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Robert E. Schoen, MD, MPH Professor of Medicine & Epidemiology
Chief, Division of Gastroenterology University of Pittsburgh, Pittsburgh, PA
Advances in
Colorectal Cancer Screening
Focus
1) Screening at younger age: 45 – 49? 2) Blood based screening for cancer 3) Surveillance colonoscopy
U.S. CRC Annual % Change
Mortality ’84 - ’02 ’01 – ‘10
Male -1.9 -3.0
Female -1.8 -3.0
Incidence
’95 - ’98 ’98 - ’04 ’01 – ‘10
1.1 -2.8 -3.8
1.9 -2.4 -3.2
Espey, Cancer 2007;Oct 15 Siegel R. CA Cancer J Clin 2014:64:104
Siegel R. CA Cancer J Clin 2014:64:104
U.S. CRC Incidence and Mortality Trends
A qualified recommendation indicates there is clear evidence of benefit but less certainty about the balance of benefits and harms
The ACS recommends that adults aged 45 yr and older with an average risk of CRC undergo regular screening
The recommendation to begin screening at age 45y is a qualified recommendation
American Cancer Society: Changes Age to Initiate Screening
Wolf. CA Cancer J Clin 2018;68:250-281
Should we begin CRC screening at age 45?
NO
U.S. CRC Incidence by Age
Siegel R. CA Cancer J Clin 2014:64:104
CRC Incidence 45-49 Relative to Older Age Groups
Rate at 45-49 (33/100K):
Age Proportional Rate
50-54 55-59 60-65 65-69 70-74 75-79
0.53 0.47 0.37 0.28 0.23 0.18
45-49 CRC Rate is a Fraction
of Older Age Groups
In 2015:
Rising Incidence CRC in Young Adults
• Assumed 1.59 fold increase in incidence ratio:
Peterse, Cancer 2018
40 y.o. in 2015 40 y.o. in 1975
Uncertainties • Is the incidence in 1975 accurately
estimated? - How much of increase in incidence is true and how much is due to ↑’d colonoscopy use?
• Does young onset CRC follow similar natural history/adenoma progression?
• Will screening be as effective in mitigating CRC in younger ages as it is in older folks?
• Modeling is not reality – it’s an approximation
• Modeling is dependent on assumptions which are estimates
• Moreover, the translation of modeling results into public policy is complex with no set guideline or formula
Modeling
U.S.P.S.T.F. on Screening for CRC
FSG q5 years: Modeling suggests FSG provides less
benefit than when combined with FIT or with other strategies
JAMA. 2016;315(23):2564-2575!
• Model rejecting the reality of 4 RCTs with >450K subjects
• Models are based on 100% compliance!
• USPSTF rejected model conclusions – endorsed FSG screening
FSG q5yr vs. FSG q10y + FIT q1y
. 62.4%
NHIS: % of U.S. Adults Up to Date with Screening: 2000-2015
We still have a lot of work to do
Disparity in Screening for CRC
Ethnicity Hispanic 49.8 Non-Hispanic 64.2
Education < HS 46.1 College Grad 70.6
Annual Income < 15k 47.6 > 75k 72.9
Insurance Yes 65.7 No 35.6
MMWR 2010;59:808
Randomized Trial of CS vs FIT vs Usual Care
CS FIT Usual
Parkland Hospital in Dallas – N = 5,999
38.4
41
51.7
1o Outcome 2 FIT’s Any
28.0
41.5
65
10.7
10.7
39
Of 162 FIT+, 83 (51%) did not undergo CS
Singal, JAMA 2017: 318:506
% Compliant
We should focus our efforts on groups more likely to benefit; adding lower risk folks will dilute the number who benefit
overall
• New guidelines are encouraging screening a lower risk group when we already don’t sufficiently screen higher risk group
• I suspect we will see a lot of healthy 45 year olds getting tested – Kale- eating marathoners
• Over 21 million people between 45-49 – crowd out capacity for getting those who need it tested
Impression
Intended
CRCpreven,onin45-49yearagegroup
CRCpreven,oninhigh-riskminoritygroups
Increaseinscreeningratesin≥50yearagegroup
Unintended
Diversionofresourcestolower-riskpopula,on
Increaseinscreeningdispari,es
Substan,alcost
Lostopportunitytostudyscreeningeffec,venessinyoungeradults
Actualbenefitsmayfallshortofpredic,ons
Liang. Gastroenterology 2018
Consequences
FIT test + Stool DNA
• Sales up 168% to 266M 2017 • Project 420M in 2018 • Revenue/Cologuard test: $500.00 • Screened 571K in 2017 • Planning to position themselves in
market place for 45-50
Blood-based Screening for Cancer
Bert Vogelstein
Ken Kinzler
Nick Papadopoulos
ctDNA: Circulating Tumor DNA • As cancer cells turn over, release DNA into
adjacent media • Blood, stool, urine, pancreatic juice, cysts,
cervical mucous, CSF, saliva, bronchial, etc. • Detecting Mutant DNA – somatic mutations
within driver genes that are responsible for clonal growth
• Exquisite specificity – normal cells do not clonally expand, rarely harbor these somatic mutations, and not in this concentration
Challenges
• Biological: 1) Are there detectable amounts of
DNA from neoplastic cells present in the biological fluid?
2) Somatic mutations vary - panel 3) Mutations not specific to one cancer
Challenges
• Sensitivity – can be <1 mutant molecule/ml of plasma: requires large volume plasma for testing
• Application: How to identify tissue of origin – same gene mutations drive multiple tumors
Digital Genomics: Safe-SeqS
Method for detection and
quantification of rare mutations
Safe Sequencing System
Kinde I et al. PNAS 108:9530-9535, 2011
Kinde I et al. PNAS 2011;108:9530-9535
*
*
Sequencing or Replication Error
Amplification to Distinguish Replication Error vs. Mutation
vs. Legitimate Mutation
ctDNA in Colorectal Cancer: Resectable vs. Advanced Cancer
Be$egowdaetal.SciTranslMed.2014Feb19;6(224):224ra24.
Colorectal: 73% (stage I-III)
¡ 1,005 Cancer Patients § 209 Breast § 288 Colorectal § 45 Esophageal § 44 Liver § 104 Lung § 54 Ovarian § 93 Pancreatic § 68 Stomach
¡ 812 Healthy Controls
¡ No Distant Metastases § 20% Stage I § 49% Stage II § 31% Stage III
¡ Median Age 64 years
CohenJ,etal.Science2018
CancerSEEK Test
61 amplicons, average 33 bp length, in 16 genes, 2001 genomic positions
Protein Markers
• ctDNA not sensitive enough proteins • Use high cut offs to insure maximum
specificity • 8 proteins useful
Protein Markers Used in CancerSEEK
• CA-125 • CA19-9 • CEA • HGF • Myeloperoxidase • OPN • Prolactin • TIMP-1
CancerSEEK:Detec,on• N= 1005 (288 CRC: Stage I-III)
• Median Age 64 years
Cohen,etal.Science2018
Ovary Liver Colon Lung BreastPancreasStomach Esoph
• 70% Median Sensitivity (p < 10-96 one-sided binominal) • >99% Specificity (7 of 812 Healthy Controls) • Range (33% to 98%)
69% to 98%
78% 73%
43%
Cohen,etal.Science2018
Tissue Confirmation
• Mutation in plasma identical to mutation in tumor in 138/153 (90%)
• Concordance between plasma and tumor: present in all tumor types – ranging from 100% in ovarian/pancreas to 82% in stomach
N=153
YES
Cancer Site of Origin?
• Machine learning in 626 patients with positive test
• Uses ctDNA mutation, protein biomarker, gender
Top Prediction was correct in a median of 63% of the cases.
(p < 10-47 one-sided binomial test)
Top 2 Prediction identified the site in a median of 83% of the cases.
(p < 10-77 one-sided binomial test)
¡ Mostpatientsinthisstudywerediagnosedonthebasisofsymptomaticdisease.
¡ Controlsforthisstudywerelimitedtohealthyindividuals.
¡ Ten-foldcross-validationwasusedfordevelopingthealgorithms-notseparatevalidationcohort.
¡ TheproportionofcancerstypeswasnotrepresentativeofthoseintheUnitedStates.
¡ EstablishingtheclinicalutilityofCancerSEEKwillrequireprospectivestudies.
Cancer Screening: Summary
• CRC screening proven effective • Evidence/Support for screening 45 –
49 yr olds is tepid • Blood based screening on horizon
Surveillance Colonoscopy
25% of Colonoscopy
is for Surveillance
Anticipate Significant Increase in Future Demand For Surveillance Colonoscopy
• Increased Screening • Increasing Adenoma Detection Increased Surveillance
CRC screening begets polyps
Current Surveillance Recommendations
Click B, Pinsky PF, Hickey T, Doroudi M, Schoen RE
University of Pittsburgh, NCI, IMS
Click. JAMA 2018:319:2021
JAMA | Original Investigation
Association of Colonoscopy Adenoma Findings With Long-term Colorectal Cancer Incidence Benjamin Click, MD; Paul F. Pinsky, PhD; Tom Hickey, BS; Maryam Doroudi, PhD, MPH; Robert E. Schoen, MD, MPH
To examine the relationship between adenoma findings on colonoscopy and long-term, subsequent CRC incidence
Aim
AA N=2,882
NAA N=5,068
NA N=7,985
CS N=15,935
≥ 1 cm N= 2,178
< 1 cm N= 704
≥ 3 N= 572
1-2 N= 4,496
Long-term CRC Incidence
Long-term CRC Incidence
Although no cancer difference in NAA vs NA More Surveillance in NAA group
Summary: Surveillance Colonoscopy
• General and widespread recognition that surveillance colonoscopy requires further study
• Surveillance is costly and of uncertain benefit
• A randomized design will provide the strongest, most definitive answers
USPSTF Modeling: Why not FSG q5y?
Model COLs LYG
CRC Deaths Averted
ER <39
Outcome per 1000 40 year olds:
LYG >247 Rec’d
1820
2289
221
256
20
23
Yes
Yes
No
Yes
No
Yes
Knudsen, JAMA 2016; 315 USPSTF, JAMA 2016:315
Sig q5
Sig q10 + FIT q1
FIT q1
Col q10
244
270
22
24
1757
4049