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High-purity CTC RNA sequencing identifies prostate cancer lineage phenotypes prognostic for clinical outcomes.

Marina N Sharifi1, Jamie M Sperger2, Amy K Taylor3

  • 1University of Wisconsin-Madison, Madison, WI, United States.

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Liquid biopsies reveal circulating tumor cell (CTC) phenotypes linked to poor survival in metastatic prostate cancer. Identifying these CTC profiles can predict treatment resistance and guide therapy selection for better patient outcomes.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Treatment resistance is a major challenge in metastatic prostate cancer, often driven by androgen receptor (AR) alterations and lineage plasticity.
  • Studying the evolution of lineage transitions during treatment is difficult due to limitations in obtaining serial tissue biopsies.

Purpose of the Study:

  • To develop and validate a novel circulating tumor cell (CTC) isolation and RNA sequencing approach for analyzing lineage states in metastatic prostate cancer.
  • To correlate CTC transcriptional phenotypes with patient survival and treatment response.

Main Methods:

  • Collected 273 CTC samples from 117 metastatic prostate cancer patients using a novel isolation technique.
  • Performed RNA sequencing on CTC samples with sufficient tumor purity (146 samples from 70 patients).
  • Identified four distinct CTC transcriptional phenotypes mirroring known lineage states.

Main Results:

  • Four CTC phenotypes were identified, corresponding to lineage states observed in tissue biopsies.
  • Patients with a luminal-B-like CTC phenotype (persistent AR signaling, high proliferation) and neuroendocrine CTC phenotype showed significantly shorter survival.
  • In a prospective substudy, the pre-treatment CTC luminal-B-like phenotype predicted early progression on 177Lu-PSMA-617 therapy.

Conclusions:

  • Circulating tumor cell (CTC) RNA sequencing provides a viable method to study lineage plasticity in treatment-resistant metastatic prostate cancer.
  • Specific CTC phenotypes, particularly luminal-B-like and neuroendocrine, are associated with poor prognosis and can predict treatment response.
  • This approach using liquid biopsies offers a promising tool for monitoring disease progression and guiding therapeutic strategies.