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ABSTRACT: The purpose of our study was to investigate whether fast and slow components of the apparent diffusion coefficient (ADC) from diffusion-weighted MR images could predict prostate cancer progression in patients managed by active surveillance.
Eighty-one patients managed by active surveillance underwent diffusion-weighted MRI in addition to T2-weighted MRI using an endorectal technique. ADCs from tumor regions of interest were calculated using all b values (ADC(all)), b = 0-300 s/mm(2) (ADC(fast)), and b = 300-800 s/mm(2) (ADC(slow)). These parameters and tumor volumes were compared in those upgraded at subsequent biopsy (n = 14) versus those histologically stable (n = 41) and in evaluable patients who progressed to radical treatment (n = 16) versus those who did not (n = 64). Cox's regression was used to analyze the effect of parameter mean on time to treatment.
ADC(all), ADC(fast), and ADC(slow) in patients upgraded on repeat biopsy were significantly lower than those who were stable (1,070 ± 110 vs 1,356 ± 357 × 10(-6)mm(2)/s, p < 0.001; 1,283 ± 188 vs 1,526 ± 397 × 10(-6)mm(2)/s, p = 0.004; 843 ± 74 vs 1,105 ± 285 × 10(-6) mm(2)/s, p < 0.001, respectively). Tumor volume was significantly higher in the upgraded group (0.86 ± 0.9 vs 0.26 ± 0.25 cm(3), p = 0.02). The lower ADC(slow) in patients who subsequently progressed to radical treatment approached significance (922 ± 256 vs 1,054 ± 235 × 10(-6) mm(2)/s, p = 0.053; hazard ratio, 0.991 for time to treatment). Tumor volume was significantly higher in the treated group (0.86 ± 0.85 cm(3) vs 0.32 ± 0.33 cm(3), p = 0.02). ADC(slow) and tumor volume were significant but independent predictors of upgrade on biopsy (p = 0.01 and 0.002, respectively).
Both fast and slow diffusion components were significantly lower in tumors that were subsequently upgraded on histology. Both tumor volume and the true diffusion ADC(slow) were significant but independent predictors of histologic progression.
American Journal of Roentgenology 03/2011; 196(3):586-91. · 2.78 Impact Factor
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Alison H M Reid,
Gerhardt Attard,
Daniel C Danila,
Nikhil Babu Oommen,
David Olmos,
Peter C Fong,
L Rhoda Molife,
Joanne Hunt,
Christina Messiou, Christopher Parker,
David Dearnaley,
Joost F Swennenhuis,
Leon W M M Terstappen,
Gloria Lee,
Thian Kheoh,
Arturo Molina,
Charles J Ryan,
Eric Small,
Howard I Scher,
Johann S de Bono
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ABSTRACT: The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate, an oral, specific, irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant prostate cancer (CRPC).
In this multicenter, two-stage, phase II study, abiraterone acetate 1,000 mg was administered once daily continuously. The primary end point was achievement of a prostate-specific antigen (PSA) decline of > or = 50% in at least seven of 35 patients. Per an attained phase II design, more than 35 patients could be enrolled if the primary end point was met. Secondary objectives included: PSA declines of > or = 30% and > or = 90%; rate of RECIST (Response Evaluation Criteria in Solid Tumors) responses and duration on study; time to PSA progression; safety and tolerability; and circulating tumor cell (CTC) enumeration.
Docetaxel-treated patients with CRPC (N = 47) were enrolled. PSA declines of > or = 30%, > or = 50% and > or = 90% were seen in 68% (32 of 47), 51% (24 of 47), and 15% (seven of 47) of patients, respectively. Partial responses (by RECIST) were reported in eight (27%) of 30 patients with measurable disease. Median time to PSA progression was 169 days (95% CI, 113 to 281 days). The median number of weeks on study was 24, and 12 (25.5%) of 47 patients remained on study > or = 48 weeks. CTCs were enumerated in 34 patients; 27 (79%) of 34 patients had at least five CTCs at baseline. Eleven (41%) of 27 patients had a decline from at least five to less than 5 CTCs, and 18 (67%) of 27 had a > or = 30% decline in CTCs after starting treatment with abiraterone acetate. Abiraterone acetate was well tolerated.
Abiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC. Randomized, phase III trials of abiraterone acetate are underway to define the future role of this agent.
Journal of Clinical Oncology 02/2010; 28(9):1489-95. · 18.37 Impact Factor
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Gerhardt Attard,
Alison H M Reid,
Roger A'Hern, Christopher Parker,
Nikhil Babu Oommen,
Elizabeth Folkerd,
Christina Messiou,
L Rhoda Molife,
Gal Maier,
Emilda Thompson,
David Olmos,
Rajesh Sinha,
Gloria Lee,
Mitch Dowsett,
Stan B Kaye,
David Dearnaley,
Thian Kheoh,
Arturo Molina,
Johann S de Bono
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ABSTRACT: It has been postulated that castration-resistant prostate cancer (CRPC) commonly remains hormone dependent. Abiraterone acetate is a potent, selective, and orally available inhibitor of CYP17, the key enzyme in androgen and estrogen biosynthesis.
This was a phase I/II study of abiraterone acetate in castrate, chemotherapy-naive CRPC patients (n = 54) with phase II expansion at 1,000 mg (n = 42) using a two-stage design to reject the null hypothesis if more than seven patients had a prostate-specific antigen (PSA) decline of > or = 50% (null hypothesis = 0.1; alternative hypothesis = 0.3; alpha = .05; beta = .14). Computed tomography scans every 12 weeks and circulating tumor cell (CTC) enumeration were performed. Prospective reversal of resistance at progression by adding dexamethasone 0.5 mg/d to suppress adrenocorticotropic hormone and upstream steroids was pursued.
A decline in PSA of > or = 50% was observed in 28 (67%) of 42 phase II patients, and declines of > or = 90% were observed in eight (19%) of 42 patients. Independent radiologic evaluation reported partial responses (Response Evaluation Criteria in Solid Tumors) in nine (37.5%) of 24 phase II patients with measurable disease. Decreases in CTC counts were also documented. The median time to PSA progression (TTPP) on abiraterone acetate alone for all phase II patients was 225 days (95% CI, 162 to 287 days). Exploratory analyses were performed on all 54 phase I/II patients; the addition of dexamethasone at disease progression reversed resistance in 33% of patients regardless of prior treatment with dexamethasone, and pretreatment serum androgen and estradiol levels were associated with a probability of > or = 50% PSA decline and TTPP on abiraterone acetate and dexamethasone.
CYP17 blockade by abiraterone acetate results in declines in PSA and CTC counts and radiologic responses, confirming that CRPC commonly remains hormone driven.
Journal of Clinical Oncology 06/2009; 27(23):3742-8. · 18.37 Impact Factor
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Gerhardt Attard,
Joost F Swennenhuis,
David Olmos,
Alison H M Reid,
Elaine Vickers,
Roger A'Hern,
Rianne Levink,
Frank Coumans,
Joana Moreira,
Ruth Riisnaes, [......],
Ronald Sipkema,
Craig P Carden, Christopher Parker,
David Dearnaley,
Stan B Kaye,
Colin S Cooper,
Arturo Molina,
Michael E Cox,
Leon W M M Terstappen,
Johann S de Bono
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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.
Cancer Research 05/2009; 69(7):2912-8. · 7.86 Impact Factor
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ABSTRACT: Fusion of the hormone-regulated gene TMPRSS2 with ERG occurs in 50-70% of prostate cancers; fusions of ETV1 with one of several partners occur in approximately 10% of prostate cancers. These two translocations are mutually exclusive. The presence of subclasses of these chromosomal rearrangements may indicate worse prognosis, with the subclass 2+Edel, which has duplication of TMPRSS2:ERG fusion sequences, indicating particularly poor survival. However as this case shows, significant heterogeneity can exist with ERG and ETV1 rearrangements occurring in both prostate intra-epithelial neoplasia and cancer in the same prostatectomy specimen and with adjacent cancer areas containing a single copy, duplication and even triplication of the rearranged locus. As the majority of ETS gene fusions are hormone regulated, they could explain the pathogenesis underlying exquisitely hormone-sensitive prostate cancer. This is exemplified by the case presented here of a patient diagnosed in 1991 who remains asymptomatic and chemotherapy-naïve after having long-lasting tumour responses to multiple lines of systemic hormonal treatments.
Journal of clinical pathology 01/2009; 62(4):373-6. · 2.43 Impact Factor
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ABSTRACT: A method for enumerating circulating tumor cells (CTC) has received regulatory clearance. The primary objective of this prospective study was to establish the relationship between posttreatment CTC count and overall survival (OS) in castration-resistant prostate cancer (CRPC). Secondary objectives included determining the prognostic utility of CTC measurement before initiating therapy, and the relationship of CTC to prostate-specific antigen (PSA) changes and OS at these and other time points.
Blood was drawn from CRPC patients with progressive disease starting a new line of chemotherapy before treatment and monthly thereafter. Patients were stratified into predetermined Favorable or Unfavorable groups (<5 and > or =5 CTC/7.5mL).
Two hundred thirty-one of 276 enrolled patients (84%) were evaluable. Patients with Unfavorable pretreatment CTC (57%) had shorter OS (median OS, 11.5 versus 21.7 months; Cox hazard ratio, 3.3; P < 0.0001). Unfavorable posttreatment CTC counts also predicted shorter OS at 2 to 5, 6 to 8, 9 to 12, and 13 to 20 weeks (median OS, 6.7-9.5 versus 19.6-20.7 months; Cox hazard ratio, 3.6-6.5; P < 0.0001). CTC counts predicted OS better than PSA decrement algorithms at all time points; area under the receiver operator curve for CTC was 81% to 87% and 58% to 68% for 30% PSA reduction (P = 0.0218). Prognosis for patients with (a) Unfavorable baseline CTC who converted to Favorable CTC improved (6.8 to 21.3 months); (b) Favorable baseline CTC who converted to Unfavorable worsened (>26 to 9.3 months).
CTC are the most accurate and independent predictor of OS in CRPC. These data led to Food and Drug Administration clearance of this assay for the evaluation of CRPC.
Clinical Cancer Research 11/2008; 14(19):6302-9. · 7.74 Impact Factor
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Gerhardt Attard,
Alison H M Reid,
Timothy A Yap,
Florence Raynaud,
Mitch Dowsett,
Sarah Settatree,
Mary Barrett, Christopher Parker,
Vanessa Martins,
Elizabeth Folkerd,
Jeremy Clark,
Colin S Cooper,
Stan B Kaye,
David Dearnaley,
Gloria Lee,
Johann S de Bono
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ABSTRACT: Studies indicate that castration-resistant prostate cancer (CRPC) remains driven by ligand-dependent androgen receptor (AR) signaling. To evaluate this, a trial of abiraterone acetate-a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis-was pursued.
Chemotherapy-naïve men (n = 21) who had prostate cancer that was resistant to multiple hormonal therapies were treated in this phase I study of once-daily, continuous abiraterone acetate, which escalated through five doses (250 to 2,000 mg) in three-patient cohorts.
Abiraterone acetate was well tolerated. The anticipated toxicities attributable to a syndrome of secondary mineralocorticoid excess-namely hypertension, hypokalemia, and lower-limb edema-were successfully managed with a mineralocorticoid receptor antagonist. Antitumor activity was observed at all doses; however, because of a plateau in pharmacodynamic effect, 1,000 mg was selected for cohort expansion (n = 9). Abiraterone acetate administration was associated with increased levels of adrenocorticotropic hormone and steroids upstream of CYP17 and with suppression of serum testosterone, downstream androgenic steroids, and estradiol in all patients. Declines in prostate-specific antigen >or= 30%, 50%, and 90% were observed in 14 (66%), 12 (57%), and 6 (29%) patients, respectively, and lasted between 69 to >or= 578 days. Radiologic regression, normalization of lactate dehydrogenase, and improved symptoms with a reduction in analgesic use were documented.
CYP17 blockade by abiraterone acetate is safe and has significant antitumor activity in CRPC. These data confirm that CRPC commonly remains dependent on ligand-activated AR signaling.
Journal of Clinical Oncology 10/2008; 26(28):4563-71. · 18.37 Impact Factor
