MCED Testing for Cancer Diagnosis: Progress and Roadblocks

Research has suggested that multi-cancer early detection (MCED) tests have the potential to fulfill unmet needs in cancer diagnosis and care.1-8 However, experts say that cost-related barriers, potential regulatory roadblocks, and other issues must be addressed before MCED testing can be used more widely.

“MCEDs aim to detect multiple cancer types in asymptomatic individuals and may be especially useful for cancers that don’t have established early detection methods or screening guidelines,” said Eric Klein, MD, distinguished scientist at GRAIL in Menlo Park, California.

He added that the development of MCED tests “addresses a significant unmet need by expanding detection to include the 71% of cancers that are missed by current screening modalities for breast, cervical, colorectal, lung, and prostate cancers.”

At present, there are no MCED tests approved by the US Food and Drug Administration (FDA) or reimbursed by insurance companies, but some MCEDs can be ordered by health care providers as laboratory-developed tests (LDTs) under Clinical Laboratory Improvement Act (CLIA) regulations.9

Although there are multiple MCED tests in development, the only commercially available test is GRAIL’s Galleri, noted John B. Kisiel, MD, a gastroenterologist and professor at Mayo Clinic in Rochester, Minnesota.

Studies have suggested that Galleri can detect a cancer signal across more than 50 cancer types and predict the cancer site of origin if a signal is detected.2-4 Two other MCED tests, CancerSEEK (the precursor to Cancerguard) and SeekInCare, have been shown to detect more than 20 cancer types.5,6 And the SPOT-MAS and PanSEER tests can each detect 5 cancer types.7,8

The tests have demonstrated varied results as far as sensitivity, specificity, positive predictive value (PPV), and negative predictive value, but results with each test also vary by cancer type and disease stage.

Possible Regulatory Roadblock for MCED Testing

The evolution and availability of MCED tests may be impacted by recently proposed changes to LDT regulation.10 Historically, the FDA has regulated in vitro diagnostic (IVD) tests made outside of laboratories, but LDTs have been exempt from this oversight.

Last October, the FDA published a proposed rule that would amend its regulations to clarify that LDTs are medical devices under the Federal Food, Drug, and Cosmetic Act.The FDA would therefore phase out its general enforcement discretion approach for LDTs, and LDTs would be subjected to the same oversight as other IVD tests.

The FDA says the goal of this proposed change is to protect public health by providing greater assurance of the safety and effectiveness of LDTs, considering the rapidly increasing production and use of these tests.

Among its examples of the risks associated with LDTs, the FDA cited an article describing an oncologist’s experience with false results from the Galleri test.11 The oncologist reported 2 false positives and 28 false negatives produced by roughly 2000 Galleri tests administered over approximately 18 months. Galleri’s sensitivity was 6.7% in this case, but studies have suggested the test’s sensitivity is much higher. It was 51.5% in the CCGA study and 66.3% in the SYMPLIFY study.2,4

“Like all screening tests, MCEDs have some limitations, including false-positive and false-negative results and the potential to detect indolent cancers, and they do not detect all cancer types,” Dr Klein noted. “On the other hand, the positive predictive values of available tests are far higher than currently recommended screening tests.”

Galleri had a PPV of 38% in the PATHFINDER study, 44.4% in the CCGA study, and 75.5% in the SYMPLIFY study.2-4 Studies showed that SPOT-MAS had a PPV of 60%, CancerSEEK had a PPV of 19.4%, and SeekInCare had a PPV of 11.5%.5-7 In comparison, screening mammography for breast cancer and low-dose CT for lung cancer have demonstrated PPVs below 10%.12

If the FDA’s proposed changes are enacted, they could improve the quality and accuracy of MCED tests, having a positive impact on clinician confidence and patient outcomes, according to Julia Trosman, PhD, director and co-founder of the Center for Business Models in Healthcare in Chicago.

“Increased accuracy and the FDA stamp of approval may facilitate earlier reimbursement by both private payers and the Centers for Medicare and Medicaid Services [CMS], as we saw with tumor sequencing tests, especially if CMS and the FDA collaborate in a similar fashion as they did on the new drug application for tumor sequencing,” Dr Trosman said. A joint statement from the CMS and FDA noted that CMS supports the FDA’s proposed rule on LDTs.13

“Conversely, based on how burdensome the FDA application and process will be, the costs for labs offering MCEDs may increase, which, in turn, may be passed on to consumers paying out of pocket or insurers covering the test,” Dr Trosman said. Enactment of the rule may also lead to a reduction in the number of labs offering MCED testing, she added.

In response to a request for comment regarding the potential impact of the proposed LDT rule on Galleri specifically, a GRAIL spokesperson said, “We are actively engaging with FDA for submission of our breakthrough Galleri test under a premarket approval application. GRAIL’s clinical laboratory is regulated by governmental authorities including CMS under CLIA, and the Galleri test is approved by the New York State Department of Health.” 

The FDA’s target date for the final rule on LDTs is April 2024, and the agency expects to gradually end its current enforcement approach for LDTs over a subsequent 4-year phaseout period.10,14

Other Barriers to Wider Use of MCED Testing

Cost is a major barrier to wider use of MCED testing, according to Sana Raoof, MD, PhD, a resident at Memorial Sloan Kettering Cancer Center in New York, New York.

Although people who can afford to pay out of pocket can already access MCED testing, cost represents a significant barrier to expanding MCED access to greater numbers of patients, she noted.

“There is a toss-up between waiting for more evidence of benefit vs taking an approach where we perhaps make decisions about conditional approvals and insurance coverage based on preliminary data so that all individuals may access these molecular screening tests,” Dr Raoof said. “Longer clinical trials and definitive evidence can instead be used for final approval decisions. This is one possible approach to minimize the disparity in access.”

Dr Kisiel noted that another issue, which is tied to cost, is coordinating downstream testing for patients with positive MCED test results. This “requires clinical resources and may incur additional costs, some of which may be out of pocket before MCEDs are broadly adopted,” he said.

Dr Raoof added that there is a need for guidelines outlining optimal protocols for working up a positive MCED test, and Dr Kisiel highlighted the need for guidance around counseling patients.

“It would be ideal for providers and health care systems to have a ‘playbook’ or protocol for counseling patients on MCED test expectations and results, as counseling patients on this technology requires time and may be overwhelming for busy practitioners,” Dr Kisiel said.

He also noted that more research on MCED testing is needed across various patient populations. “We do not yet fully know the performance of MCEDs in high-risk populations or how often to use them in average-risk or increased-risk patients,” Dr Kisiel said. “Additionally, there is not sufficient data to suggest that MCEDs should be used to replace standard of care cancer screening. Ongoing efforts to validate the effectiveness of MCED testing in diverse populations will also promote more widespread adoption.”

Current and Future Research on MCED Testing

Current research on MCED testing includes studies aiming to refine test performance and optimize diagnostic work-ups following positive test results, Dr Klein said. “In addition, we are engaged in implementation research to understand how best to introduce these tools into routine care and how to educate both clinicians and patients about their utility and limitations,” he added.

From Dr Raoof’s perspective, the most exciting trial in the MCED space at present is a randomized controlled trial (NHS-Galleri) investigating “whether using the methylation-based GRAIL test will reduce late-stage cancers.”15 The trial is being conducted in the UK with 140,000 asymptomatic adults aged 50 to 77 years.

According to Dr Kisiel, the focus of ongoing MCED research falls under 2 broad domains.

“Test manufacturers are likely to focus on regulatory approval and reimbursement, with questions tailored to defining the intended use population in terms of age, risk level, and other factors, and then measuring test performance in those patients,” Dr Kisiel said. Such studies will enroll large numbers of patients who will be retested annually to help determine the ideal testing frequency, he added.  

“These studies will cost hundreds of millions or even billions of dollars but could help us learn the optimal pathways to cancer diagnosis or resolution of false-positive test results,” Dr Kisiel said. “These companies and academic collaborators are also modeling the potential long-term costs and cost-effectiveness of MCED testing.”

The second broad area of research may elucidate issues that could ultimately result in society endorsement and guideline adoption for MCED testing, Dr Kisiel said.

“This will require demonstration of benefits such as improved survival by down-staging cancers or even reducing mortality from specific cancers, especially those that we can’t already effectively screen for,” he explained. Research will also need to demonstrate that the broader adoption of MCED testing will not result in unnecessary invasive procedures or overdiagnosis of indolent cancers, according to Dr Kisiel.

“We hope to see that MCEDs improve access to cancer screening for underserved populations rather than increasing disparities, especially on the basis of wealth gaps,” Dr Kisiel said. He also added that patients should not avoid standard cancer screening, which can reduce mortality in colorectal, breast, cervical, and lung cancer “before we can establish that MCEDs can do the same.”

Disclosures: Dr Klein is an employee of GRAIL. Dr Raoof is a consultant to Verily, Exact Sciences, and GRAIL. Dr Kisiel is an inventor of intellectual property in the field of MCED that is licensed to Exact Sciences by Mayo Clinic, and Exact Sciences is a sponsor of his research. He may receive royalties and research funding from these relationships, both paid to Mayo Clinic. Dr Trosman disclosed NIH funding for a 2023 study on private payers’ perspectives on MCED.

This article originally appeared on Cancer Therapy Advisor

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