Liquid Biopsies Smooth Way For Personalized Medicine

What if just two vials of your blood could tell doctors which cancer treatment would work best for you?

In the COLOMATE clinical trial, John Strickler is using a blood test that detects DNA from tumors to select therapies for people with colorectal cancer. (photo by Les Todd)By design, some of the newest and most exciting cancer treatments don’t work for everybody. Instead, they target tumors that have a specific genetic mutation or characteristic. A treatment like this might be a miracle drug for a patient whose tumors have that mutation, while doing nothing at all for a patient whose tumors don’t.

Distinguishing between those patients ahead of time is essential to unlocking the powerof personalized medicine.

It’s a complicated task because a tumor can have more than a dozen mutations, and they can change over time and from spot to spot within a person’s body.

That’s where the liquid biopsy comes in. A liquid biopsy is an analysis of blood (or other bodily fluid) to learn about the genetics and other characteristics of a patient’s cancer.

“Liquid biopsies can potentially get you to the right treatment for a patient much quicker than an invasive tissue biopsy,” says John Strickler, MD, an assistant professor of medicine who specializes in gastrointestinal (GI) cancers. “With two vials of blood, we can know what is going on in the tumor.”

Liquid biopsies have many advantages over traditional tissue biopsies. They are quicker,cheaper, and safer for patients. They are easy to repeat to see if the genetic profile of the tumor has changed, which commonly happens when tumors develop resistance to treatment. Liquid biopsies also work well in cases where cancerous tissue is hard to access or doesn’t yield enough tissue to analyze.

And, a liquid biopsy can provide a more comprehensive picture of all the cancer throughout the body, rather than information from just the spot where solid tissue was sampled. A tissue biopsy in one area can easily miss crucial mutations elsewhere.

In several of Strickler’s patients with metastatic GI cancers, a liquid biopsy showed rare mutations that the tissue biopsy didn’t, allowing him to try a targeted therapy that wouldn’t otherwise have been indicated.

These patients had meaningful improvements in survival with better quality of life. In other words: relief from symptoms and more time with loved ones.

“The liquid biopsies are a valuable tool,” he says. “They are convenient, cost-effective, and safe. They help us provide better care, and they are something we can use to make our existing treatments better.”

Liquid Biopsies in Clinical Trials  

AA LANDMARK TRIAL: Andrew Armstrong used liquid biopsies in a clinical trial called PROPHECY. The results showed that a liquid biopsy test that detects circulating tumor cells in the blood could help guide the selection of treatment for men with advanced prostate cancer. One of the tests used in the trial is covered by Medicare and is available at Duke. (photo by Alex Boerner)t present, liquid biopsies aren’t used routinely in the care of any cancer except lung cancer. But Strickler expects that clinical trials will change that. He’s doing his part to move things along by conducting several clinical trials using liquid biopsies in patients with colorectal cancer.

Strickler has just launched a new trial, COLOMATE, in which he will be using liquid biopsies to match patients to the therapies most likely to help them, including some offered through clinical trials.

The multi-center trial aims to recruit more than 500 patients with metastatic colorectal cancer whose cancer has progressed after at least two lines of standard chemotherapy. It will be the largest clinical trial using liquid biopsies with colorectal cancer to date.

“The hope is, number one, that we can use results from the liquid biopsies to give patients better outcomes than they would have received from standard treatment,” he says, “and,two, show that liquid biopsies can be used in the GI oncology clinic to improve our care because it’s safe, easy, and efficient.”

The type of liquid biopsy that will be used in the COLOMATE trial analyzes bits of DNA in the bloodstream that have come from tumors. It’s called cell-free DNA (cfDNA) because it’s no longer inside a cell.“

The liquid biopsy is capturing fragments of DNA from the tumor and sequencing that as if it were tumor tissue,” he says.That genetic profile will show if there are particular mutations that might make the cancer susceptible to a targeted therapy. Some of the mutations might be the original drivers of the cancer, such as the human epidermal growth factor receptor 2 (HER-2), while other mutations might have arisen as a result of treatment.

Strickler notes that the cfDNA liquid biopsy has been widely available for several years in a very different application: it can be used in pregnant women as a way to check fetal DNA for Down Syndrome.

Another type of liquid biopsy gathers whole tumor cells from the bloodstream. These cells are called circulating tumor cells (CTC). Like all cells, they contain RNA, which contains instructions for making proteins. The RNA or its proteins can be analyzed for evidence of mutations.

Andrew Armstrong, MD, professor of medicine, surgery, and pharmacology and cancer biology, is a medical oncologist who specializes in prostate cancer and other genitourinary cancers. Armstrong used CTC liquid biopsies in a clinical trial called PROPHECY. The results were presented last year and are published in the Journal of Clinical Oncology.

The 118 men in the PROPHECY trial all had metastatic prostate cancer that had become resistant to the first-line hormone therapy. The typical next step is anti-androgen therapy via the drugs abiraterone or enzalutamide, or both.

“The current practice is, the doctor prescribes these drugs andhopes they work,” Armstrong says.

Unfortunately, they don’t work for everyone. One suspected culprit is an androgen receptor variant called AR-V7, which is thought to block the action of those drugs. The PROPHECY trial demonstrated that, indeed, the men whose CTCs tested positive for AR-V7 did not benefit from either drug. Of the men who tested negative for AR-V7, many had a good response to the treatment.

“These men need effective therapies quickly,” Armstrong says. “The trial suggests that the liquid biopsy could help guide optimal treatment selection. In men with AR-V7-driven prostate cancer, chemotherapy or a clinical trial may be the best option rather than anti-androgen therapy.”

The trial compared two different CTC assays, which used different techniques for seeking out AR-V7.

“Both tests were successful, and there was a pretty strong correlation between the two in the same patient,” Armstrong says.

One of the tests, provided by Epic Sciences, is covered by Medicare and is available at Duke. Neither test is approved yet by the Food and Drug Administration, although it’s possible that the data from PROPHECY could change that.

Joshua Lang, MD, an associate professor of hematology/oncology at the University of Wisconsin, who was not involved in PROPHECY, says the study design and implementation were strong, and the fact that it was a multisite trial makes the results generalizable.

“It’s really a landmark trial in the study of liquid biopsies,” he says.

Armstrong recently collaborated with a researcher in Duke's Pratt School of Engineering who developed a way of using sound waves to find and gently sort CTCs in blood. The new technique was designed by Tony Jun Huang, PhD, the William Bevan Professor of Mechanical Engineering and Materials Science, in collaboration with colleagues at MIT and Nanyang Technological University (Singapore). It improves on current technology by steering the cells into a chamber acoustically rather than by physical contact. This opens up the possibility of one day being able to collect undamaged cancer cells from a patient in order to grow them in the lab and test different drugs on them.

A Smarter Future

Invented by Tony Jun Huang of Duke's Pratt School of Engineering, this device, about the size of a penny, uses sound waves to find and gently separate cancer cells from a blood sample. Because the cancer cells are undmaged after passing through the device, they can be profiled in the lab. Oncologist Andrew Armstrong has collaborated with Huang on this work.Right now, both Strickler and Armstrong are testing liquid biopsies primarily in patients with advanced disease. For one thing, people with early stage disease don’t always have cfDNA or CTCs available in their blood. For another, part of the liquid biopsy’s usefulness is in picking up mutations that developed during treatment.

However, as the technology continues to improve, it may eventually be used in newly diagnosed patients, or perhaps as a tool to diagnose cancer before it’s even visible on a scan.

And as cancer researchers continue to design new therapies, there will be more opportunities to use liquid biopsies to make sure the right treatments get to the right patients.

Both Strickler and Armstrong are optimistic about the future of the technology.

“Using liquid biopsies helps us be smarter about how we are selecting therapies for patients,” Strickler says. Armstrong says, “This is what personalized medicine is all about."

This article appeared in the Spring 2019 issue of Breakthroughs, a magazine produced twice yearly by Duke Cancer Institute Office of Development. Subscribe to Breakthroughs.

 

CIRCLE PHOTO (TOP): GI oncologist John Strickler, MD, consults with Andrew Nixon, PhD, who runs The Phase 1 Biomarker Research Laboratory. (photo by Les Todd)