In May 2020, research conducted by Epic Health Research Network revealed a drop between 86-94 percent in preventive cancer screenings for cervical, colon, and breast cancer performed nationwide compared with equivalent weeks from 2017 to 2019.1

The decline in screening in the wake of the COVID-19 pandemic can be in part attributed to patients’ hesitation to visit health centers and other complications of the pandemic, but the statistics are concerning.

Cancer screening seeks to identify cancer in people before they have any symptoms when it may be easier to treat, and regular screening plays an important role in avoiding difficult and costly treatment and, in many cases, saves lives. Guidelines have been developed around screening for some cancers, including breast, cervical, colorectal, endometrial, lung, and prostate cancer, but there are many cancer types for which there are no current effective screening tools or guidelines.2

While the benefits of screening are clear, there are barriers to regular screening for many, ranging from fear or hesitancy to undergo invasive screening tests, like colonoscopy, to difficulties accessing care or not having the flexibility to take time off work. Scientists and physicians continue to strive toward developing more accurate screening tools that will improve compliance rates and make screening easier and more accessible.

“We've been working for decades now to understand how to identify cancers early before they've had a chance to spread,” says Kevin Schulman MD, MBA, Professor of Medicine at Stanford University. “Especially for solid tumor cancers like breast cancer or colon cancer, which, if found early, can often be treated effectively, there’s significant opportunity in early detection.”

Improving screening technology and broadening the scope of screening to include additional cancer types is the ongoing goal of screening research. “If a better screening test was available that would help us detect the disease even earlier and would be less of a burden for patients—less invasive or time consuming, for example—that could be a real benefit,” Dr. Schulman says.

Hope on the Horizon: Blood Tests for Cancer Screening

Against the backdrop of challenge and opportunity in cancer screening, new blood tests that can detect cancer in early stages, often before a person has any symptoms, are an exciting development.

Blood tests to screen for cancer are not new. Hematologic cancers, like lymphoma and leukemia, are often first identified through a blood test (and confirmed by additional diagnostic tools), and the PSA (prostate-specific antigen) test is a blood test used to screen for prostate cancer.

This new category of screening test is different in that it uses genomic technology developed to identify circulating pieces of solid cancer tumor DNA, or ctDNA, in the bloodstream. To date, these tests have been used to provide genetic information about tumors in patients already diagnosed with cancer, which can help guide treatment decisions and monitor the effectiveness of specific therapies. Now, blood tests developed to screen for cancer, are building on that genomic technology to detect early-stage cancer before a patient experiences any symptoms.

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Two Screening Tests to Watch

Galleri by GRAIL

Galleri™ is a multi-cancer early detection (MCED) test, developed by GRAIL. An MCED test detects and localizes small amounts of circulating tumor signal in the blood and can detect many cancer types through one blood draw. Josh Ofman, MD, Chief Medical Officer and Head of External Affairs at GRAIL, says, “Galleri is a first-of-its-kind, multi-cancer early detection (MCED) blood test, capable of detecting more than 50 types of cancer—45 of which lack recommended screenings today.”

The Galleri test is intended for use in those with an “elevated risk of cancer,” which, Dr. Ofman says, includes those 50 and older who don’t have any symptoms, and it has been developed as “a complement to existing annual single cancer screening tests such as mammograms and colonoscopies to maximize early cancer detection.”

The test is available to patients through a prescription from a provider. After a blood sample is collected, it is processed in GRAIL’s lab, and results are delivered to the ordering healthcare provider within 10 business days.

If results indicate a “cancer signal detected” result, Dr. Ofman says, “in most cases, the Galleri test report provides predicted cancer signal localization, indicating where in the body the cancer is located, which helps physicians determine the appropriate diagnostic workup.” For patients who receive a “no cancer signal detected” result, Dr. Ofman says, the test report will remind individuals to continue with their standard-of-care cancer screenings.

A paper published in Annals of Oncology revealed final study results of the Circulating Cell-free Genome Atlas (CCGA) study investigating the performance of the Galleri test.3  The paper reported that “in 2,823 people already diagnosed with cancer and 1,254 people without cancer, [the Galleri test] detected cancer signals from more than 50 different types of cancer and found that across all four cancer stages (I, II, III, IV), the test correctly identified when cancer was present (the sensitivity or true positive rate) in 51.5 percent of cases. The test’s specificity (the true negative rate) was 99.5 percent, meaning that the test wrongly detected cancer (the false positive rate) in only 0.5 percent of cases.”

The fact that the sensitivity of the Galleri test identifies the presence of ctDNA of cancers that up to now we have not been able to screen for is a significant advance. The sensitivity of the test varied across tumor types, the paper’s authors noted. “In solid tumors that do not have any screening options, such as esophageal, liver and pancreatic cancers, overall sensitivity of the test was twice that for solid tumors that do have screening options, such as breast, bowel, cervical and prostate cancers: 65.6 percent compared to 33.7 percent. Overall sensitivity in cancers of the blood, such as lymphoma and myeloma, was 55.1 percent.”4

The Galleri test is available now to patients in the US. Galleri requires a prescription and can only be ordered by a licensed healthcare provider. GRAIL plans to seek FDA approval for Galleri following its initial introduction as a Laboratory Developed Test (LDT). “Introducing Galleri as an LDT enables us to get this transformative technology that’s in our hands today into the hands of doctors and their patients, while we pursue FDA approval,” Ofman said.

GRAIL received Breakthrough Device Designation from the FDA and are in ongoing conversations with the agency. The GRAIL laboratory is CLIA certified (Clinical Laboratory Improvement Amendments) and CAP-accredited (College of American Pathologists).

LUNAR-2 by Guardant Health

The LUNAR-2 assay is another blood test for cancer screening showing promise. LUNAR-2 is a liquid biopsy being developed by Guardant Health to detect colorectal cancer (CRC) in an average-risk adult population.

Kathryn Lang, MD, vice president of Health Outcomes and Evidence at Guardant Health, says the LUNAR-2 assay reflects the widespread momentum behind utilizing genomic technology to propel screening and increase early detection. “There is an awful lot of push right now to bring much more advanced testing to the field of screening; it’s really exploding right now.”

Guardant Health has already developed and gained FDA approval of a liquid biopsy test (Guardant360® CDx) for advanced-stage cancer patients, which help doctors recommend targeted therapies based on the unique mutations of a tumor. The company also recently introduced a new test (Guardant Reveal™), which can detect signs of residual cancer in early-stage colorectal cancer patients.

Dr. Lang notes that LUNAR-2 builds on this technology. “The current testing technology requires some development to catch cancer earlier because the signal in early-stage cancers is not as strong—there’s just less cancer there, so the test requires a bit more refinement to be useful as a screening tool.”

That refinement is reflected in what Dr. Lang says is a “multi-modal” test. “The LUNAR-2 assay detects markers of cancer in three different areas of the genome,” she notes. “We’re looking for the building blocks, or the language of the cancer that we can find, but for this test we have to add some things on to look for the earliest stage cancer: the methylation marker, or the extra signals on those building blocks of the of DNA that can be associated with cancer, and wherein the actual DNA certain proteins are positioned, which can also be highly correlated with cancer.”

While the genomic technology can sound complicated, Dr. Lang says, “the LUNAR-2 assay has been designed to return a result that denotes simply ‘present’ or ‘absent,’” meaning that markers of colorectal cancer are present in a patient’s blood or are not present.

If the screening test result reflects “present,” a patient would be guided by their physician to undergo a diagnostic procedure or test, which in this case will be a colonoscopy. This distinction between a “screening” test and a “diagnostic” test is significant, she notes, because while the screening test can be a good indicator, a patient would still need to seek further testing to confirm the result and receive a final diagnosis.

The Guardant Health test is being developed for “average risk” patients, which Dr. Lang says would be defined as “somebody 45 or older who has absolutely no symptoms of colorectal cancer—no changes in bowel habits, no weight loss, no bleeding or other symptoms—and has no first-degree relatives who have had CRC or any other high-risk features like a familial predisposition or any conditions, like inflammatory bowel disease. If none of those are present, then you are average risk, and these tests are being developed for those average-risk individuals.”

In data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Guardant Health reported that the LUNAR-2 assay achieved overall sensitivity of 91 percent in early-stage CRC (Stage I, II, and III), and specificity of 94 percent.5 In a press release highlighting the data, Guardant Health also noted that “no differences in sensitivity for CRC detection were observed in patients presenting with asymptomatic disease, compared to those patients who were symptomatic, despite the lower cell-free DNA (cfDNA) tumor fractions observed in asymptomatic patients, suggesting the test will have clinically meaningful performance in an average-risk screening population.”6

The LUNAR-2 test is currently being evaluated through the ECLIPSE trial, a 10,000 patient registrational study, and results are expected in 2022. From there, the test will need to go through the FDA-approval process. “The FDA process takes about 12 to 18 months,” Dr. Lang says. “We're setting a very high bar for ourselves, and we expect to be going through a very significant process to prove that this is safe and valuable to patients.”

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Potential Complications and Considerations for Patients and Providers

While the Galleri and LUNAR-2 tests reflect the promise of blood tests as screening tools, there are notable issues related to early-stage screening tests and the roll-out among patients and providers.

“A potential complication of tests developed to detect cancer at very early stages is that a blood test may detect signs of cancer that our immune system would have eliminated on its own before it progressed to a state that requires treatment,” Dr. Schulman says. “This has been a real challenge in screening for prostate cancer, for instance. Many men will develop early-stage prostate cancer, but very few will die from it. We've gotten a little bit more cautious about how we screen for prostate cancer as a result.”

Dr. Lang notes that in the case of the LUNAR-2 assay, designed to screen for colorectal cancer, “there is a huge body of evidence that if the signal [for colorectal cancer] is detected, that colorectal cancer does not disappear on its own and does require treatment.” But, she adds, this isn’t the case for all cancer types. “Not all cancers are created equal, but for CRC, early detection is critical as treatment of early-stage colorectal cancer can be effective. The five-year survival rate for CRC is excellent—about 95 percent.”

Another issue for patients to consider is the potential for these highly sensitive tests to generate false positives, which may lead to invasive diagnostic tests, and false negatives, which would mean a cancer was present that wasn’t detected.

“We have seen the impact of false positives from highly sensitive tests in the high-resolution CT scans administered to cigarette smokers that we screen for lung cancer,” Dr. Schulman says. “These tests find a lot of cancers but have a high false positive rate—about 20 percent.” For patients who get a false positive, the diagnostic testing and follow-up that comes next can be a significant burden, physically, emotionally, and financially. “The worst test is one that leads to lots of people getting scared and getting a very involved workup.”

So while the idea of early screening and the potential for significant benefit to patients is exciting, Dr. Schulman urges caution. “There's this challenge to make sure we're finding things that really will progress and not things that won't progress, and that's very hard. It's still really early, and there’s a lot we still need to understand about these tests.”

In the case of the Galleri test, the most-recent study results report false positives in only 0.5 percent of cases, which is very low compared with other screening tools that exist today, but patients should always discuss this aspect of screening tests with their provider in advance.7

Ted Snelgrove, CEO of Curve Biosciences, has spent more than 25 years in the field of molecular diagnostics and personalized medicine and says that it’s important for patients considering these tests to understand the balance of specificity and sensitivity built into the design.

“In building algorithms that translate raw genomic data into clinical test results, computational biologists can weight the math to optimize the natural tradeoffs between sensitivity and specificity,” he says. “If it’s designed to be more sensitive, it picks up more tumors, but it will likely be at the expense of lower specificity (more false positives).” These limits are inherent to the underlying technologies that quantify ctDNA from bodily fluids, and individual tests may require different algorithms to reflect context-driven priorities for assessing risk.

Being able to understand this feature of test design and articulate the issue to patients is something that providers will need to become comfortable with as tests become more widely available. “This is critical for ordering physicians because they have to know how to frame alternatives when they get results back as positive or negative and be able to explain the levels of confidence for any results that are presented to patients,” Snelgrove says.

In fact, providers will face a range of challenges as liquid biopsies are introduced as screening tools. Continuing education will become essential across health systems that adopt these tests to ensure providers can offer clear information and guidance. In some ways, the testing technology is emerging faster than the rest of medicine is evolving, so providers will need to be trained so they are confident they can process and act on the insights these tests can generate.

Snelgrove says, “Primary care doctors and internists will need to get up to speed on how to manage these tests—ordering and explaining the results and helping patients understand how this can affect their plans once results are in.” Not all providers have training in genomic technologies or biostatistics, and there will be a steep learning curve over the next decade.

Health systems and insurers will also need to create appropriate guidelines for patients to benefit from the tests. “I liken this in some ways to the Tesla story,” he says. “They developed this novel technology for building electronic vehicles, but the macro-challenge has been creating the battery-charging infrastructure that is now being deployed across the country so the cars can be practical to own and operate. In the same way, these novel genomic tests are like the electronic car, so now we need to devise and scale the decision support systems in medicine to manage routine cancer screening for people who are otherwise asymptomatic.”

A Pivotal Moment in Cancer Screening

Ultimately, blood tests developed for cancer screening present an opportunity for more cancers to be identified early when they are more treatable.

“Cancer is expected to become the leading cause of death in the US this year, in large part because the majority of cancers are found too late when outcomes are poor,” Dr. Ofman says. “Recommended screening tests save lives, but only cover five cancer types in the US. In fact, 71 percent of cancer deaths in the US have no recommended early detection screening.”

The ability of the Galleri test to detect cancer without existing screening guidelines has the potential to provide significant benefit. “Finding cancer early, when treatment is more likely to be successful, is one of the most significant opportunities we have to reduce the burden of cancer. If used at scale alongside existing screening tests, the Galleri test could have a profound impact on how cancer is detected and, ultimately, on public health,” Dr. Ofman says.

In the case of the LUNAR-2 assay, which is being developed as a first-line screening test for CRC, Dr. Lang says, “We believe it’s important to expand first-line screening because to get to the best outcomes possible in the US we need to get to a compliance or screening level of those eligible of about 80 percent.” Right now, she notes, “the Centers for Disease Control and Prevention (CDC) says we've maxed out at about 65- 69 percent (and that's not equal across the U S—certain states are a lot less than that and certain states are a lot higher).”

LUNAR-2, which can be performed in a doctor’s office, has the potential to remove two key barriers to CRC screening. It can be completed during an office visit, which means patients don’t have to go to a separate appointment at a different facility; and, it’s non-invasive. “A first-line test performed in the office would allow us to get a lot more people tested, which is really the promise of blood-based colorectal cancer screening,” Dr. Lang says.

Looking Ahead

As with all decisions you make about your health, a decision to move forward with any screening should be informed and made in consultation with your healthcare provider.

“If patients want to go forward with a blood test for cancer screening,” says Dr. Schulman, “it’s important to understand the risks, which could include finding a false positive or a false negative. And, unfortunately, patients also need to be aware that though they’re taking a screening test meant to identify early-stage cancer, there's no guarantee that they won’t learn they have a later-stage cancer, one that can’t be as easily treated.”

As the Guardant Health tests and others continue through development and testing phases, Dr. Lang says, the most important thing patients should takeaway is the importance of screening overall. “It's incredibly important to get screened. Don’t put off screening today because you’re waiting for a blood test; make your screening appointment now and know we’re working hard to provide more screening options in the future—for CRC and other cancer types.”

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References

1. Epic Health Research Network. Preventive cancer screenings during COVID-19 pandemic. Published 2020. Accessed July 1, 2020. https://ehrn.org/wp-content/uploads/Preventive-Cancer-Screenings-during-COVID-19-Pandemic.pdf

2. American Cancer Society Guidelines for the Early Detection of Cancer. American Cancer Society website. Available at: https://www.cancer.org/healthy/find-cancer-early/american-cancer-society-guidelines-for-the-early-detection-of-cancer.html#written_by. Accessed June 26, 2021.

3. “Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set”, by Eric Klein et al. Annals of Oncology. doi: https://doi.org/10.1016/j.annonc.2021.05.806

4. Ibid

5. https://investors.guardanthealth.com/press-releases/press-releases/2021/Guardant-Health-Presents-Data-at-2021-ASCO-Annual-Meeting-Showing-Blood-Test-Highly-Accurate-in-Detecting-Colorectal-Cancer-in-Patients-With-Early-Stage-Cancer/default.aspx

6. Ibid

7. “Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set”, by Eric Klein et al. Annals of Oncology. doi: https://doi.org/10.1016/j.annonc.2021.05.806