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Posts Tagged ‘management of prostate cancer’


Liquid Biopsy Assay May Predict Drug Resistance

Curator: Larry H. Bernstein, MD, FCAP

 

Liquid Biopsy Assay May Predict Drug Resistance in Prostate Cancer Patients

NEW YORK (GenomeWeb) – Researchers from the University of Trento in Italy and the Institute of Cancer Research, London have shown that a next-generation sequencing-based assay that evaluates alterations to the androgen receptor genes from prostate cancer patients’ blood, may be able to explain why patients with castration-resistant prostate cancer develop resistance to androgen inhibitors.

Reporting the results of a 97-patient study in Science Translational Medicine today, the researchers found that patients without alterations to the AR gene before being started on abiraterone had significantly longer overall and progression-free survival compared to patients with mutations in the AR gene or with copy number gains of AR. In addition, they identified two point mutations associated with the development of resistance.

The study is important because although prostate cancer patients can usually initially be treated with androgen deprivation therapy, the majority eventually progress and develop castration-resistant prostate cancer. Typically, these patients are treated with drugs that inhibit the AR gene, but these drugs are not curative and patients usually develop resistance within one year, according to an accompanying editorial about the study.

“Understanding the molecular events driving this drug resistance is critical and may enable the identification of new therapeutic targets and biomarkers for use in clinical decision-making,” the researchers from the University of Washington and Johns Hopkins University wrote in the editorial.

To try and figure out the molecular drivers of resistance, researchers sequenced the entire coding region of the AR gene in 217 plasma samples from 80 patients with castration-resistant prostate cancer who were being treated with the AR inhibitor abiraterone.

Mutations to the AR gene tend to be rare in prostate cancer before primary hormone treatment, but emerge with castration resistance. The researchers wanted to test whether mutations to and copy number gains of AR were associated with resistance to abiraterone. Because obtaining serial biopsy samples would be very invasive and challenging, they settled on a noninvasive approach to evaluate circulating tumor DNA in patients’ plasma.

From 97 total patients, they were able to obtain enough ctDNA to evaluate 217 samples from 80 patients.

With regards to load of ctDNA, the team found that pre-treatment samples tended to have less ctDNA than samples analyzed at disease progression. In addition, patients with a lower ctDNA burden tended to have better outcomes.

The team found that 81 of 217 samples from 32 out of 80 patients had a copy number gain to AR. In addition, 41 plasma samples from 16 patients had somatic nonsynonymous mutations to AR.

Overall, patients with either a copy number gain of AR or point mutations to AR fared worse than patients with a normal AR gene. Out of 80 patients, 36, or 45 percent, had either a copy number gain or a point mutation. Those patients were 4.9 times less likely to have a greater than 50 percent decline in prostate specific antigen after being treated with abiraterone and were 7.8 times less likely to have a 90 percent decline in PSA levels.

Patients with normal AR also had significantly longer overall and progression-free survival when compared to patients with an AR gain or point mutation.

In addition, the team was able to identify two point mutations that were not present in patients’ baseline samples but that occurred over the course of treatment. Seven patients developed these mutations in the AR gene, which the researchers hypothesized occurred due to selective pressure from the drug.

By contrast, patients with AR copy number gains did not experience any further gains of the gene during treatment.

Other studies have previously supported a link between AR gain and resistance to abiraterone, however, one previous study also found AR gains to be associated with abiraterone sensitivity, the authors wrote. “Future studies may shed light on the explanation for this discordance, including possible genomic differences between prostate tumors and plasma DNA,” they wrote.

 

Detecting resistance before it starts

Science Translational Medicine   04 Nov 2015; 7(312)

Androgen receptor targeting is the cornerstone of prostate cancer treatment. Even when the tumors become “castration-resistant” or no longer sensitive to androgen deprivation, androgen signaling can still be effectively targeted by newer drugs such as abiraterone and enzalutamide, which also inhibit the androgen signaling axis. Romanel et al. analyzed tumor DNA samples from the blood of 97 patients with castration-resistant prostate cancer at different times during the course of treatment with abiraterone. Although some new mutations emerged during therapy, the authors found that androgen receptor amplifications were present from the beginning and correlated with abiraterone resistance, suggesting that detection of these amplifications should be useful for identifying abiraterone-resistant cancers before starting treatment.

 

 

Plasma AR and abiraterone-resistant prostate cancer

 

 

 

 

 

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4:00PM 11/12/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com

4:00 p.m. Panel Discussion Novel Approaches to Personalized Medicine

Novel Approaches to Personalized Medicine

Genetic and genomic knowledge is helping the development of new drugs, therapies and prognostic tests. As a result, there are new approaches, new partnerships and new business models that are emerging. In some cases, diseases that were considered incurable not too long ago are now being tackled with highly targeted therapies. In other cases the uncertainties associated with assessing potential aggressiveness of disease are being eliminated. This panel will provide examples of new business paradigms that are emerging from the application of personalized medicine.

Novel Approaches to Personalized Medicine

Moderator:

Meghan FitzGerald, Ph.D. @cardinalhealth
President, Cardinal Health Specialty Solutions

Chief Genome Officer – next steps in companies, Genomics Index will replace the Biotech Index

Most Interesting person in Genomics: Marc Levin,

Panelists:

2. Chris Garabedian @Sarepta
President and CEO, Sarepta

  • Applications of genomics to Infectious diseases, therapeutics – design of drugs, Duchenne Muscular Dystrophy (DMD)
  • technology safe working, one drug very effective, 60 alternative drugs, not enough patients to power clinical trials

 

4. Shawn Marcell
President & CEO, Metamark Genetics

  • Prostatic Cancer – Use of genomics tools to diagnose and treat Prostate cancer
  • US market is the best for Genomics innovations because venture capital Market is mature, FDA is negotiable, CMP well established
  • Business model: platform, good test big market, commercialize, clinical data — PM has a different Business model: Delivery of Test results need to be different
  • IPO 2016

 

1. Scott Schell, M.D., Ph.D. – surgical oncology @KEWGroup
President and CEO, KEW Group

  • Large scale platform, strategic partnerships with Oncology Practices,
  • Immuno oncologists, repository of data
  • 80% of cancers are treated in the community 20% at Academic centers. Integration of knowledge, patients wish to stay in the community
  • phase I approval at record high levels

3. Gabriel Bien-Willner, M.D., Ph.D. @MolecularHealth
Medical Director, MolecularHealth, Inc.

  • Diagnostics Tools in Analytics. Clinicians do not have the training in Genomics – position firm to create Lab reports and consulting MDs using Analytics for Clinicians

 

 

– See more at: http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf

@HarvardPMConf

#PMConf

@SachsAssociates

@cardinalhealth

@Sarepta

@KEWGroup

@MolecularHealth

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Following (or not) the guidelines for use of imaging in management of prostate cancer.

Writer and curator: Dror Nir, PhD

Over diagnosis and over treatment is a trend of the last two decades. It leads to increase in health-care costs and human-misery.

The following headline on Medscape; Swedes Show That We Can Improve Imaging in Prostate Cancer elicited my curiosity.

I was expecting “good news” – well, not this time!

In spite the “general language” the study that the above mentioned headline refers to is not addressing the global use of imaging in prostate cancer patients’ pathway but is specific to use of radionuclide bone-scans as part of patients’ staging.  The “bad-news” are that realization that the Swedish government had to invest many man-years to achieve “success” in reducing unnecessary use of such imaging in low risk patients. Moreover, the paper reveals under-use of such imaging technology for staging high risk prostate cancer patients.

Based on this paper, one could come to the conclusion that in reality, we are facing long lasting non-conformity with established guidelines related to the use of “full-body” imaging as part of the prostate cancer patients’ pathway in Europe and USA.

Here is a link to the original paper:

Prostate Cancer Imaging Trends After a Nationwide Effort to Discourage Inappropriate Prostate Cancer Imaging, Danil V. MakarovStacy LoebDavid UlmertLinda DrevinMats Lambe and Pär Stattin Correspondence to: Pär Stattin, MD, PhD, Department of Surgery and Perioperative Sciences, Urology and Andrology, Umeå University, SE- 901 87 Umeå, Sweden (e-mail:par.stattin@urologi.umu.se).

JNCI J Natl Cancer Inst (2013)doi: 10.1093/jnci/djt175

 

For convenience, here are the highlights:

  • Reducing inappropriate use of imaging to stage incident prostate cancer is a challenging problem highlighted recently as a Physician Quality Reporting System quality measure and by the American Society of Clinical Oncology and the American Urological Association in the Choosing Wisely campaign.

 

  • Since 2000, the National Prostate Cancer Register (NPCR) of Sweden has led an effort to decrease national rates of inappropriate prostate cancer imaging by disseminating utilization data along with the latest imaging guidelines to urologists in Sweden.

  • Results Thirty-six percent of men underwent imaging within 6 months of prostate cancer diagnosis. Overall, imaging use decreased over time, particularly in the low-risk category, among whom the imaging rate decreased from 45% to 3% (P < .001), but also in the high-risk category, among whom the rate decreased from 63% to 47% (P < .001). Despite substantial regional variation, all regions experienced clinically and statistically (P < .001) significant decreases in prostate cancer imaging.

 

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  • These results may inform current efforts to promote guideline-concordant imaging in the United States and internationally.

  • In 1998, the baseline low-risk prostate cancer imaging rate in Sweden was 45%. Per the NCCN guidelines (7), none of these men should have received bone imaging unless they presented with symptoms suggestive of bone pain (8,24). In the United States, the imaging rate among men with low-risk prostate cancer has been reported to be 19% to 74% in a community cohort and 10% to 48% in a Surveillance Epidemiology and End Results (SEER)–Medicare cohort (10–13,16). It is challenging to compare these rates directly across the two countries because the NPCR aggregates all staging imaging into one variable. However, our sampling revealed that 88% of those undergoing imaging had at least a bone scan, whereas only 11% had any CTs and 10% had any MRI. This suggests that baseline rates of bone scan among low-risk men in Sweden were similar to those among their low-risk counterparts in the United States, whereas rates of axial imaging were likely much lower. During the study period, rates of prostate cancer imaging among low-risk men in Sweden decreased to 3%, substantially lower than those reported in the United States at any time.

  • Miller et al. describe a decline in imaging associated with a small-scale intervention administered in three urology practices located in the United States participating in a quality-improvement consortium. Our study’s contribution is to demonstrate that a similar strategy can be applied effectively at a national scale with an associated decline in inappropriate imaging rates, a finding of great interest for policy makers in the United States seeking to improve health-care quality.

  • In 1998, the baseline high-risk prostate cancer imaging rates in Sweden were 63%, and decreased by 43% in 2008 (rising slightly to 47% in 2009). Based on our risk category definitions and the guidelines advocated in Sweden, all of these men should have undergone an imaging evaluation (8,24). Swedish rates of prostate cancer imaging among men with high-risk disease are considerably lower than those reported from the SEER–Medicare cohort, where 70% to 75% underwent bone scan and 57% to 58% underwent CT (13,16). These already low rates of imaging among men with high-risk prostate cancer only decreased further during the NPCR’s effort to promote guideline-concordant imaging. Clearly in both countries, imaging for high-risk prostate cancer remains underused despite the general overuse of imaging and numerous guidelines encouraging its appropriate use (3–9).

Similar items I have covered on this this Open Access Online Scientific Journal:

Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

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