"Oh, this is to just to help me for my work in Washington DC in a few weeks." It is sometimes difficult to explain the latest in cancer research. Olivia is 11 but she is curious and asked a million questions. I have been asked to serve on a workgroup at the FDA for tumor agnostic clinical trial design. She really wanted to understand what this was about. This was my explanation to her:
Your cells are complex machines. A cancerous tumor is a cluster of non-functioning cells. It is not like a single broken down car on the side of the road with its hazard lights politely blinking, which you can slip into the other lane to make room for. A tumor is hundred car pile up, that shuts down the freeway in both directions.
Doctors initially defined cancer geographically, by where the defective cells had originated: breast cancer, colon cancer, skin cancer... They would treat every traffic jam in Topeka as a "Kansas problem." In Kansas, they would try different approaches to deal with the collection of wreckage, looking for what would work best. Surgical tow trucks would haul out the debris. Sometimes, fires could level a junkyard. But aside from this not being terribly effective, it was also hard to distinguish between cars that were just stuck in the traffic, and the broken cars that were truly causing the problem. Progress was painfully slow. Few investigators collaborated outside of their specialty (The researcher's equivalent of 'What happens in Vegas, stays in Vegas!')
With better technology, scientists began looking more closely, at cancer DNA. Compared to shiny new cars coming out of the factory, many of those on the road have dings and dents. Researchers have discovered some defects, like a radio that wouldn't work. While interesting, this sort of alteration wouldn't really matter at all. Some researchers found other changes that would stop the windshield wipers from working, or perhaps the headlights, which does not hinder the function of the car directly. You can still drive, of course. But without these safety features, it is far more likely that a car crash will happen-- especially during inclement weather or at night.
I explained to Olivia that neither Lauren nor Brent have functioning headlights nor windshield wipers. It has been very dark and rainy for the RamerNation. We have seen so many car crashes. The past few years have been like having front row seats at the demolition derby.
Once a cancer collision happens, and the traffic jam gets noticed, doctors try to clear the scene, while the scientists try to sort out the cause. In recent years, researchers have been able to look even more carefully at the wrecked cars and debris to better establish why and how they are not functioning--Are they out of gas? Have they run over glass and blown out the tires? Is there a problem with the motor? Is there a problem with the brakes, the battery? Identifying the specific cause of malfunction helps scientists to develop strategies to fix the problem. These important observations and mutational discoveries, seen across tumor type, signaled the very beginning of targeted therapy.
With the recent advances in developing targeted agents, researchers have begun to sort cancers according to their system failure (the mutation), rather than by the location (tissue of origin), which makes enormous sense. When we understand what is preventing cells from functioning properly, we can begin to develop and administer a targeted fix. (It kind of doesn't matter where in the country the 'flat tire induced car crash' happened from a repair standpoint, unless you are in need of a surgical tow-truck. In that case a tumor specific specialty makes sense. Go with the guy that knows the roads best. A neurosurgeon clearly should not do your hysterectomy.)
So, in these new cancer studies, all cars with flat tires will be collected, regardless if they have broken down in NYC, LA or Atlanta, and they will be given "fix-a-flat, " as an example, or perhaps a new set of tires. Similarly, all cars with dead batteries from across the spectrum will be gathered in order to be jump-started, or given replacement batteries. To be perfectly clear, these trials sort patients by mutational target, rather than by tumor type. The treatment will target a particular mutation that is causing cells to not work properly, independent of what tissue the cancer presents in the body. So, rather than creating a "breast cancer trial" researchers are beginning to design tumor agnostic trials that might include patients with lung cancer, breast cancer, pancreatic cancer and brain tumor, all with the same mutation.
Cancer patients generally feel overwhelmed, frustrated and scared silly: They are late for work, unable to go to the grocery store or to take their kids to school because of a giant pile up that they never saw coming and don't understand. They often cluster together on the side of the freeway, waving matched colored ribbons like flags at a parade. They believe that banding together will bring awareness and solve the tumor specific problem entirely--"Don't mess with Texas!" This made so much sense initially, when cancer was taboo, and we knew so little. We have since learned that it is essential to work together, across tumor type: From California, to the New York Island.
This new culture is an absolute dream for someone with LFS who tends to juggle far too many ribbons, and each month brings a new cancer to celebrate, for lack of a better term. Being a cancer independent, unaffiliated with a particular party...describing those challenges could be it's own blog post.
Patients are only beginning to understand that the "why" their car doesn't work matters so much more than the location: of all the breakdowns in New Jersey, only some are flat tires. Every malfunctioning car in Trenton would not benefit from new tires, especially if it turns out that a good portion of these vehicles aren't running because of a bad alternator. This is why response rates, if you sort by tumor type, are so terribly low.
On the other hand, by ignoring tissue of origin and instead sorting by mutational type (sometimes called a "basket trial") researchers have seen much higher response rates in early phase trials, and these seem to require fewer numbers of patients to enroll before the FDA grants drug approval, evident in the record number of new drugs for cancer. Witnessing this kind of progress is an exciting and hopeful change. Targeted therapies are easier on patients. There are more of them every day.
But for patients to even qualify for this kind of trial, they must have genetic analysis of their cancer done. This is a further challenge, when only 5% of adult cancer patients currently enroll in clinical trials, when they are easily identified. I hope to help researchers understand the barriers that patients face, and to suggest trial designs and strategies that will help bridge this divide and hopefully address the disparities. We will collaborate, work with advocacy organizations and hopefully have more successful accruals. I know that the oncology world is changing rapidly, and this is encouraging. I am grateful to be a part of that change.
In 10 days, Lauren will have scans again. This is the necessary traffic report for a girl whose cells, lacking wipers and headlights, have sped through streets riddled with giant potholes and other hazards. In a monsoon. At midnight.
We welcome your prayers.
ASCO Tumor agnostic workshop
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