E. Shelley Hwang, MD, MPH
Multicancer early detection (MCED) tests are beginning to enter clinical practice, but how useful will they be? “This is an exciting field, with many competing technologies. MCED assays will be coming across your desk in the near future if they haven’t already. But they are not a panacea. They are tests we need to be very thoughtful about,” said E. Shelley Hwang, MD, MPH, the Mary and Deryl Hart Distinguished Professor of Surgical Oncology and Radiation at Duke University, who described these “blood biopsies” at the 2024 Miami Breast Cancer Conference.1
It has been suggested that shifting the diagnosis of all stage IV cancers to stage III would reduce cancer-related deaths by 15%.2 The majority of cancers are not detected with available cancer screening modalities; hence, the robust interest in developing better assays that has opened the door for MCEDs.
What Are MCEDs?
MCEDs are based on the detection of tumor components such as circulating tumor DNA (ctDNA) and cell-free DNA (cfDNA). Because these factors are shed in the circulation, most assays are blood-based. The findings are often combined with machine learning algorithms. Although they have obvious benefits, especially in disease settings with no other effective screening methods, they can be associated with false-positives, overtreatment, and expense.
The tests’ sensitivity along with positive predictive value and negative predictive value are important in assessing their performance, ie, the likelihood that a positive test really indicates cancer and that a negative test truly does not. A combination of these factors helps determine whether MCEDs are worthwhile in specific situations.
Over the entire landscape of MCEDs, the sensitivity is high—80% to 100%—but the positive predictive value can be quite low—40% to 55%.2 “The issue is that when you administer these MCEDs across a large population, up to 1% of the tested population will have a positive result, and not all of those patients will actually have cancer,” she said.
- MCEDs furthest along in development include the following:
- Galleri: DNA methylation, available with prescription
- Trucheck: Circulating tumor cells; available to the public without prescription
- CancerSEEK/Cancerguard: cfDNA plus protein markers; not currently available to the public
- Noncoding RNA assay: not currently available to the public
- Signatera: cfDNA mutation analysis; approved for coverage by the Centers for Medicare & Medicaid Services (CMS) to assess for measurable residual disease (MRD) in the neoadjuvant setting.
Galleri
The Circulating Cell-Free Genome Atlas (CCGA) study, based on data from The Cancer Genome Atlas, evaluated the Galleri test in 15,254 participants.3 More than half the patients were known to have cancer, and more than 50 cancer types were represented. The test generally performed well, not only in finding cancer but in identifying the type. Its positive predictive value was 43%, its false-positive rate was 0.7%, and its sensitivity was 44% for stage I to III cancers and 67% for stage I to III disease in prespecified cancer types.
Subsequent to the CCGA study, the PATHFINDER study evaluated Galleri in 6,662 patients not known to have cancer.4 The assay found 35 true-positive cancer cases and 57 false-positives, including 5 breast cancers, all of which were recurrences. Of 28 participants diagnosed with new primaries, approximately half were found at stage I or II. “This test did what it proposed to do. The cancers were mostly those for which there are no effective screening strategies,” Dr. Hwang observed. “This was proof of concept that these cancers can be detected at a much earlier stage than would otherwise manifest with symptoms.”
Follow-up diagnostic testing for these patients usually included laboratory tests and imaging, but many also underwent some kind of procedure—which in four patients was surgery. “Despite the excitement over the potential for early diagnosis with these tests, it’s important to keep in mind what the repercussions can be,” she commented.
Based on the PATHFINDER study, CMS is working with the biotechnology company that developed Galleri to further evaluate MCED tests for Medicare beneficiaries.
CancerSEEK
CancerSEEK is a polymerase chain reaction–based cfDNA assay that looks at 61 amplicons in 16 genes and also takes into account 8 cancer proteins. Its reported sensitivity in a study of 1,005 individuals was approximately 40% for stage I disease, approximately 70% for stage II disease, and almost 80% for stage III cancer, at a specificity of 91%; it localized the anatomic site in 83%.5 However, sensitivity varied widely, from a high of 98% in ovarian cancer to a low of 33% in breast cancer.
CancerSEEK was evaluated in the DETECT-A study of 10,006 women without cancer.6 The test’s positive predictive value was only 6%, which compared poorly with the 43% for Galleri in PATHFINDER; however, but combined with any type of imaging, the positive predictive value rose to 41%. “These results are intriguing. It’s up to us as a community to start developing ways in which this sort of test can be most valuable,” Dr. Hwang commented.
Trucheck
Trucheck is one of several assays looking at circulating ensembles of tumor-associated cells (C-ETACs). In a study of 10,625 individuals, the presence of C-ETACs was associated with a 230-fold higher risk for the development of cancer at 1 year.7 However, only 6,884 patients had sufficient follow-up, and the findings were based on just nine cancer diagnoses among 259 C-ETAC–positive patients, compared with one cancer among 6,625 C-ETAC–negative patients.
“So, that’s the kind of ratio we are thinking about when we’re doing indiscriminate testing of the population without taking into account what their risks are,” she pointed out. “Based on this study, the manufacturer is doing direct-to-consumer marketing. You can order the Trucheck Intelli multicancer screening test yourself on the manufacturer’s website for £1,035.” (Trucheck Intelli is marketed for the detection of approximately 70 types of solid tumors, whereas Trucheck FemmeSafe screens specifically for cancers of the breast, ovaries, endometrium, and cervix.)
Noncoding RNA Tests
Exai Bio’s noncoding RNA assay is based on these concepts: orphan noncoding RNAs are indicative of cancer and present in the blood; cell-free RNAs are stable, resilient, and continually released from tumor cells; tumor-derived orphan noncoding RNAs are abundant in the blood; and orphan noncoding and cell-free RNAs provide novel markers as compared with ctDNA or cfDNA.7
Based on “very robust and very compelling data,” it appears this test could represent a new type of nucleotide that can be tested for in the blood, Dr. Hwang said. In one study of 279 individuals with breast cancer and ductal carcinoma in situ (DCIS),8 the test achieved an “outstanding” 85% sensitivity at a sensitivity of 90%, she said. It differs from other tests in that its sensitivity is high, regardless of the disease stage or tumor size. Sensitivity ranged from 78% for DCIS to 100% for stage IV disease, and from 78% for isolated tumor cells to 90% for stage T3 disease. “Definitely keep an eye on this space,” she said.
Signatera for MRD Detection
“We have a test for MRD after neoadjuvant therapy,” Dr. Hwang said. The Signatera assay, which identifies ctDNA, was recently approved for Medicare coverage by CMS, for use after neoadjuvant therapy. In a study of 283 patients, early clearance of ctDNA in patients with triple-negative breast cancer was associated with a good response; ctDNA dynamics during neoadjuvant chemotherapy predicted clinical outcomes; and ctDNA negativity was associated with improved survival despite the presence of residual cancer.9 Sensitivity was demonstrated regardless of tumor type.
“[The study showed] a nice reduction in the amount of ctDNA, which corresponded to response to chemotherapy…,” said Dr. Hwang. “The outcomes tracked nicely with the assay results…. Patients who were ctDNA-negative had the best outcomes, whereas those with no clearance at all had the worst. This could be an easy way for patients to be considered for additional therapy or clinical trials.”
DISCLOSURE: Dr. Hwang has served as a consultant for Exai Bio and Lumicell.
REFERENCES
1. Hwang ES: Updates on multicancer early detection tests in breast cancer screening. 2024 Miami Breast Cancer Conference. Presented March 9, 2024.
2. Guerra CE, Sharma PV, Castillo BS: Multi-cancer early detection: The new frontier in cancer early detection. Annu Rev Med 75:67-81, 2024.
3. Liu MC, Jamshidi A, Venn O, et al: Genome-wide cell-free DNA methylation signatures and effect on tissue of origin performance. J Clin Oncol 37(suppl 15):3049, 2019.
4. Schrag D, Beer TM, McDonnell CH 3rd, et al: Blood-based tests for multicancer early detection (PATHFINDER): A prospective cohort study. Lancet 402:1251-1260, 2023.
5. Cohen JD, Li L, Wang Y, et al: Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 359:926-930, 2018.
6. Lennon AM, Buchanan AH, Kinde I, et al: Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science 369:eabb9601, 2020.
7. Ranade A, Bhatt A, Page R, et al: Hallmark circulating tumor-associated cell clusters signify 230 times higher one-year cancer risk. Cancer Prev Res (Phila) 14:11-16, 2021.
8. Fish L, Zhang S, Yu JX, et al: Cancer cells exploit an orphan RNA to drive metastatic progression. Nat Med 24:1743-1751, 2018.
9. Magbanua MJM, Swigart LB, Ahmed Z, et al: Clinical significance and biology of circulating tumor DNA in high-risk early-stage HER2-negative breast cancer receiving neoadjuvant chemotherapy. Cancer Cell 41:1091-1102, 2023.
