ESMO 2021: Circulating Tumor Cell Morphologic Sub-Types Present Prior to Treatment in the CARD Trial Identify Therapy Resistance

(UroToday.com) The European Society of Medical Oncology (ESMO) 2021 virtual annual meeting’s prostate cancer session included a presentation by Dr. Johann de Bono presenting data assessing the impact of circulating tumor cell (CTC) morphologic sub-types prior to treatment in the CARD trial.1 In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer who had received docetaxel and progressed ≤ 12 months with the alternative androgen receptor-targeted agent. There is a current unmet need to identify superior monitoring tools of treatment efficacy so that patients do not remain on ineffective therapies when they no longer clinically benefit from them. CTC counts are a validated pretreatment prognostic measure, as well as a validated tool for response monitoring. The objective of this pre-planned CARD EPIC biomarker study was to analyze the morphology of CTC subtypes in a liquid biopsy.

 

 Blood samples collected at screening, Cycle 2 Day 1, and end of therapy were blinded and sent to Epic Sciences for analysis:

 

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Chromosomal instability within CTCs and Shannon Index were assessed using nuclear and cytoplasmic morphology. CTC phenotypes were correlated with rPFS and OS using Kaplan-Meier estimates and multivariable Cox proportional hazard models.

 At screening, Cycle 2 Day 1, and end of therapy, 215, 188, and 141 samples were evaluable, respectively. Chromosomal instability positive CTCs increased from screening to Cycle 2 Day 1 to end of therapy in the androgen receptor-targeted agent arm, whereas in the cabazitaxel arm chromosomal instability positive CTC levels were stable during treatment. In the cabazitaxel arm, patients with chromosomal instability positive CTCs at screening had significantly shorter rPFS and OS than those with chromosomal instability negative CTCs. In the androgen receptor-targeted agent arm, rPFS and OS remained shorter than with cabazitaxel regardless of chromosomal instability status.:

 

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Blood samples harboring chromosomal instability positive CTCs had increased morphologic diversity (higher Shannon index, P < 0.0001) and 44% had CTCs (21% of patients overall) that were small, circular, and had high nuclear to cytoplasm ratios similar to criteria for small-cell or neuroendocrine transformation.

 

Dr. de Bono concluded his presentation of CTCs in the CARD trial with the following take-home messages:

  • Chromosomal instability positive CTCs at screening were associated with shorter OS and rPFS in the CARD study
  • The presence of chromosomal instability positive CTCs were associated with poor survival and treatment response in the cabazitaxel arm, however in the androgen-signaling-targeted inhibitor arm, poor survival response was observed regardless of biomarker
  • The phenotypic diversity of detected CTCs suggests that multiple mechanisms may drive therapy resistance and that alternative therapies, combinations, or clinical trials may be more suitable for patients harboring these CTC phenotypes


Presented by: Johann S. de Bono, MD, MSc, PhD, FRCP, FMedSci, Division of Clinical Studies, Royal Marsden Hospital and The Institute of Cancer Research, London, UK

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.

References:

  1. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med 2019 Dec 26;381(26):2506-2518.

 

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