Of liquid biopsies, CTCs, and first-line treatment for mCRPC

A paper to be presented at the Genitourinary Cancers Synposium today, suggests that use of a liquid biopsy and analysis of single circulating tumor cells (CTCs) may be helpful in determining therapy for men with metastatic, castration-resistant prostate cancer (mCRPC).

The paper by Scher et al. (abstract no. 163; “Single CTC characterization to identify phenotypic and genomic heterogeneity as a mechanism of resistance to AR signaling directed therapies in mCRPC patients”) describes how they used blood samples and digital pathology of thousands of CTCs to identify which patients with mCRPC were likely to respond better to initial therapy with drugs like docetaxel, cabzitaxel, abiraterone acetate, and enzalutamide. However, we should note that this testing system is not yet ready for “prime time” and will need to be evaluated in appropriate clinical trials. The paper is also discussed in a commentary on the Medscape web site.

Basically, Scher and his colleagues did the following:

First, they collected 221 blood samples from 179 patients scheduled to start treatment with either one of the new androgen resistance agents like abiraterone and enzalutamide (n = 150) or a taxane like docetaxel or cabazitaxel (n = 71). A detailed analysis of these samples identfied  9225 individual CTCs, all of which were carefully characterized based on a variety of data points and then categorized into 15 phenotypically distinct CTC subtypes.

Next, the authors analyzed the original 221 blood samples for the frequency and heterogeneity of the 15 CTC subtypes and monitored the patients for relevant clinical endpoints over the course of their treatment.

Thirdly, they individually sequenced the genes for a subset of the CTCs (n = 350) to assess the CTCs for genomic heterogeneity.

Here are the study findings:

  • There was a diverse spectrum of CTC phenotypes identified in patients receiving each type of therapy.
  • In patients being treated with androgen resistance agents, high CTC heterogeneity predicts
    • 6-month progression-free survival (odds ratio [OR] = 2.57, p = 0.01)
    • Shorter overall survival (hazard ratio [HR] = 4.5, p < 0.001).
  • Also in patients being treated with androgen resistance agents, specific CTC phenotypes predict
    • 6-month progression-free survival (OR = 5.0, p < 0.001)
    • Shorter overall survival (HR = 5.8, p < 0.001).
  • There was no association between CTC heterogeneity scores and taxane resistance.
  • Individual gene sequencing of CTCs (NGS analysis) identified a number of specific genetic/genomic drivers of disease progression.

Scher et al. conclude that

Single CTC characterization of phenotype and genotype supports the concept of tumor heterogeneity as a driver of disease resistance. The heterogeneity observed supports the potential value of single cell characterization to identify rare somatic sub-clonal alterations and can aid in the development of rational therapeutic trials.

It will be clear that there is still a good deal of work to be done before one can use such methods in clinical practice to determine whether one or other form of treatment might be best for a specific individual patient with mCRPC — but the possibilities are intriguing.

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