Review article
Stool screening for colorectal cancer: evolution from occult blood to molecular markers

https://doi.org/10.1016/S0009-8981(01)00712-4Get rights and content

Abstract

Background: Colorectal cancer is the second leading cause of malignant death, and better preventive strategies are needed. Participation rates for colorectal cancer screening remain low due, in part, to perceived discomfort, potential harm, and high costs with available tools. Methods: Stool testing, unlike other conventional screening approaches, is noninvasive and requires no cathartic preparation. However, widely used fecal blood tests yield frequent false-negative and false-positive results that lower screening effectiveness and raise program costs. There is a compelling biological rationale to target DNA alterations exfoliated from neoplasms into stool, and multiple DNA markers would need to be assayed because of the genetic heterogeneity of colorectal neoplasia. Early clinical studies with this multi-target DNA-based stool assay approach suggest high sensitivity for both colorectal cancer and premalignant adenomatous polyps while maintaining high specificity. Conclusions: This apparently accurate and user-friendly new approach holds promise to improve the effectiveness, efficiency, and appeal of colorectal cancer screening. Large-scale clinical studies are clearly warranted to corroborate the early results.

Introduction

Colorectal cancer remains the second leading cause of malignant mortality in industrialized nations, accounting for more than 10% of all cancer deaths [1], and is the most common fatal cancer among nonsmokers [2]. Because of its orderly natural history and location within a readily accessible organ, colorectal neoplasia appears ideally suited for preventive intervention. The lifetime incidence of colorectal cancer among persons in the general US population is sufficiently high at 6% [1], or 1 in 18, to justify mass screening. However, screening efforts have been compromised by performance limitations and low penetrance of current screening tools. More optimally tailored screening tools are needed that would exhibit the combined features of high sensitivity and specificity for screen-relevant neoplasia (advanced adenomas and curable-stage cancers), minimal invasiveness, safety, affordability, and broad acceptability by the general population, health care providers, and third party payers.

Stool screening has several important advantages over other screening methods and warrants expanded investigation, as its theoretical potential has not been achieved. This common approach to colorectal screening has historically relied on the detection of occult blood, which has proven to be an inherently insensitive and nonspecific marker for screen-relevant neoplasia. Application of more accurate fecal markers could substantially improve the effectiveness and efficiency of screening outcomes. There is a strong biological rationale to target DNA alterations exfoliated from neoplasms, and early clinical data are compelling.

New approaches to colorectal cancer screening must be considered against the context of conventional methods. This overview points out limitations of fecal occult blood testing and other currently used screening tools, presents a rationale to target exfoliated markers in stool, and summarizes early data on the performance of DNA-based stool assays.

Section snippets

Fecal occult blood testing

Fecal occult blood tests (FOBTs) have been used to screen colorectal cancer for nearly three decades and continue to be the most frequently used screening tool in North America [3], [4]. While several types of FOBTs are available (as reviewed in Ref. [5]), the guaiac-impregnated Hemoccult card (Smith Kline Diagnostics, San Jose, CA) is most commonly employed. Guaiac test reactivity can be augmented by rehydrating the fecal smear before adding the peroxide catalyst or by reformulating card

Drawbacks of other conventional screening approaches

Acknowledging the performance limitations of FOBTs, the US Congress has approved Medicare coverage of flexible sigmoidoscopy, barium colon X-ray, and, most recently, colonoscopy as alternatives for average-risk colorectal cancer screening. Based on predictive modeling [35], [36], [37], the cost-effectiveness estimates of these modalities are similar to those for FOBT screening and compare favorably to cost-effectiveness benchmarks of breast cancer and cervical cancer screening. However, each of

Appeal of stool screening with exfoliated markers

Stool testing has several compelling advantages over other approaches to colorectal cancer screening. Stool screening is uniquely noninvasive, requires no unpleasant cathartic preparation, can be performed on mailed-in specimens without a mandated health center visit, and, unlike sigmoidoscopy, reflects the full length of the colorectum. Use of markers with performance characteristics clearly superior to occult blood would make stool screening more attractive by improving its effectiveness with

Multi-target DNA-based stool assay

The feasibility of a multi-target DNA-based assay system has recently been reported [92]. A prototype multicomponent test was employed (EXACT Sciences, Maynard, MA). Following recovery of human DNA from stool using a sequence-specific hybrid capture technique, assay components targeted point mutations at any of 15 mutational hot spots on K-ras, APC (Fig. 5), and p53 genes; mutations on Bat-26, a microsatellite instability marker (Fig. 6); and “long” DNA. This latter marker, long or

Closing comments

Much greater participation in screening will be required to meaningfully impact colorectal cancer mortality. In the United States, participation rates with colorectal cancer screening are currently less than 30% in both genders compared to screening rates for breast and cervical cancer of 70–80% [97]. Several professional organizations, including the American Cancer Society [97], have established guidelines for colorectal cancer screening with options to employ any of the available modalities

Acknowledgements

Mayo Foundation is a minor equity investor in EXACT Sciences. D. Ahlquist is a member of the EXACT Sciences' scientific advisory board but holds no stock personally and has received no consulting fees. A. Shuber is employed by EXACT Sciences.

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