1. Stool DNA test and FOB test in the screening and diagnosis of CRC
VASILEIOS PANTERIS
Consultant Gastroenterologist
“Sismanogleio-Am. Flemig” Hospital
COLORECTAL CANCER Progress and Prospects
20th Anniversary of the HSGO

2. Colorectal cancer burden worldwide
3rd rank in incidence
4th rank in mortality

3. Colorectal cancer burden
Europe:
2nd rank incidence
2nd rank mortality
Asia:
4rd rank in incidence
4th rank in mortality

4. Colorectal cancer burden by subcontinents
Highest incidence rate in Australia/New Zealand and the lowest in Western Africa
Highest mortality rates in both sexes in Central and Eastern Europe and the lowest in Western Africa

5. Colorectal cancer burden by world socioecomic status
Almost 55% of the cases occur in more developed regions

6. Colorectal cancer burden in Greece-UK
3rd rank incidence
2nd rank mortality

7. Colorectal cancer burden- Trends in mortality between Greece-UK
Greek mortality : 5.5% %
UK mortality : % %

9. SCREENING
FOBT
gFOBT
1998 CMS approved
FIT
2003 CMS approved
MT-sDNA
2014 CMS approved
SIGMO+FOBT
COLONOSCOPY

10. Screening goals In a screening programme:
An effective test needs to be applied to over 70% of the population at risk.
All the necessary infrastructure and resources have to be in place
Organized screening is much more cost-effective than unorganized or opportunistic
screening.
Organized screening causes less harm than opportunistic screening, because it avoids
over-screening and over-treatment.
WHO cancer control

11. “I DONT WANT ANYONE TO DIE WHEN GOD HAS PROVIDED AN OPPORTUNITY FOR US TO LIVE LONGER” Dawn 32y, Kenya, WHO Cancer control

12. Cancer screening recommendations
American Cancer Society & Multi-Society Task Force Screening Recommendation
European Cancer Screening Recommendations
Armaroli P, 2015
Smith R, 2016
Robertson D, 2017

13. European screening programmes –data 2016
20-68%
2-10%
Navarro M, 2017

14. American, Western Pacific & East Asian screening programmes –data 2016
16-63%
1-10%
Navarro M, 2017

15. Technical aspects of the tests
Guaiac FOBT relies on peroxidase activity between added oxygen peroxide and guaiac impregnated paper of the test which is catalyzed by the presence of the heme component of hemoglobin when blood is present in stool, producing a blue color that is read as positive. Heme in red meat or peroxidase activity in vegetables can cause false positive results. Vit C has anti-oxidant inhibiting the color reaction thereby producing false negative results.
FIT (fecal immunochemical test) works specifically by detecting the globin component of human hemoglobin by the use of monoclonal or polyclonal antibodies raised againgst it.
MultiTarget-sDNA test works by detecting DNA alterations present in tumor cells exfolliated into feces. It searches 10 DNA biomarkers (included methylated NDRG4 and BMP3 gene promoter regions, 7 Kras point mutations, β-actin as reference) and fecal hemoglobin (with immunochemical reaction) to produce a composite score with a qualitative dichotomous presentation but based on a quantitative algorithmic value

16. gFOBT: Hemoccult II & Hemoccult Sensa
SCREENING
FOBT
gFOBT
1998 CMS approved
1st generation with sensitivity <50%
High sensitivity >70%

17. Qualitative Quantitative
FIT brands for which studies have been conducted The qualitative are CLIA approved but not the quantitative in USA Different collection device-cut off hemoglobin valus-different buffers-no international quality control standard
Qualitative
Quantitative
Daly J, 2017

18. Multitarget because it detects aberrant DNA and human hemoglobin.
MT-sDNA test
SCREENING
FOBT
MT-sDNA
2014 CMS approved
Multitarget because it detects aberrant DNA and human hemoglobin.
Cologuard is produced by Exact Sciences Corporation co-developed with Mayo Clinic

19. Comparison between FECAL TESTS
3 samples required- use of spatula
Decreased sample reliability by time from collection to analysis
No optimal threshold for hemoglobin detection
Iannone A, 2016

20. Comparison between fecal tests as screening tools
DIAGNOSTIC PERFORMANCE
ACCEPTANCE & PARTICIPATION
COST-EFFECTIVENESS

21. gFOBT (Hemoccult) reduces mortality of CRC 4 RCTs with biennial gFOBT and attendance 53-67% 16% risk reduction and 25% reduction per protocol

22. Diagnostic performance gFOBT for CRC
With verification bias without verification bias
Sensitivity 70%-specificity 88% Sensitivity 36%-specificity 96%
Rosman A, 2010

23. Diagnostic performance FIT for CRC
Decreased Sensitivity 71% when colonoscopy is used as the gold standard to all patients irrespective of test result
Sensitivity: 79% specificity: 94% for CRC
Lee J, 2014 meta-analysis

24. Diagnostic performance FIT for CRC
Hemoglobin cut off <20μg/g feces or equivalent to 100ng/ml buffer
Hemoglobin cut off 20-50μg/g
As the cutoff level increases, sensitivity falls from 86% % with minor increase in specificity from 91% to 96%
Lee J, 2014 meta-analysis

25. Comparison of gFOBT and FIT ORs for detection of advanced colorectal neoplasms
Lack of difference is based on inclusion of 1 RCT using Hemoccult Sensa with increased sensitivity
Based on RCTs no statistically significant difference
OR: 1.5 ( )
Zhu M, 2010 meta-analysis

26. Comparison between different fecal tests
Bailey J, 2016

27. Comparison of gFOBT and FIT ORs for detection of advanced colorectal neoplasms
Based on RCTs statistically significant difference
OR: 2.28 ( )
Hassan C, 2012 meta-analysis

28. Interval cancers and false negatives for FIT
Incidence of interval cancers after 3 rounds of biennial FIT with OC-Sensor at cut off level of 10μg/g in Netherland’s screening program: 23%
More cancers at stage II & IV
More cancers at stage IV
91%
85%
36mo
Vlugt M, 2017

29. Interval cancers and false negatives for FIT
Chiu H, 2013

30. Comparison of gFOBT and FIT Participation rates
More likely to participate using FIT with OR: 1.16 ( )
More likely to participate using FIT with OR: 1.21 ( )
Vart G, 2012 meta-analysis
Hassan C, 2012 meta-analysis
Reasons: 1. fewer fecal samples
2. Less messy by using a brush and not spatula
3. No dietary restrictions
4. Storage and return of kit

31. Comparison of gFOBT and FIT Participation rates
Reasons: 1. fewer fecal samples
2. Less messy by using a brush and not spatula
3. No dietary restrictions
4. Storage and return of kit
5. GP/Health practitioner endorsement
Beliefs and practices of U.S Primary Care Physicians
54% believed FIT was effective
38% not knowing the effectiveness
Nadel M, 2010

32. Performance of annual FIT after 4 rounds
OC-Sensor Diana with cut off 20μg/g in community-based CRC program
Retrospective cohort study with median 4 years follow up
1 round
2round
3round
4round
Participation
48,2
75,3
83,4
86,1
Positivity 5
3,9
3,7
4,3
Sensitivity CRC
84,5
75,4
73,4 78
Positive predictive value 14 10
8,4
Increasing participation after round 1
High sensitivity over several rounds
Feasible and effective
Jensen C, 2016

33. Comparison between gFOBT vs FIT Cost-effectiveness
Incremental cost effectiveness (ICER) in Canadian dollars with the cost of gFOBT: 5-20$ and FIT: 10-40$
Overview of cost effectiveness
At willingness to pay 50000$ per QALY gained the likelihood of being cost-effective is 15% with FIT and <1% with gFOBT and same compliance
Telford J, 2010

34. FIT in respect to gFOBT provides better sensitivity
accepted specificity
more sensitive for advanced lesions
simpler to perform (one sample, user friendly)
slightly more costly
But still misses proximal, nonpolypoid, medium sized adenomas & early cancers
Is MT-sDNA the solution for non-invasive screening?
Must have a high single application sensitivity for early stage cancer and advanced adenomas with accepted participation rate and cost

35. MT-sDNA test
10 DNA biomarkers (included methylated NDRG4 and BMP3 gene promoter regions, 7 Kras point mutations, β-actin as reference) and fecal hemoglobin
The test can theoretically intervene in earlier stages of adenoma-carcinoma sequence as tumoral DNA is constantly excreted with feces and degrades slower in respect to hemoglobin. Even in the case of negative DNA markers the test can result positive at the presence of fecal hemoglobin

36. sDNA test
Earlier studies with 1st generation tests yielded discouraging results of
moderate sensitivity 60% CRC
25% Advanced adenoma
But revealed that methylation markers were more sensitive than mutation markers for both cases
Yang H, 2013 meta-analysis

37. MT-sDNA test
RCT with multitarget test showing substantial increase in sensitivity even for earlier stage cancers and precancerous lesions in proximal location
Imperiale T, 2014

38. MT-sDNA test
Imperiale T, 2014

39. MT-sDNA test
The problem with specificity of the test is probably because the mere existence of an aberrant methylation or point mutation is a necessary but not a sufficient condition to cause cancer

40. MT-sDNA test
Participation was high 88% in non-compliant Medicare patients Prince M, 2017
Colonoscopists aware of a positive MT-sDNA test detect more polyps and flat proximal lesions (40%vs 9%, p=0,0017) Johnson D, 2017
Yearly FIT and colonoscopy are more cost effective than MT-sDNA test every 3 years for organized programs and stable participation of 50%
with kit cost of 493$
MT-sDNA test every 3y in organized programs to be cost effective : would need to be either around 60% less costly or achieve 70% stable participation Or
In opportunistic programs maintaining its cost would need to achieve 1.7 fold higher participation rates than yearly FIT in the order of at least 70% to be cost effective
Ladabaum U, 2016

41. HARMS OF SCREENING COLONOSCOPY SIGMOIDOSCOPY PERFORATION 1/2500
CRC mortality
HARMS OF SCREENING
Ongoing RCTs for colono vs FIT
Interventions
Completion date
NordICC
Colono vs non-screening
June 2026
COLONPREV
Colono vs biennial FIT
November 2021
CONFIRM
Colono vs annual FIT
September 2027
COLONOSCOPY
SIGMOIDOSCOPY
PERFORATION
1/2500
1/10000
MAJOR BLEEDING
2/2500
2/10000
Lin J, 2016
COLONPREV
Preliminary results
COLONOSCOPY, No
FIT, No
Odds Ratio
P Value
CANCER
Proximal 6 11
0,56
0,26
Distal 25 23
1,22
0,49
ANVANCED ADENOMA
514
231
2,30
<0,001
Complications 24 10
4,81
0,001
Elmunzer J, 2015
Quintero E, Hassan C, 2010 meta-analysis

42. Fecal tests aim mainly to timely detect cancers as early as possible with ease, safety and cost-effectiveness and not to search and eliminate all precancerous adenomas
Fecal tests are the best compromise between financial costs and societal demands for large national screening programs for reducing CRC mortality