Advances in Fecal Tests for Colorectal Cancer Screening

textabstractColorectal cancer (CRC) forms an important public health problem, especially in developed countries. CRC screening tests can be used to identify asymptomatic individuals with CRC precursors and (early) cancer. Removal of these lesions reduces CRC incidence and prevents CRC-related mortality. There are a range of screening tests available, each with advantages and disadvantages. Stool screening tests can broadly be divided into fecal occult blood tests (FOBTs) and molecular biomarker test, such as DNA/RNA marker tests, protein markers, and fecal microbiome marker tests. Guaiac fecal occult blood tests (gFOBT) have been demonstrated in large randomized screening trials to reduce CRC mortality. Fecal immunochemical tests (FIT) have superior adherence, usability, and accuracy as compared to gFOBT. Advantage of the use of quantitative FITs in CRC screening programs is the cut-off level that can be adjusted. Molecular biomarker DNA tests have shown to detect significantly more cancers than FIT. By combining biomarker DNA tests with FIT, sensitivity for advanced adenomas can be increased significantly. However, it has lower specificity thus demands more colonoscopy resources, is more cumbersome, and costly. The adherence has not been assessed in population screening trials. For these reasons, FIT is therefore at present regarded as the preferred method of non-invasive CRC screening. This chapter will review the current status of fecal test-based CRC screening

Adherence to colorectal cancer screening: Four rounds of faecal immunochemical test-based screening

Background:The effectiveness of faecal immunochemical test (FIT)-based screening programs is highly dependent on consistent participation over multiple rounds. We evaluated adherence to FIT screening over four rounds and aimed to identify determinants of participation behaviour.Methods:A total of 23 339 randomly selected asymptomatic persons aged 50-74 years were invited for biennial FIT-based colorectal cancer screening between 2006 and 2014. All were invited for every consecutive round, except for those who had moved out of the area, passed the upper age limit, or had tested positive in a previous screening round. A reminder letter was sent to non-responders. We calculated participation rates per round, response rates to a reminder letter, and differences in participation between subgroups defined by age, sex, and socioeconomic status (SES).Results:Over the four rounds, participation rates increased significantly, from 60% (95% CI 60-61), 60% (95% CI 59-60), 62% (95% CI 61-63) to 63% (95% CI 62-64; P for trend<0.001) with significantly higher participation rates in women in all rounds (P<0.001). Of the 17 312 invitees eligible for at least two rounds of FIT screening, 12 455 (72%) participated at least once, whereas 4857 (28%) never participated; 8271 (48%) attended all rounds when eligible. Consistent participation was associated with older age, female sex, and higher SES. Offering a reminder letter after the initial invite in the first round increased uptake with 12%; in subsequent screening rounds this resulted in an additional uptake of up to 10%.Conclusions:In four rounds of a pilot biennial FIT-screening program, we observed a consistently high and increasing participation rate, whereas sending reminders remain effective. The substantial proportion of inconsistent participants suggests the existence of incidental barriers to participation, which, if possible, should be identified and removed

Improvement of non-invasive tests of liver steatosis and fibrosis as indicators for nonalcoholic fatty liver disease in type 2 diabetes mellitus patients with elevated cardiovascular risk profile using the PPAR-α/γ agonist aleglitazar

Background Peroxisome proliferator-activated receptor (PPAR) agonists may have favorable outcomes on non-alcoholic fatty liver disease. This study serves as proof of concept to evaluate whether dual PPAR-α/γ agonists improve non-invasive tests of liver steatosis and fibrosis. Methods This is a post-hoc analysis of a randomized, double-blind, placebo-controlled, multi-center trial comprising 7226 patients with type 2 diabetes mellitus and recent coronary artery disease randomized to receive aleglitazar, a PPAR-α/γ agonists, or placebo for two years. Main outcomes were change in non-invasive tests for liver steatosis and fibrosis: Liver Fat Score (LFS), Liver Accumulation Product (LAP), Fibrosis-4 (FIB-4), and NAFLD Fibrosis Score (NFS). Results LFS, LAP and FIB-4 decreased upon treatment, whereas scores in the placebo group remained the same or increased (P<0.001). NFS responded differently but remained consistently lower than placebo. In the treatment group more participants shifted to a lower FIB-4 and NFS category, or improved in respect to the LAP cut-off values compared to the placebo group (P<0.001 for FIB-4 and LAP, P<0.004 for NFS). LFS had a low discriminative power in this study. Conclusion This post-hoc analysis showed improvement of non-invasive tests of liver steatosis and fibrosis after starting dual PPAR-α/γ agonist treatment, adding to the evidence that this pathway has potential in non-alcoholic fatty liver disease treatment

Missed colorectal cancers in a fecal immunochemical test-based screening program:Molecular profiling of interval carcinomas

BACKGROUND For optimizing fecal immunochemical test (FIT)-based screening programs, reducing the rate of missed colorectal cancers (CRCs) by FIT (FIT-interval CRCs) is an important aspect. Knowledge of the molecular make-up of these missed lesions could facilitate more accurate detection of all (precursor) lesions. AIM To compare the molecular make-up of FIT-interval CRCs to lesions that are detected by FIT [screen-detected CRCs (SD-CRCs)]. METHODS FIT-interval CRCs observed in a Dutch pilot-program of FIT-based screening were compared to a control group of SD-CRCs in a 1:2 ratio, resulting in 27 FIT-interval CRC and 54 SD-CRCs. Molecular analyses included microsatellite instability (MSI), CpG island methylator phenotype (CIMP), DNA sequence mutations and copy number alterations (CNAs).RESULTS Although no significant differences were reached, FIT-interval CRCs were more often CIMP positive and MSI positive (33% CIMP in FIT-interval CRCs vs 21% in SD-CRCs (P = 0.274); 19% MSI in FIT-interval CRCs vs 12% in SD-CRCs (P = 0.469)), and showed more often serrated pathway associated features such as BRAF (30% vs 12%, P = 0.090) and PTEN (15% vs 2.4%, P = 0.063) mutations. APC mutations, a classic feature of the adenoma-carcinoma-sequence, were more abundant in SD-CRCs (68% vs 40% in FIT-interval CRCs P = 0.035). Regarding CNAs differences between the two groups; FIT-interval CRCs less often showed gains at the regions 8p11.22-q24.3 (P = 0.009), and more often gains at 20p13-p12.1 (P = 0.039). CONCLUSION Serrated pathway associated molecular features seem to be more common in FIT-interval CRCs, while classic adenoma carcinoma pathway associated molecular features seem to be more common in SD-CRCs. This indicates that proximal serrated lesions may be overrepresented among FITinterval CRCs

Change in NITs of liver steatosis and fibrosis from baseline.

Value at baseline for A: Median LFS of 0.60 for placebo and 0.63 for aleglitazar, B: Mean LAP of 69.5 for placebo and 67.8 for aleglitazar, C: Mean FIB-4 of 1.40 for placebo and 1.44 for aleglitazar, D: Mean NFS of -0.50 for placebo and -0.41 for aleglitazar. Error bars indicate 95% CIs. Change from baseline is significantly different in the aleglitazar and the placebo group at all timepoints ≥3 mohs for all proxies (all P<0.001).</p

Fecal immunochemical test-based colorectal cancer screening: The gender dilemma

Despite differences between men and women in incidence of colorectal cancer (CRC) and its precursors, screening programs consistently use the same strategy for both genders. The objective of this article is to illustrate the effects of gender-tailored screening, including the effects on miss rates of advanced neoplasia (AN). Participants (age 50-75 years) in a colonoscopy screening program were asked to complete a fecal immunochemical test (FIT) before colonoscopy. Positivity rates, sensitivity and specificity for detection of AN at multiple cut-offs were determined. Absolute numbers of detected and missed AN per 1000 screenees were calculated. In total 1,256 individuals underwent FIT and colonoscopy, 51% male (median age 61 years; IQR 56-66) and 49% female (median age 60 years; IQR 55-65). At all cut-offs men had higher positivity rates than women, ranging from 3.8% to 10.8% versus 3.2% to 4.8%. Sensitivity for AN was higher in men than women; 40%-25% and 35%-22%, respectively. More AN were found and missed in absolute numbers in men at all cut-offs. More AN were both detected and missed in men compared to women at all cut-offs. Gender-tailored cut-offs could either level sensitivity in men and women (i.e., lower cut-off in women) or level the amount of missed lesions (i.e., lower cut-off in men

Changes in absolute values of non-invasive tests over time.

Changes in absolute values of non-invasive tests over time.</p

Change in FIB-4 and NFS category from baseline until 24 months follow-up.

Proportion of randomized patients that either improved (changed to a lower category), worsened (changed to a higher category) or did not change in category. Proportion of change is significantly different between treatment and placebo for FIB-4 (A) and NFS (B). FIB-4: Both improvement and worsening PPP = 0.024.</p

Baseline characteristics of the patients in the aleglitazar group compared with the placebo group.

Baseline characteristics of the patients in the aleglitazar group compared with the placebo group.</p

Change in AST/ALT ratio and BMI from baseline.

Value at baseline for A: Mean AST/ALT of 1.21 for placebo and 1.22 for aleglitazar, B: Mean BMI of 29.5 kg/m2 for placebo and 29.3 kg/m2 for aleglitazar. Error bars indicate 95% CIs. Change from baseline is significantly different in the aleglitazar and the placebo group at all timepoints ≥1 month for both AST/ALT ratio and BMI (all P<0.001).</p