Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer

Gerhardt Attard, Joost F Swennenhuis, David Olmos, Alison H M Reid, Elaine Vickers, Roger A'Hern, Rianne Levink, Frank Coumans, Joana Moreira, Ruth Riisnaes, Nikhil Babu Oommen, George Hawche, Charles Jameson, Emilda Thompson, Ronald Sipkema, Craig P Carden, Christopher Parker, David Dearnaley, Stan B Kaye, Colin S CooperArturo Molina, Michael E Cox, Leon W M M Terstappen, Johann S de Bono

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452 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)2912-8
Number of pages7
JournalCancer Research
Volume69
Issue number7
DOIs
Publication statusPublished - 1 Apr 2009

Keywords

  • Androstenols
  • Antigens, Neoplasm
  • Cell Adhesion Molecules
  • Gene Order
  • Humans
  • Immunomagnetic Separation
  • In Situ Hybridization, Fluorescence
  • Keratins
  • Male
  • Neoplasms, Hormone-Dependent
  • Neoplastic Cells, Circulating
  • Oncogene Proteins, Fusion
  • PTEN Phosphohydrolase
  • Prostatic Neoplasms
  • Receptors, Androgen
  • Trans-Activators

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