Biotech Strategy Blog

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

Posts from the ‘Diagnostics’ category

On Friday, I headed uptown to attend the Miami Breast Cancer Conference (#MBCC14) held at the Fontainebleau Hotel and organised by the Physicians Education Resource (PER).  It was fun to grab a local Deco Bike and furiously cycle over 45 blocks in under half an hour – most probably the only attendee who arrived on two wheels that day!

MBCC14: Dr Lance Liotta

MBCC14: Dr Lance Liotta

Now, I haven’t attended this event since it was at the Loews Hotel in midtown, which was rather low key and fairly small.  Certainly there wasn’t a big exhibition area then, as far I can recall.  Fast forward a decade on and the event is MUCH bigger, with an excellent Academic panel and an interesting mix of didactic talks and case studies.  The stage setting is also much more impressive, as you can see in the photo right.

To give you some basic background, the audience polls at the beginning of the first day were really useful to put things into context:

  1. The majority of attendees (88%) were physicians (mix of Community medical oncologists, radiation oncologists and surgical oncologists)
  2. 49% of respondents treated 1–5 patients with breast cancer per week
  3. 25% of respondents treated 6–10 patients with breast cancer per week

Being a scientist, and having missed the San Antonio Breast Cancer Symposium (SABCS) due to an overlap with the American Society of Hematology (ASH) meeting in December, I was particularly keen to catch up on the new developments in genomics and molecular profiling, with early morning talks from Drs Lance Liotta (George Mason Univ) and Debu Tripathy (USC).  There were also updates on neoadjuvant treatment for breast cancer by Drs Kathy Albain (Loyola) and Hal Burstein (Dana Farber).  Neoadjuvant therapy prior to surgery is an area that is seeing many new trials and potential therapies emerge.

In today’s post, the attention is on the important topic molecular profiling. This is something I believe we will see much more of going forward.  Two separate articles will follow on personalised treatment in advanced breast cancer (including TNBC) and also on neoadjuvant developments.

Genomics can sometimes be a bit of a dry topic, at least to some people, as anyone who has sat through slide after slide of those fuzzy green-red assays in systems biology sessions at AACR will attest. This time, much to my pleasant surprise, it was different…

What I heard blew my mind and changed the way I think about some aspects of breast cancer.

Now I’m not joking or trying to hype progress here, but sometimes you experience an epiphany when you least expect it.

To read more about this revelation, you can sign up or sign in below.

Lance Liotta always gives well organised presentations and illustrates the key facts on proteomics (a tough subject for many to follow) with critical learning points.  At this year’s MBCC, he focused his talk on a vision for combining genomic mapping with proteomic analysis of the metastatic lesion.  Part of the challenge with using genomics is the sheer heterogeneity and complexity of every single patient’s tumour.  He also had a second talk in the afternoon that was equally interesting, but more about that in another post.

One of the main findings from the SideOut trial (run by TGen and George Mason, sponsored by the Side Out Foundation; reported at ASCO 2013 – download the poster here) a proof-of-concept study, which showed that molecular profiling often yielded a treatment recommendation that was different from the one recommended by the treating physician:

Source: L Liotta, MBCC

Source: L Liotta, MBCC

You can see that some of the regimens mentioned here are quite noticeably different – patient #103 is particularly fascinating, for example.

Here’s my quick summary of some of the main points from his first talk:

  1. Basic concept of SideOut I: map the signaling network of metastatic tumour cells to understand which growth or survival pathways are functionally in use in the tissue microenvironment.
  2. Combine this information with genomic analysis from biopsies to determine true drivers from passengers.
  3. Use a combination of genomics and proteomics to recommend appropriate therapies.
  4. The trial was largely successful at generating good responses to therapy and demonstrating PFS – 40% of patients exceeded the PFS ratio of 1.3 and three pats still continue on therapy for 199, 254 and 816 days.
  5. 60% of patient samples had activation of drug targets in only 3 major clusters i.e.
    1. pan-HER-AKT
    2. EGFR/Src/ERK/mTOR
    3. IGF/RAF/MEK/PLK1
  6. Improved treatment may therefore be facilitated by biomarker-led understanding of subgroup molecular targets, which may predict benefit from currently approved agents and newer targeted drugs.
  7. Subclones are selected out based on selective pressure i.e. survival in a secondary tissue or organ during metastasis or survival in the face of therapy (adaptive resistance).  This is something we need to learn more about as our knowledge of the biology of the disease improves.

Following the success of this trial, SIDEOUT II has now opened in 9 sites looking at metastatic breast cancer patients progressing after 1–3 lines of therapy. The study will investigate genome sequencing, protein pathway mapping and multiplexed IHC before using all of the information available to provide a molecular rationale for individualising therapy.

For the SideOut I study, Liotta gave a nice example of a typical patient case study, as shown below.  The idea was to illustrate how they investigators tackled this difficult case and used the genomic and proteomic data to make better clinical decisions.  Note the patient had TNBC, yet had different findings for HER2 status based on two different tests – this isn’t an uncommon finding with lab results, unfortunately:

Source: L Liotta, MBCC

Source: L Liotta, MBCC

After the proteomic and genomic analysis, this is what they ended up with. Note the recommended treatment regimen that resulted – not something you would normally consider with such a detailed work-up!

Source: L Liotta MBCC

Source: L Liotta MBCC

To put this in better context – consider the attendee poll on what tests the physicians would order based on the biopsy of a metastatic lesion suggested that 60% would run ER, PR and HER2 only, while less than a third would test for ER, PR, HER2 and genomic profiling.  Personally, I was really surprised that so few respondents would consider genomic sequencing in the metastatic setting given the sheer molecular complexity that exists.  Clearly, there is a molecular world beyond hitting ER, PR and HER2.

Ultimately, the proof of the pudding in any clinical trial is outcome – how well did the patients do when molecular profiling was used to guide therapy?  Remember that many of these patients had quite advanced disease and were considered difficult to treat.

The answer is quite well, as this waterfall plot demonstrates:

Sideout waterfall plot

 

We have to wonder how can we possibly expect to treat any patient successfully, if we don’t know what driver mutations and targets exist?  In this respect, lung cancer has truly come out of the shadows and leap-frogged breast cancer in terms of molecular profiling and targeted therapies, at least in Academia.

In the future, it may be possible to better define triple negative breast cancers (TNBC) by what the are, rather than what they’re not i.e. ER, PR, HER2 negative, which is a broad catch-all and a very heterogenous population indeed.

Meanwhile, tomorrow we will continue the personalized theme and cover another mind blowing talk that demonstrated how far we really have to go before we can possibly expect to see major shifts in outcome based on the underlying biology and matching appropriate targeted therapy.

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Foundation Medicine ($FMI) will be presenting on Jan 15th at the J.P. Morgan Annual Healthcare Conference, which we will be following remotely on the blog.

Yesterday, Foundation Medicine announced an extension to their agreement with Novartis to provide molecular information and genomic profiling for clinical oncology programs, extending the existing collaboration through September 2016. The agreement also includes an option for Novartis to extend the term for an additional two year period.

A number of readers have written to me over the last couple of months after noting my enthusiasm for this technological approach and asking – what’s so interesting about diagnostics and genomics or – will it become mainstream?

Just after the ASH 2013 annual meeting,  I had the privilege to interview Dr Vincent Miller, Chief Medical Officer of Foundation Medicine and discuss his perspectives on the genomic sequencing field and where they are going.

To learn more about these sentiments and insights, subscribers can log-in or you can purchase access to BSB Premium Content below… 

Detecting thyroid cancer early and avoiding unnecessary surgery is the potential promise of a new cancer diagnostic test, known as the Afirma® gene expression classifier test, developed by South San Francisco company, Veracyte.

Human thyroid with cancer nodules.
Photo Credit: Dr Jeffrey Norton/NCI

According to the American Society of Cancer (ACS), with 56,540 cases expected this year, thyroid cancer is the fastest increasing cancer in the United States.

The most common symptom of thyroid cancer is a lump or nodule in the neck. To diagnose cancer, cells are taken by a fine needle from the nodule and examined to see if they are malignant (cancerous) or benign (not cancerous).

The market for the Afirma® diagnostic test from Veracyte is the 15 to 30% of fine-needle aspirations of thyroid nodules that yield indeterminate cytologic findings i.e. you can’t tell if cancerous cells are present or not.

Faced with the uncertainty of “indeterminate” findings, many people elect to have surgery to remove the nodules or thyroid gland. Often the surgery shows that the cells were benign after all.

According to Veracyte, the Afirma® gene-expression classifier test “evaluates the expression patterns of 142 genes to classify indeterminate thyroid nodule FNA samples as benign or suspicious for cancer.”  In other words, it takes the “indeterminate” samples and helps further identify those that do have cancerous cells from those that don’t.

How accurate is the Afirma® gene-expression classifier test?

The New England Journal of Medicine reported earlier this week (online first) in an original article, “Preoperative Diagnosis of Benign Thyroid Nodules with Indeterminate Cytology“, the results of a clinical trial sponsored by Veracyte with 3789 patients at 49 clinical sites.

The paper by Erik Alexander and research colleagues from Brigham and Women’s Hospital and Harvard Medical School Boston, showed that the Afirma® gene-expression classifier test had a 92% sensitivity.  It correctly identified malignancy in 78 out of 85 suspicious nodules (95% confidence interval 84 to 97). The specificity of the test was, however, only 52% (95% CI, 44 to 59).

Details of the trial and the in-depth results can be found in the NEJM paper (open access). Veracyte have also produced a short video, available on YouTube, that discusses the New England Journal of Medicine results:

What do the NEJM clinical trial results mean?

In looking at the efficacy of diagnostic tests, it’s important to understand the distinction between sensitivity and specificity.  Further information on this can be found in an open access paper on Clinical tests: sensitivity and specificity authored by Abdul Lalkhen and Anthony McCluskey. Using the definitions they provide:

Sensitivity = ability of the test to identify those with the disease, in this case those with thyroid nodules that contain cancerous cells.  92% sensitivity means that 92 out of 100 people with an indeterminate thyroid nodule that has malignant cells will have the cancer detected, but 8 will be missed. So the Afirma® test can’t be relied upon to pick up every case of cancerous cells in the 15-30% of people who have nodules with indeterminate cytology.

Specificity = ability of the test to correctly identify those patients without the disease.  A test such as Afirma® with 52% specificity correctly reports 52% of patients without the disease as negative (true negative), but 48% of the patients without the disease are incorrectly labeled as test positive (false positive) i.e. you have evidence of cancerous cells when you don’t.

A diagnostic test that shows high sensitivity and low specificity means that many patients will be told they have cancerous cells, when in fact they don’t. This will subject them to potentially unnecessary treatment or surgery. The test may also miss a small number of people who are told they don’t have cancer, when in fact they do.

The willingness to tolerate the risk from a diagnostic test of possible undetected cancer or misdiagnosed cancer is one for each patient to consider and discuss with their doctor.

What are the implications of this test on clinical practice?

An insightful editorial by J. Larry Jameson, MD PhD, Professor of Medicine and Dean of the Perelman School of Medicine at the University of Pennsylvania accompanies the NEJM trial results, and puts the data into context for clinical practice.

“If results of the gene-expression classifier test were used to inform clinical decision making, it might be possible to reduce surgery for nodules with indeterminate cytology by at least one third, or about 25,000 operations per year,”

Jameson says in his editorial on Minimizing Unnecessary Surgery for Thyroid Nodules. He goes on to note that this would represent “substantial cost savings” and would “reduce unnecessary surgery.” There is also a caveat according to Jameson:

 “The risk of this approach is that 5 to 10% of nodules classified as benign (false negatives) are likely to be malignant, particularly those that are cytologically indeterminate but suggestive of cancer.”

The risk of a false negative (classified as benign but in fact malignant i.e. you do have cancer) suggests the need for repeat testing and monitoring of those at high risk:

“For patients being monitored, it will be important to have a low threshold to repeat fine-needle aspiration if ultrasonographic findings indicate rapid growth or characteristics suggestive of cancer.”

As for those patients who receive a false positive (classified as malignant when in fact benign i.e. you don’t have cancer), no mention is made of the potential need to confirm the diagnosis before treatment such as surgery is undertaken.  While it’s possible that these “indeterminate” patients might have had surgery anyway, the issue of how to deal with false positives could have merited some discussion.

Dean Jameson’s conclusion is that, “this new gene-expression classifier test is a welcome addition to the tools available for informed decision making about the management of thyroid nodules.”

However, reimbursement is key to success for any diagnostic. There’s no point in having an expensive test, no matter how good it may be, if insurance companies won’t pay for it.

How much does the Afirma® diagnostic test cost and is it reimbursed by insurance companies?

Bonnie Anderson, Veracyte’s cofounder and CEO in response to my inquiry about the cost of the test, replied by email that:

“The list price is approximately $4,200, which is a fraction of the cost of a thyroid surgery (approximately $10,000 to $15,000).  The test is covered for all Medicare patients and is being reimbursed by many insurance companies on a case-by-case basis at negotiated rates.  The company has a program in place to ensure that patients do not incur out-of-pocket costs in cases where an insurance carrier does not pay.”

At $4,200 a go, Veracyte believe the test is cost-effective. In support of this the company offers a published cost-effectiveness analysis from Johns Hopkins that was undertaken through a Veracyte research grant. It is beyond the scope of this post to review this.

However, it will be interesting to see whether the test is reimbursed in Europe, and how e.g. the Diagnostics Advisory Committee of the UK National Institute of Clinical Effectiveness (NICE) views the Johns Hopkins cost-effectiveness analysis.

Veracyte partners with Genzyme for promotion and marketing

Earlier this year, Veracyte announced a co-promotion partnership with Genzyme (sanofi-aventis), under which Genzyme would market and promote the test in the United States and globally.

The sales and marketing muscle of a large company suggests that sanofi-aventis believe there is a global market opportunity.

Other companies with diagnostics in development will be closely watching the extent to which the Afirma® gene-expression classifier test is adopted in clinical practice.

A diagnostic test that offers the promise of improved cancer detection in thyroid nodules with indeterminate cytology, and a consequent reduction in unnecessary thyroid surgery is worth paying for in my opinion.

In the future, could gene sequencing make diagnostic tests unnecessary if we are able to use next generation sequencing to identify possible aberrations that are linked to cancer by means of a multi-panel assay when the patient enters the hospital?

The world of gene sequencing and bioinformatics is fast moving and I expect we will see rapid progress over the next few years. The interview on Pharma Strategy Blog with Dr Razelle Kurzrock from MD Anderson is well worth reading if you are interested in this area.

 

A standing room only audience at the recent annual meeting of the American Association for Cancer Research (AACR) heard from several distinguished speakers on what the future of cancer drug therapy is likely to look like: combinations of novel cancer agents.

This AACR session was one of the highlights of the meeting and would have merited from being part of the plenary program.

Jeffrey Engelman from MGH persuasively presented on why we need combination therapies to overcome resistance. He noted that:

  • Most cancers are not sensitive to currently available single-agent therapies
  • Even when sensitive to single-agent therapies, cancers develop resistance, often necessitating combinations

One of the challenges of this approach will be “identifying effective combinations,” he said.

Roy Herbst from Yale, presented on some of the practical challenges involved with the early phase testing of two drugs, and challenged the audience with a critical question:

“Do we possess the necessary translational tools that will help us identify the right drug combinations, ratios and schedules with the right patient?”

Stuart Lutzker from Genentech described their experiences of clinical trials with rational drug combination of trastuzumab and pertuzumab for HER2+ breast cancer.  He concluded that:

“Rational drug combinations have begun to yield exciting Phase III results and should be preferred over empiric drug combinations.”

The Pharma Strategy Blog video interview with Gordon Mills from ECCO/ESMO 2011 in Stockholm offers some interesting insights into how MD Anderson are helping to facilitate academia-industry combination trials with novel compounds from different companies in order to achieve more rational drug design and improve outcomes for people with cancer.

If two or more novel cancer drugs are required to interrupt key pathways or to avoid adaptive resistance, what does this mean for the regulatory strategy?

Janet Woodcock addressed some of these challenges in her AACR presentation, and discussed how the:

“FDA would not want to approve a combination regimen with two new agents unless each contributed to the effect.”

Draft guidance on “Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination” was published by the Agency in December 2010. Click here for a PDF copy.

The document gives examples of a number of different phase II trial designs that can be used to demonstrate the contribution each drug makes to the combination, and the additive effect seen.

As an example, if each drug in a combination has activity and can be administered individually then the guidance document suggests a multi-arm phase II trial may be needed that compares the impact of either drug alone versus the combination and standard of care.  An adaptive trial may also be used if appropriate.

Dr Woodcock noted that future cancer drug development is likely to include increasing use of combinations, adaptive trials to evaluate various drug and diagnostic combinations and increasing attention to the use of novel biomarkers.

The message I took home from the AACR annual meeting is that the future of cancer therapy is in combinations, and we can expect more clinical trials with two unapproved agents (novel-novel combinations) in the future.

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Head and neck cancer is not something we hear much about when it comes to new therapies, yet it is the sixth most common non-skin cancer in the world.

Head and neck squamous cell carcinoma (HNSCC) has an incidence of 600,000 cases a year, with 50,000 of those occurring in the United States.

Outcomes remain disappointing for patients, with disease free survival (DFS) rates of only 30-40% for patients with locally advanced HNSCC.  Five-year survival rates of around 50% have improved little for many years.

Zalutumumab failed to show OS benefit

The challenge of drug development in this area was highlighted by the failure of the phase III trial for zalutumumab (Genmab).  Zalutumumab was a monoclonal antibody against the epidermal growth factor receptor (EGFR).

Despite promising phase II data, the phase III trial did not show an improvement in overall survival against best supportive care (BSC) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who had failed standard platinum-based chemotherapy.  Genmab subsequently dropped zalutumumab from its pipeline in June 2011.

These results are interesting because they raise the question of why this agent failed when Erbitux (cetuximab), an EGFR monoclonal from Lilly/BMS succeeded?  Cetuximab is approved in the first-line setting in combination with radiation and in the relapsed setting with 5FU and as a single therapy in refractory patients.  Clearly not all EGFR therapies are equal.

Oncolytics Biotech Phase III trial ongoing

Another company trying to crack head & neck cancer is Canadian based Oncolytics Biotech, who have started a phase III trial with REOLYSIN® in combination with paclitaxel and carboplatin for patients with platinum-failed head and neck cancers.  A poster on their phase II data was presented at the AACR-EORTC molecular targets meeting in San Francisco last year (Abstract C22).

Reolysin is a proprietary formulation of the human reovirus (respiratory enteric orphan virus).  According to the company website, “in tumour cells with an activated Ras pathway, reovirus is able to freely replicate and eventually kill the host tumour cells.” It’s beyond the scope of this post to go into the science of oncolytic viruses.

The company recently announced CDN $18.5M of additional financing. According to the clinicaltrials.gov site, the primary completion date for the 280 patient, 53 site trial (NCT01166542) is estimated to be June this year.  The primary endpoint is again overall survival (OS) and it will be interesting to see whether they can succeed.

Which brings me to some interesting science in HNSCC that caught my attention earlier this week.

Low-level expression of miR-375 correlates with poor outcome & metastasis

Research published online first on January 9, 2012 in the American Journal of Pathology by the Albert Einstein College of Medicine and Montefiore Medical Center in New York showed that low-level expression of micro RNA-375 (miR-375) correlated with poor outcome in tumors of HNSCC patients.

Sally Church, Ph.D on Pharma Strategy Blog recently wrote about how microRNA (miRNA) can be used as a potential biomarker in breast cancer, allowing for earlier detection.

She noted, “miRNA looks to be a promising fledgling area for biomarker research in the early detection of cancer.”

Thomas Harris and colleagues showed that HNSCC patients with low miR-375 tumor-to-normal (T:N) expression ratio had a worse prognosis.

miRNA expression status was assessed as a ratio of miR-375 expression in the tumor relative to adjacent normal tissue collected from the same patient to provide a normalized ratio across the study population.

The Kaplan Meier curves in their paper show the significant correlation.  The data showed that:

Patients with lower miR-375 T:N expression were more likely to die of disease (HR: 12.8, 95% CI: 3.4 to 48.6) than those with higher miR-375 T:N.

The authors suggest that the correlation between low miR-375 tumor versus normal tissue expression and outcome may be due to the effects of miR-375 on tumor cell invasion.

The identification of a potential biomarker associated with head and neck cancer prognosis is promising.  The paper concluded that:

The identification of patients with a poor prognosis, especially in the case of early-stage disease, could lead to additional therapeutic interventions, such as suppressing tumor cell invasiveness, to achieve better outcomes.

Geoffrey Childs, Ph.DGeoffrey Childs, Ph.D, the co-senior of the author of the paper noted in a news release:

we hope that miR-375 will become part of a laboratory test to determine which patients have potentially lethal tumors and therefore should be treated aggressively following initial diagnosis.

There is an unmet medical need for novel therapeutics in HSNCC. Hopefully, new drug development targets will follow from the identification of biomarkers and a greater understanding of the molecular biology.

ResearchBlogging.orgHarris, T., Jimenez, L., Kawachi, N., Fan, J., Chen, J., Belbin, T., Ramnauth, A., Loudig, O., Keller, C., Smith, R., Prystowsky, M., Schlecht, N., Segall, J., & Childs, G. (2012). Low-Level Expression of miR-375 Correlates with Poor Outcome and Metastasis While Altering the Invasive Properties of Head and Neck Squamous Cell Carcinomas The American Journal of Pathology DOI: 10.1016/j.ajpath.2011.12.004

BIO-2011-Interational-Convention-Washington-DC

I am excited to be attending, for the first time, the Biotechnology Industry Organization (BIO) international convention that takes place in Washington DC in just over a week’s time from Monday June 27 to Thursday, June 30th.

This meeting has something for everyone interested in the biotechnology industry whether it be deal making, partnering, licensing, drug discovery or personalized medicine. There are 16 specialized tracks where industry experts provide insight and best practices.

In addition, there are numerous networking and social events plus an exhibit hall that showcases the world’s biotech regions and how they are promoting innovation.

At meetings where there are parallel sessions, I apply “the law of two feet” (thanks to Podcamp for this) that says if you are not getting what you want from the session, it’s OK to walk out and go to another one.

My top 10 sessions at BIO reflect my personal interests in innovation, science and new product development:

Tuesday June 28

  • How will we afford Personalized Medicines?
  • The Biomarkers Consortium: Facilitating the Development and Qualification of Biological Markers
  • Personalized Oncology: The emergence of Personalized Medicine Strategies in Oncology Clinical Development and Deal Making
  • Navigating the New Law on Licensing Biosimilars

Wednesday June 29

  • Lessons from a Mature Public-Private Partnership. The Alzheimer’s Disease Neuroimaging Initiative
  • Emerging Markets. The Future of Growth for Biologics?
  • The Role of Imaging Biomarkers in Early Phase CNS Drug Development
  • The Promise of MicroRNA-based Therapeutics in Cancer

Thursday Jun 30

  • After the Fall. Venture Capital and the Biotech Funding Landscape
  • Regulatory Issues for Tissue Engineered Products

If you have plans to be at BIO 2011 do say hello after one of the sessions or receptions. You can reach me at the meeting via twitter (@3NT).  See you in DC!

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Launch of Zytiga (abiraterone acetate) at 2011 annual meeting of American Urological Association (AUA) in Washington DCThe market for prostate cancer therapies is set to expand from $1 billion currently to $5 billion by 2015, according to analysts reported by this morning’s Washington Post/Bloomberg news.  This is perhaps no surprise given the recent approval of abiraterone acetate (Zytiga®) from Ortho Biotech (JNJ).

New clinical data on prostate cancer clinical trial results is expected at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago this weekend from many of the prostate cancer therapies in development such as MDV3100, TAK700, ARN-509, cabozantinib (XL184), ipilimumab, custirsen (OGX-11), BPX-101, alpharadin, denosumab (Xgeva®) and Prostvac-VF.

Indeed, one could argue that prostate cancer is becoming a competitive marketplace.  Any emerging biotechnology company that is not already developing a prostate cancer drug is likely to find it a hard market in which to create a blockbuster.  By the time any drug comes to market, there will be incumbents with effective products who have captured market share.

Prostate cancer is an exciting market to watch from a marketing strategy and patient perspective, as several companies potentially bring new products to market over the next few years.

However, the bottom line is that patients will live longer as a result of all the innovation that is taking place.  Not only that but physician education and awareness of how to treat this disease is also likely to improve as they seek out knowledge on new therapies and treatments.  This to many will make a major difference.  At the recent American Urological Association (AUA) annual meeting, the sessions on treatment of prostate cancer were standing room only.  There is clearly a demand for knowledge out there as the treatment paradigms change.

At the other end of the spectrum, there is also innovation taking place in terms of improved diagnosis and treatment of prostate cancer.  Whether we should screen all men for PSA remains a controversial topic, although use of risk calculators do appear to offer less false positives.  Indeed, calculating risk is going to be one of the key areas that primary care physicians and urologists need to focus on, particularly in the light of the PIVOT trial data that was presented at AUA, showing radical prostatectomy (with risks including incontinence and erectile dysfunction) was not better than watchful waiting in low-risk, early stage disease.

However, a presentation I am looking forward to at ASCO 2011 is on circulating tumor cells (CTC) and whether these can be a prognostic or even a predictive biomarker.   Both the phase III MDV3100 and abiraterone acetate clinical trials captured CTC data.  It will be exciting news at ASCO 2011 if circulating tumor cells that require only a blood sample offer an improvement over PSA not only for detection of prostate cancer, but in monitoring the disease over time.

I will be at ASCO 2011 this weekend, and look forward to writing more on prostate cancer from the conference!

The highlight of the recent Association of Health Care Journalists (AHCJ) annual meeting in Philadelphia (Health Journalism 2011) for me was the presentation by Kacy Cullen from the Center for Brain Injury and Repair in the Department of Neurosurgery at the University of Pennsylvania.

© Kacy Cullen, University of Pennsylvania

Dr Cullen presented his research on blast-induced traumatic brain injury (bTBI) and the development of a nanomaterial containing photonic crystals that change color upon exposure to blast pressure.

In the same way that a radiation dosimeter badge records exposure to cumulative radiation for a hospital worker, so a helmet-mounted color badge would change color based on a soldier’s exposure to blast pressure; a common occurrence with improvised explosive devices (IED).

In a paper published in NeuroImage, Cullen and colleagues describe in detail a blast-injury dosimeter (BID) made from photosensitive polymers that is like a colored sticker.  This nanomaterial contains microscopic, diamond-like photonic crystals, whose ability to refract light is damaged in a precise way by the pressure from explosive blasts.

The result is a change in color that is related to the degree of pressure and blast intensity. What’s more because the photonic crystals are structurally damaged by the blast, further exposure leads to more widespread microstructural alterations and a further change in color.  In essence, the crystals have a memory for cumulative blast exposure.

Why is this important?

Many soldiers are exposed to blasts, but show no overt symptoms of traumatic brain injury.  Research has shown that repeated hits to the helmet of a football player can lead to brain injury without the obvious signs of a concussion.  Traumatic brain injury as a result of repeated exposure to blasts may also lead to mild cognitive impairment and the possibility of increased risk for dementia, Alzheimer’s disease later in life.  This has been seen in NFL players.

The research by Cullen and colleagues is still in the early stages of development.  In their paper they acknowledge some of the next steps such as calibrating the color changes to levels of blast exposure, and correlating these with traumatic brain injury.  Any blast injury dosimeter will also need to be field tested.

However, this work is promising and an example of how nanotechnology may impact the detection and diagnosis of those soldiers at risk of traumatic brain injury.

War related scientific research often leads to civilian applications. In the future, I could see nanotechnology stickers that change color with cumulative impact on the helmets of NFL, college or high school football players.

You can read more about this innovative research on how color changing photonic crystals detect blast exposure in the journal NeuroImage.

Update June 30, 2011

If you are interested in the exciting and innovative research being undertaken by Kacy Cullen and his team, there is now a website for The Cullen Laboratory and their work on Neural Engineering in Neurotrauma.

ResearchBlogging.orgCullen, D., Xu, Y., Reneer, D., Browne, K., Geddes, J., Yang, S., & Smith, D. (2011). Color changing photonic crystals detect blast exposure NeuroImage, 54 DOI: 10.1016/j.neuroimage.2010.10.076

Changes in brain structure, function and molecular processes occur several years before clinical symptoms of Alzheimer’s disease (AD) become apparent.

The big question then, is can you detect patients who are cognitively normal, but will go on to develop AD before they show symptoms, i.e. pre-symptomatic patients?  The answer is “Yes” according to results published in the April 19, 2011 issue of Neurology by Brad Dickerson and colleagues.

In this small study, the team of researchers from two centers (Massachusetts General Hospital and Rush University in Chicago) followed a small sample of cognitively normal (CN) subjects over time with magnetic resonance imaging (MRI) and then sought to identify what structural changes had taken place in those subjects who were initially cognitively normal, but went on to develop AD, on average 11.1 years later.

The researchers found that changes in brain cortical thickness were associated with AD:

AD-signature cortical thinning in CN-AD converters in both samples was remarkably similar, about 0.2 mm (p < 0.05)

They concluded that:

By focusing on cortical regions known to be affected in AD dementia, subtle but reliable atrophy is identifiable in asymptomatic individuals nearly a decade before dementia, making this measure a potentially important imaging biomarker of early neurodegeneration.

Some of the limitations of this research and questions that come to mind are:

  • Small sample size: only 8 individuals who developed AD and 25 in the cognitively normal control group.
  • Reproducibility: the 0.2mm difference seen is small and the extent to which other centers may be able to reproduce this measurement is uncertain
  • Accuracy of detection: in any screening tool the issue of false positives and negatives arises i.e. in a larger sample size will there be a margin for error that results in some people being included in the pre-symptomatic AD group, when they may be normal?  Also will the proposed measurement remain valid in a large population of patients with other disease symptoms and chronic illnesses?
  • Validity of biomarker: are the changes in cortical thickness causally linked to AD or just an incidental correlation i.e. is this a valid biomarker?

Brad Dickerson in the excellent Neurology podcast available with this publication clearly sees this currently as a research tool, especially given the requirement for considerable computer power to make these types of cortical measurements in the brain.  The podcast interview is well worth listening to.

The MRI biomarker proposed by Dickerson is therefore not something that is really applicable to screen the general population at the moment.

However, the promise from this and other biomarker research is that at some point in the not too distant future we will be able to detect those at risk of developing AD. Those patients could then be given neuroprotective drugs that may delay the onset of the clinical symptoms of AD such as memory loss and cognitive impairment.

Biomarkers that identify those at risk of developing AD will also be useful as inclusion and screening tools for clinical trials of drugs aimed at slowing disease progression in pre-symptomatic patients.

Alzheimer’s disease has been called “The challenge of the Second Century,” we still have a long way to go before this is overcome.

Story Source:  BBC Health

ResearchBlogging.orgDickerson, B., Stoub, T., Shah, R., Sperling, R., Killiany, R., Albert, M., Hyman, B., Blacker, D., & deToledo-Morrell, L. (2011). Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults Neurology, 76 (16), 1395-1402 DOI: 10.1212/WNL.0b013e3182166e96

Faced with the opportunity to read around 900+ posters yesterday afternoon in the first of the six main poster sessions from Sunday to Wednesday here at the AACR annual meeting, any selection of a “poster of the day” is extremely subjective.  All the posters here have considerable scientific merit having passed a rigorous peer-review selection process.

Faced with a smorgasboard of choice, one ends up focusing on areas of personal interest. One area I have recently started to write about on this blog is the impact nanotechnology may have on cancer research and in particular how nanoparticles in the form of diamonds can be used to reach into tumors.

So “my poster of the day” from Sunday April 3rd, Day 2 of AACR is  “Multistate Nanoparticle Delivery System for Deep Penetration into Tumor Tissue.” It is Abstract#548 on the AACR website, and is from a team of researchers at the Department of Chemistry at MIT, Massachusetts General Hospital and Harvard Medical School.

The published poster by Cliff Wong and colleagues is “a proof-of-principle demonstration that a size changing nanoparticle can facilitate delivery into the dense collagen matrix of a tumor.

The authors conclude, that what they have developed is: “the potential for customized delivery of nanoparticles by using genomic and molecular data to achieve optimal delivery for a particular patient.”

Heralding the future potential of their research, the poster states that as result of this work they now can “design a series of customized nanoparticles that are activated by a variety of tumor-associated proteases such as cathepsin B and urokinase plasminogen activator (uPA).

One question that this research raises to me is to what extent different tumors may require a different sized nanoparticles to deliver drug to the target area? If we do need different sized nanoparticles, then how do we determine which is the best size/combination?

I’m excited at the possibility that not only may we have personalized medicine, but that nanotechnology may enable customized drug delivery.

The heart of the AACR annual meeting to me is the posters, and they frequently stimulate questions that may generate novel new approaches or trigger new research avenues or opportunities to make a difference in the lives of future cancer patients.

 

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