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Who and when should we screen for prostate cancer?

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Who and when should we screen for prostate cancer? Interviews with key opinion leaders

Sigrid CarlssonMichael LeapmanPeter CarrollFritz SchröderPeter C. AlbertsenDragan IlicMichael BarryDominick L. Frosch and Andrew Vickers

BMC Medicine2015; 13:288   http://dx.doi.org:/10.1186/s12916-015-0526-x

Prostate cancer screening using prostate-specific antigen (PSA) is highly controversial. In this Q & A, Guest Editors for BMC Medicine’s ‘Spotlight on Prostate Cancer’ article collection, Sigrid Carlsson and Andrew Vickers, invite some of the world’s key opinion leaders to discuss who, and when, to screen for prostate cancer. In response to the points of view from the invited experts, the Guest Editors summarize the experts’ views and give their own personal opinions on PSA screening.

Introduction

Sigrid Carlsson (Fig. 1a ) and Andrew Vickers (Fig. 1b )

Sigrid Carlsson and Andrew Vickers are the guest editors of BMC Medicine’s ‘Spotlight on Prostate Cancer’ article collection.

Screening for prostate cancer with prostate-specific antigen (PSA) is controversial. Screening is currently transitioning from being an all-or-nothing-question, to finding new ways of individualized testing. However, consensus remains to be reached within guideline groups and worldwide experts regarding who – and when – to screen, if at all. In this Q & A, we invite seven of the world’s key opinion leaders in the field, both proponents and skeptics, to elaborate on what they believe the current screening policy should be. The authors have all published widely on PSA, and comprise a wide variety of experience in areas such as urology, epidemiology, evidence-based medicine, and medical decision-making.

Currently, only one guideline group, the United States Preventive Services Task Force (USPSTF), recommends against screening for all men [1]. Most other guideline groups recommend shared decision-making, involving a discussion of the pros and cons of screening [2]. To aid in decision-making, some propose using a risk-stratified approach taking into account multiple factors along with a PSA measurement [3]. However, the specifics of such an approach are a subject of debate; for instance, the appropriate age limits of screening remain to be defined. Randomized screening trials, including the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Göteborg trial [4, 5] have provided evidence that regular PSA-screening can reduce prostate cancer mortality by 21–44 % at 13–14 years of follow-up; the age groups studied in these trials were 55–69 and 50–64 years, respectively. Thus, the question remains regarding the screening of men outside this age range. There is a growing body of evidence on the benefits of commencing screening in the mid-40s. While the American Urological Association (AUA) bases its recommendation on the 55–69 age group based on the ERSPC results [6], the European Urological Association recommends a baseline PSA be obtained at 40–45 years of age [7].

Our personal view is that PSA screening should indeed involve shared decision-making, but we believe the focus should primarily be on behavior, rather than preference. For this purpose, we have published a decision-support tool called the ‘Simple Schema’ [8], which acknowledges that the majority of harms of screening result from unnecessary treatment of low-risk disease and therefore focuses on the importance of active surveillance as the appropriate, evidence-based management strategy for low-risk cancer [911]. We further believe that PSA screening should be a risk-stratified approach aimed at detecting lethal prostate cancer. This is based on evidence that only a small proportion of men with moderately elevated PSA have aggressive disease [5] and that overdiagnosis is strongly influenced by age and PSA levels. For instance, we have shown that almost half of the excess incidence of cancer associated with PSA testing occurs in men over 70 [12] – a group in which screening is likely of little, if any, benefit [5, 13] – and that the effects of screening men in their 60s is highly dependent on their PSA level, with an excellent ratio of harms to benefits in patients with PSA ≥2 ng/mL but zero benefit in patients with a lower PSA [14]. Therefore, the current guidelines in place at Memorial Sloan Kettering Cancer Center restrict screening in men over 60 to those with above average PSAs and dramatically restrict screening in men over 70 to a small number of men with exceptional health and high PSA [15]. Additionally, biopsy is recommended only after a repeat PSA and further work-up, and the frequency of screening is stratified depending on baseline PSA, which has been shown to be a very strong predictor of long-term prostate cancer metastasis and death [1618].

Who and when to screen, and not to screen, for prostate cancer: the proponents’ view

Michael Leapman (Fig.  2 ), Peter Carroll (Fig.  3 ), and Fritz Schröder (Fig.  4 )

M Leapman & P Carroll: Prostate cancer is a highly prevalent disease that exhibits considerable variation in clinical behavior; some men will enjoy long lives with low-grade disease without treatment, while a significant, but smaller number may succumb to a devastating metastatic burden. Therefore, the current challenge faced in the early management of prostate cancer is to identify and treat disease in men likely to obtain benefit while sparing unnecessary detection and, most importantly, treatment in those who will not.

Compelling randomized evidence suggests that PSA screening of asymptomatic men is associated with a significant reduction in death from prostate cancer. The recent 13-year update of the ERSPC trial, a multi-centered study examining prostate cancer mortality among participants aged 50–74 receiving regular PSA screening compared with no routine screening, has demonstrated a relative risk of death from prostate cancer of 0.79 (95 % CI, 0.69–0.91, P = 0.001) in favor of screening men aged 55–69 years. Moreover, when adjusting for non-participation, the reduction in risk increased to 27 % (95 % CI, 0.61–0.88, P < 0.0007) [5]. Naturally, screening can only reduce mortality by effecting treatment of clinically significant disease, as was observed in the ERSPC experience, in which substantially more cancers were diagnosed and subsequently treated [19].

It is true that eliminating PSA screening will obviously decrease the number of ‘insignificant’ prostate cancer cases detected; however, this would come at the imprudent expense of ignoring disease in intermediate and high-risk patients who may stand to benefit substantially. Indeed, the rationale for treatment in appropriate patients is redoubled by randomized evidence suggesting improvement in survival and metastatic progression with timely treatment of threatening cancers [20]. However, an overall improvement in prostate cancer mortality is alone insufficient to justify expansive screening and treatment of all men if such a strategy will expose those harboring non-lethal tumors to a non-trivial risk of adverse quality of life outcomes; one should not screen if overdiagnosis is followed by overtreatment [21].

Ultimately, the landscape of early prostate cancer detection may not truly be cast in a monochromatic decision palette, namely to screen with PSA or not to screen. Rational practices including the screening of healthy men with a long life expectancy starting at age 45, cessation of screening in those with significant co-morbidity and those of advanced age, extending the interval of screening in most men (2–4 years), and discontinuing screening for those with low-risk profiles at certain ages alone would significantly improve the efficiency of early detection. In addition, nuanced strategies for prostate cancer detection and management represent an auspicious frontier. Although not validated in randomized trials of screening techniques, assays incorporating novel PSA isoforms – including the 4-Kallikrein panel [22] and the Prostate Health Index [23] – appear to add much needed specificity for the detection of high-grade (Gleason ≥7) prostate cancer at a diagnostic prostate biopsy, thereby potentially reducing the number of unnecessary biopsies performed. Advanced imaging modalities, including multi-parametric MRI, may also better refine the candidacy and yield of biopsy [24]. Among newly diagnosed patients, tumor-based risk stratification methods [25] and favorable long-term experiences with active surveillance [10] are poised to improve the confidence and quality with which incidental tumors are managed. Such measures, being currently clinically implemented, are highly promising means to cultivate better screening; these methods will highlight prostate cancer requiring attention while disregarding or proposing active surveillance of those that do not.

F Schröder: In my view, the time for population-based screening has not come and may never do so. The main reason for my pessimistic view on this issue is the high probability (of approximately 40 %) of diagnosing cancers which will not progress clinically, cause symptoms, or lead to death (overdiagnosis) [5]. While there are methods available to decrease overdiagnosis, such as the use of risk calculators and multiparametric MRI of the prostate, these have not been sufficiently validated in multicenter use to establish their accuracy in routine clinical practice. As a main contributor and former principal investigator of the ERSPC screening trial, I am delighted to see increasing worldwide acceptance of the recommendation of our group, including in US, European, and Russian guidelines to apply ‘shared decision-making’. We recommend the use of a procedure developed on the basis of ERSPC data, which is freely available on the website of the SIU [26].

A Vickers and S Carlsson [to M Leapman and P Carroll]: Could you please clarify what you think current policy should be and whether all men should be screened?

M Leapman & P Carroll: On the basis of randomized screening trials, PSA screening should be offered to healthy individuals without known risk factors for prostate cancer beginning at age 45 [5, 27]. No stark policy, however, will account for the complexities involved with screening and early diagnosis of prostate cancer. As a result, screening of asymptomatic men should be approached in the setting of a shared decision between a patient and physician cognizant of the individual’s age, health status, personal preferences, and risk factors including family history, race, prior PSA, and biopsy status. As noted above, the efficiency of screening can be improved and contemporary screening guidelines are incorporating refinements as suggested [28].

A Vickers and S Carlsson: You say that “ discontinuing screening for those with low baseline risk profiles [would]significantly improve the efficiency of [PSA] screening ”. Could you give a specific example of the profile of a man for whom screening should be discontinued?

M Leapman & P Carroll: Obviously, those in poor health or of advanced age do not benefit from early detection efforts. The optimal frequency of PSA testing has not been explicitly compared in a randomized fashion, but screening at 2–4 year intervals appears appropriate in low-risk patients based on PSA levels. Baseline PSA status may offer a valuable insight into a patient’s further risk for harboring or developing significant prostate cancer. Persuasive evidence from a Swedish population-based cohort examining PSA levels at age 60 suggests that men with levels <1 ng/mL possess a low (near zero) risk of prostate cancer death in extended follow-up [14, 17]. It would be reasonable to forego further screening of a 60-year-old without other known risk factors with baseline PSA <1 in the absence of cause.

in the state of Michigan, where nearly half of all patients diagnosed with low-risk disease are initially managed with active surveillance [30]

F Schröder: Weighing pros and cons of a medical procedure will always remain the responsibility of the person at risk. We, as doctors and urologists, have to help by addressing the questions arising after reading the first section of the decision aid, which is only one page.

Who and when to screen, and not to screen, for prostate cancer: the skeptics’ view

Peter C Albertsen (Fig.  5 ) and Dragan Ilic (Fig.  6)

should PSA be avoided entirely in asymptomatic men, or should screening be restricted to certain subgroups and, if so, whom?

P Albertsen: Few cancers generate as much controversy as prostate cancer concerning screening, diagnosis, and treatment. From 1977 to 2005, the lifetime risk of prostate cancer diagnosis in the US increased from 7.3 % to 17 % [31, 32]. During this same period, the lifetime risk of dying from prostate cancer fell from 3.0 % to 2.4 %.

My views on prostate cancer screening and treatment have been shaped by my training in urology at Johns Hopkins and epidemiology and public health at the University of Wisconsin, as well as by my patients. One patient in particular had a powerful influence. He was referred for treatment of a localized prostate cancer and underwent successful surgery. His postoperative PSA was undetectable and all surgical margins were negative. I told him he was cured only to have him return 2 years later with widespread metastases. I treated him successfully with anti-androgen therapy for an additional 16 years. According to the Halsted model of cancer progression he should have been cured by surgery [33]. I had the original specimen re-cut to document negative margins and concluded that we had a poor understanding of the natural history of this disease and the efficacy of treatment.

To address this problem, I developed a Markov model of prostate cancer progression. With the assistance of Jack Wennberg’s research group, the model was published in JAMA [34]. At the time, it was severely criticized by the urologic community, but when reviewed today the model bears a remarkable resemblance to data recently published by the SPCG-4 [35]. The sensitivity analysis indicated that data concerning the natural history of this disease was most critical to estimating the relative value of intervention. This is why I gathered data on the natural history of this disease from patients enrolled in the Connecticut tumor registry and published them in JAMA in 1998 and 2005 [36, 37].

My training in epidemiology taught me to view healthcare delivery from a public health perspective. Screening programs were best assessed by addressing four key questions: (1) Is prostate cancer a suitable disease for screening? (2) Is treatment for prostate cancer effective? (3) Is PSA an effective screening test for this disease? (4) Does screening result in any harm?

Only recently have we begun to appreciate that a large number of men harbor indolent disease, as clearly demonstrated by data from the Finasteride Chemoprevention trial [39]. Many pathologists now question whether Gleason 3 + 3 tumors are sufficiently aggressive to cause morbidity [40]. Indeed, recent data from the ERSPC trials suggest that half of all screen-detected cancers are indolent [5].

The efficacy of treatment also poses problems. Most urologists and radiation therapists assume that surgery and radiation are curative. However, what do the data say? The SPCG-4 suggests that some men are cured by surgery, but many men are not [35]. Further, men with high-grade disease often die from prostate cancer despite surgery and that surgery is primarily palliative for men aged over 65. With regards to radiation, even less information concerning its efficacy is available to date.

How well does PSA perform as a screening tool? Unfortunately, many lethal tumors produce low amounts of PSA and are missed by screening studies. Additionally, prostate enlargement, prostatitis, and surgical manipulation can lead to a significant number of false positive values. Finally, screening can result in considerable morbidity as documented by the USPSTF report [1].

I have been an advocate of active surveillance for men with low-grade disease [9]. Data from the ProTECT trial should provide important new data concerning efficacy when published in the spring of 2016 [41]. Ideally, screening should only identify men destined to suffer from clinically significant disease and patients should only be offered treatments that yield substantial benefit.

D Ilic: Prostate cancer is a leading cancer affecting men worldwide [42]. Despite its high prevalence, the current evidence suggests that screening asymptomatic men for prostate cancer is not warranted [1, 43]. The most recent Cochrane systematic review identified five randomized controlled trials examining the effectiveness of screening [43]. A meta-analysis of data from those five trials determined no significant difference in prostate cancer mortality between men randomised to screening in comparison to those who were not (risk ratio (RR) = 1.00; 95 % CI, 0.86–1.17) [43].

Only two of the five randomized controlled trials included in the 2013 systematic review were determined to methodologically present a low-risk of bias [43]. The point of interest lies in the differing results and conclusions offered by two studies: the ERSPC and the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial [27, 44].

In 2014, the ERSPC published 13-year follow-up data, reporting a 21 % reduction in the risk of prostate cancer mortality through screening (RR = 0.79; 95 % CI, 0.69–0.91) [5]. A sub-group analysis of prostate cancer mortality by age at randomization identified a significant decrease in prostate cancer mortality in the 65–69 year age group (RR = 0.69; 95 % CI, 0.55–0.87). No statistically significant difference in prostate cancer mortality was observed between screening and control groups in men aged <54, 55–59, and 60–64 years [5]. The results also suggest that screening is not beneficial in men aged over 70 years (RR = 1.17; 95 % CI, 0.82–1.66). The ERSPC study authors concluded that, “…the time for population-based screening has not yet arrived…” [5].

P Albertsen: Based upon what we know in 2015, PSA testing does benefit some men. For this reason I strongly support the recommendations of the AUA. These guidelines were based extensively on the data provided by the ERSPC. However, we need to do better. I am aware of your work with Hans Lilja, suggesting that a PSA value at age 50 is predictive of the long-term probability of developing clinically significant prostate cancer [18]. I believe we can refine the group of men who should be tested. We also need to incorporate the natural increase in PSA that comes with prostate enlargement that occurs when a man ages through his 50s and 60s. A graphic chart that tracks PSA levels or, possibly, percent free-PSA or the new prostate health index test against age and prostate volume, similar to a pediatric growth chart, might be helpful. Men consistently falling outside the 90th percentile, for example, might undergo MRI testing before considering a prostate biopsy. All of these refinements should be aimed at lowering the incidence of low-volume, low-grade cancer. In my mind, we have yet to define a best practice screening and treatment algorithm. While the AUA recommendations are a start, we have not agreed upon the test(s) needed, the frequency of their application, the value of imaging versus biopsies, nor on which treatments work best for which patients.

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Opening Ceremony and Award Presentations from the 2015 AACR Meeting in Philadelphia PA; Pennsylvania Convention Center, Sunday April 19, 2015: 8:15 AM

 

Reporter: Stephen J. Williams, Ph.D.

The following contain notes from the Sunday April 19, 2015 AACR Meeting (Pennsylvania Convention Center, Philadelphia PA) 8:15 AM Opening Ceremony and Awards Presentation

Ninth Annual AACR Team Science Award

Recipient: Designing Androgen Receptor (AR) Inhibitor Team

The Designing AR Inhibitors Team is a multi-institutional team that is composed of Charles Sawyers, MD, PhD, team leader, director of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center in New York, AACR past-president, and Howard Hughes Medical Institute investigator; Howard Scher, MD, chief of genitourinary oncology service and D. Wayne Calloway chair in urologic oncology at Memorial Sloan Kettering; and Michael Jung, PhD, distinguished professor in the Department of Chemistry and Biochemistry at the UCLA.

The team was honored for their collective work in discovering and developing the novel antiandrogen enzalutamide (Xtandi) for the treatment of metastatic castration-resistant prostate cancer in a collaboration that started ten years ago.

Twelfth Annual AACR Award for Lifetime Achievement in Cancer Research

Recipient: Mario R. Capecchi, Ph.D.

Dr. Capecchi is a geneticist who won the Nobel prize for creating technologies that resulted in the first knockout mouse. For this work, Capecchi won the 2007 Nobel prize for medicine or physiology, along with Martin Evans and Oliver Smithies, who also contributed.

AACR Distinguished Public Service Award

Recipient : Miri Ziv Director General of Israel Cancermiri_ziv_180_s_002

  • Instrumental in getting national Israeli mammography screening
  • Efforts led to national skin cancer screening program in Israel
  • Prevention/control programs
  • In 1995 representative to European Breast League

Ninth Annual AACR Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research

Recipient: Donald S. Coffey, Ph.D.

Dr. Coffey discovered the nuclear matrix and made pivotal discoveries understanding the process of DNA synthesis. He is the leader of the National Prostate Coalition and efforts led to the development of the Prostate Specific Antigen (PSA) as a prostate cancer biomarker. Now his lab is assessing the role of chaos, fractals and complexity in the self-organization of DNA, cells and tissue in relation to tumor biology.

In a side note, both Dr. Foti and Dr. Coffey had the same mentor, Dr. Sydney Weinhouse and Professor Leslie Helleman, who both studied the oxidation of free fatty acids and took Otto Warburg’s hypothesis a step further to understand how more complex cancer metabolism was than Otto had imagined.

Other award winners were:

Dr. Richard Pasdur of the FDA who won the Public Service Award

In memorial

Dr. Upton (M.D.) pathologist head of NCI and established EPA

Dr. Emmanuel Farber, M.D., Ph.D. – biology of tobacco control and issued the historical Surgeon

General’s report on smoking

Dr. June Biedler, Ph.D. – showed multidrug resistance and defined cytogenetics of  neuroblastoma

 

Other related articles on Cancer History and Social Media Coverage were published in this Open Access Online Scientific Journal, include the following:

Cancer Biology and Genomics for Disease Diagnosis

Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

Methodology for Conference Coverage using Social Media: 2014 MassBio Annual Meeting 4/3 – 4/4 2014, Royal Sonesta Hotel, Cambridge, MA

List of Breakthroughs in Cancer Research and Oncology Drug Development by Awardees of The Israel Cancer Research Fund

2013 American Cancer Research Association Award for Outstanding Achievement in Chemistry in Cancer Research: Professor Alexander Levitzki

 

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Urological Cancers of Men

Reporter and Curator: Larry H. Bernstein, MD, FCAP

 

Impact of the U.S. Preventive Services Task Force Recommendations Against PSA Screening on Prostate Biopsy and Cancer Detection Rates.

B Bhindi, M Mamdani, GS Kulkarni, A Finelli, RJ Hamilton, J Trachtenberg, et al.
The Journal of Urology 12/2014; http://dx.doi.org:/10.1016/j.juro.2014.11.096

To determine if the USPSTF recommendation against PSA screening was associated with a change in biopsy and cancer detection rates.

We conducted a time series analysis (10/2008-06/2013) of prostate biopsies performed at University Health Network (Toronto). Biopsies for active surveillance or solely targeting MRI-detected lesions were excluded. Interventional auto-regressive integrated moving average (ARIMA) models with step functions were used to examine changes in the number of biopsies performed and cancers detected per month. Low risk PC (LRPC) was defined as no Gleason pattern ≥4, ≤3 cores involved or ≤1/3 of total number of cores involved, and no core with >50% cancer involvement. Intermediate-to-high grade PC (I-HGPC) was defined as Gleason 7-10.

A total of 3408 biopsies were performed and 1601 (47.0%) PCs were detected (LRPC=563 (16.5%); I-HGPC=914 (26.8%)). The median number of biopsies per month decreased from 58.0 (IQR=54.5-63.0) before recommendations to 35.5 (IQR=27.0-41.0) afterward (p=0.003), while median number of patients undergoing their first-time biopsies decreased from 42.5 (IQR=37.5-45.5) to 24.0 (IQR=19.0-32.5, p=0.025). The median number of LRPCs detected per month decreased from 8.5 (IQR=6.5-10.5) to 5.5 (IQR=4.0-7.0, p=0.012), while the median number of I-HGPCs per month decreased from 17.5 (IQR=14.5-21.5) to 10.0 (IQR=9.0-12.0, p<0.001).

Following the USPSTF recommendation, the number of biopsies performed (total and first-time biopsies), based on referrals from our catchment area, have decreased. This is likely due to decreased use of PSA-screening. Although encouraging that fewer low risk PCs are being diagnosed, the sudden decrease in the detection rate of Gleason 7-10 PCs is concerning.

 

Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study.

E Lalonde, AS Ishkanian, J Sykes, M Fraser, H Ross-Adams, N Erho, et al.
The Lancet Oncology 12/2014; 15(13):1521-32.
http://dx.doi.org:/10.1016/S1470-2045(14)71021-6

Clinical prognostic groupings for localised prostate cancers are imprecise, with 30-50% of patients recurring after image-guided radiotherapy or radical prostatectomy. We aimed to test combined genomic and microenvironmental indices in prostate cancer to improve risk stratification and complement clinical prognostic factors.

We used DNA-based indices alone or in combination with intra-prostatic hypoxia measurements to develop four prognostic indices in 126 low-risk to intermediate-risk patients (Toronto cohort) who will receive image-guided radiotherapy. We validated these indices in two independent cohorts of 154 (Memorial Sloan Kettering Cancer Center cohort [MSKCC] cohort) and 117 (Cambridge cohort) radical prostatectomy specimens from low-risk to high-risk patients. We applied unsupervised and supervised machine learning techniques to the copy-number profiles of 126 pre-image-guided radiotherapy diagnostic biopsies to develop prognostic signatures. Our primary endpoint was the development of a set of prognostic measures capable of stratifying patients for risk of biochemical relapse 5 years after primary treatment.

Biochemical relapse was associated with indices of tumour hypoxia, genomic instability, and genomic subtypes based on multivariate analyses. We identified four genomic subtypes for prostate cancer, which had different 5-year biochemical relapse-free survival. Genomic instability is prognostic for relapse in both image-guided radiotherapy (multivariate analysis hazard ratio [HR] 4·5 [95% CI 2·1-9·8]; p=0·00013; area under the receiver operator curve [AUC] 0·70 [95% CI 0·65-0·76]) and radical prostatectomy (4·0 [1·6-9·7]; p=0·0024; AUC 0·57 [0·52-0·61]) patients with prostate cancer, and its effect is magnified by intratumoral hypoxia (3·8 [1·2-12]; p=0·019; AUC 0·67 [0·61-0·73]). A novel 100-loci DNA signature accurately classified treatment outcome in the MSKCC low-risk to intermediate-risk cohort (multivariate analysis HR 6·1 [95% CI 2·0-19]; p=0·0015; AUC 0·74 [95% CI 0·65-0·83]). In the independent MSKCC and Cambridge cohorts, this signature identified low-risk to high-risk patients who were most likely to fail treatment within 18 months (combined cohorts multivariate analysis HR 2·9 [95% CI 1·4-6·0]; p=0·0039; AUC 0·68 [95% CI 0·63-0·73]), and was better at predicting biochemical relapse than 23 previously published RNA signatures.

This is the first study of cancer outcome to integrate DNA-based and microenvironment-based failure indices to predict patient outcome. Patients exhibiting these aggressive features after biopsy should be entered into treatment intensification trials.
Prostate cancer: Is prostatectomy for Gleason score 6 a treatment failure?

Theodorus H van der Kwast, Monique J Roobol
Nature Reviews Urology 12/2014; http://dx.doi.org:/10.1038/nrurol.2014.335

Molecular and clinical support for a four-tiered grading system for bladder cancer based on the WHO 1973 and 2004 classifications
BWG van Rhijn, M Musquera, L Liu, AN Vis, TCM Zuiverloon, GJLH van Leenders, WJ Kirkels, EC Zwarthoff, ER Boevé, …, TH van der Kwast

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 11/2014; http://dx.doi.org:/10.1038/modpathol.2014.154

Currently, the use of two classification systems for bladder cancer grade is advocated in clinical guidelines because the WHO2004 classification has not been sufficiently validated with biological markers and follow-up. The slides of 325 primary non-muscle invasive bladder cancers from three hospitals were reviewed by one uro-pathologist in two separate sessions for the WHO1973 (G1, G2 and G3) and 2004 (papillary urothelial neoplasm of low malignant potential (LMP), low-grade (LG) and high-grade (HG)) classifications. FGFR3 status was examined with PCR-SNaPshot analysis. Expression of Ki-67, P53 and P27 was analyzed by immuno-histochemistry. Clinical recurrence and progression were determined. We performed validation and cross-validation of the two systems for grade with molecular markers and clinical outcome. Multivariable analyses were done to predict prognosis and pT1 bladder cancer. Grade review resulted in 88 G1, 149 G2 and 88 G3 lesions (WHO1973) and 79 LMP, 101 LG and 145 HG lesions (WHO2004). Molecular validation of both grading systems showed that FGFR3 mutations were associated with lower grades whereas altered expression (Ki-67, P53 and P27) was found in higher grades. Clinical validation showed that the two classification systems were both significant predictors for progression but not for recurrence. Cross-validation of both WHO systems showed a significant stepwise increase in biological (molecular markers) and clinical (progression) potential along the line: G1-LG-G2-HG-G3. The LMP and G1 categories had a similar clinical and molecular profile. On the basis of molecular biology and multivariable clinical data, our results support a four-tiered grading system using the 1973 and 2004 WHO classifications with one low-grade (LMP/LG/G1) category that includes LMP, two intermediate grade (LG/G2 and HG/G2) categories and one high-grade (HG/G3) category.Modern Pathology advance online publication, 28 November 2014; doi:10.1038/modpathol.2014.154.

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Controlling focused-treatment of Prostate cancer with MRI

Writer and reporter: Dror Nir, PhD.

In recent years there is a growing trend of treating prostate cancer in a way that will preserve, at least partially, the functionality of this organ. When patients are presenting at biopsy a low-grade localized disease, they might be offered focused treatment of the cancer lesion. One of the option is treatment by high-intensity focused ultrasound (HIFU).

The offering of such treatments created the need of controlling their outcome while the prostate is still inside the patient’s body. The most commonly used protocol is following up the patient’s PSA levels and performing “control” biopsies. The biopsies part is at best case; extremely unpleasant. It also bears some risk for complications.

Therefore, urologists are constantly seeking an imaging based protocol that will enable them to assess the treatment outcome without the need for biopsy. The publication I bring below presents the possibility of using MRI for this task. Although it is not recent, it contains many images that makes the story very clear for the reader.  The main weakness of the study is the small number of patients – only 15.

MR Imaging of Prostate after Treatment with High-Intensity Focused Ultrasound

Alexander P. S. Kirkham, FRCR, Mark Emberton, FRCS, Ivan M. Hoh, MRCS, Rowland O. Illing, MRCS, A. Alex Freeman, FRCP and Clare Allen, FRCR

From the Department of Imaging, University College London Hospitals NHS Foundation Trust, England (A.P.S.K., C.A.); Institute of Urology (M.E., I.M.H., R.O.I.) and Department of Histopathology (A.A.F.), University College London, England.

Address correspondence to A.P.S.K., Imaging Department, University College Hospital, 235 Euston Road, London, England NW1 2BU (e-mail: alexkirkham@yahoo.com).

Radiology March 2008; 246 (3) – 833-844.

Abstract

Purpose: To prospectively evaluate magnetic resonance (MR) imaging findings after high-intensity focused ultrasound (HIFU) treatment of the prostate and to correlate them with clinical and histologic findings.

Materials and Methods: Local ethics committee approval and informed consent were obtained. Fifteen consecutive men aged 46–70 years with organ-confined prostate cancer underwent ultrasonographically guided ablation of the whole prostate. Postoperative MR images were obtained within 1 month (12 patients), at 1–3 months (five patients), and in all patients at 6 months. Prostate volume was measured on T2-weighted images, and enhancing tissue was measured on dynamic images after intravenous administration of gadopentetate dimeglumine. Prostate-specific antigen (PSA) level was measured at regular intervals, and transrectal biopsy was performed in each patient at 6 months after treatment.

Results: Initial post-HIFU images showed a central nonenhancing area, surrounded by an enhancing rim. At 6 months, the prostate was small (median volume reduction, 61%) and was of predominantly low signal intensity on T2-weighted images. The volume of prostate enhancing on the initial posttreatment image correlated well with serum PSA level nadir (Spearman r = 0.90, P < .001) and with volume at 6 months (Pearsonr = 0.80, P = .001). The three patients with the highest volume of enhancing prostate at the initial posttreatment acquisition had persistent cancer at 6-month biopsy.

Conclusion: MR imaging results of the prostate show a consistent sequence of changes after treatment with HIFU and can provide information to the operator about completeness of treatment.

There is currently little to offer men with localized prostate cancer between the two extremes of watchful waiting and radical treatment—most commonly prostatectomy or radiation therapy (1). Ablation of the gland has been proposed as an alternative that has the potential to completely treat the tumor while minimizing the sexual and urinary morbidity that still accompany established radical therapies (2). Several techniques have been used in the prostate—including microwave (3) and radiofrequency (4) ablation, cryotherapy (5), photodynamic therapy (6), and high-intensity focused ultrasound (HIFU) treatment (7).

HIFU is, in several respects, ideally suited to the prostate. In contrast to extracorporeal devices for the liver and kidney (8), with the transrectal approach, there is little movement of the target because of respiration or reflection by overlying bone. A focal distance of 3 or 4 cm allows the generation of coagulative necrosis in treatment voxels less than 0.2 mL and allows a treatment volume that conforms to the shape of the prostate (9)—a degree of precision that may be beyond that of other techniques. Even so, complete ablation is likely to affect periprostatic tissues, including the neurovascular bundles containing the cavernosal nerves (10) and the external urethral sphincter. Preservation of these structures—and the patient’s erectile and urinary function—must be balanced against full treatment of the gland.

Although impotence rates after HIFU treatment approach 50% (11), it is likely that in its current clinical implementation, the prostate is not being fully ablated: In published series, the recurrence rates for cancer range between 25% and 38% (7,11,12). To our knowledge, no groups have reported mean reductions in prostate volume of more than 50% (12,13), and several groups have found it difficult to treat the anterior gland (14).

If we are to improve outcomes, a fundamental requirement for HIFU treatment (and ablative technologies in general) is a method that provides anatomic information to the operator about areas that have been over- or undertreated. This might lead to modifications in future technique, and if obtained soon after treatment, might indicate the need for further ablation. Such a method might also help predict outcome earlier than established measures, such as prostate-specific antigen (PSA) measurement and biopsy.

Magnetic resonance (MR) imaging has great potential in this setting, and Rouviere et al (14) have described the appearance of the prostate on contrast material–enhanced MR images obtained up to 5 months after HIFU treatment. Rouviere et al found a good correlation between the theoretical treatment volume and the volume of nonenhancing prostate on a subsequent acquisition. The aim of our study was to prospectively evaluate MR imaging findings after HIFU treatment of the prostate and to correlate them with clinical and histologic findings.

 

MATERIALS AND METHODS

Misonix (the European distributors of the Sonablate device) funded the phase-II European study and provided equipment and reimbursed the hospital for costs. The company has funded two authors (I.M.H. and R.O.I.) through educational awards. One author (M.E.) has acted as a paid consultant to Misonix and also received honoraria for training and teaching. Authors other than I.M.H., R.O.I., and M.E. had control of the information and data submitted for publication. Misonix was not involved in the analysis of data or the writing of this article.

Patients

We included the first 15 men at University College Hospital (age range, 46–70 years; mean age, 59 years) who were taking part in a registered phase-II multicenter European study of HIFU therapy for organ-confined prostate cancer (Table 1). The study was approved by the local ethics committee, and full written consent was obtained from each patient. The patients understood that HIFU is an experimental treatment whose long-term outcome is unknown and were offered full conventional treatment as an alternative. The study was limited to men with a serum PSA level 15 μg/L or less, Gleason score less than 8, prostate volume less than 40 mL, life expectancy more than 5 years, and age less than 80 years. There was no limit to the number of biopsy cores that had a positive finding or the amount of cancer in each core removed. Patients with a history of previous prostate surgery were excluded, as were men who had undergone androgen deprivation therapy in the 6 months prior to recruitment or had intragland prostatic calcification more than 1 cm in diameter.

Table 1.  Patients and Demographics

 table 1

 * Ratio of cores with a positive finding to cores obtained.

 † Image not available for analysis; volume was calculated by using US measurements.

The Sonablate 500 (Focus Surgery, Indianapolis, Ind) consists of a power generator, water cooling system (the Sonachill), a treatment probe, and a positioning system. The probe contains two curved rectangular piezoceramic transducers with a driving frequency of 4 MHz and focal lengths of 30 and 40 mm. During treatment, these may be driven at low energy to provide real-time diagnostic imaging or at high energy for therapeutic ablation (in situ intensity, 1300–2200 W/cm2). The probe is covered with a condom, under which cold (17°–18°C) degassed water is circulated to help protect the rectum from thermal injury.

Patients were prepared before the procedure with two phosphate enemas to empty the rectum. Oral bowel preparation was used in some patients. Treatment was performed with general anesthesia in the lithotomy position and was performed or closely supervised in every case by an author (M.E., 2 years of experience in HIFU treatment). After gentle dilation of the anal sphincter, the treatment probe was introduced with a covering of ultrasonographic (US) gel to couple it to the rectal mucosa and was held in position with an articulated arm attached to the operating table. A 16-F Foley urethral catheter was inserted using sterile technique, and a 10-mL balloon was inflated to allow the bladder neck and median sagittal plane to be seen accurately. It was removed before treatment began.

Treatment was planned by using US-acquired volumes consisting of stacks of both sagittal and transverse sections (voxel size, 2 × 3 × 30 mm) and was applied in rows that extended in the craniocaudal axis, interleaved to avoid interference from adjacent, recently treated areas. After each 3-second period of ablation, diagnostic transverse and sagittal images in the plane of treatment were obtained to permit tailoring of the energy delivery in the next voxel according to visible changes on the gray-scale image. This is an important difference from the device used by Rouviere’s group (14), in which power is planned before the treatment begins. We aimed to set the power for each voxel at a level that produced hyperechoic change due to cavitation (as described by Illing et al [15]), and we invariably treated the whole anterior prostate. Neurovascular bundles were not identified at treatment (the Sonablate device does not yet have color Doppler capability); rather, we aimed to avoid treating outside the capsule where they lie posterolaterally (10). The time between the first ablation and the point at which treatment was considered complete was 3.0–4.4 hours (mean, 3.6 hours). A 16-F urethral catheter was placed immediately after the treatment and was left in place for 2 weeks.

MR Imaging

For most preoperative examinations and for all post-HIFU imaging, we used an MR machine (Symphony or Avanto; Siemens, Erlangen, Germany) with 1.5-T magnet and a pelvic-phased array coil. Except where stated, a full protocol of T1- and T2-weighted turbo spin-echo (Siemens) images and a dynamic fat-saturated postcontrast volume acquisition were used for both preoperative diagnostic and planning imaging and for postoperative assessment of HIFU treatment (Table 2). The contrast material used was 20 mL of gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany) given intravenously at 3 mL/sec.

Table 2. MR Sequences Used at Prostate Imaging

table 2

We aimed to image patients less than 1 month after treatment and did so in 12 patients. The remaining three patients were imaged between 1 and 3 months after treatment. Two patients were imaged in both time periods. Every patient underwent a 6-month MR examination.

Image Analysis

All volume measurements (except where stated) were acquired by using planimetry of contiguous 3-mm sections (16). T2-weighted images were used for measurement of prostatic volume both before and after treatment. The amount of intermediate- or high-signal-intensity material (ie, higher than muscle) remaining within the prostate was also measured on the 6-month posttreatment T2-weighted image.

The volume of nonenhancing prostate tissue at the post-HIFU acquisition was measured by using the final dynamic postcontrast image. On the initial posttreatment image, we also measured the volume of extraprostatic tissue that was both of low signal intensity on the T1-weighted image and nonenhancing. The distance between this tissue and the rectal mucosa was measured at its narrowest point. The mean thickness of the enhancing rim surrounding the treatment volume was measured on transverse postcontrast T1-weighted spin-echo images and was calculated by dividing the area of the rim by its circumference.

The volume of persistently enhancing prostate tissue on the initial image was calculated by subtracting the nonenhancing volume from the total volume of prostate on the T2-weighted image. This could be calculated in 13 patients; one patient did not receive contrast material at the post-HIFU MR acquisition, and the other was imaged more than 2 months after treatment.

All measurements were performed by a first-year radiology fellow (A.P.S.K.) without knowledge of PSA and histologic results. Two other observers independently measured the three key parameters that were used for correlation calculations for each patient: (a) the volume of nonenhancing prostate on the initial image, (b) the total volume of the prostate on the initial image, and (c) the final prostate volume at 6 months. One was a consultant uroradiologist with more than 10 years of experience in the interpretation of prostate MR images (C.A.); the other was a third-year urology research fellow with an interest in prostate imaging (R.O.I.). For each parameter, the mean of the three observers’ measurements was calculated and used for further analysis.

PSA Measurement and Prostate Biopsy

Serum PSA level was measured before and at 1.5, 3, and 6 months after HIFU treatment. The nadir was defined as the lowest of the three values.

Biopsies were performed by an author (A.P.S.K., with 4 years of experience in prostate biopsy) by using a transrectal approach with US guidance and an 18-gauge needle with a 2-cm throw soon after the 6-month MR examination. The number of cores obtained depended on the amount of residual prostate and varied between two and 10 (median, eight cores).

Erectile Function and Continence

The International Index of Erectile Function was used to assess erectile function both before and 3 months after HIFU treatment in each patient (17). The most important question was, “How often were your erections hard enough for penetration [with or without phosphodiesterase type 5 inhibitors]?” A score of 2 (a few times in 4 weeks) to 5 (always) was, for the purposes of this article, considered evidence of intact erectile function.

Men were asked to complete the International Continence Society–validated continence function questionnaire at baseline and at 3 and 6 months after therapy. The question deemed to be most informative was how often the patient required the use of pads or adult diapers. Responses could include “never,” “not more than one per day,” “1–2 per day,” or “more than 3 per day.”

Statistical Analysis

To assess the variance of results between observers, we used the intraclass correlation coefficient (18) applied to measurements obtained by three observers of the calculated volume of enhancing prostate on the initial post-HIFU image and the 6-month prostate volume.

The Spearman rank test was used to assess the correlation between enhancing prostate volume and serum PSA level nadir, and the Pearson test was used to examine the correlation between initial enhancing prostate volume and final prostate volume. Only the patients who were imaged less than 1 month after treatment were included in the analysis. These tests were performed by using software (GraphPad Prism for Mac, version 3; http://www.graphpad.com).

Because some of the covariance of volumes measured after treatment was likely to be due to their correlation with pretreatment prostate volume, we also applied a correction: The values were expressed as a proportion of the pretreatment volume, and a further correlation measurement was performed by using the Pearson test. In each case, a P value of less than .02 was considered to indicate a significant difference.

 

RESULTS

Up to 1 Month After Treatment

T2-weighted images.—Compared with that on the preoperative image, the prostate volume increased in every case (Table 1 and Table E1, Fig 1). The signal intensity from the prostate on T2-weighted images within the first month was always heterogeneous and variable. It was impossible to predict from the findings on T2-weighted images which areas of the prostate would enhance after intravenous contrast material administration. The periprostatic fat was also heterogeneous in signal intensity, which was consistent with edema (Fig 2).

Figure 1: Graph of change in prostate volume after HIFU treatment. Volume rises initially (less than 1 month after treatment) and is reduced in all cases at 6 months. Numbers = patient numbers.

 Picture1

Figure 2: MR images in patient 1 (a–d) and (e–h) patient 8 show low volume of enhancing prostate at initial imaging and small residual prostate at 6 months. Posttreatment serum PSA level was less than 0.05 μg/L in both cases.

Figure 2a:

Picture2a

Figure 2b:

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Figure 2c:

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Figure 2d:

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Figure 2e:

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Figure 2f:

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Figure 2g:

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Figure 2h:

Picture2h

T1-weighted images.—The prostate was of predominantly low signal intensity, although patchy areas of intermediate or high signal intensity, likely to represent hemorrhage, were a constant finding within the gland and in all but one of 28 seminal vesicles.

Postcontrast images.—In each patient, the postcontrast images showed a central area of nonenhancing tissue. This conformed to the treatment volume and was surrounded by an enhancing rim of mean thickness of 2–8 mm (median, 4 mm) that was continuous around the prostate in most patients (Fig 2; Table E1,).

The enhancing prostate varied in size and position. Part of the enhancing rim usually lay within the prostatic capsule and continued to the prostatic apex where there was almost always some enhancing tissue between the nonenhancing prostate and the external urethral sphincter. In many patients, more central areas of enhancement were seen: at the apex or base, either posteriorly or anteriorly (Table E1), and were almost always in continuity with the rim.

In every patient, the nonenhancing, low signal intensity within the prostate extended outside the gland and involved the periprostatic fat and the levator ani muscle, particularly anterolaterally (Table E1, Figs 23). This varied considerably and tended to be most prominent in those who had no residual gland enhancement and had an undetectable serum PSA level after HIFU treatment (Table E1). In several patients, the nonenhancing area extended to involve the Denonvilliers fascia. (The distance between its margin and the rectal muscle is listed in Table E1.) In one patient, a proportion of the rectal wall enhanced avidly, but in no patient was there loss of rectal wall enhancement to suggest necrosis.

Figure 3: MR images obtained near the prostate apex show incomplete treatment and persisting high signal intensity in prostate. Serum PSA level nadir = 0.61 μg/L.

Figure 3a: Patient 4:

 Picture3a

 Figure 3b: Patient 4:

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Figure 3c: Patient 4:

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Figure 3d: Patient 4:

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At 1–3 Months

In three patients, there was a “double rim” (Fig 4) on postcontrast images obtained at 36 and 56 days after HIFU treatment. The inner component lay within the prostate and the outer at the prostatic capsule; the intervening part was of low signal intensity on both T1- and T2-weighted images.

 Figure 4: MR images of “double rim” at 56 days after HIFU treatment.

Figure 4a: Patient 3:

 Picture4a

Figure 4b: Patient 3:

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Figure 4c: Patient 3:

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Six-month Appearance

T2-weighted images.—In every patient, the volume of the prostate was reduced by more than 45% (median, 61% reduction) (Table E1). On T2-weighted images, the majority of the persisting prostate was of low signal intensity, with poor definition to the capsule and with persisting heterogeneous signal intensity to the surrounding fat. However, in 12 of 15 patients, there was persisting high or intermediate signal intensity of the prostate—up to 5.34 mL in volume and most often seen posteriorly and at the apex (Table E1, Figs 3 and 5). In many patients (for example, those in Fig 2), low-signal-intensity prostate of reduced volume surrounded a capacious prostatic cavity continuous with the urethra, which is similar to the cavity seen after transurethral resection (19).

Figure 5: MR images of incomplete treatment of tumor and positive biopsy findings in three of 10 cores at 6 months (in right lateral midzone, right lateral base, and right parasagittal base samples). Serum PSA level nadir = 1.19 μg/L.

Figure 5a: Patient 13:

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Figure 5b: Patient 13:

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Figure 5c: Patient 13:

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Figure 5d: Patient 13:

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Figure 5e: Patient 13:

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Postcontrast images.—Some small areas of nonenhancing tissue persisted in eight of 14 patients, but this was less than 1 mL in all but one (patient 13, in whom 4 mL of the gland volume of 18.7 mL was nonenhancing). The levator muscle showed a normal signal intensity.

Correlation Between Initial Imaging and Later Findings

In the 12 patients who underwent the initial acquisition within 1 month of HIFU treatment, the volume of enhancing tissue on the initial posttreatment image was positively correlated with the serum PSA level nadir (Fig 6) (Spearman r = 0.90, P < .001) and with the amount of residual tissue at 6 months (including all low-signal-intensity material that was likely to represent fibrosis or necrosis) (Fig 7) (Pearson r = 0.80, P = .001).

 Figure 6: Graph of relationship between the proportion of the prostate still enhancing on initial image and serum PSA level nadir. There is a significant positive correlation (Spearman r = 0.90, P < .001). * = patient 13, who was included in graph but not in analysis (imaged 56 days after HIFU treatment). Patients 14 and 15 are not included because they did not undergo contrast-enhanced acquisition within 2 months of HIFU treatment. μgl−1 = μg/L.

 Picture6

Figure 7: Graph of relationship between the proportion of the prostate still enhancing on initial image and final volume of prostate. There is a significant positive correlation between the variables (Pearson r = 0.80, P = .001). * = patient 13, who was included in graph but not in analysis (imaged 56 days after HIFU treatment). Patients 14 and 15 are not included because they did not undergo contrast-enhanced acquisition within 2 months of HIFU treatment.

Picture7

When posttreatment volumes are expressed as a proportion of pretreatment prostate volume, the correlation between enhancing tissue volume on the initial posttreatment image and the 6-month prostate volume persists (Pearson r = 0.70, P = .001).

Interobserver Correlation

The interobserver variation was excellent for the calculated volume of prostate enhancing on the initial post-HIFU image, with an intraclass correlation coefficient of 0.92, and was good for final prostate volume (intraclass correlation coefficient = 0.73).

Clinical Findings

In five patients (patients 1, 3, 8, 11, and 13), there was imaging evidence (at MR imaging or retrograde urethrography) of a stricture in the mid- or distal prostatic urethra, which was confirmed by using flow rate studies and treated by using self-catheterization or with graded urethral dilators. None have required formal urethrotomy. Patient 14 developed a bladder neck stricture, which was treated successfully by incision.

Before treatment, no men required pads or adult diapers for incontinence. At 6 months after the treatment, four men still required not more than one pad per day. In two cases, this was for reassurance rather than actual leakage.

In the 14 patients in whom there was intact erectile function (score 2–5 for the question, “How often were your erections hard enough for penetration?”) before HIFU treatment, it was intact in nine patients after the procedure. One patient had stopped trying to achieve erections, and four could not achieve penetration.

Histologic Findings

In the three patients in whom there was no high-signal-intensity peripheral zone at 6 months and with serum PSA level less than 0.05 μg/L, there was either no prostatic tissue or only a small group of acini in one core. The remaining patients had a variable amount of residual prostate at core biopsy.

Five patients had residual tumor. In three patients, it was seen in at least two cores (Table E1), and these three patients also had the largest volume of enhancing prostate on the initial post-HIFU MR image (Figs 6 and 7) and more than 2 mL of intermediate- or high-signal-intensity gland on T2-weighted images at 6 months.

In four of five patients with residual cancer, it could not be identified on either contrast-enhanced or T2-weighted images. In one patient (Fig 4), the early dynamic images showed prominent enhancement in the anterior gland, which was consistent with residual cancer found at the distal (ie, nonrectal) end of three right-sided biopsy cores. Such enhancement was not seen in patients with no cancer found at core biopsy.

 

DISCUSSION

We found a consistent sequence of changes at MR imaging after HIFU treatment of the whole prostate. The proportion of enhancing tissue on the initial posttreatment MR image was predictive of gland volume at 6 months and serum PSA level nadir. A strong statistical relationship between the latter and outcome has recently been demonstrated (20).

Most patients with residual cancer had evidence of incomplete ablation early (a large volume of enhancing prostate on the initial image) and late (a large volume of high-signal-intensity residual prostate on T2-weighted images at 6 months).

In some patients it was possible to achieve an undetectable serum PSA level at 6 months and entirely low signal intensity on T2-weighted images in the region of the prostate. These patients had either no or a small amount of viable prostate in one core at biopsy.

Conversely, in spite of reductions in prostate volume of more than 45% at 6 months, the majority of patients had histologic evidence of persisting viable prostate, and in a group of patients with organ-confined disease but no limit to the volume of cancer pretreatment, one-third had evidence of residual tumor.

Persisting enhancing prostatic tissue usually occurred at the periphery (or extended toward the center of the gland from it) and was particularly common at the apex and near the rectum.

Results of one previously published study (14) of post-HIFU appearances with MR imaging show a similar sequence of acute changes, although there was no attempt to quantify prostate volume at 6 months. There is also a large body of work on the MR imaging appearances with thermotherapy (whether laser [21,22] or radiofrequency [23]) and cryotherapy (24) within the prostate and other organs. The hyperenhancing rim of tissue is a constant finding in several tissues, including the liver (25), the kidney (26), and the brain (27). In the liver and the kidney, it is thin (1 mm or less) and, in most cases, has disappeared by 2 months after ablation (28). Within the prostate, the hyperenhancing rim has been shown to occur after laser ablation of benign prostatic hyperplasia (21,22) and after HIFU treatment (14).

Histologic evidence in animal models—including rabbit and porcine liver (29)—suggests that the enhancing rim corresponds to an area of inflammation and then fibrosis, with a variable amount of residual, viable tissue. How much of the rim will be viable after ablation of the prostate in humans remains uncertain. On the one hand, after HIFU treatment, core biopsy results show “partial or complete necrosis” in the rim (14). On the other, after laser ablation of benign prostatic hyperplasia, the volume of coagulative necrosis at histologic examination correlates very well with the central nonenhancing region at MR imaging, not including the rim (22). The answer is likely to be that a variable amount of the rim contains viable tissue (depending on the organ being imaged [30], the nature of the treatment, and the interval before the acquisition), and the implication is that the only reliably necrotic area at MR imaging is that which does not enhance. We have avoided the term necrosis for the nonenhancing areas of prostate seen in our current study, but from these data it is likely that the areas of prostate without enhancement are truly necrotic.

The distribution of enhancing prostate on posttreatment MR images fits with histologic evidence that “ventral, lateral and dorsal sides of the prostate” have residual viable prostatic tissue at histologic examination after HIFU treatment (31). What all of these areas have in common is proximity to the more richly vascular prostatic capsule. Is it possible that increased vascularity here results in reduced efficacy? This is another area that has been addressed by Rouviere’s group (32), who did not find a correlation between successful ablation and prostate vascularity by using power Doppler US; they conclude, as others have (33,34), that short (3-second) high-intensity bursts of focused ultrasound are unlikely to be markedly affected by blood flow. An alternate explanation is a geometric one: Centrally lying voxels are easier to treat because they may be rendered necrotic either by direct treatment or by damage to supplying vessels in the periphery.

An implication of these results is that the best strategies for minimizing complications while ensuring destruction of the cancer are likely to involve a degree of targeting: If the tumor can be imaged with MR imaging, the patient might be treated with higher power and wider margins (including periprostatic fat, muscle, or even neurovascular bundles) at the site of the cancer and with a standard intensity to the rest of the gland. An analogous approach is the wide excision, including a unilateral neurovascular bundle, of bulky tumors at radical prostatectomy (35). Such an approach may well have benefited our patients 7 and 13.

One methodologic issue that is currently unresolved relates to the timing of MR imaging. A detailed within-patient study of MR imaging changes after HIFU treatment is needed to properly describe the longitudinal changes in the appearance of the prostate. Rouviere et al (14) found that the area of nonenhancing tissue decreases by 50% at 1 month compared with that at an immediate (<1 week) post-HIFU acquisition, which suggests that for an accurate assessment of necrosis volume, the prostate should be imaged as soon as possible after treatment. Of course, perfusion would ideally be assessed during HIFU treatment so that undertreated areas could be further ablated. There is some evidence that Doppler or contrast-enhanced US (36) could play this role, but, to our knowledge, there are no studies on the correlation of immediate findings with later clinical data, such as serum PSA level or histologic examination.

We used fast low-angle shot sequences to assess enhancement because we found that the subjective assessment (together with objective measurements of signal intensity) of the dynamic series helped us identify truly nonenhancing tissue. However, the T1-weighted spin-echo postcontrast sequence would have been adequate, and we consider, as others do (22), dynamic contrast-enhanced sequences not to be an essential part of the protocol for postablation assessment. What is certain is that unenhanced T2-weighted sequences are inadequate for assessing necrosis (14,22).

Our results differ from those of other published series of HIFU treatment in the marked reduction in gland volume and absence of zonal anatomy in many patients observed at 6 months. In contrast to the study of post-HIFU MR imaging by Rouviere et al (14) who used a different device, we did not find that “HIFU-induced abnormalities seem to disappear within 3–5 months.” Rather, in several patients, it was difficult to discern any residual prostate at all at both MR and US studies. The difference probably lies in the power used for treatment and the completeness of gland coverage. The stricture rate of six of 15 is high when compared with that in published series (7,37,38) and may be related to the power used, the degree of fibrosis occurring in the prostate, and the strategy for catheterization. The latter is considered likely to be important, and we have recently changed to using a suprapubic catheter (rather than urethral) after treatment. The rate of impotence after treatment is similar to that in published series (11), as is grade I incontinence.

Our work has implications for the conduct of HIFU. The finding that the volume of enhancing prostate on the initial posttreatment image correlates well with intermediate measures, such as serum PSA level nadir and biopsy evidence of residual cancer, suggests that MR imaging can provide the operator with feedback on the effectiveness of the intervention. This information might enable modification of the technique to treat areas that have been incompletely ablated in previous patients—in our series, those areas encompassed the apex and posterior gland and rarely anterior tissue (in contrast to other study results [14]). Conversely, we might have reduced power or treatment volume at the anterolateral aspect of the gland adjacent to the levator muscle. Such feedback has been cited as a desirable attribute for ablation technology (39) and up to now has been missing.

Our study had several limitations. Although it is likely that nonenhancing areas at MR imaging represent necrosis, we do not have direct histologic evidence. Sampling error and misregistration limit the utility of core biopsies in this context. We have shown that the MR imaging appearances soon after HIFU treatment correlate with findings at 6 months, but this is not the same as outcome. A considerably longer follow-up and a larger number of patients will be necessary to determine both the ultimate efficacy of HIFU treatment and the ability of MR imaging to help predict outcome. Last, while our findings suggest that MR imaging soon after treatment may be useful to assess areas of under- and overtreatment, this is not real-time feedback and does not allow modification of the treatment as it progresses.

In summary, MR imaging results in the first 6 months after HIFU treatment show a consistent sequence of changes, and appearances in the 1st month correlate with serum PSA level nadir and imaging findings at 6 months. Such imaging results hold promise for providing feedback to the operator about the effectiveness of treatment.

 

ADVANCES IN KNOWLEDGE

  • Treatment of prostate cancer by using ablation with high-intensity focused ultrasound (HIFU) results in a consistent series of changes within the gland during 6 months seen at contrast-enhanced MR imaging.
  • Within 1 month after treatment, a central nonenhancing area is surrounded by an enhancing rim of tissue lying variably within and outside the prostate.
  • At 6 months, the gland is markedly smaller and of partly or completely low signal intensity on T2-weighted images.
  • The amount of enhancing prostate on the initial image correlates with several findings at 6 months, including serum prostate-specific antigen level nadir and prostate volume.

 

IMPLICATION FOR PATIENT CARE

  • MR imaging after HIFU treatment may provide information about completeness of tumor ablation and the need for early retreatment or close monitoring in cases of incomplete coverage.

 

Footnotes

  • Trial registration: This trial started recruiting before the trial registration requirements of the International Committee of Medical Journal Editors were formalized.

See Materials and Methods for pertinent disclosures.

Author contributions: Guarantors of integrity of entire study, A.P.S.K., I.M.H., C.A.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, A.P.S.K., M.E., I.M.H., R.O.I., C.A.; clinical studies, A.P.S.K., R.O.I., C.A.; statistical analysis, A.P.S.K.; and manuscript editing, all authors

Abbreviations:HIFU = high-intensity focused ultrasoundPSA = prostate-specific antigen

 

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In Search of Clarity on Prostate Cancer Screening, Post-Surgical Followup, and Prediction of Long Term Remission

Larry H. Bernstein, MD, FCAP, Author and Curator
Dror Nir, PhD, Curator
Aviva Lec-Ari, PhD, RN, Curator

There have been two important articles in the last several days giving perspectives on the current and evolving status of current and evolving diagnosis of prostate cancer (PCA) by experts Dror Nir, PhD and Aviva Lev-Ari, PhD, RN, Editor-in-Chief, http://Pharmaceuticalintelligence.com

The first article reviews the recent published update on PCA screening and diagnosis, as determined by review of the literature by an Expert Panel, in order to determine what is the current validated Evidence-Based Medicine Practice Guideline for American Urological Surgeons.

The method of review is rigorously laid out and follows the accepted standard for publication.  The emphasis in the study lies in the reliance on prostate specific abtigen (PSA), which has undergone an evolutioary improvement sine 1999, although substantiation of a benefit could not be trusted until almost a decade later.   The problem the is notable is the absence of discussion of improvements in cancer imaging that has also evolved in that time period, and continues to evolve with molecular probes.

Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Author-Writer: Dror Nir, PhD

https://pharmaceuticalintelligence.com/2013/05/21/early-detection-of-prostate-cancer-aua-guideline/

When reviewing the DETECTION OF PROSTATE CANCER section on the AUA website , The first thing that catches one’s attention is the image below; clearly showing two “guys” exploring with interest what could be a CT or MRI image….

But, if you bother to read the review underneath this image regarding EARLY DETECTION OF PROSTATE CANCER: AUA GUIDELINE produced by an independent group that was commissioned by the AUA to conduct a systematic review and meta-analysis of the published literature on prostate cancer detection and screening; Panel Members: H. Ballentine Carter, Peter C. Albertsen, Michael J. Barry, Ruth Etzioni, Stephen J. Freedland, Kirsten Lynn Greene, Lars Holmberg, Philip Kantoff, Badrinath R. Konety, Mohammad Hassan Murad, David F. Penson and Anthony L. Zietman – You are bound to be left with a strong feeling that something is wrong!

“The AUA commissioned an independent group to conduct a systematic review and meta-analysis of the published literature on prostate cancer detection and screening. The protocol of the systematic review was developed a priori by the expert panel. The search strategy was developed and executed by reference librarians and methodologists and spanned across multiple databases including Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials and Scopus. Controlled vocabulary supplemented with keywords was used to search for the relevant concepts of prostate cancer, screening and detection. The search focused on DRE, serum biomarkers (PSA, PSA Isoforms, PSA kinetics, free PSA, complexed PSA, proPSA, prostate health index, PSA velocity, PSA doubling time), urine biomarkers (PCA3, TMPRSS2:ERG fusion), imaging (TRUS, MRI, MRS, MR-TRUS fusion), genetics (SNPs), shared-decision making and prostate biopsy. The expert panel manually identified additional references that met the same search criteria”

While reading through the document, I was looking for the findings related to the roll of imaging in prostate cancer screening; see highlighted above. The only thing I found: “With the exception of prostate-specific antigen (PSA)-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests.”

This must mean that: Notwithstanding hundreds of men-years and tens of millions of dollars which were invested in studies aiming to assess the contribution of imaging to prostate cancer management, no convincing evidence to include imaging in the screening progress was found by a group of top-experts in a thorough and rigorously managed literature survey! And it actually  lead the AUA to declare that “Nothing new in the last 20 years”…..

My interpretation of this: It says-it-all on the quality of the clinical studies that were conducted during these years, aiming to develop an improved prostate cancer workflow based on imaging. I hope that whoever reads this post will agree that this is a point worth considering!

For those who do not want to bother reading the whole AUA guidelines document here is a peer reviewed summary:

“Early Detection of Prostate Cancer: AUA Guideline; Carter HB, Albertsen PC, Barry MJ, Etzioni R, Freedland SJ, Greene KL, Holmberg L, Kantoff P, Konety BR, Murad MH, Penson DF, Zietman AL; Journal of Urology (May 2013)”

It says:

“A systematic review was conducted and summarized evidence derived from over 300 studies that addressed the predefined outcomes of interest (prostate cancer incidence/mortality, quality of life, diagnostic accuracy and harms of testing). In addition to the quality of evidence, the panel considered values and preferences expressed in a clinical setting (patient-physician dyad) rather than having a public health perspective. Guideline statements were organized by age group in years (age<40; 40 to 54; 55 to 69; ≥70).

RESULTS: With the exception of prostate-specific antigen (PSA)-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests. The quality of evidence for the benefits of screening was moderate, and evidence for harm was high for men age 55 to 69 years. For men outside this age range, evidence was lacking for benefit, but the harms of screening, including over diagnosis and over treatment, remained. Modeled data suggested that a screening interval of two years or more may be preferred to reduce the harms of screening.

Prostate Cancer Molecular Diagnostic Market – the Players are: SRI Int’l, Genomic Health w/Cleveland Clinic, Myriad Genetics w/UCSF, GenomeDx and BioTheranostics

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/21/prostate-cancer-molecular-diagnostic-market-the-players-are-sri-intl-genomic-health-wcleveland-clinic-myriad-genetics-wucsf-genomedx-and-biotheranostics/

On February 6, 2013 we reported that DR. MARK RUBIN, LEADING PROSTATE CANCER AND GENOMICS EXPERT, TO LEAD CUTTING-EDGE CENTER FOR TARGETED, INDIVIDUALIZED PATIENT CARE BASED ON EACH PATIENT’S GENETICS

Genomically Guided Treatment after CLIA Approval: to be offered by Weill Cornell Precision Medicine Institute

On May 16, 2013 we reported a major breakthrough in the Prostate Cancer Screening

A Blood Test to Identify Aggressive Prostate Cancer: a Discovery @ SRI International, Menlo Park, CA

After nearly a decade, my collaborators and I have found the first marker that specifically identifies the approximately six to eight percent of prostate cancers that are considered “aggressive,” meaning they will migrate to other parts of the body, at which point they are very difficult to treat. Although we have confirmed this marker, there is much to be done before a clinical application can be developed.

https://pharmaceuticalintelligence.com/2013/05/16/a-blood-test-to-identify-aggressive-prostate-cancer-a-discovery-sri-international-menlo-park-ca/

Prostate Cancer MDx Competition Heating Up; New Data from Genomic Health, Myriad

May 15, 2013  By Turna Ray

Life sciences companies are gearing up for battle to capture the profitable prostate cancer molecular diagnostic market.

Genomic Health and Myriad Genetics both made presentations to the investment community last week about their genomic tests that gauge a man’s risk of prostate cancer aggressiveness. As part of its annual investor day, Myriad discussed new data on its Prolaris test, which analyzes the expression level of 46 cell cycle progression genes and stratifies men’s risk of biochemical recurrence of prostate cancer. If the test reports low gene expression, then the patient is at low risk of disease progression, while high gene expression is associated with disease progression.

Meanwhile, around the same time last week, Genomic Health launched its Oncotype DX prostate cancer test and presented data from the first validation study involving the diagnostic. The Oncotype DX prostate cancer test analyzes the expression of 17 genes within four biological pathways to gauge prostate cancer aggressiveness. The test reports a genomic prostate score from 0 to 100; the lower the score the more certain a patient can be that they can avoid treatment and continue with active surveillance. Prostate cancer patients who are deemed to be at very low risk, low risk, or intermediate risk of progressing are eligible to be tested with the Oncotype Dx test. If, based on standard clinical measures, a person’s prostate cancer is considered high risk, then he is not a candidate for Genomic Health’s test.

These molecular tests are entering the market at a time when currently available tools aren’t specific enough to distinguish between men who have an aggressive form of prostate cancer and therefore, need invasive treatments, and those that are low risk and can do well with active surveillance. According to an NIH estimate, in 2010, the annual medical costs associated with prostate cancer in the US were $12 billion.

It is estimated that each year 23 million men undergo testing for prostate specific antigen, a protein produced by the prostate gland that increases when a man has prostate cancer. Additionally, one million men get a prostate biopsy annually, while 240,000 men end up with a diagnosis for prostate cancer, and around 30,000 die from the disease. Although most of the men diagnosed with prostate cancer end up receiving surgery or radiation treatment, as many as half of these men will probably not progress, and their disease isn’t life threatening.

While PSA testing has been shown to reduce prostate cancer deaths, a man’s PSA level may be increased for reasons other than cancer. As such, broadly screening men for PSA has been controversial in the healthcare community since the test isn’t specific enough to gauge which men are at low risk of developing aggressive prostate cancer and can forgo unnecessary treatments that can have significant side effects.

Both Myriad and Genomic Health are hoping their tests will further refine prostate cancer diagnosis and help doctors gain more confidence in determining which of their patients have aggressive disease and which are at low risk.

Myriad’s advantage

In this highly competitive space, Myriad has the first mover advantage, having launched Prolaris three years ago. The company has published four studies involving the test and conducted a number of trials analyzing around 3,000 patient samples.

Researchers from UCSF and Myriad recently published the fourth validation study in the Journal of Clinical Oncology, which analyzed samples from 400 men who had undergone a radical prostatectomy. In the published study, researchers reported that 100 percent of the men whom Prolaris deemed to be at “low risk” of progression did not experience a recurrence within the five years the study was ongoing. Meanwhile, 50 percent of those the test deemed to be a “high risk” did experience recurrence during that time (PGx Reporter 3/6/2013).

New competition

Like Myriad’s BRACAnalysis test, which comprises more than 80 percent of its product revenues, Genomic Health’s Oncotype DX breast cancer recurrence tests is bringing in the majority of its product revenues. However, the company believes that its newly launched Oncotype DX prostate cancer test stands to be its largest market opportunity to date.

Last week, researchers from University of California, San Francisco, presented data from the first validation study involving the Oncotype DX prostate cancer test. The study involved nearly 400 prostate cancer patients considered low or intermediate risk by standard methods such as Gleason score and showed that when the Oncotype DX score was used in conjunction with other measures, investigators identified more patients as having very low risk disease who were appropriate for active surveillance than when they diagnosed patients without the test score.

More than one third of patients classified as low risk by standard measures in the study were deemed to be “very low risk” by Oncotype DX and therefore could choose active surveillance. Meanwhile, 10 percent of patients in the study were found by clinical measures to be at very low risk or low risk, but the Oncotype DX test deemed them as having aggressive disease that needed treatment.

Matthew Cooperberg of UCSF, who presented data from this validation study at the American Urological Association’s annual meeting last week, highlighted this feature of the Oncotype DX prostate cancer test to investors during a conference call last week. He noted that the test not only gauges which low-risk patients can confidently remain with active surveillance, but it also finds those patients who didn’t receive an accurate risk assessment based on standard clinical measures. “It’s also equally important that we identify the man who frankly should not be on active surveillance, because they’re out there,” he said.

Genomic Health has aligned its test with guidelines from the National Comprehensive Cancer Network, which has expressed concern about over-diagnosis and over-treatment in prostate cancer patients. In 2010, NCCN guidelines established a new “very low risk” category for men with clinically insignificant prostate cancer and recommended that men who fall into this category and have a life expectancy of more than 20 years should only be followed with active surveillance. In 2011, NCCN made the active surveillance criteria more stringent for men in the “very low risk” category.

In order to develop the prostate cancer test, Genomic Health collaborated with the Cleveland Clinic on six feasibility studies and selected the gene expression panel after analyzing 700 genes on tissue samples from 700 patients. The commercial test analyzes the expression of 17 genes across four biological

I am quite surprised that nothing is said about the current status of  PSA for Pca, which is far advanced today, and it also needs attention.  We are in the old SUFI tale about the blind men who grasped the trunk, or the tail, etc., and called it the elephant.

Robustness of ProsVue™ linear slope for prognostic identification of patients at reduced risk for prostate cancer recurrence: Simulation studies on effects of analytical imprecision and sampling time variation

Mark J. Sarno, Charles S. Davis
Clinical Biochemistry  Nov 2012;  45 (16–17): 1479-1484
Highlights
► We simulate effects of analytical and sampling time variation on ProsVue slope.
 ► Classification switching is minimal in both stable disease and recurrence.
 ► We provide a framework for assessment of assays using rate of change principles
Objective
The ProsVue assay measures serum total prostate-specific antigen (PSA) over three time points post-radical prostatectomy and calculates rate of change expressed as linear slope. Slopes ≤ 2.0 pg/ml/month are associated with reduced risk for prostate cancer recurrence. However, an indicator based on measurement at multiple time points, calculation of slope, and relation of slope to a binary cutoff may be subject to effects of analytical imprecision and sampling time variation. We performed simulation studies to determine the presence and magnitude of such effects.
Design and methods
Using data from a two-site precision study and a multicenter clinical trial of 304 men, we performed simulation studies to assess whether analytical imprecision and sampling time variation can drive misclassifications or classification switching of patients with stable disease or recurrence.
Results
Analytical imprecision related to expected PSA values in a stable disease population results in ≤ 1.2% misclassifications. For populations with recurrent disease, an analysis taking into account correlation between sampling time points demonstrates that classification switching across the 2.0 pg/ml/month cutoff occurs at a rate ≤ 11%. In the narrow region of overlap between populations, classification switching maximizes at 12.3%. Lastly, sampling time variation across a wide range of scenarios results in 99.7% retention of proper classification for stable disease patients with linear slopes up to the 75th percentile of the distribution.
Conclusions
These results demonstrate the robustness of the ProsVue assay and the linear slope indicator. Further, these simulation studies provide a potential framework for evaluation of future assays that rely on the rate of change principle.
As the reviewer of this paper for Clinical Biochemistry, I have never encountered such a beautiful and rigorous evaluation that is described in the outline below:
Article Outline
1. Introduction
2. Materials and Methods
2.1. Source data
2.2. Simulation 1 – Effects of analytical imprecision in patients with stable disease
2.3. Simulations 2 and 3 – Effects of analytical imprecision in patients with PCa recurrence
2.4. Simulations 4 and 5 – Simulations in highest tertile of stable disease slopes and lowest tertile of recurrent slopes
2.5. Simulation 6 – Effects of sampling time variation
2.6. Software
3. Results
3.1. Source data for simulations
3.2. Simulation 1 – Effects of analytical imprecision in patients with stable disease
3.3. Simulations 2 and 3 – Effects of analytical imprecision in patients with PCa recurrence
3.4. Simulations 4 and 5 — Simulations in highest tertile of stable disease slopes and lowest tertile of recurrent slopes
3.5. Simulation 6 – Effects of sampling time variation
4. Discussion
5. Conclusions
References

This article is followed by another in the Urology journal.

NADiA ProsVue prostate-specific antigen slope is an independent prognostic marker for identifying men at reduced risk of clinical recurrence of prostate cancer after radical prostatectomy.

Moul JW, Lilja H, Semmes OJ, Lance RS, Vessella RL, Fleisher M, Mazzola C, Sarno MJ, Stevens B, Klem RE, McDermed JE, Triebell MT, Adams TH.
Division of Urologic Surgery and Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina 27710, USA. judd.moul@duke.edu
Urology. 2012 Dec;80(6):1319-25. http://dx.doi.org/10.1016/j.urology.2012.06.080. Epub 2012 Oct 26.
OBJECTIVE:
To validate the hypothesis that men displaying serum prostate-specific antigen (PSA) slopes ≤ 2.0 pg/mL/mo after prostatectomy, measured using a new immuno-polymerase chain reaction diagnostic test (NADiA ProsVue), have a reduced risk of clinical recurrence as determined by positive biopsy, imaging findings, or death from prostate cancer.
MATERIALS AND METHODS:
From 4 clinical sites, we selected a cohort of 304 men who had been followed up for 17.6 years after prostatectomy for clinical recurrence. We assessed the prognostic value of a PSA slope cutpoint of 2.0 pg/mL/mo against established risk factors to identify men at low risk of clinical recurrence using uni- and multivariate Cox proportional hazards regression and Kaplan-Meier analyses.
RESULTS:
The univariate hazard ratio of a PSA slope >2.0 pg/mL/mo was 18.3 (95% confidence interval 10.6-31.8) compared with a slope ≤ 2.0 pg/mL/mo (P <.0001). The median disease-free survival interval was 4.8 years vs >10 years in the 2 groups (P <.0001). The multivariate hazard ratio for PSA slope with the covariates of preprostatectomy PSA, pathologic stage, and Gleason score was 9.8 (95% confidence interval 5.4-17.8), an 89.8% risk reduction for men with PSA slopes ≤ 2.0 pg/mL/mo (P <.0001). The Gleason score (<7 vs ≥ 7) was the only other significant predictor (hazard ratio 5.4, 95% confidence interval 2.1-13.8, P = .0004).
CONCLUSION:
Clinical recurrence after radical prostatectomy is difficult to predict using established risk factors. We have demonstrated that a NADiA ProsVue PSA slope of ≤ 2.0 pg/mL/mo after prostatectomy is prognostic for a reduced risk of prostate cancer recurrence and adds predictive power to the established risk factors.
Urology. 2012 Dec;80(6):1325-6; author reply 1326-7. http://dx.doi.org/10.1016/j.urology.2012.06.081. Epub 2012 Oct 26.      Collins S.
Editorial comment.
NADiA ProsVue prostate-specific antigen slope is an independent prognostic marker for identifying men at reduced risk of clinical recurrence of prostate cancer after radical prostatectomy. [Urology. 2012]

Why NADiA ProsVue?      IRIS INTERNATIONAL

Some patients who had surgery to remove the prostate may be at higher risk for recurrence. Determining the risk of recurrence is critical for these patients and their physicians in order to make the most informed decision possible about future medical management.
Physicians use post-surgical risk assessment to review a variety of parameters to help determine if the patient might develop recurrent disease.  Risk factors may include:
  • The size and proximity of the tumor at the time of surgery (whether it has grown through the prostate walls):
Through imaging tests, physicians can determine how far cancerous tissue may have spread, with indicators such as
  • extracapsular extensions (ECE, beyond the prostatic capsule) and
  • seminal vesicle invasion (SVI, presence in the walls of the vesicles surrounding the prostate).
  • The presence of cancer cells at the edge of the removed tumor (known as positive margins) or in the lymph nodes outside the prostate.
  • A high preoperative PSA level (> 20 ng/mL).
  • The tumor’s Gleason Score (if it is at least 8 or higher).
However, current risk assessment relies on subjective and imprecise information. This uncertainty can have a dramatic impact on a patient’s personal experience after prostatectomy.
The newly available NADiA ProsVue test may help provide a more clear and accurate prediction of a patient’s true risk for clinical recurrence.
The NADiA ProsVue test measures
  • the rate of change of PSA at extremely low levels over time, which can help quickly and accurately identify patients
  • who are at reduced risk for clinical recurrence.

In conjunction with other information, NADiA ProsVue may allow some men to avoid unnecessary treatments and anxiety after prostatectomy.

NADiA ProsVue is an in-vitro diagnostic assay for determining
  • rate of change of serum total prostate specific antigen (tPSA) over a period of time (slope, pg/mL per month).
The NADiA ProsVue assay is performed for patients having less than 0.1 ng/mL serum tPSA values (determined by standard-of-care assays that are FDA approved/cleared) in the first sample collected more than 6 weeks after radical prostatectomy.

What is NADiA?

NADiA stands for Nucleic Acid Detection immunoassay.  Immuno-PCR, first described by Sano and Cantor in 1992 involves combining protein antigen detection by immunoassay with the detection sensitivity and precision of real-time polymerase chain reaction (qPCR).  This amplified DNA-immunoassay approach is similar to that of an enzyme immunoassay, involving antibody binding reactions and intermediate washing steps.  The enzyme label is replaced by a strand of DNA and detected by exponential amplification using qPCR.

NADiA employs a soluble (reporter) monoclonal antibody (MAb) labeled with an assay-specific double-stranded DNA sequence.

  • The presence of this DNA label does not interfere with MAb binding, nor
  • does the MAb interfere with DNA label amplification and detection.
  • The second (capturing) MAb specific for another site on the target protein (antigen)
    is coated onto paramagnetic microparticles.

The reporter MAb-DNA conjugate is reacted with sample in a microtiter plate format to form a first immune complex with the target antigen. The immune complex is then captured onto paramagnetic particles coated with the second capture MAb, forming an insoluble sandwich immune complex. The microparticles are washed by several cycles of magnetic capture and re-suspension to remove excess reporter MAb-DNA conjugate.
The specifically bound DNA label is then detected by subjecting

  • suspended particles to qPCR conditions and monitoring the generations of amplicon in real time.


What are possible clinical applications?

Proteins play a crucial role in all biological functions. Identifying and measuring the quantity of specific proteins is fundamental to understanding the cause and evolution of many human disease processes.
There are hundreds of thousands of proteins in the human body, but the vast majority are present at extremely low concentrations. For example, only ten (10) proteins make up 90% of the mass of plasma proteins found in human serum. Twelve (12) proteins make up another 9% of the mass. The remaining proteins comprise the final 1%. Advancing medicine through the study of proteins (known as proteomics) requires powerful and sensitive tools.
http://www.irispermed.com/images/pictures/Protein_Slide_2.png

NADiA combines the specificity of an immunoassay with the detection sensitivity of qPCR and can assist efforts to provide clinical insight into many human diseases.  Any disease process involving proteins below the detection limits of today’s enzyme immunoassays (EIA) is a potential target for NADiA.
NADiA ProsVue is the first of a line of assays designed to advance human healthcare in the areas of oncology and infectious disease.

510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION

DECISION SUMMARY
A. 510(k) Number:
k101185
B. Purpose for Submission:
New device
C. Measurand:
Total Prostate specific antigen (tPSA)
D. Type of Test:
Quantitative, Immuno-PCR (Polymerase Chain Reaction)
E. Applicant:
Iris Molecular Diagnostics
F. Proprietary and Established Names:
NADiA® ProsVue™

 Intended Use:

NADiA® ProsVue™ is an in-vitro diagnostic assay for determining rate of change of serum total prostate specific antigen over a period of time (slope, pg/mL per month). The NADiA® ProsVue™ assay is performed for patients having less than 0.1 ng/mL serum total PSA values (determined by standard-of-care assays that are FDA approved/cleared) in the first sample collected more than 6 weeks after radical prostatectomy. ProsVue™ slope is indicated for use as a prognostic marker in conjunction with clinical evaluation as an aid in identifying those patients at reduced risk for recurrence of prostate cancer for the eight year period following prostatectomy.
The NADiA® ProsVue™ assay is not intended for the diagnosis or for the monitoring of prostate cancer.
 †”Recurrence” is defined as clinical recurrence, not biochemical recurrence, and was documented by positive imaging, positive biopsy, or death due to prostate cancer.

U.S. FDA approves NADiA ProsVue prognostic test for prostate cancer

Posted on September 23, 2011 by Sitemaster

According to a media release issued

Moul et al. have now conducted a retrospective, multi-center clinical trial to further evaluate the potential prognostic value of ProsVue slope at a decision threshold of 2 pg/ml/month. (One nanogram or 1 ng = 1,000 picograms or 1,000 pg.)
The retrospective analysis was based on data from 392 prostate cancer patients who had been given radical prostatectomies between November 1991 and August 2001. To be eligible for this study, all of the following data had to be available from individual patients:
  1. A first post-surgical PSA level of <100 pg/ml (i.e., <  0.1 ng/ml)
  2. Full pathologic and radiographic data
  3. Three frozen serum samples drawn between 6 weeks and 19.4 months post-surgery.
  4. Patients were not eligible if they had received adjuvant radiotherapy and/or hormone therapy after surgery and prior to completion of the three post-surgical blood draws.
The results of this retrospective study showed that:
  1. The average (median) PSA levels of the 392 patients was 6.3 ng/ml (range, 0 to 60.6 ng/ml)
  2. The average (median) post-surgical Gleason score was 7.0 (range, 4 to 10).
73 patients had received neoadjuvant hormone therapy prior to their surgery.
The pathologic stages of the patients were
pT0-2, n = 228
pT3, n = 147
pT4, n = 17
116 patients had positive margins and 8 had positive lymph nodes.
The three post-surgical PSA values were based on serum drawn
  • after median times of 4.9, 8.6, and 12.8 months and showed median values of 10.7, 23.0 and 50.7 pg/ml, respectively.
The sensitivity, specificity, PPV and NPV for a 2 pg/mL/month ProsVue slope were 75.0, 96.6, 81.4, and 95.2, respectively.
  • At a median follow-up of 10.5 years, 14 patients had died of prostate cancer and 40 had died overall.
The authors conclude the the ProsVue test “provides information previously unknown” in patients in the first year post-surgery, and that a ProsVue slope of  ≤ 2 pg/mL/month in that first year is highly associated with a lack of evidence of progression in long-term follow-up.
In theory, the ProsVue test may have some clinical value in the identification of patients who do not need long-term oncologic follow-up and in predicting the need for adjuvant radiation therapy. However, additional prospective studies will be necessary before this can be confirmed, and the practical clinical value of such a test would depend on whether it is significantly more accurate that data currently available from ultrasensitive PSA testing.
Additional information is available in a media release from the developer of the ProsVue test (IRIS International). According to that media release, the developer has submitted data to the FDA requesting approval to market this test.
The centers involved in this study included Duke University, Memorial Sloan-Kettering Cancer Center, Eastern Virginia Medical Center, and the University of Washington — all of which are highly reputable institutions.
NADiA ProsVue results are calculated as the linear slope of three NADiA ProsVue total PSA test results obtained on three serum samples collected between six weeks and 20 months post-radical prostatectomy.

by IRIS International, the U.S. Food & Drug Administration (FDA) has approved the company’s NADiA® ProsVue™ test as a prognostic marker that can “aid in identifying” men at reduced risk for recurrence of prostate cancer in the first 8 years after a prostatectomy

NADiA ProsVue: A prognostic test for identifying men at a reduced risk for prostate cancer recurrence following radical prostatectomy

J. Moul2, R. Lance1, J. Alter3, M. Sarno3, J. McDermed3
1 Eastern Virginia Medical School, Norfolk, USA
2 Duke Prostate Center, Durham, USA
3 Iris Molecular Diagnostics, Carlsbad, USA

Introduction: Clinical recurrence after radical prostatectomy (RP) is difficult to predict since established factors do not reliably stratify risk. We validated a pre-specified hypothesis that a post-RP NADiA® PSA slope cutpoint of ≤2.0 pg/mL/month (mo) identifies men at reduced risk of clinical recurrence as determined by positive biopsy, imaging or prostate cancer death. This study aimed to compare the prognostic strength of the ProsVue slope cutpoint vs. surgical margin status to identify men at very low risk of post-RP clinical recurrence.
Methods: From a cohort of 304 men, surgical margin data was available for 234 men. PSA was measured with a Nucleic Acid Detection Immunoassay (NADiA®) having a limit of quantification of 0.00065 ng (0.65 pg) per mL. Least-squares linear PSA slope (ProsVue™) was calculated using 3 serum samples drawn 1.5-20 mo post-RP. Recurrence risk using a 2.0 pg/mL/mo ProsVue cutpoint and surgical margin status were compared by two survival methods, univariate Cox proportional hazards regression analysis (table) and Kaplan-Meier plots (figure).
Results: ProsVue slope ≤2.0 pg/mL/mo was significantly associated with a reduced risk of clinical recurrence by univariate Cox analysis (HR 18.3, 95% CI, 10.6–31.8, P < 0.0001). A negative surgical margin was less significantly associated with a reduced risk of recurrence (HR 3.3, 95% CI 2.0–5.4). Median time to recurrence for men with ProsVue slope ≤2.0 pg/mL/mo and those with negative margins exceeded 17.6 years (yrs). However, median time to recurrence in men with ProsVue slope >2.0 pg/mL/mo was shorter compared to those with positive margins.

NADiA ProsVue Prostate-specific Antigen Slope Is an Independent Prognostic Marker for Identifying Men at Reduced Risk of Clinical Recurrence of Prostate Cancer After Radical Prostatectomy

Judd W. Moul, Hans Lilja, O. John Semmes, Raymond S. Lance, Robert L. Vessella, Martin Fleisher, Clarisse Mazzola, Mark J. Sarno, Barbara Stevens, Robert E. Klem, Jonathan E. McDermed, Melissa T. Triebell, Thomas H. Adams
Urology Dec 2012; 80(6): 1319-1327,

Objective
To validate the hypothesis that men displaying serum prostate-specific antigen (PSA) slopes ≤2.0 pg/mL/mo after prostatectomy, measured using a new immuno-polymerase chain reaction diagnostic test (NADiA ProsVue), have a reduced risk of clinical recurrence as determined by positive biopsy, imaging findings, or death from prostate cancer.
Materials and Methods
From 4 clinical sites, we selected a cohort of 304 men who had been followed up for 17.6 years after prostatectomy for clinical recurrence. We assessed the prognostic value of a PSA slope cutpoint of 2.0 pg/mL/mo against established risk factors to identify men at low risk of clinical recurrence using uni- and multivariate Cox proportional hazards regression and Kaplan-Meier analyses.
Results
The univariate hazard ratio of a PSA slope >2.0 pg/mL/mo was 18.3 (95% confidence interval 10.6-31.8) compared with a slope ≤2.0 pg/mL/mo (P <.0001). The median disease-free survival interval was 4.8 years vs >10 years in the 2 groups (P <.0001). The multivariate hazard ratio for PSA slope with the covariates of preprostatectomy PSA, pathologic stage, and Gleason score was 9.8 (95% confidence interval 5.4-17.8), an 89.8% risk reduction for men with PSA slopes ≤2.0 pg/mL/mo (P <.0001). The Gleason score (<7 vs ≥7) was the only other significant predictor (hazard ratio 5.4, 95% confidence interval 2.1-13.8, P = .0004).
Conclusion
Clinical recurrence after radical prostatectomy is difficult to predict using established risk factors. We have demonstrated that a NADiA ProsVue PSA slope of ≤2.0 pg/mL/mo after prostatectomy is prognostic for a reduced risk of prostate cancer recurrence and adds predictive power to the established risk factors.

Fifth–Generation Digital Immunoassay for Prostate Specific Antigen by Single Molecule Array Technology.

D.H. Wilson, D.W. Hanlon, G.K. Provuncher, L. Chang, L. Song, P.P. Patel, E.P. Ferrell, H. Lepor,A.W. Partin, D.W. Chan, L.J. Sokoll, C.D. Cheli, R.P. Thiel, D.R. Fournier, and D.C. Duffy
http://dx.doi.org/10.1373/clinchem.2011.169540

Measurement of prostate specific antigen (PSA) in prostate cancer patients following radical prostatectomy (RP) has been hindered by the limit of quantification of available assays. Because radical prostatectomy removes the tissue responsible for PSA production, postsurgical PSA is typically undetectable with current assay methods. Evidence suggests, however, that more sensitive determination of PSA status following RP could improve assessment of patient prognosis and response to treatment and better target secondary therapy for those who may benefit most. We developed an investigational digital immunoassay with a 2–logs–lower limit of quantification than current ultrasensitive third–generation PSA assays. We developed reagents for a bead–based ELISA for use with high–density arrays of femtolitervolume wells. Anti–PSA capture beads with immunocomplexes and associated enzyme labels were singulated within the wells of the arrays and interrogated for the presence of enzymatic product. We characterized analytical performance, compared its accuracy with a commercially available test, and analyzed longitudinal serum samples from a pilot study of 33 RP patients. The assay exhibited a functional sensitivity (20% interassay CV) <0.05 pg/mL, total imprecision <10% from 1 to 50 pg/mL, and excellent agreement with the comparator method. All RP samples were well within the assay measurement capability. PSA concentrations following surgery were found to be predictive of prostate cancer recurrence risk over 5 years. The robust 2–log improvement in limit of quantification relative to current ultrasensitive assays and the validated analytical performance of the assay allow for accurate assessment of PSA status after RP.

Risk of prostate cancer in two age groups base...

Risk of prostate cancer in two age groups based on Free PSA as % of Total PSA Catalona W, Partin A, Slawin K, Brawer M, Flanigan R, Patel A, Richie J, deKernion J, Walsh P, Scardino P, Lange P, Subong E, Parson R, Gasior G, Loveland K, Southwick P (1998). “Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial”. JAMA 279 (19) : 1542–7. doi:10.1001/jama.279.19.1542. PMID 9605898. (Photo credit: Wikipedia)

English: Human prostate specific antigen (PSA/...

English: Human prostate specific antigen (PSA/KLK3) with bound substrate from complex with antibody (PDB id: 2ZCK) (Photo credit: Wikipedia)

Table 1. Side-effects and effects on recovery ...

Table 1. Side-effects and effects on recovery of treatments for newly diagnosed prostate cancer. The Prostate Brachytherapy Advisory Group: http://www.prostatebrachytherapyinfo.net (Photo credit: Wikipedia)

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Curator: Aviva Lev-Ari, PhD, RN

On February 6, 2013 we reported that DR. MARK RUBIN, LEADING PROSTATE CANCER AND GENOMICS EXPERT, TO LEAD CUTTING-EDGE CENTER FOR TARGETED, INDIVIDUALIZED PATIENT CARE BASED ON EACH PATIENT’S GENETICS

Genomically Guided Treatment after CLIA Approval: to be offered by Weill Cornell Precision Medicine Institute

On May 16, 2013 we reported a major breakthrough in the Prostate Cancer Screening

A Blood Test to Identify Aggressive Prostate Cancer: a Discovery @ SRI International, Menlo Park, CA

After nearly a decade, my collaborators and I have found the first marker that specifically identifies the approximately six to eight percent of prostate cancers that are considered “aggressive,” meaning they will migrate to other parts of the body, at which point they are very difficult to treat. Although we have confirmed this marker, there is much to be done before a clinical application can be developed.

https://pharmaceuticalintelligence.com/2013/05/16/a-blood-test-to-identify-aggressive-prostate-cancer-a-discovery-sri-international-menlo-park-ca/

Prostate Cancer MDx Competition Heating Up; New Data from Genomic Health, Myriad

May 15, 2013

Life sciences companies are gearing up for battle to capture the profitable prostate cancer molecular diagnostic market.

Genomic Health and Myriad Genetics both made presentations to the investment community last week about their genomic tests that gauge a man’s risk of prostate cancer aggressiveness. As part of its annual investor day, Myriad discussed new data on its Prolaris test, which analyzes the expression level of 46 cell cycle progression genes and stratifies men’s risk of biochemical recurrence of prostate cancer. If the test reports low gene expression, then the patient is at low risk of disease progression, while high gene expression is associated with disease progression.

Meanwhile, around the same time last week, Genomic Health launched its Oncotype DX prostate cancer test and presented data from the first validation study involving the diagnostic. The Oncotype DX prostate cancer test analyzes the expression of 17 genes within four biological pathways to gauge prostate cancer aggressiveness. The test reports a genomic prostate score from 0 to 100; the lower the score the more certain a patient can be that they can avoid treatment and continue with active surveillance. Prostate cancer patients who are deemed to be at very low risk, low risk, or intermediate risk of progressing are eligible to be tested with the Oncotype Dx test. If, based on standard clinical measures, a person’s prostate cancer is considered high risk, then he is not a candidate for Genomic Health’s test.

These molecular tests are entering the market at a time when currently available tools aren’t specific enough to distinguish between men who have an aggressive form of prostate cancer and therefore, need invasive treatments, and those that are low risk and can do well with active surveillance. According to an NIH estimate, in 2010, the annual medical costs associated with prostate cancer in the US were $12 billion.

It is estimated that each year 23 million men undergo testing for prostate specific antigen, a protein produced by the prostate gland that increases when a man has prostate cancer. Additionally, one million men get a prostate biopsy annually, while 240,000 men end up with a diagnosis for prostate cancer, and around 30,000 die from the disease. Although most of the men diagnosed with prostate cancer end up receiving surgery or radiation treatment, as many as half of these men will probably not progress, and their disease isn’t life threatening.

While PSA testing has been shown to reduce prostate cancer deaths, a man’s PSA level may be increased for reasons other than cancer. As such, broadly screening men for PSA has been controversial in the healthcare community since the test isn’t specific enough to gauge which men are at low risk of developing aggressive prostate cancer and can forgo unnecessary treatments that can have significant side effects.

Both Myriad and Genomic Health are hoping their tests will further refine prostate cancer diagnosis and help doctors gain more confidence in determining which of their patients have aggressive disease and which are at low risk.

Myriad’s advantage

In this highly competitive space, Myriad has the first mover advantage, having launched Prolaris three years ago. The company has published four studies involving the test and conducted a number of trials analyzing around 3,000 patient samples.

Researchers from UCSF and Myriad recently published the fourth validation study in the Journal of Clinical Oncology, which analyzed samples from 400 men who had undergone a radical prostatectomy. In the published study, researchers reported that 100 percent of the men whom Prolaris deemed to be at “low risk” of progression did not experience a recurrence within the five years the study was ongoing. Meanwhile, 50 percent of those the test deemed to be a “high risk” did experience recurrence during that time (PGx Reporter 3/6/2013).

At a major medical conference recently, Myriad presented data from a study which tested biopsy samples from 141 patients treated with electron beam radiation therapy and found that the test score was significantly associated with patients’ outcome and provided information about disease progression beyond standard clinical measures. Although this finding needs to be further validated in a larger patient cohort, the researchers concluded that Prolaris “could be used to select high-risk men undergoing electron beam radiation therapy who may need combination therapy for their clinically localized prostate cancer.” In this study, around half of the cohort was African American.

Myriad has also shown in studies that its test can make accurate predictions from tissue from an initial prostate biopsy and from post-prostatectomy. The test has also shown in studies to be superior to the Gleason score, baseline PSA levels, and other prognostic factors in predicting prostate cancer-specific mortality.

Myriad has nearly completed hiring a 24-person sales force to drive sales of the test. Over the last year, Myriad has received more than 3,000 orders for its Prolaris test and 350 urologists have ordered it. The test carries a $3,400 price tag.

Although the company doesn’t have Medicare coverage yet for Prolaris, Myriad is conducting a study, called PROCEED, that it hopes will sway Medicare contractor Noridian to cover the diagnostic. The company has said it is on track to submit data from this registry to Medicare by late summer and expects to hear a decision about test coverage in calendar year 2014 (PGx Reporter 5/8/2013).

During the annual investor day last week, Myriad officials highlighted the gene panel for Prolaris, which features genes involved in cell cycle progression, and noted this as one of the advantages of its test over standard methods. “The Prolaris score measures how fast the tumor is growing. We look at the cell proliferation to look at a component of cancer that is not looked at by current clinical pathologic features,” Bill Rusconi, head of Myriad’s urology division, said.

“So, pathology like PSA score … only look at how far the tumor is progressed … [and] how advanced that tumor is. So, that’s only half of the picture because an advanced tumor could have been smoldering for 20 years, and may not go much further in the short term,” he noted. On the other hand, Rusconi added that a less advanced tumor could be progressing very quickly.

Another distinguishing point for the Prolaris test, according to Myriad, is that it is indicated for patients who are deemed to be at low and high risk by standard measures. Prostate cancer patients deemed to be at high risk of progression by standard clinical measures wouldn’t qualify for testing by Genomic Health’s test. Rusconi estimated that if Prolaris tested around 200,000 patients with localized prostate cancer to gauge the aggressiveness of their disease, the market opportunity for the test would be $700 million.

Myriad executives declined to comment on competing prostate cancer molecular tests, particularly Genomic Health’s product, noting that there isn’t a lot of published data to make any judgments. “We haven’t really seen any published data from any other competitor product. And so, I think in the absence of that, until data have made it through the peer review process and been in publication, it’s always difficult to understand exactly what type of information is available,” Mark Capone, president of Myriad Genetics Laboratories, told investors.

New competition

Like Myriad’s BRACAnalysis test, which comprises more than 80 percent of its product revenues, Genomic Health’s Oncotype DX breast cancer recurrence tests is bringing in the majority of its product revenues. However, the company believes that its newly launched Oncotype DX prostate cancer test stands to be its largest market opportunity to date.

Last week, researchers from University of California, San Francisco, presented data from the first validation study involving the Oncotype DX prostate cancer test. The study involved nearly 400 prostate cancer patients considered low or intermediate risk by standard methods such as Gleason score and showed that when the Oncotype DX score was used in conjunction with other measures, investigators identified more patients as having very low risk disease who were appropriate for active surveillance than when they diagnosed patients without the test score.

More than one third of patients classified as low risk by standard measures in the study were deemed to be “very low risk” by Oncotype DX and therefore could choose active surveillance. Meanwhile, 10 percent of patients in the study were found by clinical measures to be at very low risk or low risk, but the Oncotype DX test deemed them as having aggressive disease that needed treatment.

Matthew Cooperberg of UCSF, who presented data from this validation study at the American Urological Association’s annual meeting last week, highlighted this feature of the Oncotype DX prostate cancer test to investors during a conference call last week. He noted that the test not only gauges which low-risk patients can confidently remain with active surveillance, but it also finds those patients who didn’t receive an accurate risk assessment based on standard clinical measures. “It’s also equally important that we identify the man who frankly should not be on active surveillance, because they’re out there,” he said.

Genomic Health has aligned its test with guidelines from the National Comprehensive Cancer Network, which has expressed concern about over-diagnosis and over-treatment in prostate cancer patients. In 2010, NCCN guidelines established a new “very low risk” category for men with clinically insignificant prostate cancer and recommended that men who fall into this category and have a life expectancy of more than 20 years should only be followed with active surveillance. In 2011, NCCN made the active surveillance criteria more stringent for men in the “very low risk” category.

In order to develop the prostate cancer test, Genomic Health collaborated with the Cleveland Clinic on six feasibility studies and selected the gene expression panel after analyzing 700 genes on tissue samples from 700 patients. The commercial test analyzes the expression of 17 genes across four biological pathways.

Genomic Health executives suggested to investors that in determining the aggressiveness of prostate cancer a test that gauges critical genes in multiple pathways involved in the disease, as opposed to just one pathway, may be the better bet.

“After we selected those 700 [candidate] genes, we were completely agnostic as to what the best predictors would be. So, we let the genes do their thing and picked out the best performance,” said Eric Klein, chairman of Glickman Urological and Kidney Institute at the Cleveland Clinic and principal investigator for the original development studies for the Oncotype DX prostate cancer test. Referring to Myriad’s test, which assessed 46 cell cycle progression genes, Klein noted that while cell proliferation is important, it’s not the only pathway.

“So, I think one of the strengths of this assay is that it surveys the biology of the cancer better because it surveys other pathways,” he said. If a test only looks at genes in only one particular pathway, and the “score is low, you don’t know if you have missed the other underlying biology.”

This strategy of picking critical cancer-linked genes from multiple pathways has proven successful when launching Oncotype DX tests for breast cancer and colon cancer recurrence, company officials noted. Genomic Health’s prior experience launching molecular tests for cancer recurrence and the strength of the Oncotype DX brand will likely be advantages for the company.

Kim Popovits, CEO of Genomic Health, noted that the company has hired a “small sales force” to drive uptake of the prostate cancer test and reps will be targeting high-volume practices. “We have medical science liaisons that will be out there working to educate key opinion leaders with a similar approach to what we did in breast [cancer],” Popovits told investors. “We will begin to add to the sales organization as time goes on, as we see traction taking place, and as we move more towards payor reimbursement.”

The company plans to conduct a decision impact study as part of its effort to gain reimbursement coverage for the test. Genomic Health is also planning to do additional studies that will explore what level of active surveillance doctors should perform on patients who are deemed by the Oncotype DX test to be at very low or low risk.

The list price for the test is $3,820.

Other players

Although Myriad and Genomic Health are currently the main players in the prostate cancer molecular diagnostics space, the market will become an increasingly crowded one in the coming months.

Canadian firm GenomeDx is planning to launch a prostate cancer molecular diagnostic later this year, called Decipher. The company recently presented data at a medical conference on the test’s clinical validity and utility in predicting which patients are at risk of recurrence and metastasis after prostate cancer surgery. The company has said it has 22 studies underway with the Decipher test involving 4,000 patients (PGx Reporter 2/20/2013).

BioTheranostics recently published a study in the Proceedings of the National Academy of Sciences about its new 32-gene signature test, dubbed Prostate Cancer Index, which gauges PSA recurrence. In the study, which involved 270 tumor samples for patients treated with radical prostatectomy, the RT-PCR test (developed in collaboration with Massachusetts General Hospital) predicted PSA recurrence and had added value over standard measures such as Gleason score, tumor stage, surgical margin status, and pre-surgery PSA levels. The only other measure with significant prognostic value was surgical margin status.

The test could separate patients into groups based on PSA recurrence and whether they would develop metastatic disease within a 10-year period. PCI found that patients with a high risk score had a 14 percent risk of metastasis, while those in the low-risk group had a zero percent risk of metastasis. “In particular, this information may be useful at the biopsy stage, so that clinicians can better assess which patients can consider active surveillance versus those who should consider immediate treatment,” BioTheranostics CEO Richard Ding told PGx Reporter.

BioTheranostics has not yet determined when it will launch PCI. However, the company is planning additional follow-on studies to demonstrate the clinical utility of the test, including one study involving patients on active surveillance after having an initial prostate biopsy.

      Turna Ray is the editor of GenomeWeb’s Pharmacogenomics Reporter. She covers pharmacogenomics, personalized medicine, and companion diagnostics. E-mail Turna Ray or follow her GenomeWeb Twitter account at @PGxReporter.

 

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Reporter: Aviva Lev-Ari, PhD, RN

Dr. Lev-Ari was Director @ SRI International in the mid 1980s.

Denong Wang

Distinguished Scientist and Senior Program Director, Tumor Glycomics Laboratory, Center for Cancer and Metabolism
Denong Wang

Denong Wang, Ph.D., is an SRI distinguished scientist and senior program director of the Tumor Glycome Laboratoryin the Center for Cancer and Metabolism in SRI Biosciences. Wang’s long-term research interest is in the carbohydrate moieties that are critical for self/non-self recognition and induction of antibody responses.

Wang’s team has established multiple platforms of carbohydrate microarrays and introduced these glycomics tools to explore the structural and antigenic diversities of the glycome. The main research focus of his lab is in the immunogenic sugar moieties. In the past few years, his group has contributed to the identification of immunologically potent glycan markers of SARS-CoV, Bacillus anthracis exosporium, and a number of human cancers.

Wang received his Ph.D. in immunology and glycobiology with the late Professor Elvin A. Kabat at Columbia University in 1993. After that, he entered the developing field of post-genomics research. Before joining SRI in 2010, he served as head of the Functional Genomics Division at Columbia University’s Genome Center from 1998 to 2003 and was director of Stanford University’s Tumor Glycome Laboratory from 2007 to 2010.

SRI International

SRI Blog

A Blood Test to Identify Aggressive Prostate Cancer

By Denong Wang at 9:15 AM PDT, Wed May 8, 2013

tumor glycomicsProstate cancer is the second most common cancer in American men, killing nearly 30,000 per year. In 2004, I attended a conference where one of the nation’s leading researchers in the field declared that the gold-standard test for this disease was not successful at identifying dangerous invasive tumors. That triggered my interest in how to address the challenge of developing a blood test to detect the deadly form of prostate cancer.

After nearly a decade, my collaborators and I have found the first marker that specifically identifies the approximately six to eight percent of prostate cancers that are considered “aggressive,” meaning they will migrate to other parts of the body, at which point they are very difficult to treat. Although we have confirmed this marker, there is much to be done before a clinical application can be developed.

If further study confirms that the test is clinically reliable, it can provide a much-needed tool to differentiate between aggressive cancer and the majority of cases, which are slow-growing tumors with a low probability of migrating to other parts of the body (and thus don’t require special treatment, such as radical prostatectomy).

The current standard test looks at elevated blood prostate-specific antigen (PSA) levels, known as the PSA test. Dr. Thomas Stamey, an emeritus faculty member and urologist at the Stanford University School of Medicine, published his original findings in 1987 linking elevated blood PSA levels to prostate cancer. In 2004, Dr. Stamey declared that the PSA test was no longer useful for the diagnosis of prostate cancer. Rather, an elevated PSA level is now known to reflect the volume increase of a prostate, which could either be associated with a harmless increase in prostate size called benign prostatic hyperplasia (BPH), or be caused by cancer.

I began collaborating with Dr. Stamey and his Stanford colleague Dr. Donna Peehl to look for a new prostate cancer marker, hopefully one that would indicate the presence of aggressive prostate cancer through a blood test.  This is a very active area of research, with scientists exploring the idea from (1) a genomics perspective, (2) a proteomics perspective, and (3) a glycomics perspective, the latter of which entails using carbohydrate-based markers to identify cancer. My focus is the third area, where we are concentrating on how the immune system recognizes changes in the carbohydrates found on the surface of cancer cells compared with those on the surface of normal cells.  

SRI’s Tumor Glycome Laboratory has discovered a marker that appears to be associated with aggressive prostate cancer. The marker is an antibody that is produced against a carbohydrate molecule on the surface of aggressive prostate cancer cells, and is expressed in increasing levels that correlate with cancer severity. We call it a “cryptic” biomarker, since it only becomes an immunological target if something goes awry in the cell, such as a viral infection or the malignant transformation of normal cells to cancer.

This biomarker has the potential, with further development, to be used as a test to help diagnose aggressive prostate cancer. It is rewarding to have reached this point in our understanding of prostate cancer and toward a diagnostic test that ultimately could save lives.

Our research findings were published last year in the Journal of Proteomics & Bioinformatics (5:090-095, DOI:10.4172/jpb.1000218). Our latest study, published in Drug Development Research, lays the foundation for predicting which prostate cancer patients may develop more aggressive forms of the disease and directs the future design of more effective treatments [14(2):65-80, DOI: 10.1002/ddr.21063].

Anti‐Oligomannose Antibodies as Potential Serum Biomarkers of Aggressive Prostate Cancer

Abstract

This study bridges a carbohydrate microarray discovery and a large‐scale serological validation of anti‐oligomannose antibodies as novel serum biomarkers of aggressive prostate cancer (PCa). Experimentally, a Man9‐cluster‐specific enzyme‐linked immunosorbent assay was established to enable sensitive detection of anti‐Man9 antibodies in human sera. A large‐cohort of men with PCa or benign prostatic hyperplasia (BPH) whose sera were banked at Stanford University was characterized using this assay. Subjects included patients with 100% Gleason grade 3 cancer (n = 84), with Gleason grades 4 and/or 5 cancer (n = 204), and BPH controls (n = 135). Radical prostatectomy Gleason grades and biochemical (PSA) recurrence served as key parameters for serum biomarker evaluation. It was found that IgGMan9 and IgMMan9 were widely present in the sera of men with BPH, as well as those with cancer. However, these antibody reactivities were significantly increased in the subjects with the largest volumes of high grade cancer. Detection of serum IgGMan9 and IgMMan9 significantly predicted the clinical outcome of PCa post‐radical prostatectomy. Given these results, we suggest that IgGMan9 and IgMMan9 are novel serum biomarkers for monitoring aggressive progression of PCa. The potential of oligomannosyl antigens as targets for PCa subtyping and targeted immunotherapy is yet to be explored.

Authors: Denong Wang, Laila Dafik, Rosalie Nolley, Wei Huang, Russell D. Wolfinger, Lai‐Xi Wang, Donna M. Peehl
Journal: Drug Development Research
Year: 2013
Pages: n/a
DOI: 10.1002/ddr.21063
Publication date: 11-02-2013

Proteomics & Bioinformatics

N-glycan Cryptic Antigens as Active Immunological Targets in Prostate

Cancer Patients

Denong Wang*

Tumor Glycomics Laboratory, Center for Cancer Research, Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA

*Corresponding author: Dr. Denong Wang, Tumor Glycomics Laboratory,

Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo

Park, CA 94025, USA, Tel: +1 650 859-2789; Fax: +1 650 859-3153; E-mail:

denong.wang@sri.com

Received March 07, 2012; Accepted April 13, 2012; Published April 30, 2012

Citation: Wang D (2012) N-glycan Cryptic Antigens as Active Immunological

Targets in Prostate Cancer Patients. J Proteomics Bioinform 5: 090-095.

doi:10.4172/jpb.1000218

Copyright: © 2012 Wang D.

Abstract

Although tumor-associated abnormal glycosylation has been recognized for decades, information regarding host recognition of the evolving tumor glycome remains elusive. We report here a carbohydrate microarray analysis of a number of tumor-associated carbohydrates for their serum antibody reactivities and potential immunogenicity in humans. These are the precursors, cores and internal sequences of N-glycans. They are usually masked by other sugar moieties and belong to a class of glyco-antigens that are normally “cryptic”. However, viral expression of these carbohydrates may trigger host immune responses. For examples, HIV-1 and SARS-CoV display Man9 clusters and tri- or multi-antennary type II (Galβ1→4GlcNAc) chains (Tri/m-II), respectively; viral neutralizing antibodies often target these sugar moieties. We asked, therefore, whether prostate tumor expression of corresponding carbohydrates triggers antibody responses in vivo. Using carbohydrate microarrays, we analyzed a panel of human sera, including 17 samples from prostate cancer patients and 12 from men with Benign Prostatic Hyperplasia (BPH).

We observed that IgG antibodies targeting the Man9- or Tri-/m-II-autoantigens are readily detectable in the sera of men with BPH, as well as those with cancer. Importantly, these antibody activities were selectively increased in prostate cancer patients. Thus, human immune systems actively recognize these N-glycan cryptic carbohydrates and produce targeting antibodies. This finding shads a light on a class of previously less studied immunological targets of human cancers. Identifying the diagnostic, prognostic and therapeutic values of these targets will require further investigation.

http://www.omicsonline.org/0974-276X/JPB-05-090.pdf

 

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