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CCR FOCUS

Translating Scientific Advancement into Clinical Benefit for Castration-Resistant Prostate Cancer Patients

Gerhardt Attard and Johann S. de Bono

Abstract In the past 12 months, three novel therapeutics—sipuleucel-T, cabazitaxel, and abiraterone acetate— were granted Food and Drug Administration regulatory approval for the treatment of metastatic castration-resistant prostate cancer (CRPC) patients based on phase III studies that showed a survival advantage. Other agents, including the novel antiandrogen MDV3100, are at an advanced stage of clinical phase III evaluation. The treatment paradigm for CRPC has now changed significantly, and this has introduced new challenges for physicians, including selecting patients for specific therapies, developing the best sequencing and combination regimens for the several new effective agents that have recently been approved or are in development, and dissecting mechanisms of resistance that will inform the development of a new generation of therapeutics. This Focus issuereviewstheresults obtained with immunotherapies, taxane cytotoxics, and androgen receptor targeting therapeutics for CRPC, as well as the postulated mechanisms of resistance to these protocols and proposed strategies for improvement. The use of biomarkers for patient selection, monitoring of treatment activity, and acceleration of drug approval will be critical for achieving further improvements in the treatment forCRPC,andisalsodiscussedindetail.Clin Cancer Res; 17(12); 3867–75. 2011 AACR.

Introduction tor (AR) develop with sequential hormone treatments (1–3), and in vitro and in vivo evidence that increased AR The publication of this Focus issue of Clinical Cancer expression induces resistance to hormone therapies (4) Research was instigated by the recent report of 3 positive led to efforts to improve on therapeutics targeting the AR registration phase III studies in metastatic castration- axis [recently reviewed in ref. 5 and by Massard and resistant prostate cancer (CRPC; Table 1). Reporting of a Fizazi (6) in this Focus issue]. However, CRPC remains a fourth registration phase III trial, of the novel antian- fatal disease and patients invariably develop drug resis- drogen MDV3100, is expected within the next 12 tance. A long list of other therapeutic candidates have months. The total improvement in median survival been proposed and targeted clinically, mostly with lim- for an individual patient treated with 3 or 4 novel ited success. For example, phase II trials of therapeutics effective agents is unlikely to be cumulative, but it is targeting HER2 in CRPC, which was shown in robust probable that most patients with CRPC will live signifi- preclinical experiments to modulate the AR and induce cantly longer compared with 5 years ago. A decade of castration resistance (7–9), failed to identify antitumor scientific discoveries driven by increased funding for activity (10). However, the use of declines in prostate- prostate cancer research has improved our understand- specific antigen (PSA) as the primary endpoint in phase ing of the molecular biology underlying prostate cancer II studies has increased the risk of early drug attrition for progression and driven the development of new thera- potentially effective therapies. In the future, the use pies. The finding that aberrations of the androgen recep- of endpoints that are independent of AR signaling, such as changes in circulating tumor cell (CTC) count or bone imaging, could be critical for identifying active treatments in early clinical trials. Moreover, strategies that reverse resistance to androgen deprivation in pre- Authors' Affiliation: Section of Medicine, The Institute of Cancer clinical models may only be effective when AR signaling Research and the Royal Marsden NHS Foundation Trust, Sutton, has been effectively abrogated in patients, and novel United Kingdom agents may therefore prove to be most effective when Corresponding Author: Gerhardt Attard, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, Downs Road, combined with effective CYP17 inhibition of AR antag- Sutton, SM2 5PT UK. Phone: 44-779-307-7493; Fax: 44-208-642-7979; onism (Table 1). E-mail: [email protected]; [email protected] This Focus issue concentrates on discussing the results doi: 10.1158/1078-0432.CCR-11-0943 and potential for improvement of strategies with proven 2011 American Association for Cancer Research. efficacy in CRPC, namely, AR-targeting therapeutics (6),

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Table 1. Failure of active treatments for CRCP in early clinical trials: causes and possible solutions

Problem Cause Possible solution

Use of declines in PSA as the primary Active agents may fail due to an early rise Use of AR-independent activity endpoint in phase II studies. in PSA. endpoints, including changes in CTC count and bone imaging. Incomplete abrogation of AR Antitumor activity observed in preclinical models Clinical trial combinations with novel signaling in CRPC patients tested. with effective inhibition of AR signaling may treatments targeting AR, including not be effective in the presence of activated abiraterone acetate and/or MDV3100. AR. Failure to include patient Therapeutics targeting an aberration present in Biomarker-driven patient selection for subpopulations in which a <30% of the population may not recruit clinical trial recruitment. treatment would be active. sufficient patients in phase II trials to reject the null hypothesis.

taxane cytotoxics (11), and immunotherapy (12). Given BRAF and RAF-1 (15) are significantly less common, but the important role biomarkers could have in accelerating could be inhibited by therapeutics already in clinical cancer drug development and improving patient man- trials (Table 2). Similarly, the identification of overex- agement, a fourth article in this series reviews the bio- pression of SPINK1 in a subset of prostate cancers with marker landscape beyond PSA (13). Several other novel no underlying ETS gene rearrangement introduced the therapeutic strategies that target prostate cancer aberra- possibility of efficacy in therapeutically targeting SPINK1 tions are in late preclinical and early clinical develop- (16, 17). ment, and a comprehensive review of all of these approaches is beyond the scope of this series. Table 2 summarizes molecular aberrations that have been identified in prostate cancer and are targeted by thera- Treatment of Metastatic Prostate Cancer: peutics currently undergoing clinical evaluation. The A Historical Perspective discovery in 2005 by Tomlins and colleagues (14) of hormone-regulated ERG and ETV1 gene fusions led to a High doses of estrogens were shown to induce search for therapeutic strategies that inhibit either tumor responses in metastatic prostate cancer seven ERG or ETV1 or interacting proteins that are key to decades ago (5). This strategy was superseded by medical the function of ERG or ETV1. Gene fusions involving or surgical castration, and the use of estrogens for

Table 2. Molecular aberrations, therapeutic strategies, and biomarker profiles currently under evaluation

Molecular aberration Therapeutic strategy Biomarker profiles that could be used to identify sensitive patients

Activation of the PI3K/AKT Small-molecule inhibitors of PI3K or AKT Loss of PTEN, expression of phospho-AKT pathway DNA repair defects PARP inhibitors and other therapies that Loss of PTEN, chromosomal rearrangements exploit synthetic lethality Overexpression of IGF-1R Monoclonal antibodies and small-molecule IGF-1R overexpression inhibitors of IGF-1R Amplification of c-Myc Inhibitors of PIM kinase Increased c-Myc copy number Gene fusions involving RAF Small-molecule inhibitors of RAF or MEK Detection of BRAF or RAF-1 gene fusions by family of oncogenes fluorescence in situ hybridization (break-apart assays) or RT-PCR

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Treatments with Disease regulatory approval phenotype (March 2011) Novel treatments in advanced phase III development for metastatic Nonsteroidal castration-resistant prostate cancer antiandrogen, e.g., Asymptomatic, bicalutamide/ Sipuleucel-T rising PSA flutamide Ipilumimab NCT01057810 Medical or surgical castration Low dose

Bisphosphonates, RANK ligand inhibitors Alpharadin steroids, NCT00699751 estrogen Abiraterone + prednisone formulations Symptomatic, PS 1, NCT00887198 chemotherapy Orteronel + prednisone NCT01193244 Radiopharmaceuticals naïve MDV3100 Low-dose steroids as required NCT01212991 Docetaxel Novel combinations with docetaxel Cabazitaxel MDV3100 NCT00974311 Mitoxantrone Symptomatic, Orteronel + prednisone PS 1-2, NCT01193257 docetaxel Hormone treated Abiraterone + prednisone treatment (not NCT00638690 previously Alpharadin attempted) NCT00699751

Figure 1. Schematic representation of current treatment sequencing of approved drugs (March 2011; blue boxes) for metastatic CRPC. Agents in advanced phase III development are shown on the right. Red boxes represent strategies targeting AR signaling; yellow boxes represent other strategies under phase III evaluation. Arrows show patient populations for which agents are undergoing evaluation. The sequencing of abiraterone and MDV3100 in both the pre and post chemotherapy settings has not been studied and overlapping arrows are therefore used.

hormone-therapy–na€ve disease is no longer recom- and mutations in the AR that cause these drugs to become mended (Fig. 1). The efficacy of castration was improved agonistic have been detected in at least 15% to 30% of upon by the development of small-molecule AR antago- patients after development of resistance (3). In fact, the nists. In 2000, a meta-analysis of clinical trials published previously used term "maximum androgen blockade" between 1983 and 1987 that evaluated the combination could now be replaced by a more appropriate definition, of initiation of castration with either the nonsteroidal such as "dual targeting of the AR," to reflect the current antiandrogens nilutamide or flutamide or the steroidal limitations of this strategy. Nonetheless, antiandrogens compound cyproterone acetate showed a 5-year improve- are currently a common addition to castration at disease ment in overall survival (OS) of 2% to 3%, although the progression (indicated by a rise in PSA or clinical or range of uncertainty was 0% to 5%, compared to castra- radiological worsening of disease) and are associated with tion alone (18). The limited improvement in OS observed declines in PSA in 40% to 60% of patients. They can also when antiandrogens are combined with castration may be used as monotherapy in preference to castration as a be a result of the pharmacologic limitations of the agents first-line treatment for metastatic patients in whom avoid- used, and does not necessarily mean that the strategy of ance of the side effects of castration is important. A series combining androgen deprivation with AR antagonism is of phase II and phase III trials that were not powered to ineffective. For example, currently approved antiandro- detect improvements in OS reported tumor responses gens are reversible inhibitors of the AR, have a several- with estrogens, steroids, and ketoconazole in CRPC resis- fold lower affinity for the AR compared with androgens, tant to antiandrogens; however, none of these strategies

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has shown a survival benefit (19). Mitoxantrone chemotherapy in combination with prednisone received regulatory approval for treatment of CRPC based on an improvement in quality of life for CRPC patients. Two large randomized studies that compared 3-weekly docetaxel and daily prednisone with 1-weekly docetaxel and daily prednisone or 3-weekly mitoxantrone and predni- Treatment discontinuation due to toxicity versus comparator sone (TAX-327) and 3-weekly docetaxel and estramustine with mitoxantrone and estramustine (SWOG-9916) were the first therapeutic studies to show an improvement in OS for CRPC patients (2.5 months for TAX-327, later Reduction in death rate updated to 2.9 months; Table 3; refs. 20–22). Bispho- sphonates and, more recently, inhibitors of receptor acti- k vator of NF- B ligand (RANKL) achieved registration for ratio the treatment of CRPC based on a reduction in first on- study skeletal-related events: a composite endpoint that -value Hazard 0.0001 0.646 35% 18.7% versus 22.8% 0.0001 0.70 30% 18% versus 8% P < included pathologic fracture, radiation therapy, surgery to < bone, or spinal cord compression (23, 24). This treatment scheme is summarized in Fig. 1.

Targeting AR Signaling in CRPC Improvement in OS (months) The past decade witnessed a paradigm shift in CRPC treatment with the clinical confirmation that a significant proportion of CRPCs remain dependent on ligand

activation of the AR (6). Inhibition of CYP17-depen- patients enrolled 755 4.1 (25.8 versus 21.7) 0.032 0.76 22% 0.9% Number of dent hormone synthesis, which was initially attempted ve using the nonspecific CYP inhibitor ketoconazole € ve 770 1.9 (17.5 versus 15.6) 0.02 0.80 20% 16% versus 10% ve 1006 2.4 (18.9 versus 16.5) 0.009 0.775 24% 11% versus 10% (25), has now been proven to be a valid therapeutic € € approach with the use of the selective and potent CYP17 inhibitor abiraterone acetate. The recently reported placebo-controlled, registration phase III study of abiraterone acetate and prednisone in doce-

taxel-treated patients confirmed a significant survival (15% docetaxel-treated) Docetaxel-treated 1195 3.9 (14.8 versus 10.9) Docetaxel-treated 516 2.4 (15.1 versus 12.7) Disease state Chemotherapy-na Chemotherapy-na advantage with minimal toxicity, leading to FDA 85% chemotherapy-na approval of this agent for the treatment of patients in the postdocetaxel setting (April 2011; ref. 26). Also, as discussed by Massard and Fizazi (6) in this issue of Clinical Cancer Research, phase I and II clinical trials of prednisone prednisone prednisone abiraterone acetate reported significant activity in che- prednisone Placebo with Mitoxantrone with Comparator arm Mitoxantrone with motherapy-na€ve CRPC patients (27–29), and abirater- Mitoxantrone with one acetate may be as effective in the chemotherapy- na€ve setting as it is postchemotherapy (as evaluated in a multicenter, global, placebo-controlled phase III study [NCT00887198] due for reporting in the next 24 months; Table 4). Similarly, the novel antiandrogen with prednisone prednisone estramustine MDV3100, which was rationally designed and selected prednisone Effective treatment arm for significant activity in bicalutamide-resistant preclinical models (30), is highly active in chemotherapy- na€ve and docetaxel-treated CRPC patients who previously progressed on the antiandrogens bicalutamide or flutamide and other hormonal therapies (31). Phase Registration phase III studies showing an improvement in survival for patients with progressive, metastatic CRPC as of April 2011 III survival data for MDV3100 in both chemotherapy- na€ve and docetaxel-pretreated patients are expected COU-301, 2010 (26) Abiraterone acetate IMPACT, 2010 (36)Tropic, 2010 (40) Sipuleucel-T vaccine Placebo Cabazitaxel with SWOG-9916, 2004 (21) Docetaxel with within the next 24 months, and it is hoped that Table 3. Trial name, year of publication/reporting, (reference) TAX327, 2004 (20, 22) Docetaxel with MDV3100 will become another therapeutic option

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Table 4. Treatments in advanced phase III development for progressive metastatic CRPC

Experimental arm Comparator arm Disease state clinicaltrials.gov Identifier number

Daily MDV-3100 and prednisone (AFFIRM) Placebo and prednisone Docetaxel-treated NCT00974311 Daily abiraterone acetate and prednisone Placebo and prednisone Chemotherapy-na€ve NCT00887198 (COU-302) Daily MDV-3100 (PREVAIL) Placebo Chemotherapy-na€ve NCT01212991 Daily orteronel and prednisone Placebo and prednisone Docetaxel-treated NCT01193257 Daily orteronel and prednisone Placebo and prednisone Chemotherapy-na€ve NCT01193244 Ipilimumab Placebo and prednisone Chemotherapy-na€ve NCT01057810 Alpharadin Placebo Chemotherapy-na€ve and NCT00699751 docetaxel treated

NOTE: See Table 4 in ref. 11 for a list of phase III trials evaluating the pairing of novel agents with docetaxel. Also see Fig. 1 for placement of trials in the CRPC-management paradigm.

for treating this disease (Table 4). Evaluation of the phase I and II results for abiraterone acetate and long-term combination of AR blockade with abirater- MDV3100, a variety of novel agents targeting AR entered one acetate and/or MDV3100 in combination with clinical evaluation for CRPC (recently reviewed in ref. 5). castration at development of metastases or adjuvantly We previously proposed that continued activation of in nonmetastatic, high-risk, locally advanced disease is the AR and/or other steroid receptor signaling pathways now required. In both registration phase III trials, results in drug resistance in a significant propor- abiraterone acetate was combined with prednisone tion of CRPC patients progressing on abiraterone acetate or prednisolone to maximize efficacy and minimize and/or MDV3100, and further targeting of this pathway toxicity from secondary mineralocorticoid excess. Abir- is a valid approach (reviewed in ref. 1). However, as is aterone acetate can be administered alone with miner- thecasewithallnewagents targeting the AR ligand- alocorticoid receptor antagonists to minimize toxicity binding domain that are currently under clinical evalua- from mineralocorticoid excess (32), a strategy that may tion, cross-resistance could be high, and novel be required in early disease when long-term use of approaches such as direct inhibition of the AR amino- steroids may not be tolerated. However, spironolactone terminal domain (36) may be required to achieve the potently activates AR signaling (33) and should there- next significant improvement in outcome for CRPC fore be avoided in this patient population. patients. The division of patients with CRPC into chemotherapy-na€ve and docetaxel-treated populations for evaluation of AR-targeting agents has been driven more by practical considerations than by scientific logic, namely, Defining a Role for Immunotherapy in the the requirement to select a population that will mini- Treatment of CRPC mize the lead time for obtaining regulatory approval for a novel agent. However, emerging evidence that the The year 2010 saw the publication of the positive mechanism of action of taxanes in prostate cancer IMPACT phase III study of sipuleucel-T (ref. 37; Table 3). may be due at least in part to the disruption of mem- This was soon followed by the publication of a phase II brane-to-nucleus shuttling of steroid receptors (34, 35) study of a PSA-targeted poxviral vaccine, which also suggests that one may observe cross-resistance between reported an improvement in median survival, a secondary hormone therapies and taxanes, with response rates to endpoint in this study (38). Other immunotherapy either agent decreasing after sequential treatment. This approaches are also being evaluated in CRPC phase III may introduce important considerations for treatment studies, including the monoclonal antibody to CTLA4, sequencing that have not been suitably studied to date. ipilimumab, which is being investigated in both che- Similarly, the combination of hormone therapies such as motherapy-na€ve and docetaxel-treated patients (http:// abiraterone acetate and MDV3100 with docetaxel in clinicaltrials.gov, identifier numbers NCT01057810 and CRPC patients warrants evaluation, but improved effi- NCT00861614, respectively; Table 4). CTLA4 is a negative cacy from such a combination is certainly not a fore- regulator of T cells, and ipilimumab has been reported to gone conclusion. Predictably, following reporting of the confer a survival advantage in malignant melanoma

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through postulated enhancement of the immune response are often administered several more cycles of docetaxel. (39). The majority of patients tolerate treatment well, but Moreover, a number of retrospective analyses have side effects can be very severe, with a treatment-related reported secondary responses in re-treated patients mortality of 2% (39). In contrast, minimal toxicity has who had progressed after stopping first-line docetaxel been reported with vaccine therapy. Other approaches (41). However, the absence of robust biomarkers of for stimulating antitumor immunity are also undergoing response and progression for CRPC makes it difficult evaluation, including blockade of PD-1, an inhibitory to select patients who continue to be docetaxel-sensitive receptor expressed on the surface of activated T cells for readministration of this taxane. Most studies used (40). As proposed by Gulley and Drake (12) in this Focus PSA-based criteria, e.g., by rechallenging patients issue, the most appropriate time to use immunotherapy is who showed a decline in PSA of 50% with no probably when the tumor load is lowest and the induced increase for at least 3 months after stopping treatment. immune response has the best chance of significantly In the absence of robust survival data for re-treatment affecting the upward slope of tumor growth. This intro- with docetaxel, it is hard to interpret these findings. duces the possibility of using an approved vaccine therapy, The recently reported TROPIC study (Table 1) showed such as sipuleucel-T, at development of castration that the use of cabazitaxel in patients previously resistance, thus allowing a significant time interval from treated with docetaxel is effective and improves initiation of steroids or chemotherapy (Fig. 1). Gulley and median survival by 2.4 months (42). Significant Drake also discuss the combination of more than one response rates were reported for patients who had immunotherapy agent or of immunotherapy with other previously progressed during docetaxel treatment as well treatments. as within 12 weeks of completing docetaxel. This In the absence of biomarkers of response or robust suggests that in addition to the secondary responses pharmacodynamic endpoints for immunotherapy, it one would expect from re-treatment with docetaxel, is not clear whether the significant improvements the pharmacologic properties of cabazitaxel might in median survival reported to date are due to very further improve on the antitumor activity of prolonged responses in a small subpopulation of docetaxel. This approach is now undergoing clinical patients or a more modest improvement across all evaluation in a direct comparison of docetaxel and patients. Also, physicians face challenges in continu- cabazitaxel. In view of the risks reported for this agent, ing immunotherapy in patients with a rising PSA and cabazitaxel should be administered with the appropriate no objective evidence of benefit, in terms of both precautions by oncologists with expertise in managing justification of cost and patient reassurance. Greater neutropenic sepsis. efforts to understand the mechanism of action under- Nonetheless, taxane resistance is inevitable for most lying treatment and to develop pharmacodynamic patients with CRPC, and remains one of the key endpoints will be required in future immunotherapy challenges in the treatment of this disease. As dis- clinical trials if significant improvements are to be cussed by Madan and colleagues (11), it may be made in antitumor efficacy and cost-effectiveness. possible to delay the time-to-progression on taxanes Immunotherapy approaches for hormone-sensitive by interrupting treatment after an arbitrary measure of disease are also undergoing evaluation, but in the tumor response is achieved, by combining it with absence of surrogates of response, the long lead time another novel or established drug, or by combining to meet a primary endpoint of OS and the impact of both of these strategies. The first strategy is limited by cross-over to other agents after the trial therapeutic the unavailability of a suitable surrogate of tumor intervention will make such studies challenging to response that could indicate the correct time to inter- conduct and interpret. rupt treatment. Tumor responses in the absence of a declineinPSAarewelldescribed, and declines in PSA may not truly represent a tumor response. The second strategy is undergoing extensive evaluation, with at Chemotherapy for CRPC: Beyond Single-Agent least 7 different novel agents in phase III docetaxel- Docetaxel combination clinical trials (see Table 4 in ref. 11). The mechanisms underlying taxane resistance are not com- After the publication of the TAX327 and SWOG-9916 pletely understood, although a number of hypotheses registration phase III studies (20, 21), docetaxel exist (see Table 1 in ref. 11). These mechanisms could replaced mitoxantrone as the first-line cytotoxic choice be CRPC-specific, such as alterations in inhibition of for palliation of symptoms in metastatic CRPC patients. AR signaling, or cancer-generic, such as tubulin muta- The TAX327 and SWOG-9916 studies aimed to give tions. Interestingly, castrated patients show increased patients 10 cycles of treatment; however, patients clearance of docetaxel compared with noncastrated who show an ongoing response and tolerate treatment patients, which could explain the relatively good tol-

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erability of docetaxel in CRPC but may also contribute targeted selection for treatments will become more to treatment failure (43). appealing.

Biomarker-Driven Therapeutic Development Future Strategies for CRPC As is evident from this Focus issue, significant advances have been made in prostate cancer research in the past As discussed by Danila and colleagues (13) in this decade. We propose a new treatment pathway for CRPC issue, robust intermediate endpoints or surrogate bio- that includes agents in advanced phase III development markers of treatment response are urgently needed for (Fig. 1). In addition to the continuing requirement for CRPC. A number of novel biomarkers are undergoing novel effective drugs and therapeutic strategies, several evaluation as potential surrogates of response, probably new challenges now confront physicians treating CRPC. foremost among which is the CTC count. A CTC count of These challenges include developing the best sequencing <5, compared with 5, respectively, before or after one and combination regimens for the several new effective or more cycles of cytotoxic treatment for CRPC is asso- agents that have recently been approved or are in devel- ciated with longer survival (44). Demonstration of sur- opment, dissecting mechanisms of resistance that will rogacy requires evaluation of CTC in several positive inform the development of a new generation of thera- therapeutic phase III trials. These studies are ongoing, peutics, and conducting well-powered, hypothesis-testing including the recently reported phase III study of abir- studies (5). aterone acetate in docetaxel-treated patients. An improved understanding of the molecular biology underlying CRPC is also driving the evaluation of pre- Disclosure of Potential Conflicts of Interest dictive biomarkers that could be used to enrich for patients who are more likely to respond to a specific G.AttardandJ.S.deBonoareemployees of The Institute of Cancer treatment. The discovery of hormone-driven ERG gene Research, which has a commercial interest in the development of abiraterone acetate. J.S. de Bono has served as a paid consultant for fusions in 50% to 70% of prostate cancers provided a Johnson & Johnson, Medivation, Astellas, Dendreon, and AstraZeneca. compelling explanation for the hormone-driven nature G. Attard has served as a paid consultant for Millennium Pharmaceu- of prostate cancer (14). Genomic changes, such as rear- ticalsandVeridexandasanuncompensated advisor for Johnson & Johnson. G. Attard is on The Institute of Cancer Research list of rangements of ERG or gain of AR, can be robustly rewards to inventors of abiraterone acetate. evaluatedinCTCandtissueviafluorescencein situ hybridization (45), allowing the stratification of patients into different molecular subgroups that could have dif- Grant Support ferential responses to specific therapies. In a recent study, massively parallel, high-resolution, deep sequencing of Cancer Research UK and the Department of Health [Cancer Research UK program grant and Experimental Cancer Medical Centre grant (C51/ prostate tumors was used to identify multiple novel A7401) to Section of Medicine, Institute of Cancer Research]; Prostate somatic mutations and chromosomal rearrangements Cancer Foundation Young Investigator Award (G. Attard); and National Health Service funding to the Royal Marsden Hospital National Institute (46). As deep-sequencing technology and other whole- for Health Research Biomedical Research Centre. genome and expression-analysis platforms become more cost-effective, strategies involving comprehensive mole- Received April 12, 2011; revised April 28, 2011; accepted April 28, 2011; cular evaluations, subclassification of all patients, and published online June 16, 2011.

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