Personalized Medicine [Part 2] - Time for a Reality Check?

Despite the enormous promise of personalized or precision medicine coming from the  genomics era, I think we need to collectively take a deep breath and also ponder the reality of just how far this new technology can take us.

Without in any way diminishing the huge potential of the "$1000 genome" era, I think there are at least two important areas where we need to do a reality check.

 The first of these I have already written about - the need for debate in society about how we want to view privacy and confidentiality, and how are we going to deal with the influx of personal, genetic information that could overwhelm and confuse us despite good intentions to the contrary.

The second area stems (no pun intended) from the reality that cancer is, at its heart, a set of diseases marked by tremendous  genetic instability. The reason that so many cancers are hard to treat is because every time you think you have it pinned down, it morphs into something a bit different.

For example, when a number of the first Gleevec patients started to relapse, the sound of people jumping OFF the bandwagon was an audible thud. Skeptics said "see, we knew it couldn't really work so easily!" Subsequent studies showed, however, that Gleevec indeed worked exactly as advertised, but in the interim, the cancers had “evolved” – they developed some secondary mutations that essentially allowed the Gleevec roadblock to be bypassed.  If  you put roadblocks up on the main highways, cancer will find a way to take a side road to get out of town. If you block the side roads, cancer often will find some other route.

So, the advent of an international consortium like ICGC  that is  so very powerful, coupled with the fact that gene sequencing costs are spiralling downward, leads us logically to anticipate a new era of personalized and precision medicine. The idea is out there that if every patient’s tumour could be biopsied and his/her cancer genome sequenced so that we can determine and understand the underlying genetic defects, then we will be able to choose a tailored therapeutic regimen to treat that patient and his/her cancer in a more targeted way than ever before possible.

But that kind of future scenario depends not only on “cheap” sequencing technologies and an enormous database of mutations associated with cancers (both of which are now or will soon be in our reach), but it also depends, at least in part, on one other crucial factor. If we do a biopsy on a patient’s cancer, are we confident that what we will learn will be sufficient to give us the depth and detail of understanding that we need so that we can put this therapeutic precision and personalization to the test?

As is so often the case with cancers, the answer is, maybe…..

Why the hedge? Because we haven’t yet fully accounted for the idea that tumours are undoubtedly NOT homogeneous, that is, they do not have a uniform structure or character. There may well  be many different types of cancer cells even in a single patient’s cancer. We call this “tumour heterogeneity” which in simple terms means that the tumour may be a “dog’s breakfast” of different kinds of cells and different kinds of mutations.

As Dr. Dan Longo wrote in an editorial entitled Tumor Heterogeneity and Personalized Medicine in the March 8, 2012 issue of the New England Journal of Medicine:  

“A new world has been anticipated in which patients will undergo a needle biopsy of a tumor in the outpatient clinic, and a little while later, an active treatment will be devised for each patient on the basis of the distinctive genetic characteristics of the tumor,” he wrote.  “But a serious flaw in the imagined future of oncology is its underestimation of tumor heterogeneity.”

This “complication” came to the fore earlier this month with the publication of a very important study, entitled IntratumorHeterogeneity and Branched Evolution Revealed by Multiregion Sequencing published in the same New England Journal of Medicine issue. 

That’s a very technical title, and indeed a very specialized and technical paper, but the bottom line of it is this: a team of researchers led by Drs. Marco Gerlinger and Charles Swanton from London, UK found that there was an astonishing degree of genetic variation in biopsies from the same tumour from the same patient. In fact, multiple biopsies taken from single patients with kidney cancer (renal carcinoma) showed that there were many different mutations in each biopsy, and that not all of them showed up in all of the biopsies. In fact, the majority (over 60% of the mutations) did NOT show up across all of the biopsies.

Even worse, the researchers found that the mutations and gene “signatures” found in one region of the tumour were consistent with what we would currently have said is a good prognosis, whereas gene “signatures” found in a different part of the very same tumour were consistent with what we would have expected to be a poor prognosis!

This study, if typical for other tumours, suggests that a simple, i.e., non-invasive biopsy of a limited region of a tumour might NOT be at all sufficient to proceed with a very targeted therapeutic regimen. What if we targeted treatment to the wrong cells, cells that maybe by chance only represented 10% of the tumour?  What if we chose not to treat aggressively based on an ostensibly great prognosis from the biopsied material, only to find out later to our detriment that we were fooled by a “sampling error” of lamentable proportions?

So, bottom line, looking at both sides of the coin of "personalized medicine" (e.g., this post and the previous post), what does this all mean?

Are genomics, DNA sequencing and the building of mutation databases of enormous proportion tantamount going to lead us single-handedly to the Holy Grail of cancer treatments? Hardly.

Does the Swanton et al. study on genetic variation in kidney cancers mean that we are wasting our time with  the pursuit of genomics and precision cancer therapies? Again, hardly.

Like all things cancer, black and white approaches are simply not the way to go. This may be a bump in the road, as some have alluded, but if it is, it is not the end of the road by any means. We will learn some breathtaking insights from genomics, but it will be only one powerful tool in the arsenal, not the whole answer.

As one blogger eloquently put it in describing the kidney cancer study (Jessica Wapner, March 9, 2012, in a PublicLibrary of Science blog)

“It’s for this reason that the idea of personalized medicine—and here we are talking specifically about drugs targeted against the genetic make-up of an individual cancer, not about a whole-person regimen for life based on your personal DNA quirks—is one that has to be held with a long-view. It took decades for the first useful chemotherapy drug to be discovered. If we absorb the notion that targeted therapy is still in its nascent stage, then this new study isn’t a bump in the road, but rather another description of the scenery.”

Personalized Medicine [Part 1] – The PROMISE...

Whether you call it personalized medicine, or precision medicine, or whatever, the promise of the $1000 (or less) genome has captured the imaginations and aspirations of the public and the research community alike.

This excitement is not ill-considered. One can assume that there are going to be vast improvements in our ability to prevent, diagnose, treat and cure cancers as we learn more and more about the mutations that drive the diseases.

As  Colin Hill contributed to Forbes on Feb 9, 2012 in his post “Beyond the $1000 Genome on the Forbes website.

“Larger availability of complete genomic data will have a profound near-term impact on cancer research. The ability to rapidly and economically sequence individual patient tumours will help us to better understand the biological mechanisms of cancer and will facilitate data-driven patient stratification. This, in turn, will facilitate more effective clinical trials and speed the development of new therapies.

The significant near-term growth of rich genomic data will impact the patient care side too. Companies ... will use this data to perform molecular analysis of tumours that will assist in pinpointing the optimal treatment strategies for individuals with cancer.”

But of course, no matter how cheaply it can be done, sequencing a single patient’s genome is not going to tell us much if we don't know what we are looking for. How will we know a “bad” mutation from a “neutral” mutation? As we saw with Craig Venter’s genome, his natural amount of genetic variability, and presumably yours and mine as well, is very high, and yet Craig Venter is by all accounts a healthy man.

Well, the supposition is that if we look at enough DNA sequences of enough cancer patients then a pattern will start to emerge and we will start to see certain mutations showing up over and over. How many will there be? Will some mutations be more directly linked to actual “causation” of the cancer (so called “driver” mutations) or will some be there as a consequence of the cancer and not actually involved in the origin or progression (so-called “passenger” mutations). Will we be able to tell the difference?

Answers to these crucial kinds of questions require a lot more data than we currently have. And that is where and how the International Cancer Genome Consortium (or ICGC) was formed.

Inaugural Meeting of Genome Scientists in Toronto 2007

Much like the Herculean world-wide effort to collaborate in determining the very first human reference genome sequence, the ICGC is also a massive consortium (website at http://icgc.org/) . The ICGC is a consortium not so much of scientists but of whole countries. The consortium was formed in 2008 after an inaugural meeting (Toronto) and report in 2007, to bring a global effort to bear in sequencing enough genomes for each of perhaps 50 or more types of important cancers so that we could start to answer some of the questions posed above. It is estimated that perhaps several hundred genome sequences derived from patients with any individual type of cancer may needed in order to be able to have statistical confidence of which mutations may indeed be the “drivers” vs. those that may simply be the “passengers”. If you consider the effort, and cost, of sequencing hundreds of genomes for each of perhaps 50 types of cancer, you start to see the enormity of the task, and why a consortium of countries in needed.

The ICGC is therefore funded in the main by governments and government agencies (federal and provincial here in Canada) of countries, along with some notable cancer charities and other funders. Each participating member country of the consortium is expected to invest at least $20 Million overall to that country’s activities. Furthermore, a commitment to fully, openly and quickly share ALL data with other qualified researchers world-wide is an absolute requirement for membership.

The secretariat of the ICGC is in Toronto, at the Ontario Institute for Cancer Research (OICR; http://oicr.on.ca), and Dr. Tom Hudson, an internationally renowned genomics researcher who is President and Scientific Director of the OICR heads the Executive.

OICR also operates the main data coordination centre for the consortium. Tom took me on a tour of the OICR server room about a year ago and I can tell you it is like something out of the movies :) The air conditioning costs alone for  just keeping the server room(s) cool must be enormous!

The goal of all of this of course is to have an international database of “signatures” of dozens of types of cancers, with enough confidence that we can start to use that data to better understand cancers at the gene and molecular levels, and be better able to determine predisposition to cancers (leading to better prevention strategies); to determine better and more pin-point diagnostic and marker mutations (leading to earlier diagnosis and better interventions), and to determine many new therapeutic targets for treating and curing more and more cancers.

In Canada, we have taken a leadership role for three different types of cancer – Pancreatic Cancer (ductal adenocarcinoma of the pancreas; collaborating and funding organizations can be found here; Brain Cancer (pediatric medulloblastoma; collaborating and funding organizations can be found here; and Prostate Cancer (adenocarcinoma of the prostate; collaborating and funding organizations can be found here.

 

Whether the ICGC actually achieves all of its lofty goals is of course yet to be fully seen. What is clear is that a major undertaking like this brings out what I consider to be the very best in science and scientists: the desire and willingness to not compete but instead to openly collaborate, to share data, and to work for the common good in ways that no single researcher or even a single country could manage.

This is so-called “big science” at its best and we should all be pleased that it is being undertaken in the international arena, and in the collegial and cooperative manner that it is.