Liquid biopsy continues its evolution in guiding cancer care
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Often regarded in oncology as a complementary diagnostic or early detection tool, liquid biopsy has moved into routine clinical use to help guide treatment decisions in the era of targeted, molecular-based therapies.
Next-generation sequencing of blood samples that provides a comprehensive molecular profile is the emerging gold standard, but the term liquid biopsy can also refer to simpler tests that measure minimal residual disease after a previous therapeutic intervention.
Liquid biopsy technology can do more than detect disease at early stages — it can monitor response to therapies, provide insight into how a disease evolves and uncover key targets and drug resistance mechanisms, according to Wafik S. El-Deiry, MD, PhD, FACP, associate dean for oncologic sciences at Warren Alpert Medical School and director of the Legorreta Cancer Center at Brown University.
“A lot of people [in oncology] are not aware of how powerful this technology is,” he told Healio. “There's a lot of information in those liquid biopsies, and I think it's important for our colleagues all around the country to learn about the utility of what can be learned to treat specific tumor types.”
The information derived from a liquid biopsy vs. a tissue sample is not superior, it’s just different, El-Deiry noted. It provides clinicians with a unique profile that complements, rather than replaces, solid tissue biopsy.
“Liquid biopsy gives you a readout on the whole body that may have molecular heterogeneity among metastatic lesions and not just a specific mass or a tiny sliver of the primary tumor,” he said.
El-Deiry described liquid biopsies as “the tumor markers of the future.”
“They are fast, and they provide incredibly valuable information — not just about which genes are mutated that relate to specific tumors, but also their amounts and how they change in response to treatment,” he said.
Healio examined the state of the art for liquid biopsy to guide treatment after diagnosis of lung and gastrointestinal cancers.
Lung cancer
The number of genetically targeted therapies for lung cancer has put those who treat the disease at the cutting edge of liquid biopsy technology.
The FDA has approved at least 10 genetically targeted therapies for treatment of lung cancer, according to Christine M. Lovly, MD, PhD, associate professor of medicine in the division of hematology-oncology and Ingram associate professor of cancer research at Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center.
“We use liquid biopsies as part of our diagnostic tools for finding tumor-specific mutations that are tagged to FDA-approved targeted therapies that have a genomic biomarker,” she told Healio. “I think uptake of liquid biopsy for diagnostic purposes has been very quick among those who treat lung cancer.”
Liquid biopsy technology has played a fundamental role in the emergence of precision-based molecular oncology, according to Christian Rolfo, MD, PhD, MBA, professor and associate director for clinical research at Center for Thoracic Oncology at Mount Sinai’s Tisch Cancer Institute and president of the International Society of Liquid Biopsy.
The information gleaned from liquid biopsies has transformed lung cancer treatment, Rolfo said.
“Precision oncology has radically changed the way we treat patients, including the drugs that we provide and the assessment of the patient after treatment — all because of the way we have implemented this liquid technology,” he told Healio.
Rolfo and colleagues from Mount Sinai published a study validating the utility of a blood biomarker, detected through liquid biopsy, to predict patient responses to immunotherapy for lung cancer. The researchers found an association between higher levels of extracellular vesicle PD-L1 expression in the blood of patients with non-small cell lung cancer who did not respond to anti-PD-1 therapy. The biomarker also helped predict PFS and OS, the investigators noted.
Realizing its possibilities, Rolfo, Lovly and other lung cancer specialists have become increasingly comfortable with liquid biopsy technology, and community-level physicians are leading the effort to get routine insurance coverage of next-generation sequencing for patients, he said.
Next-generation sequencing of both tissue and liquid samples should be seen as complementary tests and not a replacement for one another, Lovly said.
“We call them both next-generation sequencing, but they are not even the same tests,” she noted. “They are different tests with different levels of genes and different sensitivities and specificities.”
For example, tissue biopsies currently are the gold-standard method to confirm tumor histology and the origin of the tumor, Lovly said. In addition, eligibility for certain therapies requires determination of biomarkers specifically derived from tissue samples in the case of PD-L1, she added.
However, in cases where tissue DNA quantity is insufficient, it may be more feasible to conduct next-generation sequencing with a liquid sample, Lovly said.
“The downside is that not every patient with cancer will have tumor DNA floating in the blood, and so liquid biopsy is not 100% accurate for all patients,” she said. “For reasons that we don't understand, some patients have tumors that do not shed DNA into the bloodstream.”
Rolfo agreed and said that no matter which cancer type is being evaluated, liquid biopsy is a complementary approach to guide treatment.
Nevertheless, liquid biopsy is becoming widely adopted among the lung cancer community to help determine treatment approaches and monitor patient progress, he added.
“With [tissue] biopsy you cannot see indicators that the patient is responding,” he said. “This can be accomplished in a noninvasive manner using next-generation sequencing analysis. It’s a simple blood draw and it is easy to repeat.”
GI cancer
Liquid biopsy is not as well-established among GI cancer specialists, El-Deiry said. These clinicians are still educating themselves about the benefits and limitations of the emerging technology, he added.
However, there is an overall positive attitude toward adoption, El-Deiry said.
There are ample reasons why GI cancer specialists should increasingly look toward liquid biopsy to help guide treatment after diagnosis, according to Pashtoon M. Kasi, MD, MS, director of colon cancer research at Weill Cornell Medicine and director for liquid biopsy research at Englander Institute of Precision Medicine.
First, assays are becoming more accurate, he noted. Second, many GI cancers shed a lot of DNA into the bloodstream, making these tumors ideal candidates for next-generation sequencing via circulating tumor DNA and/or liquid biopsies in general.
"[Liquid biopsy] has been underutilized and underrecognized over the years and has recently gained traction as we have more data and more options for our patients,” he told Healio. These options include newer precision-based therapeutics, such as first-line agents and immunotherapies for colorectal cancer, Kasi noted. The quick turnaround (7 to 9 days) allows for rapid genotyping and identification of subsets who may benefit from a more precision medicine-based approach.
Issues in obtaining tissue samples for some GI cancer specimens make liquid biopsy an attractive alternative, Kasi said.
“For some GI cancers, getting tissue is not always safe or feasible,” he said. “It is also not uncommon to not have enough tissue for next-generation sequencing and/or the specimen may not be at the treating oncologist’s institution, leading to significant delays in getting results back due to delays in procuring tissue.”
Professional guidelines are also evolving to recommend use of liquid biopsy for genomic profiling of certain GI cancer types, even as a preferred option to tissue biopsy, Kasi said. This shift has occurred not because liquid biopsy is superior, but rather because liquid samples are more likely to be available than tissue, he said.
Obtaining enough sample tissue is often an issue in the real-world setting, he noted. This is especially true for diseases such as cholangiocarcinoma, where often getting enough tissue is a problem. And completing genotyping is very relevant, because research has shown multiple actionable biomarkers amenable to targeted therapy.
Kasi presented a poster at this year’s ASCO Quality Care Symposium outlining which tumor types were most amenable to liquid biopsy based on the proportion of samples that exhibited enough circulating tumor DNA to reliability test for related biomarkers. His group found that 92% of samples from patients with cholangiocarcinoma had circulating tumor DNA despite current guidelines not recommending use of liquid biopsy for the disease.
Colorectal cancer also scored high in the analysis with tumor shed detected in 92% of samples, on par with lung cancer (91%).
Another major advantage of liquid biopsy is the turnaround time, Kasi said. Some companies offer results in 7 to 9 days for next-generation sequencing panels, he said, whereas tissue biopsy can routinely take a month or more to get results, owing mainly to procurement of tissue. But the ease of getting a noninvasive blood draw at the time of visit, including home phlebotomy, is what makes liquid biopsies attractive as a complementary and/or a liquid- or plasma-first approach.
Future directions
Like many of his colleagues, Kasi believes the optimal role of liquid biopsy is to augment a clinician’s overview of a patient's disease and not as a replacement for tissue biopsy.
“I see it as a complementary technology for cancer treatment that will evolve over time,” he told Healio.
El-Deiry said he has been preaching the benefits of liquid biopsy for several years, and over that time companies have provided a greater variety of more accurate tests.
He acknowledged that liquid biopsy is not 100% reliable for all patients, but his colleagues had the same complaint about tumor markers more than 2 decades ago.
“[Tumor markers] may be unreliable in a very small percentage of cases, but in the vast majority of patients, they are very reliable,” he said. “This same lesson can likely be applied to liquid biopsy.”
El-Deiry foresees use of the technology to determine “detectability” of residual disease for solid tumors, and that patients with advanced disease whose circulating tumor DNA becomes undetectable — indicative of disease clearance for a certain period — may eventually require no further treatment.
“For some patients, you can have a small amount of disease that may remain present and lead to relapse eventually off of therapy,” El-Deiry said. “But then there are going to be people in whom it's undetectable who may be cured. It takes time to prove all this, but that is what I see on the horizon.”
Other important areas include monitoring of tumor evolution and emergent resistance mechanisms with therapy, or the extinction of resistance mechanisms off therapy or with therapy breaks, El-Deiry added.
“Addressing therapy resistance effectively and in an individualized way will remain an ongoing challenge in oncology, but we now have these modern liquid biopsy tools,” he said.
Lovly agreed that overall use of liquid biopsy technology will increase among oncologists. She sees it moving into newer areas of care, including dynamic or longitudinal assessments of how a tumor is changing in response to treatment.
“We are evolving toward this in the future, but this is certainly not the standard of care yet,” she said, adding that dynamic assessment approaches are being explored in clinical trials.
The results of liquid biopsies can be complicated and difficult to interpret, even for the most experienced clinicians, Lovly noted.
She suggested that clinicians consult molecular tumor boards at their institution or inquire with the diagnostics provider, many of which have access to genomic scientists to help customers interpret the results.
“It is not just that we need to develop this technology, but we have to drive implementation in the right way,” Lovly told Healio. “It takes a village to make all of this cancer care come together.”
See related commentary, “Liquid biopsy takes on pancreatic cancer,” by Todd C. Knepper, PharmD
References:
- de Miguel-Perez D, et al. J Exp Clin Cancer Res. 2022;doi:10.1186/s13046-022-02379-1.
- Kasi PM, et al. Abstract 412. Presented at: ASCO Quality Care Symposium; Sept. 30-Oct. 1, 2022; Chicago.
For more information:
Wafik S. El-Deiry, MD, PhD, FACP, can be reached at Legorreta Cancer Center at Brown University, 70 Ship St., Room 537, Providence, RI 02912; email: wafik_el-deiry@brown.edu.
Pashtoon M. Kasi, MD, MS, can be reached at Weill Cornell Medicine, Gastrointestinal Oncology, 1305 York Ave., 12th Floor, New York, NY 10021; email: pmk4001@med.cornell.edu.
Christine M. Lovly, MD, PhD, can be reached at Vanderbilt-Ingram Cancer Center, 2220 Pierce Ave. South, 777 Preston Research Building, Nashville, TN 37232; email: christine.lovly@vumc.org.
Christian Rolfo, MD, PhD, MBA, can be reached at Mount Sinai, One Gustave Levy Place, Box 1079, New York, NY 10029; email: christian.rolfo@mssm.edu.
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Kasi PM, et al. Abstract 412. Presented at: ASCO Quality Care Symposium; Sept. 30-Oct. 1, 2022; Chicago.
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