Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer.
Hormone-driven expression of the ERG oncogene after fusion with TMPRSS2 occurs in 30% to 70% of therapy-naive prostate cancers. Its relevance in castration-resistant prostate cancer (CRPC) remains controversial as ERG is not expressed in some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 patients (54 chemotherapy-naive patients and 35 docetaxel-treated patients) treated in phase I/phase II clinical trials of an orally available, highly specific CYP17 inhibitor, abiraterone acetate, that ablates the synthesis of androgens and estrogens that drive TMPRSS2-ERG fusions. We isolated circulating tumor cells (CTC) by anti-epithelial cell adhesion molecule immunomagnetic selection followed by cytokeratin and CD45 immunofluorescence and 4',6-diamidino-2-phenylindole staining. We used multicolor fluorescence in situ hybridization to show that CRPC CTCs, metastases, and prostate tissue invariably had the same ERG gene status as therapy-naive tumors (n=31). We then used quantitative reverse transcription-PCR to show that ERG expression was maintained in CRPC. We also observed homogeneity in ERG gene rearrangement status in CTCs (n=48) in contrast to significant heterogeneity of AR copy number gain and PTEN loss, suggesting that rearrangement of ERG may be an earlier event in prostate carcinogenesis. We finally report a significant association between ERG rearrangements in therapy-naive tumors, CRPCs, and CTCs and magnitude of prostate-specific antigen decline (P=0.007) in CRPC patients treated with abiraterone acetate. These data confirm that CTCs are malignant in origin and indicate that hormone-regulated expression of ERG persists in CRPC.
Attard
Gerhardt
G
The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Swennenhuis
Joost F
JF
Olmos
David
D
Reid
Alison H M
AH
Vickers
Elaine
E
A'Hern
Roger
R
Levink
Rianne
R
Coumans
Frank
F
Moreira
Joana
J
Riisnaes
Ruth
R
Oommen
Nikhil Babu
NB
Hawche
George
G
Jameson
Charles
C
Thompson
Emilda
E
Sipkema
Ronald
R
Carden
Craig P
CP
Parker
Christopher
C
Dearnaley
David
D
Kaye
Stan B
SB
Cooper
Colin S
CS
Molina
Arturo
A
Cox
Michael E
ME
Terstappen
Leon W M M
LW
de Bono
Johann S
JS