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