Τίτλος:
Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Background Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC). Objective To evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations. Design, setting, and participants In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160 mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment. Outcome measurements and statistical analysis Androgen signaling components (androgen receptor [AR], AR splice variant 7 (ARV7), v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography-tandem mass spectrometry; AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied. Results and limitations Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9-29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ≥50% and ≥90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (>75%) and CYP17 (>10%) expression were associated with benefit (p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). Limited patient numbers warrant further validation. Conclusions The observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance. Patient summary We report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature. Trial registration ClinicalTrials.gov identifier NCT01091103.
Συγγραφείς:
Efstathiou, E.
Titus, M.
Wen, S.
Hoang, A.
Karlou, M.
Ashe, R.
Tu, S.M.
Aparicio, A.
Troncoso, P.
Mohler, J.
Logothetis, C.J.
Περιοδικό:
European urology oncology
Λέξεις-κλειδιά:
androgen receptor; androstenedione; cytochrome P450 17; enzalutamide; hydrocortisone; prostate specific antigen; testosterone; androgen receptor; antineoplastic agent; enzalutamide; glucocorticoid receptor; isoprotein; Ki 67 antigen; oncogene proteins v-ets; oncoprotein; phenylthiohydantoin; prostate specific antigen; steroid 17alpha monooxygenase; testosterone, adult; aged; androgen blood level; Article; Avian erythroblastosis oncovirus; bone marrow; bone marrow biopsy; bone metastasis; cancer growth; cancer resistance; castration resistant prostate cancer; cellular distribution; copy number variation; depression; drug effect; drug withdrawal; face edema; human; human tissue; liquid chromatography; major clinical study; male; oncogene; phase 2 clinical trial; priority journal; protein expression; real time polymerase chain reaction; side effect; signal transduction; tandem mass spectrometry; analogs and derivatives; blood; Bone Marrow Neoplasms; Bone Neoplasms; cell nucleus; clinical trial; cytoplasm; drug effects; drug resistance; gene dosage; genetics; metabolism; middle aged; pathology; prospective study; Prostatic Neoplasms, Castration-Resistant; secondary; very elderly, Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bone Marrow; Bone Marrow Neoplasms; Bone Neoplasms; Cell Nucleus; Cytoplasm; Drug Resistance, Neoplasm; Gene Dosage; Humans; Ki-67 Antigen; Male; Middle Aged; Phenylthiohydantoin; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Receptors, Glucocorticoid; Retroviridae Proteins, Oncogenic; Signal Transduction; Steroid 17-alpha-Hydroxylase; Testosterone
DOI:
10.1016/j.eururo.2014.05.005
