Liquid Biopsy for CRC Screening May Not Be Ready for Prime Time

While screening for colorectal cancer (CRC) with a blood-based test would result in better outcomes than no screening at all, it would likely result in worse outcomes than currently available tests -- while increasing costs -- according to two modeling studies published in Gastroenterology.

In the first, models suggested that compared with no screening at all, a blood-based test with a minimum performance sensitivity of 74% and a specificity of 90% -- the minimum criteria set by Centers for Medicare & Medicaid Services (CMS) -- would result in reduced CRC incidence and mortality and increased quality-adjusted life-years (QALY) gained for an average-risk screening population. And it would be cost-effective.

However, when compared with other screening alternatives using three microsimulation models for CRC, blood-based testing fell short, according to Rosita van den Puttelaar, MSc, of the Erasmus Medical Center in Rotterdam, the Netherlands, and colleagues.

Without screening there would have been 77-88 CRC cases and 32-36 CRC deaths per 1,000 individuals, costing $5.3-$5.8 million, the researchers determined.

Compared with no screening, each method -- blood-based testing, fecal immunochemical testing (FIT), multitargeted stool DNA test with FIT (sDNA-FIT), and colonoscopy -- reduced the number of CRC cases and deaths, but the benefit was lowest with the blood-based method:

• Blood-based test: 19-33 fewer cases and 16-21 fewer deaths per 1,000
• FIT: 38-60 and 24-29, respectively
• sDNA-FIT: 33-57 and 22-28
• Colonoscopy: 48-73 and 25-32

Compared with FIT screening, blood-based screening resulted in 39-68 fewer QALYs per 1,000 individuals while increasing costs by $4.0-$4.8 million; compared with colonoscopy, blood-based screening resulted in 45-84 fewer QALYs while increasing costs by $2.3-$3.4 million; and compared with sDNA-FIT, the blood-based method resulted in 26-59 fewer QALYs per 1,000 while increasing costs by $1.3-$2.1 million.

Compared with no screening, blood-based screening was cost-effective, with an additional cost of $25,600-$43,700 per QALY gained.

But FIT remained more effective in QALYs gained and less costly than blood-based screening even when uptake of blood-based screening was 20 percentage points higher than uptake of FIT.

In the second study, researchers led by Uri Ladabaum, MD, of the Stanford University School of Medicine in Redwood City, California, used a Markov model to determine that screening every 3 years with a blood-based test meeting minimum CMS thresholds would reduce CRC incidence by 40% and mortality by 52% versus no screening.

But they deemed that the findings were "less profound" than those seen with alternative screening methods, with reductions of 68%-79% and 73%-81%, respectively, achieved with sDNA testing every 3 years, annual FIT, or colonoscopy every 10 years.

Assuming it costs the same as sDNA, the blood-based test cost $28,500 per QALY gained versus no screening. However, the authors found that FIT, colonoscopy, and sDNA were less costly and more effective.

The authors also determined that in order for a blood-based test criteria to match the clinical outcomes seen with FIT, it would have to achieve a 1.8-fold, 1.5-fold, and 1.4-fold increase in the participation rate in order to match FIT's impact on CRC incidence, CRC mortality and QALYs/person, respectively.

However, "in settings with annual FIT participation rates >60%-70% (which is unrealistic in opportunistic screening), even a 100% participation rate with a blood test with the minimum CMS thresholds could not deliver outcomes comparable to those with annual FIT," they added.

"Because liquid biopsy is predicted to be less effective and more costly than currently established screening programs, it cannot be recommended to replace established effective screening methods," wrote David Lieberman, MD, of Oregon Health and Sciences University in Portland, along with a panel of experts, in an accompanying commentary in Clinical Gastroenterology and Hepatology.

The commenters -- several of whom were also involved in the modeling studies -- suggested that liquid biopsy "offers a simple process that could encourage more people to participate in screening."

However, "substituting [liquid biopsy] for a currently effective test would worsen patient outcomes and increase cost," they noted.

Lieberman and colleagues added that focusing on sensitivity to detect colorectal cancer alone is insufficient. They noted that a key driver of the effectiveness of liquid biopsy is the detection of advanced adenomas, and that modeling showed that increasing advanced adenoma sensitivity "modestly" would be more beneficial than improving CRC sensitivity to 95%.

They suggested the following sensitivities as potential benchmarks for an effective blood test for CRC: >90% for stage I-III CRC and ≥40%-50% for advanced adenomas.