Innovations in the development of liquid biopsy platforms over the past decade have led to a growing number of regulatory approvals for blood-based tests that are transforming precision cancer care for patients with advanced disease. In 2013, the U.S. Food and Drug Administration (FDA) approved the first liquid biopsy test, the CellSearch® CTC enumeration platform, to monitor patients with advanced metastatic breast, colon, and prostate cancers based on the cancers’ level of circulating tumor cells. Three years later, the FDA approved the first circulating tumor DNA (ctDNA) blood-based genetic test to detect epidermal growth factor receptor (EGFR) gene mutations in patients with non–small cell lung cancer (NSCLC). Called the cobas EGFR Mutation Test v2, the product was approved as a companion diagnostic for osimertinib. It has since received FDA approval as a companion diagnostic for a broader group of therapies for NSCLC, including all five EGFR tyrosine kinase inhibitor therapies targeting EGFR mutations L858R and exon 19 deletions.
Blood-based liquid biopsy technology is providing a quick and noninvasive way to analyze tumors using biomarkers circulating in the blood. It is transforming precision cancer care for patients with advanced disease with potential usefulness for patients with early-stage cancer as well. Photo: Getty Images
Over the ensuing years, liquid biopsy tests, which provide a quick and noninvasive way to analyze tumors using biomarkers circulating in the blood, have been refined with the use of next-generation sequencing to target many cancer-related genes in advanced cancer. These tests have increased their range of clinical applications in cancer treatment to now include monitoring cancer growth, detecting genetic mutations, identifying signs of relapse, and predicting sensitivity to immunotherapy.
In 2020, the FDA approved two comprehensive genomic profiling liquid biopsy tests. They now can detect genomic alterations in multiple solid tumor types from cell-free ctDNA in patients’ blood and use next-generation sequencing technology to identify tumor mutations and help determine which patients are most likely to benefit from targeted therapies. The tests include Guardant360 CDx, which can detect changes in more than 60 different genes, and FoundationOne Liquid CDx, which can identify mutations or alterations in more than 300 genes relevant in solid tumors, as well as determine microsatellite instability–high status and blood tumor mutation burden, helping clinicians to understand the likelihood of response to checkpoint inhibitors.
Guardant360 CDx, manufactured by Guardant Health, was FDA approved as a companion diagnostic for osimertib for patients with EGFR-mutant NSCLC. The test also provides information on other gene mutations, including KRAS and BRAF. Foundation Medicine’s FoundationOne Liquid CDx is approved as a companion diagnostic for the poly (ADP ribose) polymerase inhibitor rucaparib for the treatment of advanced metastatic prostate cancer with BRCA1/2 mutations, as well as three tyrosine kinase inhibitors, including gefitinib, osimertinib, and erlotinib, approved for the first-line treatment of EGFR-mutant NSCLC.1 The test’s clinical utility has also been expanded to include information on genes relevant in other solid tumors, including breast, ovarian, and gastrointestinal cancers.
This past October, FoundationOne Liquid CDx was approved by the FDA for additional indications, including to identify mutations in BRCA1/2 genes in patients with ovarian cancer eligible for treatment with rucaparib; to identify ALK rearrangements in patients with NSCLC eligible for treatment with alectinib; and to identify mutations in the PIK3CA gene in patients with breast cancer eligible for treatment with alpelisib.2
And the number of regulatory approvals continues to grow. This past summer, the FDA granted expanded indications approval to Guardant360 CDx to include patients with NSCLC with EGFR exon 20 insertion mutations in plasma who may benefit from treatment with amivantamab-vmjw and patients with KRAS G12C mutations in plasma who may benefit from treatment with sotorasib.3 The agency also expanded approval to FoundationOne Liquid CDx as a companion diagnostic to help identify patients with BRCA1/2 mutations and/or ATM alterations in metastatic colorectal cancer for whom treatment with olaparib may be appropriate, as well as for patients with metastatic NSCLC with MET exon 14 skipping mutations for whom treatment with capmatinib may be appropriate.
Changing the Paradigm in Cancer Screening
The approvals are fueling clinical momentum in the use of liquid biopsies as an alternative to traditional tissue biopsies, which are more invasive to perform, may not always be feasible to obtain because of the tumor’s location, and take longer to deliver results, potentially delaying the time to treatment. According to the results from a recent pilot study comparing a next-generation platform liquid biopsy with standard-of-care tissue-based testing in patients with metastatic lung cancer, liquid biopsy provided analysis on the tumor approximately 10 days faster than tissue biopsy.4
Despite the increasing popularity of liquid biopsy testing in oncology care, currently their use is limited to the advanced-stage cancer setting, although two blood-based early cancer detection tests are under clinical trial investigation and may be making their way onto the market soon, potentially changing the paradigm in cancer screening. The results from two studies presented during the 2021 ASCO Annual Meeting show intriguing findings in detecting early cancer in individuals, including those with asymptomatic disease.
The interim results from the large interventional prospective PATHFINDER study evaluating Galleri™, a multicancer early detection test that uses targeted methylation-based cell-free DNA analysis to detect multiple cancer types and simultaneously predict cancer signal origin, show that the test correctly detected a cancer signal in a broad range of malignancies, and more than half of the cancers were detected at an early stage.5 A subsequent study of Galleri, which was developed by Grail (the company has since been purchased by Illumina), found that the test accurately detected cancer signals across more than 50 cancer types, with an overall sensitivity for cancer signal detection of 51.5%. However, the test was most accurate in detecting cancer in more advanced stages of disease: 90.1% for stage IV; 77% for stage III; 40.4% for stage II; and dropping to 16.8% for stage I.6
The second early-detection test garnering attention is LUNAR-2, a multimodal blood-based colorectal neoplasia detection assay from Guardant Health that incorporates ctDNA assessment of somatic mutations and tumor-derived methylation and fragmentomic (nucleic acid fragments across the genome) patterns. The results from the large ECLIPSE trial show that overall sensitivity in detecting colorectal cancer was 91%, with a high sensitivity across all stages of disease: 88% for stages I and II and 93% for stage III. In addition, there were no differences in sensitivity for patients with asymptomatic colorectal cancer compared with those with symptomatic disease.7
Although not meant to replace common standard screening tests, such as colonoscopy, mammography, low-dose helical computed tomography for lung cancer, prostate-specific antigen, or Pap test, the utility of these early detection tests in cancer screening is coming under scrutiny.
“I think the advantage of a test like Galleri is that it can pick up some cancers for which we have no screening, such as for pancreatic cancer,” said Julie Gralow, MD, FACP, FASCO, Chief Medical Officer and Executive Vice President of ASCO. “Now, in my mind, it’s not as useful or impactful if it is mainly picking up stage IV disease, because that is already incurable for most cancers. These tests have to do better than that.”
Determining Clinical Guidelines for Blood-Based Technology
Despite all the progress being made in blood-based technology, there are still no standards to address preanalytic criteria, such as extraction methods, and analytic criteria, such as determination of ctDNA or circulating tumor cell positivity assay cutoffs. In a joint review by ASCO and the College of American Pathologists, in 2018, on the use of ctDNA assays for solid tumors, including preanalytic variables, analytic validity, interpretation and reporting, and clinical validity and utility, they concluded that “there is still insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer.”8
Furthermore, although accuracy in obtaining a precise tumor profile has improved, liquid biopsy tests still carry the risk for false-positive or false-negative results, prompting the FDA to recommend confirmation of a negative result from Guardant360 CDx and FoundationOne Liquid CDx with a tissue biopsy test. The 2021 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for molecular and biomarker analysis of NSCLC also specify that cell-free/circulating tumor DNA testing should not replace a histologic tissue diagnosis unless a patient is medically unfit for invasive tissue sampling.9
However, a recent consensus statement was issued from the International Association for the Study of Lung Cancer (IASLC) on the use of liquid biopsy in advanced NSCLC. It concluded that although liquid biopsy in patients with oncogene-addicted NSCLC is complementary to tissue-based analysis, it is also acceptable as the initial approach for biomarker evaluation at diagnosis and for monitoring the efficacy of targeted therapies, as well as for identifying the mechanisms of acquired resistance to targeted therapies.10
To learn more about how ctDNA blood-based biopsy tests are currently being used in oncology care in the advanced cancer care setting and their potential in early-stage disease, and how the technology is impacting oncology practices, The ASCO Post talked with Justin Odegaard, MD, PhD, Vice President, Clinical Development for Guardant Health; Geoffrey R. Oxnard, MD, Vice President, Head of Clinical Development at Foundation Medicine; Kathryn Lang, MBBS, MRCP, Vice President, Outcomes and Evidence at Guardant Health; Minetta C. Liu, MD, Professor and Research Chair, Department of Oncology; Consultant, Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology; Co-Director of the Genomics in Action Strategic Priority at the Mayo Clinic in Rochester, Minnesota; and a lead investigator on the Galleri studies; and Julie Gralow, MD, FACP, FASCO, Chief Medical Officer and Executive Vice President of ASCO.
Using Liquid Biopsies in the Advanced Cancer Care Setting—and Future Directions
A Conversation With Justin Odegaard, MD, PhD, Vice President, Clinical Development for Guardant Health
Please talk about the overall progress being made in the development of liquid biopsy testing for profiling tumor mutations and treatment monitoring in the advanced care setting.
The field of liquid biopsy has come a long way over the past several years. About 5 years ago, liquid biopsy was an unproven technology. It had a lot of promise, but there wasn’t a lot of data around how it was useful in the clinic. Today, we see liquid biopsy as part of the standard of care in tissue genotyping for patients with advanced cancer. If we think about tomorrow’s standard of care, the best evidence for liquid biopsy’s staying power is that it is being increasingly integrated into the pivotal studies of new therapeutic agents, and the technology will be part of tomorrow’s standard of care as well.
Over the next 5 years, liquid biopsy will be much more about enabling standards of care in oncology for new applications, including the detection of molecular measurable residual disease (MRD) and in cancer screening and treatment selection in earlier-stage disease, where you can improve survival for patients.
“Over the next 5 years, liquid biopsy will be much more about enabling standards of care in oncology for new applications….”— Justin Odegaard, MD, PhD
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How accurate are liquid biopsy tests compared with conventional tissue biopsies in the detection of targetable genomic alterations in cancer? Will tissue biopsies become obsolete in the future?
The IASLC consensus statement speaks to where the field is today. Liquid biopsy is being integrated into the standard of cancer care and improving it. But, in my view, we are not talking about replacing the current standard of care of tissue testing with liquid biopsy testing or that one method is better than the other. Rather, we are saying these tools are complementary, just like magnetic resonance imaging and computed tomography are complementary tools in radiology; each has its strengths and weaknesses, and one may be a better choice in an individual patient’s care.
In terms of accuracy, FDA approval of these tests, as well as drug studies, show that liquid biopsy is accurate. Liquid biopsy is also safe; it can sum up all the patient’s tumor burden throughout the body, not just at the location of a single tumor site. It also can be repeated over time and deliver genomic profiling results in a week, which is critical to ensuring patients have this information before they begin therapy.
In addition to diagnosing cancer, guiding treatment decisions, and monitoring for treatment resistance, what other applications might be on the horizon for liquid biopsy?
In the near term, studies are underway investigating commercial liquid biopsy tests for tracking MRD after curative-intent therapy, usually surgery, looking for markers of disease in patients who otherwise appear to be cured. We know that a substantial proportion of that population of patients will have a fatal recurrence, and we need to identify those patients long before recurrence becomes clinically apparent.
Right now, there are two main commercial products available for physicians to detect MRD in patients with specific cancers, including colorectal cancer, Guardant’s Reveal and Natera’s Signatera, which are also being investigated in clinical trials across multiple cancer types. Early data are showing that you can identify those patients who will have a very poor long-term prognosis.
If you take this MRD technology and apply it to surveillance of patients who may or may not be cured of their cancer, there is a lot of excitement around the concept that we might be able to move metastatic disease treatment, which is the standard of care, to the micrometastatic space. Here, the goal would be to treat disease before it is clinically apparent or, if the disease is widespread, before the tumor has grown enough diversity in the microenvironment and would be difficult to treat with the current standard of care.
We have also seen the application of such serial liquid biopsy testing in the context of metastatic disease, where you can assess ctDNA quantitively in the first couple of weeks following treatment initiation to predict long-term clinical benefit of that treatment, a concept we call molecular response. Here, liquid biopsy serves a prognostic function, giving clinicians a crystal ball to know whether a patient needs to be switched to a different therapy, or it can offer encouragement as to know when to stick with a rough course of treatment because it is evident the tumor is responding well even if it can’t be seen on imaging scans yet.
In short, these tests give clinicians another opportunity to intervene if a treatment is not working and to intervene early.
What uncertainties remain with liquid biopsies that need to be resolved, such as determining the standardization of preanalytic criteria for the timing of blood collection and extraction methods and of analytic criteria, such as the determination of ctDNA or circulating tumor cell positivity assay cutoffs?
It is important to acknowledge that liquid biopsy testing has come a long way, but it is still a fairly new technology. There are areas we still need to investigate and areas that we can optimize and improve.
As we move into some emerging standards of care and growing applications such as MRD tracking or molecular response in the advanced cancer setting, there are more uncertainties that have not been settled with FDA approval of liquid biopsy products or drug studies showing these tests are clinically meaningful. Those uncertainties need to be investigated before these products can be integrated into clinical standard of care.
It is fair to say there are unknowns that remain with this technology. However, we need to strike a balance between the unknowns remaining and the utility of these tests.
A Conversation With Geoffrey R. Oxnard, MD, Vice President,
Head of Clinical Development at Foundation Medicine
How ubiquitous is the use of liquid biopsy in the clinic? Is this technology being incorporated into the clinical workflow, transforming the practice of oncology?
In my experience, once oncologists start to use liquid biopsy tests and get results in a matter of 7 to 10 days, they use the technology more and more. But there can be a learning curve that involves understanding how to determine the right patients for a liquid biopsy vs a tissue-based biopsy.
Let’s think about some different use cases. For example, if a patient is being treated with chemotherapy and the physician needs to plan the next step, the patient’s tumor might not be shedding enough ctDNA into the blood, making the test less sensitive. In that case, the patient would be a better candidate for genomic analysis of his or her tumor specimen. However, if the patient’s cancer is progressing following treatment, and the physician needs to quickly decide on the next course of therapy, that patient would be a good candidate for a liquid biopsy, with a tissue biopsy reserved if the liquid biopsy result is negative.
Physicians will get the most satisfying results when they understand how best to use these tools for specific patients within their oncology practice. Interestingly, even a negative liquid biopsy can tell clinicians something about a patient’s tumor they can use in planning the patient’s care. For example, I recently had a patient with EGFR-resistant NSCLC. When I received a negative result on a liquid biopsy test, I told the patient, “There’s good news and bad news. The good news is there is no ctDNA in your blood. This means it is a lower-shedding cancer, which is a good prognostic indicator, and we have time to plan the next steps. The bad news is, the test didn’t reveal any actionable mutations in your tumor, and I have to do a tissue biopsy to determine the next steps in your treatment.”
Overall, my experience is that once clinicians start using this technology and understand its reliability and usefulness, they adopt it quickly into their practice.
What training do oncologists need in their practice to utilize this advanced technology and recommend the test to patients and accurately interpret the results?
The good news is that liquid biopsy is logistically easy to obtain. It merely requires a blood draw in the clinic or even can be collected via mobile phlebotomy. This is in contrast with tissue genomics, which can require additional logistical workflows to retrieve adequate tissue samples to enable successful tissue next-generation sequencing. The key challenge is figuring out when to use a liquid biopsy.
There are some patient cases in which our standard has been tissue testing, even if the specimen is scant or many years old. For these cases, where the poor-quality tissue specimen may be inadequate for analysis, we might consider prioritizing liquid biopsy first, with tissue analysis used as a backup.
What we may need as oncologists is an additional infrastructure in place to determine when the tissue is not sufficient for tumor testing, so we make the right choice for our patient. We have worked very hard to build the infrastructure that supports tissue testing, and we now need to adapt that infrastructure to logically determine whether tissue or liquid testing should be ordered first for each specific patient case.
How might ctDNA liquid biopsy tests be used during follow-up surveillance to identify survivors at high risk of relapse?
Blood tests are so easy to perform, and clinicians are always looking for creative ways to use them. Monitoring is exactly such a case, and there are now a lot of compelling data to show that repeat analysis of ctDNA once a patient is on therapy can tell oncologists if the treatment is working, as well as detect the emergence of resistance. But what is the best tool for this application? And how do we build a treatment paradigm around such a technology?
The intuitive initial use case is in clinical trials, where serial assessment of ctDNA can help to characterize drug effect. This is increasingly becoming standard for a wide range of clinical trials. There are also some creative applications in routine clinical care in which monitoring can help to determine whether a new treatment is working or not and give a patient a signal of whether a change to a new treatment is needed.
Perhaps the most exciting new horizon is monitoring patients who have completed curative therapy to determine their risk of recurrence. The ability to have ctDNA-based detection of invisible cancer DNA in a patient who otherwise clinically and by imaging has no evidence of cancer is technically challenging. This will require exquisitely sensitive techniques that can detect a cancer signal well below the ability of our routine liquid biopsy tools.
The way we approach this problem is by sequencing the tumor specimen first to know what mutations to look for. We then need to test the blood specifically for that tumor’s DNA changes and expect to find signal present in less than 0.1% of the plasma DNA. But with these technical approaches poised to enter the clinic, we do believe we can detect the risk of relapse and, hopefully, refine a patient’s curative therapy to increase the chance of durable benefit.
The Potential for Early-Detection Liquid Biopsy Tests in Cancer Screening
A Conversation With Kathryn Lang, MBBS, MRCP, Vice -President, Outcomes and Evidence at Guardant Health
The results from your study investigating LUNAR-2 in detecting colorectal cancer in average-risk adults found that the overall sensitivity of the test was 91%, and there were no differences in sensitivity for asymptomatic colorectal cancer compared with symptomatic colorectal cancer. How might these results advance the potential for a simple blood biopsy to screen colorectal cancer in asymptomatic healthy patients?
Blood screening for cancer, particularly for colorectal cancer, is a very important innovation. Colorectal cancer screening saves lives. We know that the act of simply being screened reduces one’s risk of colorectal cancer death by about two-thirds.
We also know there is low compliance with colonoscopy and stool-based screening in the United States. This test provides a way for patients to have colorectal cancer screening at the point of care with their primary care physician. We all have very busy lives and trying to fit in cancer screenings can be challenging for individuals.
Having a reliable, accurate blood test that can be done in a doctor’s office could potentially revolutionize the number of lives we could save from colorectal cancer.
If LUNAR-2 is approved by the FDA, is the intention to use the test in place of stool-based or colonoscopy screening or in conjunction with these tests?
LUNAR-2 is a first-line noninvasive screening tool for colorectal cancer, similar to other screening methods physicians use, such as the fecal immunochemical test and Cologuard DNA fecal immunochemical test. This gives patients more options.
“Having a reliable, accurate blood test that can be done in a doctor’s office could potentially revolutionize the number of lives we could save from colorectal cancer.”— Kathryn Lang, MBBS, MRCP
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If a patient tests positive on a noninvasive test, the next important step is to follow up with a diagnostic colonoscopy, which could then find the cancer and move the patient to treatment. This offers patients more options if they don’t want stool-based or colonoscopy screenings.
When will you have the final results from the ECLIPSE study and be ready to present data to the FDA for approval of LUNAR-2?
We will complete the study this year and plan to submit data to the FDA for its review next year. We anticipate that LUNAR-2 could be approved by the FDA by 2023.
A Conversation With Minetta C. Liu, MD, Co-Director of the Genomics in Action Strategic Priority, Mayo Clinic
The results from the Circulating Cell-Free Genome Atlas Study show that the Galleri liquid biopsy assay had a low detection rate of 16.8% at stage I; 40.4% at stage II; 77% at stage III; and 90.1% at stage IV. Why is there variation in the detection rate? Isn’t the value of this type of test its ability to detect cancer at the earliest stage,s when the cancer is most treatable and curable?
The ability to detect ctDNA in the bloodstream is related to many factors. DNA shedding is a function of both tumor burden and tumor biology. Studies repeatedly demonstrate higher levels of ctDNA in patients with metastatic disease than in patients with earlier stages of disease.
There is a growing recognition that tumor biology also plays a role in that some tumor types are more likely than others to actively secrete DNA and other cellular components into the blood. We are just starting to understand the interplay between these two factors. We also need to consider the technical limitations related to the lower limit of ctDNA detection in blood. It is for all these reasons that the sensitivity of Galleri and other multicancer early-detection tests improves with increasing stage of disease.
We want to keep working harder to be able to identify more stage I and II cancers. One can also argue that we don’t want to find every stage I cancer because we may not need to act on every stage I cancer; that’s where these numbers can be deceiving in some ways. This test gives us a good place to start.
Galleri is not yet approved by the FDA but is currently being sold by prescription under an FDA Clinical Laboratory Improvement Amendments waiver for $949 as a screening tool for individuals older than age 50 at elevated risk for cancer. Under what circumstances are physicians using the test? What is considered an “elevated risk” for these individuals: a family history of cancer and age? What about young adults who are at increasing risk for colorectal cancer?
The test just recently became available for physicians to order for their patients, so it is too early to understand practice patterns. Education for both providers and patients is critical before and after the test is performed, particularly because patients self-pay and official guidelines are not yet available.
It is critical to understand that multicancer early-detection blood tests like Galleri are meant to complement, not replace, existing cancer screening practices. Patients should proceed with colonoscopy or stool testing, mammograms, Pap smears, low-chest computed tomography scans, prostate-specific antigen testing, and other evaluations as appropriate based on their age and personal or family medical history.
Galleri is not covered by insurance or endorsed by national guidelines because clinical utility has yet to be demonstrated. We have to study the frequency of testing and establish plans for follow-up if the blood test detects a cancer signal, but no cancer is identified. There are still a lot of questions to answer.
In your study, Galleri had a high sensitivity rate of 67.6% across stages I–III in 12 cancer types, including pancreatic cancer. In the future, is it likely Galleri could be used as an additional test patients get during their annual physical to screen for cancers such as pancreatic cancer, for which there is no current screening test?
The default thinking is to have a multicancer blood-based early-detection test included as part of a routine annual physical. The ideal target population remains to be defined. We are all at some baseline risk for developing cancer irrespective of age, but screening should focus on those with an elevated risk to maintain an acceptable risk/benefit ratio.
Grail’s PATHFINDER pilot implementation study provides evidence to support safety and the ability to detect cancer in asymptomatic patients. Larger studies must be done in different patient subgroups to determine the usefulness of multicancer early-detection tests in various target populations.
We will soon have some real-world evidence because Galleri is available for use, and physicians will order it because of patient demand. We need concerted efforts to collect and analyze the observational data to understand the potential for clinical utility and to help us develop clinical testing guidelines.
ASCO’s Perspective on Liquid Biopsy Testing in Advanced- and Early-Stage Cancer Settings
A Conversation With Julie Gralow, MD, FACP, FASCO, Chief Medical Officer and Executive Vice President of ASCO
Please talk about the impact Guardant360 CDx and FoundationOne Liquid CDx tests are having on patient care in the advanced-stage cancer setting. Is liquid biopsy testing helping to propel precision medicine approaches for patients with cancer?
The standard before these tests were approved by the FDA was to do a tissue biopsy at the tumor site and then do next-generation sequencing to determine any targetable mutations for treatment decision-making. The advantage of moving to liquid biopsy testing is multifold. First, it is much easier for the patient to have a tube of blood drawn compared with putting a needle in the patient’s liver, lung, or lymph node. Second, because liquid biopsies are easier to get than tissue biopsies, you can do more real-time testing of at least what the dominant clone is that is shedding out the DNA.
Although liquid biopsy tests have become standard of care in certain tumor types, including lung, breast, prostate, and ovarian, looking for certain targetable mutations, they also represent challenges because often they find less DNA than a tissue biopsy. At this time, they have been proven to work best in cancers that are aggressively growing and shedding a lot of DNA.
For example, if you do a blood-based biopsy in a patient with metastatic lung cancer that is progressing, you will find tumor DNA. If you do that test in a patient with triple-negative breast cancer that has metastasized to the liver, you are also likely to find the tumor DNA in the blood. However, a common situation in breast cancer is that the primary site of the disease is in the bone and maybe some small lymph nodes, and it is not growing very quickly, so the tumor is not shedding a lot of DNA. In that setting, you are likely to get a noninformative result, with no DNA found. But in this exact situation, it is difficult to get tissue to biopsy as well.
“There are more questions that have to be answered, including how often should these tests be performed, every year, every 5 years? In addition, who will pay for these tests?”— Julie Gralow, MD, FACP, FASCO
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We are already using these two tests, which incorporate next-generation sequencing to tailor the best treatment, and they work very well in some settings. We are going to need to perfect these tests and achieve higher sensitivity in certain settings, for example, in cancers that are not shedding a lot of DNA. Until then, liquid biopsies will not replace tissue-based biopsies.
NCCN Guidelines specify that cell-free/circulating tumor DNA testing should not replace a histologic tissue diagnosis unless a patient is medically unfit for invasive tissue sampling.7 However, a recent study by Brice et al in the Journal of Clinical Oncology found that liquid biopsies may be used as the new standard in front-line treatment decision-making for patients with stage IV NSCLC.11 Is ASCO considering guidelines for the clinical use of liquid biopsy?
The last time ASCO published recommendations for tissue and liquid biopsies was in a joint review with the College of American Pathologists in 2018. This review concluded that although some ctDNA assays have demonstrated clinical validity with certain types of advanced cancer, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer.8 Clearly, more data have been published since then.
ASCO reviews its existing guidelines regularly and updates them when new evidence warrants a modification. We also now have a process in place to rapidly update guidelines when new data are presented that warrant an immediate change in practice or when high-level data from randomized phase III trials are thought to offer substantial benefit to patients.
There are two liquid biopsy early-detection tests making their way through research: the LUNAR-2 test to detect colorectal cancer in asymptomatic, average-risk individuals and the Galleri test, which has demonstrated the ability to detect more than 50 types of cancer, including pancreatic, across cancer stages. If these tests receive FDA approval, will they become part of the routine clinical care of asymptomatic patients to determine whether they have cancer?
The LUNAR-2 test is focused on colorectal cancer, and FDA approval will mean, that, yes, it can detect the cancer. It does not require that the test be compared with the standard of care and show that it’s better.
The LUNAR-2 test looks pretty good for sensitivity in picking up early-stage colorectal cancer. But the issue with colorectal cancer is we already have the absolute gold standard for detection, colonoscopy. We also have stool-based fecal immunochemical test cards. The advantage of colonoscopy is that it detects precancerous polyps unlikely to be shedding DNA. Once the polyp is removed, the danger that it can turn into cancer is removed, and the patient doesn’t need surgery.
Even though it is great that the LUNAR-2 test picks up stage I colon cancer, I’d like to see an assay that’s at least as good as colonoscopy in picking up polyps to prevent cancer. We do not have data on whether LUNAR-2 picks up polyps. It probably doesn’t because polyps aren’t shedding a lot of DNA. As a patient, I would much rather have a polyp removed than have to deal with stage I (or higher) colon cancer. I don’t think the test will replace colonoscopy, but it could supplement it, especially in high-risk individuals.
I want to make sure that we use the right wording and that we educate our primary care physicians on how to use these tests. Oncologists will not be talking to these patients about cancer detection; it will be primary care physicians, who may not have as much experience in interpreting the results from ctDNA and may require some help.
I have less enthusiasm in using this approach at present, including the Galleri test, for cancers that already have proven screening options, for example, mammography for breast cancer. However, I do think one of the advantages of Galleri is that it can pick up cancers for which we have no screening, such as pancreatic cancer. Still, it is not a good assay if it is mainly picking up stage IV cancers, because they are usually incurable. For stage I tumors, the test has a sensitivity rate of just 16.8%, and that is not good enough. You want to catch cancer at stage I or II, even for rare cancers, to have the best chance of cure.
These early-detection tests are interesting, with a lot of potential, and we will see if they become incorporated into clinical guidelines and receive FDA approval. There are more questions to be answered, including how often should these tests be performed, every year, every 5 years? In addition, who will pay for these tests? It could be expensive to test every American annually, and we are going to have to justify that cost by saving lives.
DISCLOSURE: Dr. Odegaard is Vice President, Clinical Development, at Guardant Health. Dr. Oxnard is Vice President, Head of Clinical Development, at Foundation Medicine. Dr. Lang is Vice President, Outcomes and Evidence, at Guardant Health. Dr. Liu is a lead investigator on the Circulating Cell-Free Genome Atlas Study and other related clinical trials. The Mayo Clinic received funding from Grail to support those trials. Dr. Liu reported receiving no personal remuneration. Dr. Gralow has served as a consultant or advisor to the following companies during the past 2 years, each of which was for less than $5,000 in a calendar year: Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
1. National Cancer Institute: FDA approves blood tests that can help guide cancer treatment. Available at www.cancer.gov/news-events/cancer-currents-blog/2020/fda-guardant-360-foundation-one-cancer-liquid-biopsy. Accessed September 20, 2021.
2. U.S. Food and Drug Administration: FDA approves liquid biopsy NGS companion diagnostic test for multiple cancers and biomarkers. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-liquid-biopsy-ngs-companion-diagnostic-test-multiple-cancers-and-biomarkers. Accessed September 20, 2021.
3. U.S. Food and Drug Administration: Guardant360 CDx—P200010/S002. Available at www.fda.gov/medical-devices/recently-approved-devices/guardant360-cdx-p200010s002. Accessed September 20, 2021.
4. Sehayek MO, Onn A, Roisman LC, et al: The turnaround time impact of liquid biopsy in comparison with tissue biopsy in advanced NSCLC. IASLC 2020 Lung Cancer Hot Topic: Liquid Biopsy Virtual Conference. Abstract VP01.33.
5. Beer TM, McDonnell CH, Nadauld L, et al: Interim results of PATHFINDER, a clinical use study using a methylation-based multi-cancer early detection test. 2021 ASCO Annual Meeting Abstract 3010. Presented June 4, 2021.
6. Klein EA, Richards D, Cohn A, et al: Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol 32:1167-1177, 2021.
7. Lee J, Kim HC, Kim ST, et al: Multimodal circulating tumor DNA colorectal neoplasia detection assay for asymptomatic and early-stage colorectal cancer. 2021 ASCO Annual Meeting. Abstract 3536. Presented June 4, 2021.
8. Merker JD, Oxnard GR, Compton C, et al: Circulating Tumor DNA Analysis in Patients with Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. J Clin Oncol 36:1631-1641, 2018.
9. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 5.2021. Available at www.nccn.org/guidelines/guidelines-detail?category=1&id=1450. Accessed September 20, 2021.
10. International Association for the Study of Lung Cancer: IASLC issues consensus updated report on liquid biopsy. Available at www.iaslc.org/iaslc-news/press-release/iaslc-issues-consensus-updated-report-liquid-biopsies. Accessed September 20, 2021.
11. Brice K, Raez LE, Dumais K, et al: Liquid biopsies for the front-line therapy in non-small cell lung cancer. 2021 ASCO Annual Meeting. Abstract e21103. Presented June 4, 2021.