Tag Archives: genetics

Cancer Genetics – it’s complicated – and exciting!

Incredible advances in cancer genetics have revolutionized how we think about cancer. These advances are now being applied to patient care. A brief response to the question “how is our growing knowledge of cancer genetics impacting on cancer research and cancer medicine?” is to say “it’s complicated – and exciting!” That is not a very helpful answer. Here, I will summarize the big picture with the understanding that this brief summary will not even touch on some of the rapidly evolving, nuanced, yet very exciting concepts in cancer genetics.

Let’s start out with a review and discussion of why the genetics revolution in cancer is so important.

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Climate change in clinical research – mastering buckets and umbrellas

This spring, we once again had heavy rains in Iowa with rivers and reservoirs approaching capacity, umbrellas in our hands and buckets on the floor to catch water from leaky roofs. The climate certainly seems to be changing, and there is new urgency in developing a master plan to respond to this new reality. Fortunately, this year’s flooding caused less damage than in prior years in part because communities and organizations have started to work together to manage the increased water flow.

The climate for cancer research is also changing dramatically, and this is having a major impact on how we conduct clinical cancer research. We now know that cancers are driven by genetic changes, and cancers that look the same under the microscope can have very different genetic drivers. There is growing evidence that patients benefit from treatments that are tailored to each patient based on the genetic makeup of their cancer. This major leap forward in our understanding of the biology of cancer is taking place at a time when financial support for cancer research is shrinking. Researchers are overflowing with ideas and desperately want to move their research discoveries downstream to where they can help more patients. This requires doing clinical cancer research in new ways, and is where umbrellas and buckets come in.

In an “umbrella trial,” patients with a given type of cancer are assigned a specific treatment arm based on the molecular makeup of their cancer. Umbrella trials have many different arms under the umbrella of a single trial. Patients are assigned to an arm on the trial based on the molecular makeup of their cancer. Umbrella trials allow us to test a variety of targeted drugs at the same time in the patients who are most likely to benefit, i.e. those with cancers that have the specific molecular abnormality targeted by the drug. However, such studies are not easy – their modular structure is quite complex and can lead to various arms being moved in and out of the study as new drugs become available and results from testing of other drugs become clear.

In a “bucket trial” (also called a basket trial), cancers of different types are tested to see if they have a particular molecular abnormality. If they do, the patients with that abnormality are eligible to be treated with a new drug that targets that particular abnormality. The advantage of this approach is that it allows us to test new treatments across cancer types. On the other hand, we often have to test many patients to find the handful that have the abnormality targeted by the new treatment. This is inefficient for the research team that needs to explain the trial, get informed consent, and do the molecular testing on “a bucketful” of patients to find just a few who are eligible for the study. It can be incredibly frustrating for a patient who agrees to be tested, only to be told she is not eligible to be treated on the study because her cancer does not have the appropriate target.

Putting aspects of umbrella trials (exploring different treatments based on the molecular makeup of the cancer) and bucket trials (looking across different cancer types for response to a given targeted therapy) together can result in a “master protocol” such as the NCI MATCH trial that I discussed in a previous blog. In a master protocol, patients with a variety of cancers undergo molecular testing and are assigned a treatment arm based on the makeup of their tumor. Given the hundreds of possible genetic abnormalities that we now know can drive cancers, a truly comprehensive master protocol would have a very large number of arms and would be changing constantly. Each arm would only cover a small fraction of all the patients, yet a large fraction of patients would be eligible for at least one arm. Such a protocol would require unprecedented cooperation by cancer centers across the country if it is to be successful, yet would also accelerate progress.

Our current system for providing administrative and regulatory oversight of clinical trials was designed before umbrellas, buckets and master protocols were being considered. It was designed when most clinical trials involved testing a given treatment in a given cancer type at a single institution. Every clinical trial available at a given institution was only made available to patients after it was reviewed by an institutional committee responsible for assuring the trial was scientifically strong and another committee that assured protection of patient rights.

With the new trial designs, even the largest cancer centers will likely enroll only 1 or 2 patients onto many arms of a study. Putting each arm of each study through the scientific and ethics committees of each institution separately, as we have done for decades, would require a huge and duplicative administrative effort that, in this era of shrinking resources, would prevent such studies from being successful. What is needed is a new approach to administration, oversight and regulation of clinical cancer trials that is more efficient yet still assures safety and protection of patient rights. This requires reassessing the value of long standing policies, and working together more effectively, not only in conducting clinical cancer trials, but also in administering and overseeing them.

It is not an easy transition, but the cancer research community has started working within our own institutions, with each other, with the NCI and with other regulatory agencies to adjust to the new climate and enhance the efficiency of performing molecularly targeted, collaborative, modular clinical cancer trials such as umbrella trials, bucket trials and master protocols. Included in this effort is development of systems that allow for strong central review and oversight of clinical trials so the effort does not need to be duplicated independently at multiple individual institutions.

The climate is indeed changing, and we need to stay ahead of these changes if we are to guide the flood of new discoveries into improved care for our patients.

NCI MATCH

On a recent trip out of town, I had a bit of a disagreement with my rental car. I wanted to find NPR and listen to the news. First I tried the preset buttons on the radio, which led me to talk show hosts yelling at each other and golden oldies – not what I was looking for. I then tried scanning up and down the dial, where I found mostly Justin Bieber and Katy Perry (I would not have known who the “artists” were without the help of the hyper-kinetic DJ). I eventually gave up. Continue reading

To boldly go …

OK, I admit it.  When I was a kid I was into Star Trek (even had a picture of the starship Enterprise on my wall).  Not the Star Trek movies or the newfangled “Next Generation” or “Deep Space 9” series, but the original series first broadcast in the 1960s.   I was fascinated by the transporters, flip-top communicators, and medical “tricorder” that was waved over the patient by Doctor McCoy (called “Bones” by the future Iowan Captain Kirk) to make a medical diagnosis in seconds.

Fast forward 45 years …  I am still waiting on the transporters, but Star Trek’s flip-top communicators seem quaint compared to today’s smart phones.     How about the medical tricorder?  We have CT, MRI and PET scanners that were not on the starship Enterprise radar screen 45 years ago.  This week, at the University of Iowa, we rolled out another type of medical test that goes even further into the “final frontier” of molecular medicine. Continue reading