Duke Research Blog

Following the people and events that make up the research community at Duke.

Author: Brian Du

Overdiagnosis and the Future of Cancer Medicine

For many years, the standard strategy for fighting against cancer has been to find it early with screening when the person is still healthy, then hit it with a merciless treatment regimen to make it go away.

But not all tumors will become life-threatening cancers. Many, in fact, would have caused no issues for the rest of the patients’ lives had they not been found by screening. These cases belong to the category of overdiagnosis, one of the chief complaints against population-level screening programs.

Scientists are reconsidering the way to treat tumors because the traditional hit-it-hard approach has often caused the cancer to seemingly go away, only to have a few cells survive and the entire tumor roar back later with resistance to previously effective medicine.

Dr. Marc Ryser, the professor who gave this meaty talk

In his May 23 talk to Duke Population Health, “Cancer Overdiagnosis: A Discourse on Population Health, Biologic Mechanism and Statistics,” Marc Ryser, an assistant professor at Duke’s Departments of Population Health Sciences and Mathematics, walked us through how parallel developments across different disciplines have been reshaping our cancer battle plan. He said the effort to understand the true prevalence of overdiagnosis is a point of focus in this shift.

Past to Future: the changing cancer battle plan
Credit: Marc Ryser, edit: Brian Du

Ryser started with the longstanding biological theory behind how tumors develop. Under the theory of clonal sweeps, a relatively linear progression of successive key mutations sweeps through the tumor, giving it increasing versatility until it is clinically diagnosed by a doctor as cancer.

Clonal sweeps model, each shade is a new clone that introduces a mutation credit: Sievers et al. 2016

With this as the underpinning model, the battle plan of screen early, treat hard (point A) makes sense because it would be better to break the chain of progression early rather than later when the disease is more developed and much more aggressive. So employing screening extensively across the population for the various types of cancer is the sure choice, right?

But the data at the population level for many different categories of cancers doesn’t support this view (point B). Excluding the cases of cervical cancer and colorectal cancer, which have benefited greatly from screening interventions, the incidence of advanced cases of breast cancer and other cancers have stayed at similar levels or actually continued to increase during the years of screening interventions. This has raised the question of when screening is truly the best option.

Scientists are thinking now in terms of a “benefit-harm balance” when mass-screening public health interventions are carried out. Overdiagnosis would pile up on the harms side, because it introduces unnecessary procedures that are associated with adverse effects.

Thinking this way would be a major adjustment, and it has brought with it major confusion.

Paralleling this recent development on the population level, new biological understanding of how tumors develop has also introduced confusion. Scientists have discovered that tumors are more heterogeneous than the clonal sweeps model would make it appear. Within one tumor, there may be many different subpopulations of cancer cells, of varying characteristics and dangerousness, competing and coexisting.

Additional research has since suggested a more complex, evolutionary and ecological based model known as the Big Bang-mutual evolution model. Instead of the “stepwise progression from normal to increasingly malignant cells with the acquisition of successive driver mutations, some cancers appear to evolve more like a Big Bang, where the malignant ability is already concentrated in the founder cell,” Ryser said.

As the first cell starts to replicate, its descendants evolve in parallel into different subpopulations expressing different characteristics. While more research has been published in favor of this model, some scientists remain skeptical.

Ryser’s research contributes to this ongoing discussion. In comparing the patterns by which mutations are present or absent in cancerous and benign tumors, he obtained results favoring the Big Bang-mutual evolution model. Rather than seeing a neat region of mutation within the tumor, which would align with the clonal sweeps model, he saw mutations dispersed throughout the tumor, like the spreading of newborn stars in the wake of the Big Bang.

How to think about mutations within a tumor
credit: NASA

The more-complicated Big Bang-mutual evolution model justifies an increasingly nuanced approach to cancer treatment that has been developing in the past few years. Known as precision medicine (point C), its goal is to provide the best treatment available to a person based on their unique set of characteristics: genetics, lifestyle, and environment. As cancer medicine evolves with this new paradigm, when to screen will remain a key question, as will the benefit-harm balance.

There’s another problem, though: Overdiagnosis is incredibly hard to quantify. In fact, it’s by nature not possible to directly measure it. That’s where another area of Ryser’s research seeks to find the answers. He is working to accurately model overdiagnosis to estimate its extent and impact.

Going forward, his research goal is to try to understand how to bring together different scales to best understand overdiagnosis. Considering it in the context of the multiscale developments he mentioned in his talk may be the key to better understand it.

Post by Brian Du

Meet New Blogger Brian Du

Brian survives his week in the desert.

Hi! My name is Brian Du, and I’m a sophomore from Texas. I’m a pre-med majoring in computer science. I like vacations, hiking, and hiking on vacation. Besides these hobbies, I also love learning about science and hearing a good story. These latter two are exactly why I’m excited to be writing for the Duke Research Blog.

My first exposure to science happened in third grade because my goldfish kept getting sick and dying. This made me sad and I became invested in making them well again. I would measure pH levels regularly with my dad and keep notes on the fishes’ health. Eventually the process turned into a science fair project. I remember I loved presenting because I got to point out to the judges the ‘after’ pictures of my fish, which showed them alive, healthy, and happy (I think? it’s hard to tell with fish).

One happy fish!
Source: Reddit

My fish and I go way back.

After that third-grade experiment, I kept doing science projects — almost year after year actually — since I love the research process. From framing the right questions and setting up the experiment, to running the trials and writing up and sharing my work, my enthusiasm grew with each step. Come competition day, I noticed that in interviews that went well, my excitement was contagious, so that judges grew more eager too as they listened. And so I understood: a huge part to science is communication. Science, like food or a good story, is meant to be shared with others. The scientist is a storyteller, adjusting his presentation to captivate different audiences. With judges, I spoke jargon, but during public exhibition, where I chatted with anyone who came up to me, I got creative when asked about my research. Analogies helped me link strange concepts to everyday objects and experiences. An important protein channel became a pipe, and its inhibitor molecule a rock which would clog the pipe to make it unusable.

protein channel “pipe”
edited from CThompson02

Now that I’m at Duke, there’s so many stories to tell of the rich variety of research being done right on campus! I’ve written a few articles for the Chronicle covering some of the new medicine or proteins Duke professors have been involved in developing. As I keep an ear out for more stories, I hope to share a few of them in my upcoming posts, because I know they’ll be exciting!

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