Posts Tagged ‘Genomic Health’

Icelandic Population Genomic Study Results by deCODE Genetics come to Fruition: Curation of Current genomic studies

Reporter/Curator: Stephen J. Williams, Ph.D.


UPDATED on 9/6/2017

On 9/6/2017, Aviva Lev-Ari, PhD, RN had attend a talk by Paul Nioi, PhD, Amgen, at HMS, Harvard BioTechnology Club (GSAS).

Nioi discussed his 2016 paper in NEJM, 2016, 374:2131-2141

Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

Paul Nioi, Ph.D., Asgeir Sigurdsson, B.Sc., Gudmar Thorleifsson, Ph.D., Hannes Helgason, Ph.D., Arna B. Agustsdottir, B.Sc., Gudmundur L. Norddahl, Ph.D., Anna Helgadottir, M.D., Audur Magnusdottir, Ph.D., Aslaug Jonasdottir, M.Sc., Solveig Gretarsdottir, Ph.D., Ingileif Jonsdottir, Ph.D., Valgerdur Steinthorsdottir, Ph.D., Thorunn Rafnar, Ph.D., Dorine W. Swinkels, M.D., Ph.D., Tessel E. Galesloot, Ph.D., Niels Grarup, Ph.D., Torben Jørgensen, D.M.Sc., Henrik Vestergaard, D.M.Sc., Torben Hansen, Ph.D., Torsten Lauritzen, D.M.Sc., Allan Linneberg, Ph.D., Nele Friedrich, Ph.D., Nikolaj T. Krarup, Ph.D., Mogens Fenger, Ph.D., Ulrik Abildgaard, D.M.Sc., Peter R. Hansen, D.M.Sc., Anders M. Galløe, Ph.D., Peter S. Braund, Ph.D., Christopher P. Nelson, Ph.D., Alistair S. Hall, F.R.C.P., Michael J.A. Williams, M.D., Andre M. van Rij, M.D., Gregory T. Jones, Ph.D., Riyaz S. Patel, M.D., Allan I. Levey, M.D., Ph.D., Salim Hayek, M.D., Svati H. Shah, M.D., Muredach Reilly, M.B., B.Ch., Gudmundur I. Eyjolfsson, M.D., Olof Sigurdardottir, M.D., Ph.D., Isleifur Olafsson, M.D., Ph.D., Lambertus A. Kiemeney, Ph.D., Arshed A. Quyyumi, F.R.C.P., Daniel J. Rader, M.D., William E. Kraus, M.D., Nilesh J. Samani, F.R.C.P., Oluf Pedersen, D.M.Sc., Gudmundur Thorgeirsson, M.D., Ph.D., Gisli Masson, Ph.D., Hilma Holm, M.D., Daniel Gudbjartsson, Ph.D., Patrick Sulem, M.D., Unnur Thorsteinsdottir, Ph.D., and Kari Stefansson, M.D., Ph.D.

N Engl J Med 2016; 374:2131-2141June 2, 2016DOI: 10.1056/NEJMoa1508419

Citing Articles (22)


Several sequence variants are known to have effects on serum levels of non–high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease.


We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability.


We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10−16), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10−6). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10−3).


ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.)


Amgen’s deCODE Genetics Publishes Largest Human Genome Population Study to Date

Mark Terry, BioSpace.com Breaking News Staff reported on results of one of the largest genome sequencing efforts to date, sequencing of the genomes of 2,636 people from Iceland by deCODE genetics, Inc., a division of Thousand Oaks, Calif.-based Amgen (AMGN).

Amgen had bought deCODE genetics Inc. in 2012, saving the company from bankruptcy.

There were a total of four studies, published on March 25, 2015 on the online version of Nature Genetics; titled “Large-scale whole-genome sequencing of the Icelandic population[1],” “Identification of a large set of rare complete human knockouts[2],” “The Y-chromosome point mutation rate in humans[3]” and “Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease[4].”

The project identified some new genetic variants which increase risk of Alzheimer’s disease and confirmed some variants known to increase risk of diabetes and atrial fibrillation. A more in-depth post will curate these findings but there was an interesting discrete geographic distribution of certain rare variants located around Iceland. The dataset offers a treasure trove of meaningful genetic information not only about the Icelandic population but offers numerous new targets for breast, ovarian cancer as well as Alzheimer’s disease.

View Mark Terry’s article here on Biospace.com.

“This work is a demonstration of the unique power sequencing gives us for learning more about the history of our species,” said Kari Stefansson, founder and chief executive officer of deCode and one of the lead authors in a statement, “and for contributing to new means of diagnosing, treating and preventing disease.”

The scale and ambition of the study is impressive, but perhaps more important, the research identified a new genetic variant that increases the risk of Alzheimer’s disease and already had identified an APP variant that is associated with decreased risk of Alzheimer’s Disease. It also confirmed variants that increase the risk of diabetes and a variant that results in atrial fibrillation.
The database of human genetic variation (dbSNP) contained over 50 million unique sequence variants yet this database only represents a small proportion of single nucleotide variants which is thought to exist. These “private” or rare variants undoubtedly contribute to important phenotypes, such as disease susceptibility. Non-SNV variants, like indels and structural variants, are also under-represented in public databases. The only way to fully elucidate the genetic basis of a trait is to consider all of these types of variants, and the only way to find them is by large-scale sequencing.

Curation of Population Genomic Sequencing Programs/Corporate Partnerships

Click on “Curation of genomic studies” below for full Table

Curation of genomic studies
Study Partners Population Enrolled Disease areas Analysis
Icelandic Genome


deCODE/Amgen Icelandic 2,636 Variants related to: Alzheimer’s, cardiovascular, diabetes WES + EMR; blood samples
Genome Sequencing Study Geisinger Health System/Regeneron Northeast PA, USA 100,000 Variants related to hypercholestemia, autism, obesity, other diseases WES +EMR +MyCode;

– Blood samples

The 100,000 Genomes Project National Health Service/NHS Genome Centers/ 10 companies forming Gene Consortium including Abbvie, Alexion, AstraZeneca, Biogen, Dimension, GSK, Helomics, Roche,   Takeda, UCB Rare disorders population UK Starting to recruit 100,000 Initially rare diseases, cancer, infectious diseases WES of blood, saliva and tissue samples

Ref paper

Saudi Human Genome Program 7 centers across Saudi Arabia in conjunction with King Abdulaziz City Science & Tech., King Faisal Hospital & Research Centre/Life Technologies General population Saudi Arabia 20,000 genomes over three years First focus on rare severe early onset diseases: diabetes, deafness, cardiovascular, skeletal deformation Whole genome sequence blood samples + EMR
Genome of the Netherlands (GoNL) Consortium consortium of the UMCG,LUMCErasmus MCVU university and UMCU. Samples where contributed by LifeLinesThe Leiden Longevity StudyThe Netherlands Twin Registry (NTR), The Rotterdam studies, and The Genetic Research in Isolated Populations program. All the sequencing work is done by BGI Hong Kong. Families in Netherlands 769 Variants, SNV, indels, deletions from apparently healthy individuals, family trios Whole genome NGS of whole blood no EMR

Ref paper in Nat. Genetics

Ref paper describing project

Faroese FarGen project Privately funded Faroe Islands Faroese population 50,000 Small population allows for family analysis Combine NGS with EMR and genealogy reports
Personal Genome Project Canada $4000.00 fee from participants; collaboration with University of Toronto and SickKids Organization; technical assistance with Harvard Canadian Health System Goal: 100,000 ? just started no defined analysis goals yet Whole exome and medical records
Singapore Sequencing Malay Project (SSMP) Singapore Genome Variation Project

Singapore Pharmacogenomics Project

Malaysian 100 healthy Malays from Singapore Pop. Health Study Variant analysis Deep whole genome sequencing
GenomeDenmark four Danish universities (KU, AU, DTU and AAU), two hospitals (Herlev and Vendsyssel) and two private firms (Bavarian Nordic and BGI-Europe). 150 complete genomes; first 30 published in Nature Comm. ? See link
Neuromics Consortium University of Tübingen and 18 academic and industrial partners (see link for description) European and Australian 1,100 patients with neuro-

degenerative and neuro-

muscular disease

Moved from SNP to whole exome analysis Whole Exome, RNASeq


  1. Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, Besenbacher S, Magnusson G, Halldorsson BV, Hjartarson E et al: Large-scale whole-genome sequencing of the Icelandic population. Nature genetics 2015, advance online publication.
  2. Sulem P, Helgason H, Oddson A, Stefansson H, Gudjonsson SA, Zink F, Hjartarson E, Sigurdsson GT, Jonasdottir A, Jonasdottir A et al: Identification of a large set of rare complete human knockouts. Nature genetics 2015, advance online publication.
  3. Helgason A, Einarsson AW, Gumundsdottir VB, Sigursson A, Gunnarsdottir ED, Jagadeesan A, Ebenesersdottir SS, Kong A, Stefansson K: The Y-chromosome point mutation rate in humans. Nature genetics 2015, advance online publication.
  4. Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, Sulem P, Magnusson OT, Gudjonsson SA, Unnsteinsdottir U et al: Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nature genetics 2015, advance online publication.

Other post related to DECODE, population genomics, and NGS on this site include:

Illumina Says 228,000 Human Genomes Will Be Sequenced in 2014

CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics and Computational Genomics – Part IIB

Human genome: UK to become world number 1 in DNA testing

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

Sequencing the exomes of 1,100 patients with neurodegenerative and neuromuscular diseases: A consortium of 18 European and Australian institutions

University of California Santa Cruz’s Genomics Institute will create a Map of Human Genetic Variations

Three Ancestral Populations Contributed to Modern-day Europeans: Ancient Genome Analysis

Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations

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10:15AM 11/13/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

Reporter: Aviva Lev-Ari, PhD, RN


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

10:15 a.m. Panel Discussion — IT/Big Data

IT/Big Data

The human genome is composed of 6 billion nucleotides (using the genetic alphabet of T, C, G and A). As the cost of sequencing the human genome is decreasing at a rapid rate, it might not be too far into the future that every human being will be sequenced at least once in their lifetime. The sequence data together with the clinical data are going to be used more and more frequently to make clinical decisions. If that is true, we need to have secure methods of storing, retrieving and analyzing all of these data.  Some people argue that this is a tsunami of data that we are not ready to handle. The panel will discuss the types and volumes of data that are being generated and how to deal with it.

IT/Big Data


Amy Abernethy, M.D.
Chief Medical Officer, Flatiron

Role of Informatics, SW and HW in PM. Big data and Healthcare

How Lab and Clinics can be connected. Oncologist, Hematologist use labs in clinical setting, Role of IT and Technology in the environment of the Clinicians

Compare Stanford Medical Center and Harvard Medical Center and Duke Medical Center — THREE different models in Healthcare data management

Create novel solutions: Capture the voice of the patient for integration of component: Volume, Veracity, Value

Decisions need to be made in short time frame, documentation added after the fact

No system can be perfect in all aspects

Understanding clinical record for conversion into data bases – keeping quality of data collected

Key Topics


Stephen Eck, M.D., Ph.D.
Vice President, Global Head of Oncology Medical Sciences,
Astellas, Inc.

Small data expert, great advantage to small data. Populations data allows for longitudinal studies,

Big Mac Big Data – Big is Good — Is data been collected suitable for what is it used, is it robust, limitations, of what the data analysis mean

Data analysis in Chemical Libraries – now annotated

Diversity data in NOTED by MDs, nuances are very great, Using Medical Records for building Billing Systems

Cases when the data needed is not known or not available — use data that is available — limits the scope of what Valuable solution can be arrived at

In Clinical Trial: needs of researchers, billing clinicians — in one system

Translation of data on disease to data object

Signal to Noise Problem — Thus Big data provided validity and power


J. Michael Gaziano, M.D., M.P.H., F.R.C.P.
Scientific Director, Massachusetts Veterans Epidemiology Research
and Information Center (MAVERIC), VA Boston Healthcare System;
Chief Division of Aging, Brigham and Women’s Hospital;
Professor of Medicine, Harvard Medical School

at BWH since 1987 at 75% – push forward the Genomics Agenda, VA system 25% – VA is horizontally data integrated embed research and knowledge — baseline questionnaire 200,000 phenotypes – questionnaire and Genomics data to be integrated, Data hierarchical way to be curated, Simple phenotypes, validate phenotypes, Probability to have susceptibility for actual disease, Genomics Medicine will benefit Clinicians

Data must be of visible quality, collect data via Telephone VA – on Med compliance study, on Ability to tolerate medication

–>>Annotation assisted in building a tool for Neurologist on Alzheimer’s Disease (AlzSWAN knowledge base) (see also Genotator , a Disease-Agnostic Tool for Annotation)

–>>Curation of data is very different than statistical analysis of Clinical Trial Data

–>>Integration of data at VA and at BWH are tow different models of SUCCESSFUL data integration models, accessing the data is also using a different model

–>>Data extraction from the Big data — an issue

–>>Where the answers are in the data, build algorithms that will pick up causes of disease: Alzheimer’s – very difficult to do

–>>system around all stakeholders: investment in connectivity, moving data, individual silo, HR, FIN, Clinical Research

–>>Biobank data and data quality


Krishna Yeshwant, M.D.
General Partner, Google Ventures;
Physician, Brigham and Women’s Hospital

Computer Scientist and Medical Student. Were the technology is going?

Messy situation, interaction IT and HC, Boston and Silicon Valley are focusing on Consumers, Google Engineers interested in developing Medical and HC applications — HUGE interest. Application or Wearable – new companies in this space, from Computer Science world to Medicine – Enterprise level – EMR or Consumer level – Wearable — both areas are very active in Silicon Valley

IT stuff in the hospital HARDER that IT in any other environment, great progress in last 5 years, security of data, privacy. Sequencing data cost of big data management with highest security

Constrained data vs non-constrained data

Opportunities for Government cooperation as a Lead needed for standardization of data objects


Questions from the Podium:

  • Where is the Truth: do we have all the tools or we don’t for Genomic data usage
  • Question on Interoperability
  • Big Valuable data — vs Big data
  • quality, uniform, large cohort, comprehensive Cancer Centers
  • Volume of data can compensate quality of data
  • Data from Imaging – Quality and interpretation – THREE radiologist will read cancer screening




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











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8:00AM 11/13/2014 – 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

8:00 A.M. Welcome from Gary Gottlieb, M.D.

Opening Remarks:

Partners HealthCare is the largest healthcare organization in Massachusetts and whose founding members are Brigham and Women’s Hospital and Massachusetts General Hospital. Dr. Gottlieb has long been a supporter of personalized medicine and he will provide his vision on the role of genetics and genomics in healthcare across the many hospitals that are part of Partners HealthCare.

Opening Remarks and Introduction

Scott Weiss, M.D., M.S. @PartnersNews
Scientific Director, Partners HealthCare Personalized Medicine;
Associate Director, Channing Laboratory/
Professor of Medicine, Harvard Medical School 


Engine of innovations

  • lower cost – Accountable care
  • robust IT infrastructure on the Unified Medical Records
  • Lab Molecular Medicine and Biobanks
  • 1. Lab Molecular medicine
  • 2. Biobank
  • 3. Translations Genomics: RNA Sequencing
  • 4. Medical Records integration of coded diagnosis linked to Genomics

BIOBANKS – Samples and contact patients, return actionable procedures

LIFE STYLE SURVEY – supplements the medical record

GENOTYPING and SEQUENCING – less $50 per sequence available to researcher / investigators

RECRUITMENT – subject to biobank, own Consents – e-mail patient – consent online consenting — collects 16,000 patients per month – very successful Online Consent

LAB Molecular Medicine – CLIA — genomics test and clinical care – EGFR identified as a bio-marker to cancer in 3 month a test was available. Best curated medical exon databases Emory Genetics Lab (EMVClass) and CHOP (BioCreative and MitoMAP and MitoMASTER). Labs are renowned in pharmacogenomics and interpretability.

IT – GeneInsight – IT goal Clinicians empowered by a workflow geneticist assign cases, data entered into knowledge base, case history, GENEINSIGHT Lab — geneticists enter info in a codified way will trigger a report for the Geneticist – adding specific knowledge standardized report enters Medical Record. Available in many Clinics of Partners members.

Example: Management of Patient genetic profiles – Relationships built between the lab and the Clinician

Variety of Tools are in development

GenInsight Team –>> Pathology –>> Sunquest Relationship

The Future

Genetic testing –>> other info (Pathology, Exams, Life Style Survey, Meds, Imaging) — Integrated Medical Record

Clinic of the Future-– >> Diagnostics – Genomics data and Variants integrated at the Clinician desk

Gary Gottlieb, M.D. @PartnersNews
President and CEO, Partners HealthCare

Translational Science
Partners 6,000 MDs, MGH – 200 years as Teaching Hospital of HMS, BWH – magnets in HealthCare

2001  – Center for Genomics was started at Partners, 2008 Genomics and Other Omis, Population Health, PM – Innovations at Partners.

Please Click on Link  Video on 20 years of PartnersHealthcare

Video of Dr. Gottlieb at ECRI conference 2012

Why is personalized medicine  important to Partners?

From Healthcare system to the Specific Human Conditions

  • Lab translate results to therapy
  • Biobank +50,000 specimens links to Medical Records of patients – relevant to Clinician, Genomics to Clinical Applications

Questions from the Podium

  • test results are not yet available online for patients
  • clinicians and liability – delays from Lab to decide a variant needs to be reclassified – alert is triggered. Lab needs time to accumulated knowledge before reporting a change in state.
  • Training Clinicians in above type of IT infrastructure: Labs around the Nations deal with VARIANT RECLASSIFICATION- physician education is a must, Clinicians have access to REFERENCE links.
  • All clinicians accessing this IT infrastructure — are trained. Most are not yet trained
  • Coordination within Countries and Across Nations — Platforms are Group specific – PARTNERS vs the US IT Infrastructure — Genomics access to EMR — from 20% to 70% Nationwide during the Years of the Obama Adm.
  • Shakeout in SW linking Genetic Labs to reach Gold Standard

Click to see Advanced Medical Education Partners Offers


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









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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


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.


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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Recurrence Risk for Breast Cancer

Reporter: Larry H Bernstein, MD,  FCAP


Testing recurrence risk for breast cancer
Karen Titus
June 2011 CAP Today



Gene panels for breast cancer recurrence risk have arrived. In fact, they’ve been around since the mid-2000s. And now, like guests at a wedding reception, it’s a matter of figuring out where to seat them.
Like it or not, tests such as Oncotype DX (Genomic Health Inc.), MammaPrint (Agendia), and Mammostrat (Clarient)—to name just a few—are making their presence felt.
Clinicians favor these tests for a simple reason: the results help them decide if patients with breast cancer need chemotherapy. More broadly, the tests reflect a shift in thinking among physicians, one that emphasizes molecular profiling of tumors. They’ve arrived on the scene when physicians are also starting to question the value of lymph node status to help determine treatment.George W. Sledge, MD, finds these changes remarkable. Not all that long ago, he might have pink-slipped a test that would help parse treatment decisions. When the NIH held its consensus development conference on adjuvant therapy with breast cancer in 2000, he recalls, the agreement was, basically, that everyone with a tumor greater than one centimeter ought to be treated with chemotherapy. “There’s no question that resulted in us hugely overtreating patients,” he says. “So I think a test that reduces the quantity of human suffering by half in that group is a useful test,” says Dr. Sledge, professor of medicine and pathology, Indiana University, Indianapolis, and immediate past president of the American Society of Clinical Oncology.
In clinical practice, these tests are functioning like traffic managers. “We now see fewer patients getting chemotherapy who would have gotten it before,” says Thomas Julian, MD, professor of surgery, Drexel University College of Medicine, Philadelphia, and director of breast surgical oncology for the West Penn Allegheny Health Care System, Pittsburgh. “We’re also seeing a few who are getting chemo who might not have gotten it before. So it’s changed in both directions,” says Dr. Julian, who is also senior surgical director for medical affairs for the National Surgical Adjuvant Breast and Bowel Project.
Oncotype DX is a real-time RT-PCR assay measuring RNA expression in 16 cancer-related genes and five reference genes, using paraffin-embedded tissue. Results are given as a recurrence score between zero and 100, which are translated as low risk (a score of 18 or lower), medium risk (19 to 30), or high risk (31 or above). The MammaPrint microarray assay measures expression of 70 genes in fresh tissue; it categorizes patients as either high risk, with a so-called poor signature, or low risk (a so-called good signature) for recurrence. There is no intermediate category. Mammostrat is an immunohistochemistry test measuring five markers: p53, HTF9C, CEACAM5, NDRG1, and SLC7A5. The results are combined into a quantitative risk index: low, moderate, and high. For now, only MammaPrint has FDA clearance.
The test is not useful in patients whose tumors are HER2 positive. The test nearly always will show such patients to be at high risk; moreover, the paradigm for treating such patients is with chemotherapy and trastuzumab (Herceptin). It is used for patients who are lymph node negative, ER positive, and HER2 negative, with “moderate-size tumors—say, tumors that are over a centimeter but less than four or five centimeters. Another consideration is tumor size. The test is most useful for tumors of around five millimeters or greater in size.For patients with very, very small tumors—one, two, three millimeters—there’s no need for the test. Elizabeth Hammond, MD, agrees these tests are useful, although she suspects they may best prove their mettle in second- or third-generation assays. It’s simple biology: phenotypic expression of a genetic alteration of ER or HER2 status is the result of cell-signaling pathway changes. “Looking at multiple expressions of that problem with a gene panel, either by RT-PCR or some other method, will in the long run give us better information.

Comment:  In 1982, labs were running RIA assays for Estrogen Receptor.  It was known for some time that breast cancer is estrogen-dependent.  This was a major discovery by a surgeon at University of Chicago, that led to oophorectomy with resection of the lesion.  The assay was quite elaborate and required a “scatchard plot”.  The assay was no longer used when a good histochemical stain became widely used with a progesterone receptor a few years later.  We went into the 1990’s knowing that if the patient is pre-menopausal, positive ER+/PR+ is likely, and the cancer is aggressive.  If the patient was postmenopausal, the test is more likely ER/PR negative.  This gives us a perspective on how far we have come.

Image representing Genomic Health as depicted ...

Image via CrunchBase

English: Validation chart for Agendia's MammaP...

English: Validation chart for Agendia’s MammaPrint Assay, part of the Symphony Breast Cancer Suite (Photo credit: Wikipedia)

Ovarian and breast cancer patients in a pedigr...

Ovarian and breast cancer patients in a pedigree chart of a family (Photo credit: Wikipedia)

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