Can TMPRSS2-ERG gene expression predict low response to taxane therapy?

Drugs like docetaxel and cabazitaxel (taxanes) are among the most active forms of treatment in the management of men with metastatic, castration-resistant prostate cancer (mCRPC), but they don’t work for everyone.

A newly published paper by a Barcelona, Spain-based research team (see Reig et al.) has now shown that, at least in their relatively small patient cohort, expression of the TMPRSS2-ERG gene alteration in blood from men with mCRPC is capable of  predicting resistance to docetaxel. The authors also express optimism that

it may be useful to select treatment and to avoid possible toxicities in refractory patients.

The article is discussed in a commentary on the Medscape web site, where different authorities seem to have a range of views on whether this finding will turn out to be clinically meaningful when it is tested prospectively in a larger number of men.

Reig et al.  tested their hypothesis in a cohort of 96 men, including:

  • 50 men with mCRPC treated with docetaxel-based chemotherapy
  • 22 men with mCRPC treated with cabazitaxel-based chemotherapy
  • 24 healthy controls

Here is what they found:

  • TMPRSS2-ERG gene expression was detected in
    • 0/24 of the healthy controls (0 percent)
    • 8/50 men treated with docetaxel (16 percent)
    • 5/22 men treated with cabazitaxel (23 percent)
  • Among the docetaxel-treated patients, compared to the healthy controls, TMPRSS2-ERG detection correlated with
    • A reduced PSA response rate (12.5 vs 68.3 percent, p = 0.005)
    • Shorter PSA-based progression-free survival (3.1 vs 7.5 months, p < 0.001)
    • Shorter clinical/radiological PFS (3.1 vs 8.2 months, p < 0.001)
  • Among the docetaxel-treated patients, compared to the healthy controls, TMPRSS2-ERG detection was associated with
    • PSA-based progression-free survival (hazard ratio [HR] =3.7; p = 0.009)
    • Clinical/radiological progression-free survival (HR = 6.3; p < 0.001).
  • Among the cabazitaxel-treated patients, compared to the healthy controls, TMPRSS2-ERG detection also predicted shorter PSA-based progression-free survival.
  • At time of disease progression, a switch from negative to positive TMPRSS2-ERG expression was evident in 41 percent of patients with undetected TMPRSS2-ERG at the baseline sample.

Reig et al. conclude that their data

support the potential role of TMPRSS2-ERG detection as a biomarker to tailor treatment strategies.

However, we are going to need more compelling data before it can be determined whether to test all patients for expression of the TMPRSS2-ERG gene before treating them with a taxane like docetaxel or cabazitaxel. The current data are certainly interesting but are not definitive. If you have a look at the Medscape commentary on this research, you will see why some US-based experts are a little skeptical about these pilot data.

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