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Longitudinal Profiling of Circulating Tumor DNA Reveals the Evolutionary Dynamics of Metastatic Prostate Cancer during Serial Therapy

  • 0Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Research +

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February 24, 2025

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February 24, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Longitudinal plasma ctDNA profiling reveals how prostate cancer evolves under treatment. Androgen signaling inhibitors drive more subclonal changes than chemotherapy, identifying new resistance genes.

Area Of Science

  • Oncology
  • Genomics
  • Molecular Biology

Background

  • Metastatic castration-resistant prostate cancer (mCRPC) treatment relies on clinical data, but molecular monitoring is difficult due to repeated tissue biopsy needs.
  • Circulating tumor DNA (ctDNA) offers a less invasive method for tracking cancer evolution.

Purpose Of The Study

  • To analyze the genomic and evolutionary dynamics of mCRPC using longitudinal ctDNA.
  • To understand how different therapies (androgen signaling inhibitors, chemotherapy) impact tumor evolution and resistance.
  • To identify genetic alterations associated with treatment resistance.

Main Methods

  • Simultaneous profiling of genome copy number and exome in longitudinal ctDNA from 60 mCRPC patients undergoing serial treatments.
  • Development of an evolutionary dynamic index to quantify longitudinal subclone changes.
  • Analysis of 2-10 samples per patient, collected before, during, and upon progression to therapy.

Main Results

  • Androgen signaling inhibitors induced greater subclonal selection and population structure changes compared to taxane chemotherapy.
  • Emergent subclones associated with therapy resistance showed recurrent aberrations in known and novel genes.
  • Enrichment of aberrations in PI3K-AKT signaling pathway genes was observed in resistant subclones.

Conclusions

  • Longitudinal ctDNA profiling provides insights into mCRPC evolutionary dynamics and treatment resistance.
  • Genomic analysis of ctDNA can guide precision medicine by identifying emerging resistant subclones and therapeutic targets.
  • Integration of clinical and genomic data from ctDNA is a promising framework for future clinical applications.