Download Michael Fraser, Associate Director, CPC

Next Generation Sequencing Conversations…
Michael Fraser,
Associate Director, CPC-GENE Prostate
Cancer Genomics Program,
Princess Margaret Cancer Centre
Please give us an overview of the use of NGS in Clinical Applications & Diagnostics.
We’ve reached a stage now where the technology has matured to a point whereby we can begin to think
about routinely using NGS in clinical applications. The last five to eight years have really been about
developing robust technologies to sequence genomes, and about refining the analysis tools that allow us
to accurately parse through those data, and be confident in them, which is required to apply the data to
clinical questions. So there’s obviously a lot of effort put into cataloguing of alterations that are associated
with disease. I work in cancer, and in that field development of the International Cancer Genome
Consortium and The Cancer Genome Atlas have created an enormous and growing list of alterations that
are associated with various cancer types. The next step will be to assess the clinical relevance of those
alterations, which is precisely what my own research is focused on.
Whole-genome and whole-exome sequencing have been tremendous tools for developing these types of
databases, although the cost and specimen requirements likely preclude their use as routine clinical tools.
However, as we start to refine these databases of alterations and look at how they associate with various
clinical outcomes, more bespoke platforms and tests become relevant. The power of NGS lies in its ability
to go both deep and wide; this is far beyond what we have been doing on smaller scale assays in the past.
Describe your research in the Use of NGS for Biomarker Development for Cancer Diagnostics/
Therapeutics.
Our research is centred around prostate cancer and in particular the localised, potentially curable setting.
We have a situation in prostate cancer where in the modern PSA era, 90% of guys are showing up in the
clinic with localised disease with no evidence of metastatic spread. By and large, these guys should be
curable using surgery or radiation. However, the prognostic tools we currently use are not powerful
enough to determine an individual man’s risk of having aggressive disease, and therefore we see wide
heterogeneity in response to treatment.
Our question is simply: why is this happening, and how can we better stratify men into precision medicine
protocols, based on their intrinsic tumour biology? We’re using NGS - particularly whole-genome and
whole transcriptome sequencing - to identify prognostic ‘signatures’ of treatment response. We are
profiling 500 patients that either did or did not respond well to treatment and looking for genetic patterns
that are unique to those that failed their therapy, and in particular men who failed very rapidly. This could
then be translated into a pre-treatment test based on a tumour biopsy, such that we could inform a patient,
with a very high level of certainty, that despite the fact that he has a particular set of clinical variables,
based on the intrinsic tumour genomics, he actually needs to be stratified into a higher risk group of
disease recurrence and therefore requires potentially more aggressive treatment. As of 2015, we really
can’t do that, despite the fact that we know that 30-50% of patients with localized, non-indolent disease
will fail treatment and require more aggressive treatment. We can’t, as of yet, identify those guys upfront.
And so we are using NGS, both to identify novel mutations and novel biology, but foremost to bring these
findings back into the clinic and to correlate genomic changes with how patients actually respond. And we
see a big push in the international community to start to do just that. One of the problems with doing this
type of research is that while there are physical specimens available that amenable to NGS, matching
those to robust patient outcome databases has been difficult, and I think we are starting to see a push for
that in a prospective manner.
Next Generation Sequencing Conversations…
Michael Fraser,
Associate Director, CPC-GENE Prostate
Cancer Genomics Program,
Princess Margaret Cancer Centre
What does the Future hold for Applying NGS to Oncology Drug Discovery and Development?
I think because of its ability to interrogate specimens to such a high resolution, NGS is going to become a
major tool for diagnostics and therapeutic monitoring. I think there are a number of challenges that are not
necessarily related to NGS but will affect the implementation of the use of NGS.
First, there are concerns around the ethics associated with the using of NGS, in particular because you
can identify so many things with NGS, there are growing concerns around what to do with all of this data
with respect to patient confidentiality issues.
There are also going to be issues of consenting i.e. how do we get enough numbers to actually generate
good data from clinical trials. One of the key features of NGS is the ability to discover very rare but
potentially very important variants. But to assess the importance of these alterations, you need large
numbers of patients. So a problem is generating enough patients to match what the data can actually
provide.
I think there are going to be concerns with how we make effective use of all of the archival material that
we have available. Every institution has thousands upon thousands of banked materials that can be used
for NGS. The concern is how we can develop the technologies to use these effectively and accurately,
and how we can marry those to patient outcomes. Cost is going to be a concern, too, I think. We have
obviously seen an enormous reduction in the cost of doing NGS at the whole genome level, and also at
the bespoke NGS level, but this will have to continue to make these tests clinically feasible.
For example, Illumina has done an amazing job at developing really great technologies and at the level of
whole-genome sequencing, Illumina is the gold standard for discovery. But there is very little competition
in that space at the moment and this has resulted in there being less of a downward pressure on costs
than there might otherwise be. And certainly the cost of analysing the data has not really moved because,
at the end of the day, you need people and ever-increasing compute power.
From a scientific and clinical point of view, one of the major hurdles of the use of NGS has to do with the
depth and resolution you can use these types of technologies, and the question of disease heterogeneity.
In the space that I work in this is a major concern; we know that about 80% of prostate cancer patients
have multiple regions of cancer in the same gland, and this is true of some other cancers as well. The
question is going to be how do we accurately characterise that heterogeneity and characterise the effect
that heterogeneity potentially has on the development of biomarkers. So if you have a distinct genomic
profile in say two or three regions of the same cancer type but different actual physical regions, can you
develop a biomarker based on looking at just one region or do you have to go in and probe all of those
different regions? That question of heterogeneity is one that by and large has not been that well
addressed, and I think that is going to be key because at the end of the day, we can do all of these great
things and we can sequence deeply and we can find an array of variants, but if there is a patient sitting
there who has a very heterogeneous disease, we need to understand the ramifications of this. And that
has not really been addressed.
Next Generation Sequencing Conversations…
Michael Fraser,
Associate Director, CPC-GENE Prostate
Cancer Genomics Program,
Princess Margaret Cancer Centre
Career & Experience
Michael Fraser obtained a Bachelor of Science degree from McGill University in
Physiology, and completed his Ph.D. studies in the Department of Cellular and Molecular
Medicine, University of Ottawa in the laboratory of Dr. Ben Tsang. Dr. Fraser’s Ph.D.
research focused on defining the cellular and molecular mechanisms of cisplatin
resistance in ovarian cancer.
Dr. Fraser undertook post-doctoral studies with Dr. Rob Bristow at the Ontario Cancer
Institute in Toronto, where he studied the molecular interaction between the
PI3K/AKT/PTEN axis and the DNA damage response. Dr. Fraser also has an interest in
the use of DNA damage response genes (e.g. PARP1, ATM, MRE11) as potential biomarkers of
therapeutic response.
Since 2011, Dr. Fraser has worked on the development of the Canadian Prostate Cancer Genome
Network (CPC-GENE), a multi-institutional initiative that aims to sequence the genomes of up to 500
prostate cancers, in an effort to identify genomic biomarkers of disease aggression and recurrence. In
2013, Dr. Fraser was appointed as the Associate Director of CPC-GENE Prostate Cancer Genomics
program at the Princess Margaret Cancer Centre, which integrates numerous Canadian and international
prostate cancer genomics projects.
Michael will be speaking on Day 2 of the Next Generation Sequencing USA Congress in October in
our NGS: Clinical Applications & Diagnostics stream on Developing Prognostic Biomarkers for
Localized Prostate Cancer Using Whole-Genome Sequencing.