Episode #58 Lung Cancer Biomarkers: A New Frontier in Early Detection with Dr. Lindsey Cotton

Dr. Albert Rizzo:
Welcome back to Lungcast, a monthly respiratory health podcast series from the American Lung Association and medical news site hcpive.com. I'm your host, Dr. Albert Rizzo, chief medical officer of the ALA.

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The development of biomarkers to assess or screen for underlying cancer at early stages of disease has made significant advances over the last several decades. These biomarkers utilize simple blood draws, urine, saliva, or stool specimens. They usually fall into two main categories: multi-cancer early detection tests (MCEDs) and organ-specific early detection tests.

There are only select cancers—breast, cervical, colorectal, and lung—that have USPSTF-recommended screening guidelines to date. Data supports the fact that the use of single cancer screening tests has reduced cancer-related mortality for these malignancies. However, data also shows that 70% of deaths due to cancer in the United States among those aged 50 to 79 years are caused by cancers without USPSTF-recommended screening. As a result, U.S. cancer mortality exceeds 600,000 cases per year.

This has led to the development of multi-cancer early detection tests, usually blood-based, that can screen for multiple types of cancer in a single sample. Lung cancer is often one of the results sought with these MCEDs. There are pros and cons to using MCEDs versus organ-specific biomarker screens. These include accuracy depending on cancer stage, determination of who and when to screen, consequences for patients including further testing, the cost of the biomarker test itself, and uncertain coverage by third-party payers.

To give us a more comprehensive perspective on this landscape of biomarker approaches, we are joined today by Dr. Lindsey Cotton, a clinician, scientist, and healthcare leader for over 20 years, whose medical and scientific research has focused specifically on the emerging field of early cancer detection through liquid biopsy biomarkers, especially over the last six years. She has held leadership roles in biomarker companies including Grail, Guardant Health, and Delfi Diagnostics. These companies have tests either available or in development in this biomarker space.

Today’s Lungcast discussion does not endorse or recommend any specific testing or company. I’m asking Dr. Cotton to explain the current science and understanding of these types of tests in a non-competitive space. Thank you for being with us today.

Dr. Lindsey Cotton:
Thank you, Dr. Rizzo. It's a pleasure to be here today. I'm humbled and excited for our discussion.

Dr. Rizzo:
Before we begin discussing the different aspects of MCEDs versus organ-specific tests, please level set for our listeners what some of the specific types of substances are being assayed in the blood by the different tests being used out there.

Dr. Cotton:
Yes, I think that’s a good place to start. There are many different types of analytes—different parts of cells or byproducts of cells—that are currently being used in assays. A few of the most common ones include:

• Cell-free DNA (cfDNA): DNA that is shed from cells and can be detected in the bloodstream. Tumor cells, like all cells, shed DNA, so assays can sometimes pick up mutations or fragment patterns that suggest cancer.

• RNA: Some assays look at messenger RNA or microRNAs that are associated with tumor biology.

• Proteins: Longstanding tumor markers like CEA or CA-125 fall in this category, though newer proteomic assays may look at patterns of proteins.

• Methylation patterns: This is one of the more exciting newer analytes—abnormal DNA methylation signatures that can indicate the presence and sometimes even the tissue of origin of a cancer.

• Exosomes, metabolites, or circulating tumor cells: These are also being studied, but they’re less commonly in clinical assays right now.

The unifying theme is that cancer biology spills into the bloodstream, and by capturing and analyzing those signals, we can potentially detect cancers much earlier than with imaging or symptoms.

Dr. Rizzo:
Thank you—that’s very helpful. Now, can you walk us through the main differences between a multi-cancer early detection test and an organ-specific biomarker test?

Dr. Cotton:
Of course. Organ-specific biomarker tests are designed to look for one cancer type at a time—say, a test that looks for early lung cancer by analyzing methylation in cfDNA specific to lung tumors. These can be more sensitive to one cancer, but of course, they don’t cover others.

Multi-cancer early detection (MCED) tests, on the other hand, cast a broader net. The idea is to test once and screen for many different cancers simultaneously. The promise is that you could find a pancreatic cancer, an ovarian cancer, and a lung cancer—all with a single blood draw.

The challenge, though, is performance. For each cancer type, sensitivity and specificity can vary. For example, MCED tests may have good sensitivity for certain cancers but lower sensitivity for others. False positives and false negatives are concerns, as are downstream consequences—such as unnecessary scans or biopsies if a test suggests cancer but can’t identify exactly where it is.

Dr. Rizzo:
That brings up an important point. If a test detects a “signal” for cancer, but you don’t know the organ of origin, what are the next steps for the clinician and patient?

Dr. Cotton:
That’s one of the key clinical questions. Some assays can provide a prediction of the tissue of origin—for example, based on methylation patterns—but it’s not always perfect. If a result comes back positive, the clinician has to decide on a diagnostic workup: imaging, endoscopy, maybe referral to oncology.

This is where guidelines and evidence are still evolving. We want to avoid a scenario where a patient undergoes an invasive procedure, like a biopsy, only to find nothing. At the same time, if you detect a lethal cancer at stage I that otherwise would have presented at stage IV, you’ve saved a life.

Dr. Rizzo:
That balance between benefit and harm seems like the crux of the discussion. Could you expand a little more on where the science stands now in terms of data for these tests?

Dr. Cotton:
Yes. The most mature data we have comes from large trials like the Circulating Cell-free Genome Atlas (CCGA) study for Grail’s test, and others from Guardant and Delfi. They’ve shown that multi-cancer early detection is feasible and that you can pick up cancers across dozens of types. Sensitivity increases with later stage, which makes sense—more tumor burden means more signal. The challenge is pushing that sensitivity earlier, into stage I and stage II disease.

For lung cancer specifically, these assays are picking up signals, but they are not yet a replacement for low-dose CT screening, which remains the only guideline-recommended tool. Rather, the hope is that MCEDs might one day complement existing screening—perhaps identifying people at risk who don’t meet current age or smoking criteria, or flagging those who might benefit from imaging sooner.

Dr. Rizzo:
That’s a good segue into another question. Lung cancer screening has struggled with uptake—fewer than 10% of eligible people get screened. How might MCEDs play a role in expanding access or improving adherence?

Dr. Cotton:
It’s an important consideration. A blood draw is less intimidating than a CT scan. If patients are already having blood drawn for routine labs, adding an MCED could be seamless. It could also bring in populations who don’t have access to imaging centers, or who are reluctant because of radiation concerns.

However, we must be careful not to think of MCEDs as a substitute just yet. Until there is robust evidence and guidelines, they should be viewed as complementary or investigational tools, ideally used in clinical trial settings.

Dr. Rizzo:
Very well said. Before we wrap up, what do you see as the near future in this field?

Dr. Cotton:
I think in the next five years, we’ll see several things:

1. More refined assays that increase sensitivity at earlier stages.

2. Better integration of AI and machine learning to interpret complex signals.

3. Real-world studies that tell us how MCEDs actually work in diverse populations, not just clinical trial cohorts.

4. Importantly, we’ll also need frameworks for how primary care physicians, pulmonologists, and oncologists should respond to a positive test.

It’s an incredibly exciting space, but we need to be thoughtful. The promise is enormous, but so is the responsibility to ensure patient safety and value.

Dr. Rizzo:
Dr. Cotton, thank you so much for sharing your expertise and for helping us understand this evolving landscape.

Dr. Cotton:
Thank you for having me—it’s been a great conversation.

Dr. Rizzo:
And thanks to all of you for listening to this episode of Lungcast. Don’t forget to subscribe on your favorite platform, and check out lung.org and hcplive.com for more resources and information.