Blood-Based Screening for Colon Cancer

Abstract

On April 13, 2016, the US Food and Drug Administra-tion (FDA) approved the first blood-based screening test for colon cancer. The assay (Epi proColon) relies on qualitative detection of the methylated septin 9 gene (SEPT9) and has been considered an innovation in screening. Despite multiple accepted options for colo-rectal cancer screening—including stool-based tests, such as the fecal occult blood test (FOBT) and lower endoscopy—handling, storing, and returning stool tests or prepping and undergoing an invasive procedure have limited adherence. Approximately one-fourth of eligible individuals aged 50 to 75 years have never been screened for colon cancer, and half are inadequately screened. Blood-based cancer screening has the poten-tial to address this gap. Yet physicians must question how this newly approved assay might be incorporated in routine clinical practice, and, most important, whether use of the test will reduce colorectal cancer mortality. The new blood-based screening test was ap-proved on the basis of clinical data regarding the sensi-tivity and specificity of the test for detecting colon cancer. Although case-control studies reported an estimated sensitivity and specificity for cancer detec-tion approaching 90%, 1 in a clinical trial the assay's sensitivity and specificity (68% and 79%, respectively) did not meet 1 of 2 prespecified goals (65% and 85%). 2 A subsequent clinical trial found that, com-pared with fecal immunohistochemistry testing (FIT), SEPT9 testing significantly improved sensitivity (68% vs 73%) but markedly decreased specificity (97% vs 81%). 3 The area under the receiver operator character-istic curve was greater for FIT than for SEPT9 testing (0.86 vs 0.82), suggesting worse overall test perfor-mance for the blood test. 2 Poorer performance would increase false-positive results, with all the attendant anxiety, downstream procedures, and cost. Importantly, no evidence has shown that this new assay improves disease-specific or overall mortality compared against no screening or against accepted screening methods. Sigmoidoscopy and FOBT have both demonstrated these benefits in randomized trials, while colonoscopy and FIT have not. Yet practi-cally, colonoscopy includes sigmoidoscopy, and the rationale for FIT is more closely analogous to FOBT. Thus, in both cases, extrapolation may be more rea-sonable than blood-based screening, an entirely novel method. The advantage of blood testing is the opportunity to expand the number of individuals who undergo co-lon cancer screening. Even among existing noninvasive tests for colon cancer, adherence is low: for annual FOBT, on average only half of participants return stool cards appropriately. 4 Evidence suggests that some patients