tumor evolution.
  • Longitudinal ctDNA analysis can track dynamic genetic changes during systemic therapy in mCRPC.

Purpose of the Study:

  • To evaluate longitudinal ctDNA alterations in mCRPC patients undergoing treatment with androgen receptor pathway inhibitors (ARPi), poly (ADP-ribose) polymerase inhibitors (PARPi), or taxanes.
  • To assess the association between specific genetic alterations, particularly in AR, and clinical outcomes following these treatments.
  • To understand tumor evolution and treatment resistance mechanisms through serial ctDNA profiling.

Main Methods:

  • Analysis of the GuardantINFORM clinical-genomic database, linking ctDNA profiles with claims data.
  • Inclusion of mCRPC patients with paired ctDNA samples pre- and post-treatment (ARPi, PARPi, taxanes).
  • Evaluation of pre- and post-treatment mutational differences and survival outcomes (OS, TTD, TTNT), stratified by treatment type and AR alterations.

Main Results:

  • Significant increases in mutation burden observed across all treatment cohorts post-therapy (mean increase 2.0-4.2 alterations; p<0.001).
  • Post-ARPi treatment showed increased AR amplification and specific AR mutations (L702H, T878A).
  • Post-PARPi treatment revealed alterations in HRR genes like ATM and BRCA2.
  • Post-taxane treatment demonstrated increased TP53, AR, PIK3CA, and EGFR alterations.
  • The presence of AR alterations consistently correlated with inferior clinical outcomes across all treatment groups.

Conclusions:

  • Dynamic genetic shifts occur in mCRPC patients treated with ARPi, PARPi, and taxanes.
  • AR alterations are associated with poorer clinical outcomes, underscoring their prognostic significance.
  • Longitudinal ctDNA monitoring holds potential for guiding personalized treatment strategies in mCRPC.