Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘PSA’

The recent announcement from the United States Preventative Services Task Force (USPSTF) on prostate cancer screening has stimulated a lot of debate.  “Dr Len’s Cancer Blog” from the American Cancer Society has a thoughtful piece about the “to screen or not to screen” dilemma. It is reminiscent of the breast cancer mammography debate.

Scott Hensley’s post on “Shots”, the NPR health blog also provides a good overview of the debate and issues. I confess I was surprised by the vehemence of the response from some practising urologists on twitter such as Dr Benjamin J. Davies (@daviesbj), Assistant Professor of Urology at the University of Pittsburgh School of Medicine:

What do the US Preventative Task Force authors say? In the findings published in the October 7, 2011 issue of the Annals of Internal Medicine, the conclusion from their peer-review of the literature is that:

“screening based on PSA identifies additional prostate cancers, but most trials found no statistically significant effect on prostate cancer–specific mortality.”

This is nothing new – the evidence in favor of Prostate-Specific Antigen (PSA) screening for prostate cancer has for sometime been inconclusive at best. Research published in the British Medical Journal earlier this year suggested that indiscriminate screening for prostate cancer may not be of value until we obtain more sensitive biomarkers.

All the USPSTF have done is a retrospective literature review that confirms our current state of knowledge.

Despite the amount of $$$ that have been spent on PSA clinical studies, no convincing data in support of it as a screening tool for all men has been developed. That’s not to say that it has no utility or benefit.

If PSA screening does detect some prostate cancers and early treatment may save lives particularly in those with an aggressive form of the disease, then it’s hard not ask:

  • What is the alternative if PSA screening is now discouraged?
  • Will this mean more men will not be screened, even those at high risk, with a consequent increase in prostate cancer mortality or lower overall survival?
  • Will insurers refuse to cover PSA testing moving forwards?
  • Will family physicians actively discourage PSA testing?

One limitation of the USPSTF report that struck me while reading through the analysis and recommendations, was the absence of data from the Prostate Cancer Intervention versus Observation (PIVOT) trial that was presented in the plenary session at the American Urological Association (AUA) annual meeting earlier this year.

I wrote in a previous blog post about the PIVOT data presented at AUA 2011 by Dr Wilt. This VA/NCI/AHRQ randomized clinical trial showed in a 12 year follow-up of over 5000 men with localized prostate cancer, no benefit from radical prostatectomy in low risk early stage patients.

In my opinion it is practice changing data that sadly has not yet been published in a peer-reviewed journal which is why it was not included in the USPSTF analysis. A few photographs that I took at the presentation of the PIVOT data are shown below:

The 12 year survival data showed that in those patients with PSA <=10 ng/ml there was no significant difference in survival over observation versus RP.

However in those patients with PSA > 10ng/ml there was a significant difference in mortality (p=0.03 HR=0.36) suggesting that in the small sub-group of patients with high PSA, RP did provide a benefit over “watchful waiting.” PSA measurements may therefore help in the treatment and ongoing management of patients.

If one of the challenges of PSA screening is the issue of the harms from treatment, then the PIVOT data that showed no difference in mortality through watchful waiting over radical prostatectomy (RP) except for high risk patients is important.

Roger Chou and his colleagues in their Annals paper did note this:

“When available, results from the Prostate Cancer Intervention Versus Observation Trial, which compared prostatectomy with watchful waiting for screening-detected cancer, may help clarify which patients would benefit from prostatectomy or other active treatments, potentially reducing harms from unnecessary treatment.”

The issue may, therefore, not be one that PSA screening per-se is the problem, but that in too many men, a raised PSA results in unnecessary surgery or overtreatment with its consequent risks and harms.

As reported by Alemozaffar and colleagues in the September 21, 2011 issue of the Journal of the American Medical Association (JAMA), 2 years after RP only 35% of men could maintain a functional erection.

“At 2 years after treatment, erectile dysfunction was reported by 619 of 987 (63% [95% CI, 60%-66%]) men (334/511 [65% {95% CI, 61%- 69%}] in the prostatectomy group”

That’s depressing news when coupled with other side-effects from RP or other interventions such as incontinence or problems with bowel function.

It adds further support to the idea that the potential risks versus benefits from prostate cancer surgery and deciding who should actually have surgery or other intervention, is where there’s also a need for more debate.

Men need to be able to make an informed decision. Some urologists may not be unbiased in their treatment recommendations given they have a vested interest in earning money from surgery or maintaining utilization rates of expensive robotics. Data from the PIVOT trial, when published, is evidence-based medicine that will impact their practice.

Use of prostate cancer risk calculators to assess those patients at high risk who might benefit from RP or other intervention could also help lower the harms that currently impact the utility of PSA screening.

How will men approach the PSA screening debate? Despite the USPSTF recommendations I will still be asking my physician for an annual PSA test, so long as it remains covered by my health insurance. The PSA test and digital rectal exam remain the main ways we have to detect prostate cancer early.

Psychologically I value the risk of picking up a disease early higher than the downside of a false positive. I would, however, not rush into any surgery or radiotherapy absent a clear finding that the benefits of intervention outweighed the potential harm.

My approach towards prostate cancer PSA screening again reminds me of the debate over mammography.  We all want to discover cancer early, and have the best possible treatment options as a result.

Hopefully, as our understanding of the biology of prostate cancers and associated biomarkers develop we may be able to generate new screening tests that have fewer false positives than PSA and provide for more accurate early diagnosis.

ResearchBlogging.orgAlemozaffar, M., Regan, M., Cooperberg, M., Wei, J., Michalski, J., Sandler, H., Hembroff, L., Sadetsky, N., Saigal, C., Litwin, M., Klein, E., Kibel, A., Hamstra, D., Pisters, L., Kuban, D., Kaplan, I., Wood, D., Ciezki, J., Dunn, R., Carroll, P., & Sanda, M. (2011). Prediction of Erectile Function Following Treatment for Prostate Cancer JAMA: The Journal of the American Medical Association, 306 (11), 1205-1214 DOI: 10.1001/jama.2011.1333

Roger Chou, MD, Jennifer M. Croswell, MD, MPH, Tracy Dana, MLS, Christina Bougatsos, BS, Ian Blazina, MPH, Rongwei Fu, PhD, Ken Gleitsmann, MD, MPH, Helen C. Koenig, MD, MPH, Clarence Lam, MD, MPH, Ashley Maltz, MD, MPH, J. Bruin Rugge, MD, MPH, & Kenneth Lin, MD (2011). Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force Annals of Internal Medicine, E-375 (October 7)

One of the sessions that I attended at the 2011 annual meeting of the American Urological Association (AUA) focused on research into advanced prostate cancer.  A particularly thought provoking presentation was:

Time trends of biochemical recurrence (BCR) following radical prostatectomy (RP) among 1574 BCR patients (Abstract #639)

Presented by Alex Haese from Hamburg, Germany, this paper was a retrospective analysis of 1,574 patients who had a biochemical recurrence (PSA > 0.2 mg/dl) following RP. Researchers looked at clinical progression and cancer specific survival rates and compared their findings to published United States data.

The results appeared to be somewhat depressing for European patients who experience a BCR, with a time to BCR of 1.8 years, compared to 2.1 years in the US research by Pound from Johns Hopkins and 2.4 years in the data published by Hull, at Memorial Sloan Kettering Cancer Center (MSKCC).

Once a BCR is experienced, the time to metastases is faster in Europe, 4.7 years in the research presented by Haese at AUA, as compared to 8 years in US research by Pound. Risk factors for metastasis free survival include time to BCR i.e.

“The longer the interval between RP and BCR, the greater the probability of being met-free.”

In other words delaying time to progression is associated with longer survival.

Following BCR, time to Prostate Cancer death was 6.0 years in the 1,574 European patients, compared to 13 years in the US Pound research.  Again, the data presented showed that,

“The longer the interval between RP and BCR, the greater the probability of being alive.”

This research must be put into context, as metastasis and death in BCR patients are rare (92% of the 1,574 patients with BCR were free of metastases at 5 years, 81% at 10 years).  However, for those patients who did progress, the results appear significantly different between the US and Europe.

What could explain this?

The presentation left this question unanswered, although in Q&A it was briefly touched upon. One person raised the question of whether differences in screening could be the difference in Europe vs. US?

Other questions that come to mind are whether the subject populations in the Hull and Pound data were comparable.  The German data also had more patients (1574) compared to 304 in the Pound research and 147 (Hull) raising the question that the larger sample size may be more accurate data?

Other factors that might possibly explain the difference include:

  • Androgen deprivation therapy (ADT)
  • Radiotherapy
  • Supportive care (eg bisphosphonates)

All of which tend to be more aggressively pursued as treatment options in the USA.

Overall, this presentation raised the interesting question of US/European differences in Prostate Cancer progression that hopefully will be answered by future research.

Innovation in drug delivery presents opportunities for biotechnology companies, and is an area I expect we will see major leaps forward through nanotechnology.

Nanotechnology is the application of science and engineering to materials that are between 1 and 100 nanometers (nm) in size.  The Environment Protection Agency (EPA) defines nanotechnology as “the creation and use of structures, devices, and systems that have novel properties and functions because of their small size.”

1nm is one-billionth of a meter.  To put this in context, 1nm is one seven-thousandth of the width of a red blood cell or one eighty-thousandth of the width of a human hair. These are unimaginably small materials that are engineered to operate at the molecular and atomic level.

What’s more, there are now more than 1000+ consumer products on the market that utilize nanotechnology from the titanium particles in sunscreens to the silver contained in advanced first aid strips/plasters.  Nanotechnology will impact more than $2.5 trillion of manufactured goods by 2015.

Lux Research predicts that by 2014, 16% of manufactured goods in healthcare and life sciences will include nanomaterials.

To date, the United States leads the way in the fast evolving field of nanotechnology.  Between 2001 and 2010, the U.S. Government invested $12.4 billion in nanoscale science, engineering and technology through the U.S. National Nanotechnology Initiative (NNI).

The National Cancer Institute’s “NCI Alliance for Nanotechnology in Cancer” has an excellent website that outlines the potential impact of nanotechnology.

Some of the promising new cancer diagnostics and therapies based on nanotechnology include:

  • Positron Emission Tomography (PET) imaging agents that can be used to assess the responsiveness of tumors to chemotherapy
  • Chemically engineered adenovirus nanoparticle that stimulates the immune system. This is in phase 1 trials for chronic lymphocytic leukemia (CLL).
  • Cyclodextrin-based nanoparticle that encapsulates a small-interfering RNA (siRNA) agent that shuts down a key enzyme in cancer cells
  • CRLX101, a cyclodextrin-based polymer conjugated to camptothecin is in clinical trials with solid tumor patients
  • A nanoparticle based magnetic resonance imaging (MRI) contrast agent that binds to αvβ3-intregrin, a protein found on newly developed blood vessels associated with tumor development. This is in early clinical trials
  • Technology for the detection of cancer biomarkers such as prostate specific antigen (PSA)
  • Use of carbon nanotubes to improve colorectal cancer imaging.

Emerging companies such as Bind Biosciences are focusing on targeting cancer, inflammatory, cardiovascular diseases and infectious diseases with therapeutic nanoparticles.  Their lead product BIND-014 is currently in phase 1 development.

Innovations in nanotechnology will continue to present new product opportunities for biotechnology, pharmaceutical, medical imaging and diagnostics companies, and should be on everyone’s radar.


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One of the challenges with cancer is being able to detect the disease early enough for effective treatment. The staging or progression of the cancer at time of diagnosis is correlated with 5 year overall survival (OS) rates. Biomarkers that may be expressed by a cancer are, therefore, potentially useful for diagnosis and monitoring of treatment.

There is an ongoing debate about the effectiveness of prostate specific antigen (PSA) as a biomarker for early detection of Prostate Cancer (PC). As Sally Church on Pharma Strategy Blog discusses, PSA measurements can offer false positives and up to 75% of men have a negative biopsy. There is clearly a need for alternatives to PSA measurements.

In the March 1, 2011 online edition of Clinical Cancer Research (a journal of the American Association for Cancer Research, AACR), Richard Morgan and colleagues from the Postgraduate Medical School at the University of Surrey in Guildford, assessed the potential of the Engrailed-2 (EN2) protein as a prognostic biomarker for PC.

Their research found that EN2 is secreted into the urine of men with PC (92%, n=104), but does not appear in the urine of those without PC (0%, n=11). Presence of EN2 in the urine showed a 66% sensitivity for the detection of PC without a digital rectal exam (DRE) when compared to biopsy findings of those with confirmed PC (54 of 82 men). The specificity of the test is almost 90%, i.e. it can pick out men with prostate cancer versus those without cancer.

Interestingly, there was no correlation between serum PSA levels and the presence or absence of EN2. EN2 is measured in small quantities of unprocessed urine (100μl) by means of a simple enzymatic assay.

The investigators state in their paper that a multicenter clinical trial is planned to investigate whether EN2 measurements can be used as a tool for monitoring disease progression after hormonal treatment, radiotherapy or surgery.

However, despite the promising preliminary results in this paper, it is still too early to say whether EN2 will evolve into a clinically useful predictive biomarker for PC.  The fact that EN2 was secreted in patients with non-PSA secreting PC, raises the possibility that it might have a diagnostic role to play in combination with other biomarkers.

EN2 has also been shown to be an oncogene in breast cancer, so it will be interesting to see if there is any further information presented at the forthcoming AACR annual meeting from April 2 to 6 in Orlando.

I recommend reading Pharma Strategy Blog for further insight on cancer biomarkers.

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