Colorectal Cancer Risk: Title and subTitle BreakBlack, White, or Shades of Gray?

Colorectal cancer screening may affect public health through both early diagnosis and actual cancer prevention via identification and colonoscopic removal of precursor lesions (adenomatous polyps).¹ However, currently only half of the eligible population undergoes colorectal cancer screening.² Moreover, many of these patients undergo evaluation with tests that are insensitive for detecting adenomatous polyps. Therefore, despite being eminently preventable, colorectal cancer still ranks as the second leading cause of cancer deaths in the United States.¹

Traditional approaches to screening dichotomize the population into increased-risk (eg, personal or family history or conditions such as ulcerative colitis) or average-risk (≥50 years) groups. The most recent guidelines categorize the available screening options as those that primarily identify cancers vs those that may also detect adenomas (with implications for colorectal cancer prevention).¹ Generally, tests with higher patient acceptability lack sensitivity, whereas the more accurate tests are associated with lower patient compliance (secondary to cost, discomfort, or intrusiveness).³ For instance, fecal occult blood test is widely accepted by patients but its sensitivity for advanced adenomas is only approximately 10%.^{1 ,3} Colonoscopy is arguably the single best test given its combined diagnostic and therapeutic facets, although many patients are reticent to undergo this procedure.

Although most would agree that patients at increased risk for colorectal cancer need colonoscopy, the majority of patients who develop colorectal cancer would have been a priori considered “average risk.” On the other hand, screening the entire average-risk population with colonoscopy is inefficient in that only approximately 5% to 10% will harbor advanced neoplasia (carcinomas or advanced adenomas).³ Moreover, resource constraints probably will not allow all the approximately 80% of the population aged 50 years or older who currently do not undergo colonoscopy to ever get this test performed.³ The conundrum is that most people who need colonoscopy do not get it, whereas the majority of people who undergo colonoscopy actually do not benefit from it. This dilemma provided the impetus for colorectal cancer risk stratification.

There are numerous nonfamilial colorectal cancer risk factors, including age, sex, race, diet, obesity, diabetes, smoking, and alcohol.⁴ Indeed, modifiable risk factors have been estimated to be responsible for 39% to 71% of colorectal cancers.⁵ Black individuals have a higher occurrence of and mortality from colorectal cancer. There are myriad potential explanations including both societal issues (access to health care) and biological differences (higher proportion of tumors that evolve via DNA mismatch repair insufficiency and thus may behave more aggressively).⁶

The study by Lieberman and colleagues⁷ in this issue of JAMA confirmed that black patients have a higher prevalence of adenomas sized more than 9 mm (advanced adenomas). This large database review noted that the effect size was more pronounced in women. Additionally,there was an increased proximal distribution of these adenomas that was probably related to factors such as age and sex. Nevertheless, one could make an argument for preferentially using colonoscopy over flexible sigmoidoscopy in black individuals.

These data also suggest that race should possibly be one factor in determining when to begin colorectal cancer screening. Currently, screening for the average-risk population is recommended to start at age 50 years. However, this is not infallible given that approximately 8% of colorectal cancer cases occur before 50 years.⁸ Exogenous factors can affect the age of diagnosis. For instance, alcohol and tobacco use have been associated with a markedly younger age of colorectal cancer presentation when compared with abstainers.⁹ With regard to race, the earlier median age at colorectal cancer diagnosis in black patients (approximately 6 years compared with white patients)¹⁰ provides further support for the American College of Gastroenterology's recommendation to initiate screening black patients at 45 years.⁶

A vexing problem for individualizing screening strategies is that the absolute effect size of each risk factor is relatively modest. For instance, when family history is the indication for colonoscopy (a remarkably heterogeneous group in electronic database studies), the advanced adenoma prevalence rate appears to be only marginally higher than that for those patients undergoing average-risk screening.¹¹ Thus, the goal of targeting finite colonoscopic resources to those likely to benefit by polypectomy is daunting. The standard approach of using a prescreen test (eg, fecal occult blood test or flexible sigmoidoscopy) to determine need for colonoscopy (analogous to the use of the Papanicolaou test as a gatekeeper to colposcopy for cervical cancer screening) is not ideal as these tests lack the requisite sensitivity.¹

A promising new technology is computed tomographic colography (CTC), also called virtual colonoscopy. Although requiring colonic purge, and associated with some discomfort, suboptimal sensitivity for adenomas sized less than 1 cm and radiation exposure, CTC has many appealing aspects including good performance for advanced lesions.¹² Several barriers to widespread implementation of CTC center on its lack of therapeutic capability, because approximately 25% to 35% of patients will actually have adenomas. There is some controversy whether patients with intermediate adenomas (5-9 mm) should undergo colonoscopic polypectomy, given cost-effectiveness considerations.¹ One could argue that risks of advanced features or cancer in adenomas sized less than 1 cm are low, although some patients and physicians may find unpalatable the strategy of allowing potentially premalignant lesions the opportunity to grow.¹³ Additionally, given logistic hurdles, referral for polypectomy may require a separate visit and bowel purge. This is not trivial in that the colonic preparation is often cited as the major reason for not undergoing colorectal cancer screening.¹⁴ Furthermore, the extracolonic findings that are frequently identified during CTC represent a double-edged sword. Although some findings may be clinically beneficial, more are likely to be unimportant but may still obligate further investigations increasing costs and discomfort.¹⁵ Given these issues, a possible strategy would be to use CTC in low-risk patients (less likely to require polypectomy) while reserving colonoscopy for the higher-risk patients.¹⁶

The need for more precise risk stratification extends to patients undergoing colonoscopic surveillance. Many colonoscopies are “squandered” on overly aggressive follow-up. Endoscopic findings may provide reasonable, but far from perfect, long-term risk guidance.¹⁷ One could envision incorporating other genetic and environmental risk factors to better guide surveillance colonoscopy intervals. A further complication is the issue of missed lesions, which can be mitigated, at least partially, by rigorous endoscopist quality control.¹

So what is the primary care physician to do at present? The paramount role is as an advocate since lack of physician recommendations and patient awareness are major impediments to colorectal cancer screening.¹⁸ It bears emphasis that even suboptimal regimens are better than nothing. Physicians can manipulate 3 facets of the screening program—modality, age of initiation, and test frequency. It would seem logical that patients with several risk factors should probably undergo colonoscopy. When to begin screening is less well-defined. Multiple risk factors may warrant earlier age of initiation, consonant with the American College of Gastroenterology guidelines that black patients should begin screening at age 45 years.⁶ The data on the intervals between screening tests remain unclear, with current guidelines (10 years and 5 years for negative colonoscopy and CTC, respectively) based on expert opinion rather than compelling data.¹ Thus, some individualization based on risk factors seems reasonable in clinical practice.

What is on the horizon? This is clearly an active area of research among numerous groups. Blood tests are being investigated including those using genomic and proteomic technologies that identify tumor products or host response. Research is focusing on elucidating the lower-penetrance higher-frequency genes that modulate colorectal cancer risk.¹⁹ Although genome-wide association studies have unveiled colorectal cancer susceptibility loci that may portend a modest (<2-fold) elevation of risk, a recent study indicates that germline allele-specific expression of TGFBR1 increases risk by approximately 9-fold and may account for a substantial proportion of inherited colorectal cancer cases.²⁰

Potential approaches to improve predictive abilities include using single-nucleotide polymorphism panels (related by disease pathophysiology or molecular pathways) or contextualizing with exogenous factors (eg, smoking susceptibility genes).^{20 - 21} One area of interest is in bridging bio-optics to detection of field carcinogenesis potentially allowing a rectal-based risk assessment for neoplasia elsewhere in the colon.^{22 - 23} There are numerous other emerging technologies and approaches.²³ A key concept is to maximize sensitivity to have an excellent negative predictive value. Because the idea is to eliminate the need for colonoscopy for many of the approximately 70% of patients who are actually without any adenomas, the negative predictive value is critical parameters. However, some false positives are acceptable because without the prescreen all those patients would have required more intrusive tests such as colonoscopy.

In conclusion, it is becoming clear that as physicians and patients enter the era of personalized medicine, colorectal cancer screening will evolve from simply dichotomizing patients into average or increased risk to assigning more precise gradations (“shades of gray”). Through assessing both genetic and environmental risk factors, clinicians may be able to more rationally tailor screening strategies to maximize cost-effectiveness and risk benefit. While waiting for this field to mature, using the published guidelines with evidence-based judicious modifications (such as more aggressive screening of black patients) would seem to be prudent.