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Liquid biopsies are changing how doctors learn about cancer. Instead of taking a tissue sample from a tumor, a liquid biopsy uses a simple blood draw to gather clues about what’s happening inside the body. Leading liquid biopsy expert, medical oncologist, and Associate Director of Precision Oncology at the Weill Cornell Medicine Meyer Cancer Center, Dr. Massimo Cristofanilli explains how liquid biopsies work, why they matter, and where this fast-moving technology may go next.
For many years, a tissue biopsy has been the main way to diagnose cancer and guide treatment. Historically, these tissue samples have been considered the gold standard or the traditional way to assess the histological diagnosis – or microscopic structure – of cancer. Tissue samples can also be tested for biomarkers and genetic changes that help doctors select more individualized treatments.
But, cancer can evolve. According to Dr. Cristofanilli, tumors can be very heterogeneous, meaning their makeup can vary in different places, and metastatic tumors in different parts of the body may not all look the same. Tumors can also change, adapt and evolve over time under the pressure of treatment. “That’s where liquid biopsy can be especially useful, because it is more of a real-time assessment of the disease biology,“ Dr. Cristofanilli says.
Liquid biopsy blood testing usually refers to two related approaches. One looks for circulating tumor cells (CTCs)—rare cancer cells that have escaped the tumor and entered the bloodstream. The challenge is that circulating tumor cells are extremely rare in the peripheral blood so they have to be separated out using specialized technology. One platform, CELLSEARCH®, became the first FDA-approved test for counting these cells approximately 20 years ago. Using this CELLSEARCH® technology, cancer cells can be detected even if only one in a million cells is present in the body. Researchers have found that in breast and prostate cancer, having five or more of these circulating tumor cells detected was linked to more aggressive disease patterns.
The second approach looks for circulating tumor DNA (ctDNA), often measured through what is called “cell-free DNA” tests. It is much more common for cell-free DNA to be circulating through the bloodstream. Dr. Cristofanilli explains that typically only a fraction of the cell-free DNA that is detected is actually tumor DNA, but that the technology has improved to be able to capture very small amounts of tumor-derived DNA with great sensitivity. This has opened new ways to track cancer changes over time, especially in advanced or metastatic disease.
Liquid biopsy can also be faster and less invasive than a tissue biopsy. Tissue biopsies require physically accessing the tumor to send samples for genetic testing and pathology evaluation. This typically requires surgery or a minor procedure. In the cases of smaller tumors or certain tumors that are harder to access in the body, obtaining tumor tissue can be more challenging and come with additional risks. Even after a traditional tissue biopsy has been obtained, additional time differences persist. “A report from a cell-free DNA liquid biopsy test takes anywhere between five and seven days, while a tissue biopsy with next generation sequencing (NGS) or any molecular analysis takes at least two weeks,” says Dr. Cristofanilli.
A major advantage of liquid biopsy is that the results may reflect cancer activity across multiple tumor sites throughout the body at once, for example breast cancer that originates in the breast and has spread to the liver. Dr. Cristofanilli calls this “the most exciting aspect of molecular diagnostics.”
He adds, “You have tumors shedding from multiple sites so you can better understand exactly the overall tumor burden and molecular representation of the disease.” This can be especially important when certain areas, like bone, are difficult to biopsy.
Liquid biopsy is also starting to influence how doctors think about when to change treatment. Current research is underway to determine when cell-free tumor DNA in the blood has shown signs of treatment resistance, even before scans showed visible growth of the cancer. This is referred to as “molecular progression,” meaning the cancer is showing molecular signs of change even if imaging still looks stable.
In a recent clinical trial, liquid biopsy blood tests were utilized for early detection of a treatment-resistance mutation, followed by a switch to a new type of treatment when the tumor DNA showed resistance. The research demonstrated that the treatment change significantly extended the period of tumor control compared to standard care in patients with advanced breast cancer. The study was conducted at multiple international medical centers, including at Weill Cornell Medicine and NewYork-Presbyterian. This was one of the first instances showing that treatment changes guided by liquid biopsy results brings better outcomes for patients.
Dr. Cristofanilli highlights why this is such a major shift. “This is the first time, not only that we’re treating the molecular progression, but in which we’re also able to determine the specific drug the cancer is developing resistance to, allowing us to be more targeted in our approach to change therapy – in this case, only changing one drug when otherwise the practice had been to change the entire treatment.” While still a newer area of cancer research and treatment, the idea of acting on molecular signals earlier in the course of cancer care could lead to new strategies for keeping cancer controlled longer and possibly delaying symptoms and side effects that patients experience.
In the future, Dr. Cristofanilli is especially excited about leveraging liquid biopsy for early detection and making these tools more accessible to more people. “The ability to detect very early on the presence of cancer can overcome many difficulties in terms of compliance and access to screening,” he explains. He also reinforces the need for tests that are easier and less expensive worldwide, noting that earlier cancer detection could have a huge impact in low-resource settings.
As liquid biopsy technology continues to grow and advance in sophistication—from capturing circulating tumor cells and tumor DNA to newer approaches like detecting DNA methylation signals—it may help doctors detect cancer sooner, personalize treatment more precisely, and monitor disease in ways that were not possible just a few years ago.
For an in-depth discussion on liquid biopsy and the technological advancements in this area, tune in to a recent episode of the Weill Cornell Medicine CancerCast Podcast where Dr. Cristofanilli sat down with host Dr. Manish Shah to delve into this topic. Listen on Apple Podcasts, Spotify, YouTube, or the Weill Cornell Medicine website.
