Improving colorectal cancer screening programs

Abstract

In this editorial we comment on the article by Agatsuma et al published in the World Journal of Gastroenterology. They suggest policies for more effective colorectal screening. Screening is the main policy that has led to lower mortality rates in later years among the population that was eligible for screening. Colonoscopy is the gold standard tool for screening and has preventive effects by removing precancerous or early malignant polyps. However, colonoscopy is an invasive process, and fecal tests such as the current hemoglobin immunodetection were developed, followed by endoscopy, as the general tool for population screening, avoiding logistical and economic problems. Even so, participation and adherence rates are low. Different screening options are being developed with the idea that if people could choose between the ones that best suit them, participation in population-based screening programs would increase. Blood tests, such as a recent one that detects cell-free DNA shed by tumors called circulating tumor DNA, showed a similar accuracy rate to stool tests for cancer, but were less sensitive for advanced precancerous lesions. At the time when the crosstalk between the immune system and cancer was being established as a new hallmark of cancer, novel immune system-related biomarkers and information on patients’ immune parameters, such as cell counts of different immune populations, were studied for the early detection of colorectal cancer, since they could be effective in asymptomatic people, appearing earlier in the adenoma-carcinoma development compared to the presence of fecal blood. sCD26, for example, detected 80.37% of advanced adenomas. To reach as many eligible people as possible, starting at an earlier age than current programs, the direction could be to apply tests based on blood, urine or salivary fluid to samples taken during routine visits to the primary health system.

Key Words: Mortality rates; Colorectal cancer; Screening; Biomarker; Fecal hemoglobin immunodetection; Soluble sCD26; Colonoscopy; Immunoscores

Core Tip: Although cancer cases are increasing worldwide, the decline in cancer-associated deaths in middle-aged people in recent years has demonstrated progress in cancer treatment, detection, and prevention policies. Colorectal screening, one of those successful policies, however, has some drawbacks, such as low adherence to the fecal hemoglobin immunodetection. New ways to detect colorectal cancer are being discussed.

INTRODUCTION

Cancer cases are increasing worldwide largely due to a growing population and lifestyle factors that impact people’s cancer risk. The most recent study showed that in the United Kingdom cancer cases and death rates rose by 57% in men and 48% in women during the last 25 years[1], mainly for liver, mouth, and uterine cancers, all related with risk factors including ultraviolet exposure, alcohol, obesity, or smoking. The consequences for cancer patients, healthcare staff and for the economy in general are challenging.

However, there are good news too. Several advances in cancer treatment, detection, and prevention policies, conduced to a reduction in cancer-associated death in middle-aged people during the same period[1]. In data examined for 23 cancer types, overall mortality rates fell by 37% in men and 33% in women. Cancer prevention played an important role; for example, mortality rates from cervical cancer decreased by 54.3% due to the introduction of the human papillomavirus vaccine combined with cervical screening in health services. The reduction of risk factors in recent decades, such as smoking rates, contributed to lung cancer mortality rates falling by 53.2% in men and 20.7% in women. Other cancers with screening schemes also decreased, mainly breast and gastrointestinal cancer, highlighting that early cancer diagnosis dramatically improved survival rates, that is, it helped save lives[1]. Similar results can be expected not only in developed countries but also in developing countries that are investing in public health services.

Colorectal cancer (CRC) is one of the main causes of cancer-related and general causes of deaths worldwide. Early detection through screening could prevent more than 90% of deaths, which is why many countries have implemented, or are in the process of implementing, general age-based screening programs[2-4]. The gold standard tool for screening is colonoscopy, which has preventive effects by eliminating precancerous or early malignant lesions, that is, polyps, reducing the incidence of CRC, in addition to its therapeutic function. However, colonoscopy as a general tool for population screening faces many logistical and economic drawbacks, in addition to low participation rates as it is an invasive process.

One approach has been to find good, less invasive biomarkers for early detection that could select screening participants for colonoscopy. The main success so far has been the development of fecal tests such as the current hemoglobin immunodetection (FIT), followed by endoscopy. Still, these stool testing-based screening programs show low adherence, in some populations less than half of the people who were eligible for screening[2,4].

The study of Agatsuma et al[2] in Japan highlights that more than 70% of cases are diagnosed outside of screening and identifies specific subgroups of people in relation to the diagnostic routes they followed. They suggest policies for more effective and efficient counseling of the non-adherent population, for example paying special attention to populations who do not visit hospitals for comorbidities and lack access to healthcare centers.

As many people is reluctant about collecting stools and handling or storing them, researchers are looking for other minimally invasive and resource-effective tests such as blood tests, which could also be automated. These “liquid biopsy” tests are also being used for monitoring cancer recurrence in patients undergoing cancer treatment and for other emerging cancer screening tests. Offering different screening options and allowing people to choose the one that works best for them would increase participation in population-based screening programs[3,4].

An article published recently in the New England Journal of Medicine showed that a blood test can detect cell-free DNA shed by tumors called circulating tumor DNA (ctDNA)[4]. This retrospective study detected CRC in 83% of people with confirmed disease, an accuracy rate like that of stool tests, while 16.9% of patients with a ctDNA negative test did show CRC by colonoscopy. The test was most sensitive for CRC, including early stages of the disease (I to III), but was less sensitive for advanced precancerous lesions (only the 13.2%). Another sensitivity issue of the FIT, and ctDNA test, is the detection of sessile serrated adenomas/polyps, which are, in fact, difficult to find even by colonoscopy[5]. There are also false positives with FIT, for example in people with hemorrhoids[3], or the 10.4% with positive ctDNA with the blood test.

The serum protein biomarker we were studying, sCD26, decreased in patients’ blood. sCD26 did not show any direct correlation with tumor location, degree of histologic differentiation, kind of metastasis or Dukes’ stages, but it could be related to immune cell subsets[6]. At that moment, the crosstalk between the immune system and cancer was being established and we were one of the first groups to suggest that it was necessary to collect the patients’ lymphocyte count and other immune parameters. These biomarkers, sCD26 for example, will arise earlier in the adenoma-carcinoma development compared to the presence of fecal blood, and could be effective in the asymptomatic, pre-diagnostic window of opportunity for the early detection of CRC. In fact, in our latest work[3], 80.37% of advanced adenomas were detected. Our goal in that study was to reduce false positive rate with a sequential testing strategy for FIT positive individuals offering an alternative blood test with our biomarker for a confirmation prior to colonoscopy. This kind of markers, however, in comparison with tumor neoantigens, lack specificity, so immunoscores and pan-immune inflammation values are being used for tumor classification, prognostic information, or surveillance[7,8].

CONCLUSION

There are opportunities to optimize CRC screening programs. It has been recommended that people with average risk for CRC should begin regular screenings already at age 45, earlier than the standard age of screening programs (50-55)[1]. To reach as many eligible people as possible and reduce inequalities in access, the direction might be to have a blood or, better, urine or salivary, fluid-based test for samples taken during routine visits to their doctors. Cheap and easy to handle kits might follow a sequential testing strategy.