LIQUID BIOPSY: A LEADING EDGE IN FINE-TUNING
CANCER DETECTION AND TREATMENT
Photo by John Deputy, republished with permission from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
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Children’s Oncology Group (COG) researchers are leading the push to study tiny fragments of DNA that tumors slough off in the blood as biomarkers for cancer. This growing body of “liquid biopsy” research is building momentum toward breakthroughs in detecting cancer on more microscopic levels than ever before, which could help doctors tailor treatments precisely to the needs of each patient and better predict the risk of relapse.
Dr. Brian Crompton, MD, is one of the scientists making exciting progress at the forefront of research on circulating tumor DNA (ctDNA). He got involved in ctDNA research during his postdoctoral studies, when he was collaborating on a groundbreaking project to sequence the DNA of Ewing sarcoma — a rare and fast-growing cancer of the bone and soft tissue that affects mostly children and young adults.
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By spelling out the genetic code of Ewing sarcoma cells, Dr. Crompton helped pinpoint exactly where and how mutations in cells’ DNA trigger them to become cancerous. That discovery led him to tiny bits of DNA that tumors shed into the bloodstream — back when an entirely new way of studying cancer cells and the effectiveness of treatments was just getting started.
Tracking down DNA fragments that play hard to get
When cells die, they break up and release their contents into the blood. Tiny bits of DNA break free from dying cells. The shards of cast-off DNA circulate in the blood for only an hour or so before the kidney and liver filter them out. Both healthy and cancerous DNA fragments are found in extremely low levels in the blood, which makes them hard to find.
This is where “liquid biopsy” science comes into play. It’s not yet used to diagnose someone with cancer at the outset. That’s the eventual hope, but for now scientists are using ctDNA to give them better, real-time data on how a patient is responding to treatment over time.
“We’ve never had tools that could detect microscopic disease,” Dr. Crompton said. “Liquid biopsies will help us figure out who needs more treatment and who needs less.”
Questions liquid biopsy science is helping researchers answer
Several studies have linked high levels of ctDNA in the blood with a higher risk of relapse, and lower levels of ctDNA with a lower risk of relapse. For example:
Every question researchers answer spawns new questions. And every new question leads to greater promise for bigger advances in detecting cancer and more accurately predicting how different types of cancer will respond to treatment.
As ctDNA detection technologies advance, more sensitive tests help doctors catch relapses faster and start experimental treatments sooner, giving kids with the most difficult-to-treat cancers better odds of surviving long-term.
Tracking down DNA fragments that play hard to get
When cells die, they break up and release their contents into the blood. Tiny bits of DNA break free from dying cells. The shards of cast-off DNA circulate in the blood for only an hour or so before the kidney and liver filter them out. Both healthy and cancerous DNA fragments are found in extremely low levels in the blood, which makes them hard to find.
This is where “liquid biopsy” science comes into play. It’s not yet used to diagnose someone with cancer at the outset. That’s the eventual hope, but for now scientists are using ctDNA to give them better, real-time data on how a patient is responding to treatment over time.
“We’ve never had tools that could detect microscopic disease,” Dr. Crompton said. “Liquid biopsies will help us figure out who needs more treatment and who needs less.”
Questions liquid biopsy science is helping researchers answer
Several studies have linked high levels of ctDNA in the blood with a higher risk of relapse, and lower levels of ctDNA with a lower risk of relapse. For example:
- For most patients with Ewing sarcoma, ctDNA levels plummet to undetectable levels during chemotherapy. These patients usually remain cancer-free after completing treatment.
- For a subset of patients with Ewing sarcoma, ctDNA remains detectable after treatment begins. In this group, the chances of treatment resistance or eventual relapse are very high.
- Researchers can also identify mutations in the ctDNA that arise only at relapse, suggesting that tumors can develop resistance to treatment over time. Dr. Crompton’s lab is now trying to figure out exactly where, how, and why those patients’ tumors change.
Every question researchers answer spawns new questions. And every new question leads to greater promise for bigger advances in detecting cancer and more accurately predicting how different types of cancer will respond to treatment.
As ctDNA detection technologies advance, more sensitive tests help doctors catch relapses faster and start experimental treatments sooner, giving kids with the most difficult-to-treat cancers better odds of surviving long-term.
Test tubes, temperature-control kits, and other indispensables
To study ctDNA, Dr. Crompton’s lab has spent years collecting blood samples from hundreds of kids with Ewing sarcoma and thousands of children with pediatric solid tumors — many of them from COG’s Project:EveryChild ‘biobank.” Getting all of those samples to his lab, based at Dana-Farber Cancer Institute and Boston Children’s Hospital, is a costly, multi-step process.
“Many tens of thousands of dollars go into buying the test tubes that get shipped to each center for blood collection,” Dr. Crompton said. “Then there’s a kit that keeps the blood at room temperature when they are shipped to the COG biobank. This prevents the tubes from immediately freezing in the middle of winter or boiling in the middle of the summer — ruining the sample for research — during the shipment process.”
To study ctDNA, Dr. Crompton’s lab has spent years collecting blood samples from hundreds of kids with Ewing sarcoma and thousands of children with pediatric solid tumors — many of them from COG’s Project:EveryChild ‘biobank.” Getting all of those samples to his lab, based at Dana-Farber Cancer Institute and Boston Children’s Hospital, is a costly, multi-step process.
“Many tens of thousands of dollars go into buying the test tubes that get shipped to each center for blood collection,” Dr. Crompton said. “Then there’s a kit that keeps the blood at room temperature when they are shipped to the COG biobank. This prevents the tubes from immediately freezing in the middle of winter or boiling in the middle of the summer — ruining the sample for research — during the shipment process.”
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Other essential logistical costs COG has covered include processing those blood samples when they arrive at the biobank, then shipping them out to researchers like Dr. Crompton for their approved projects.
“Every single step in that process is expensive and must be done for each trial,” Dr. Crompton said. “So, all of this cool science that we’re doing — literally 0% of it happens if the COG Foundation doesn’t support things like mission-critical blood collection tubes, packaging material, and shipping costs to get those samples banked for research.” And yet, researchers have a hard time securing funding for these types of logistical expenses. |
Brian D. Crompton, MD
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“I can write a grant to sequence 100 samples, but it’s very hard to ask, ‘Can you give me money to give to COG to collect those samples and ship them to the biopathology center, then to my lab?’” Dr. Crompton said.
The COG Foundation funded these critical efforts with support from generous donors, including the Emma Jordon Kidz Fighting Cancer Foundation, while other donors, like The Andrew McDonough B+ Foundation, have given directly to Dr. Crompton’s lab.
A leading force in pushing cancer research forward
Right now, scientists at the forefront of ctDNA research are validating answers to questions they’ve already asked. Their next step will be using ctDNA in large-scale clinical trials of experimental treatments with newly diagnosed patients — and not just for those with Ewing sarcoma.
Scientists studying other solid tumors will also use ctDNA as a tool to develop more effective treatments for osteosarcoma, Wilms tumor, neuroblastoma, rhabdomyosarcoma, and cancers of the liver and kidney.
When he talks to funders, Dr. Crompton is quick to highlight that COG’s network of more than 220 hospitals is the only one large enough to run Phase 3 trials showing whether new treatments work better than existing therapies — a critical step toward improving the standard of care.
“We’re collecting samples from the majority of patients with pediatric solid tumors in North America, which wouldn’t be possible without COG,” he said. “This is giving us the data we need to truly know that new treatments we’re studying are working — giving hope to the kids and families with these complex cancers.”
The COG Foundation funded these critical efforts with support from generous donors, including the Emma Jordon Kidz Fighting Cancer Foundation, while other donors, like The Andrew McDonough B+ Foundation, have given directly to Dr. Crompton’s lab.
A leading force in pushing cancer research forward
Right now, scientists at the forefront of ctDNA research are validating answers to questions they’ve already asked. Their next step will be using ctDNA in large-scale clinical trials of experimental treatments with newly diagnosed patients — and not just for those with Ewing sarcoma.
Scientists studying other solid tumors will also use ctDNA as a tool to develop more effective treatments for osteosarcoma, Wilms tumor, neuroblastoma, rhabdomyosarcoma, and cancers of the liver and kidney.
When he talks to funders, Dr. Crompton is quick to highlight that COG’s network of more than 220 hospitals is the only one large enough to run Phase 3 trials showing whether new treatments work better than existing therapies — a critical step toward improving the standard of care.
“We’re collecting samples from the majority of patients with pediatric solid tumors in North America, which wouldn’t be possible without COG,” he said. “This is giving us the data we need to truly know that new treatments we’re studying are working — giving hope to the kids and families with these complex cancers.”