UroToday - The TMPRSS2-ERG gene fusion occurs in 30-70% of androgen deprivation therapy (ADT) naïve prostate cancers (CaP), but its relevance in castration-resistant prostate cancer (CRPC) is less well defined. The TMPRSS2-ERG gene fusion is androgen driven. In the April 1, 2009 issue of Cancer Research, a group led by Dr. Johann de Bono evaluated patients undergoing treatment with the CYP17 inhibitor abiraterone acetate, which ablates the synthesis of androgens and estrogens that drive the TMPRSS2-ERG gene fusions. They hypothesized that androgen-dependent overexpression of ERG persisted in CRPC and that TMPRSS2-ERG tumors represented a subgroup of CaP that remained sensitive to abiraterone acetate. They hypothesized that two mechanisms of resistance to abiraterone acetate were gain of AR and loss of PTEN that could result in constitutive phosphorylation of AR, leading to ligand-independent activation.

Blood was collected monthly from 54 chemotherapy-naïve patients and 35 docetaxel-treated patients, and castration-resistant circulating tumor cells (CTCs) were isolated using an anti-epithelial cell adhesion molecule antibody-based immunomagnetic selection. CTCs were evaluated by fluorescence in situ hybridization (FISH) for ERG, AR, and PTEN gene loci.

The number of CTCs was associated with survival and a decline in count after treatment was associated with improved outcome. FISH revealed significant heterogeneity of PTEN loss and AR copy number gain. Eighty-five percent of patients had 3 copies of AR. There was no change in ERG and PTEN status in CTCs collected from patients before starting and after progression on abiraterone acetate. Also, there was no shift in AR copy number with treatment. ERG gene status was compared in tissue prior to treatment and after treatment from the same patients. CTC ERG gene status matched the ERG gene status of tumor tissues in all cases. All patients with an ERG rearrangement in the pre-therapy tissue also had it in the CRPC tissue and visa versa. Quantitative RT-PCR confirmed the FISH data.

Since there was no change in ERG gene status with castration resistance or with abiraterone acetate therapy, the investigators combined ERG data from CTCs, CRPC tumor tissue, and archival therapy-naïve tissue to obtain an ERG gene class for 77 patients. An ERG rearrangement was present in 32 patients and not in 45. The presence of an ERG rearrangement was associated with the magnitude of PSA decline on abiraterone acetate with 12 of 15 patients (80%) who had >90% decrease having an ERG rearrangement compared with only 20 of 62 patients (32%) who did not have a >90% PSA decline being ERG rearranged. The data suggests that TMPRSS2-ERG gene fusion tumors are a subgroup of CaP that are sensitive to CYP17 inhibition with abiraterone acetate.

Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A'Hern R, Levink R, Coumans F, Moreira J, Riisnaes R, Oommen NB, Hawche G, Jameson C, Thompson E, Sipkema R, Carden CP, Parker C, Dearnaley D, Kaye SB, Cooper CS, Molina A, Cox ME, Terstappen LW, de Bono JS
Cancer Res. 2009 Apr 1;69(7):2912-8
10.1158/0008-5472N-08-3667

UroToday Contributing Editor Christopher P. Evans, MD, FACS

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