Colorectal Cancer Risk Assessment and Prevention

Carol A. Burke MD, FACG, FASGE, FACPDirector, Center for Colon Polyp and Cancer Prevention

Digestive Disease InstituteCleveland Clinic

Colorectal Cancer

AdenomaAdenoma Serrated Serrated

NeoplasmNeoplasm

FAP MYH

Lynch Syndrome

Sporadic

CIN CIMP

MSI

MLH1 promotor methylationBRAF mutation

MSI

Chromosomal Instability

Pino MS, et al. NEJM 2010;339;1277

CpG Island Methylation (CIMP)

Gene Expression

Gene Silencing

Microsatellite Instability

• Repeated nucleotide sequences called “microsatellites

• DNA maintained by Mismatch Repair Genes (MMR)

Boland CR, Gastroenterology 2010;138:2073

MSH2 MSH6

MLH1 PMS2

Mismatch Repair Gene Function

Nucleotide mismatch

Normal MMR

Defective MMRMethylation

Germline mutation

TTTTTTTT CCCCCCCC TTTTTTTT AAAAAAAA CCCCCCCC

A G C T GA G C T GA G C T GA G C T GA G C T GA G C T GA G C T GA G C T G

T C G A CT C G A CT C G A CT C G A CT C G A CT C G A CT C G A CT C G A CA G C T GA G C T GA G C T GA G C T GA G C T GA G C T GA G C T GA G C T G

TTTTTTTT CCCCCCCC TTTTTTTT AAAAAAAA CCCCCCCC

A G C T GA G C T GA G C T GA G C T GA G C T GA G C T GA G C T GA G C T G A G A G A G A G A G A G A G A G AAAAAAAA T GT GT GT GT GT GT GT G

T C T C T C T C T C T C T C T C TTTTTTTT A CA CA CA CA CA CA CA C

Microsatellite Instability

A = Adenine, T = Thymine, C= Cytosine, G = Guanine

Tumor MSI Testing

NR21 BAT25 Mono27

Normal Tissue

Tumor Tissue

Courtesy Jennifer Hunt MD

MSI-High defined as mutation in > 2/5 consensus MSI sequences

MLH1 MSH2

Immunohistochemistry

Can be done on formalin fixed, archival tumor specimens

Survival and MSI Status

Yoon YS, et al. J Gastro Hepatology 2011;26:1773-1739

MSS MSI

MSI, Adjuvant Rx and Survival

No Adjuvant Therapy 5 FU based Adjuvant Therapy

Ribic CM, et al. N Engl J Med 2003:349247-57

Tumor

Status

HR for Death P

value

MSS or MSS-L

0.72 (0.53-0.99) 0.04

MSI 2.14 (0.83-5.49 0.11

Question

What is your lifetime risk of CRC?

1. 1%

2. 5%

3. 15%

4. 50%

Leading Cancers- U.S.

Siegel R, CA Cancer J Clin 2012;62:10-29

Risk Factors for Polyps and CRC

• Smoking

• Obesity

• Physical Inactivity

• African American race

• Dietary factors

– Vitamin D deficiency, fat, processed foods

• Chronic Colitis: Crohn’s, ulcerative

• Personal/Family History of polyps or CRC

Race, Stage and Survival

Stage at Diagnosis Survival

0

10

20

30

40

50

60

70

80

90

100

Local Regional Distant

Siegel R, et al. CA CANCER J CLIN 2012;62:10–29

0

5

10

15

20

25

30

35

40

45

Loca

lReg

iona

l

Dis

tant

White

Black

Question

Colorectal cancer mortality is?

1. Stable over the last decade

2. Decreased mostly to improved CRC treatment

3. Shown in RCT to be decreased due to FOBT

CRC Mortality

Edwards BK, et al. Cancer 2010:116:544

Question

What are current recommendations for average risk CRC screening?

1. Fecal Immunochemical Tests yearly

2. Flexible sigmoidoscopy every 3 years

3. Colonoscopy every 5 years

CRC Screening

1 Levin B, et al. CA Cancer J Clin 2008;58;130-1602 USPSTF Statement. Ann Intern Med 2008, 149:627-6373 Rex D, et al. Am J Gastroenterol 2009, 104:739-750

* High sensitivity methods with Hemoccult Sensa or FIT

Age: 50yrs

ACG: AA 45 yrs

US Multi-Society

Task Force1

U.S. Preventive Services Task Force2

American College

of Gastroenterology3

Method Interval for Screening

FOBT* Annual Annual Annual

Flex. Sigmoidoscopy 5 yrs 5 yrs 5 yrs

CT Colonography 5 yrs Insufficient Evidence 5 yrs

A/C Barium enema 5 yrs

Colonoscopy 10 yrs 10 yrs 10 yrs

Stool DNA ? Insufficient Evidence 3 yrs

Cancer Prevention rather than Cancer Detection test

US Cancer Screening Rates

MMWR/Jan 27, 2012/61/No. 3

Medicare CRC Screening Rates

White S, Ca Epi Bio Prev 2011;20:811

Adherence by Ethnicity

Pre-FOBT FOBT Post Colo

White 1.0 1.0 1.0

Black 0.74 (0.61-0.90) 0.66 (0.52-0.83) 0.80 (0.68-0.95)

Asian 0.90 (0.65-1.24) 0.84 (0.57-1.25) 0.77 (0.59-1.00)

Hispanic 0.91 (0.63-1.32) 0.91 (0.61-1.35) 0.73 (0.54-0.99)

Question

Greatest barrier to CRC screening is the lack of physician recommendation. What factor associated with non adherence to screening?

1. Male gender

2. Low SES

3. Lack of insurance

4. Offering only 1 option for screening

Patient Confusion regarding CRC Screening?

• Survey regarding understanding of CRC screening

• 13% of patient confused about screening

– Confused patients 2x more likely to be non-adherent

Factor associated with confusion

N =1707

OR (95% CI)

Female 1.53 (1.05–2.22)

Income < $20,000 0.46 (0.27–0.80)

Uninsured 5.87 (1.96–17.6)

> 1 screening option discussed 1.57 (1.08–2.26)

Jones R, et al. Ca Epid Bio Prev 2011;19; 2821–5

CRC Screening Adherence

Inadomi J, et al. Arch Intern Med 2012;172:575

Latinos , Asians completed > Blacks

Nonwhite adhered to FOBT, Whites to colonoscopy

Fecal Occult Blood Tests

Feature Guaiac Immunochemical

Target Peroxidase Antibody to globin

Number of Stools 3 1

Diet/Medication Restriction Yes No

Specific for LGI Bleeding No Yes

Qualitative Yes Yes

Quantitative No Yes

Mortality Decrease 16% RCT* 80% CCT

Levi Z, AIM 2007;146:244

*Hewitson P, et al. Am J Gastro 2008, 103:1541 Kumaravel V, et al. Cleve Clin J Med 2011;78:515

FIT is more Accurate than Guaiac

31

92

14

37

0

20

40

60

80

100

H II FIT

CRC

Advanced Adenoma

Park D, Am J Gastro 2010;105:2017

Adherence is Increased with FIT

Cole: RCT. Sensa: restrictions, 3 stools vs FIT no restrictions. 2 stools

Hole: No restrictions; g FOBT 3 stools; FIT one stool

.

Cole SR, et al. J Med Screen 2003; 10:117–122; Ho l L, et al Br J Cancer 2009; 100:1103–1110

(P < .001)

CRC MortalityOne time Colonoscopy vs 2 yr FIT

Lesion Colonoscopy

N= 26,703

FIT

N=26,599

OR

(95% CI)

Participation 25% 34% < 0.001

CRC 0.1% 0.1% 0.99 (0.61-1.64)

Advanced Adenoma 2% 1% 2.3 (1.97-2.69)

Non Advanced Adenoma 4.2% 0.4% 9.8 (8.10-11.85)

Complications 0.5% 0.1% 4.81 (2.26-10.20)

Quintero E, NEJM 2012;366:697

Flexible Sigmoidoscopyand CRC Incidence and Mortality

Atkin WS, et al. Lancet 2010; 375: 1624–33

Site Schoen

(N = 77,445)

FS every 3-5 yrs

Atkin

(N=57,237)

One time FS

Incidence

All

Distal

Proximal

0.79 (0.72 - 0.85)0.71 (0.64 - 0.80)0.86 (0.76 - 0.97)

0.77 (0.70 - 0.84)0.64 (0.57 - 0.72)0.98 (0.85 - 1.12)

CRC Mortality 0.74 (0.63 - 0.87) 0.69 (0.59 - 0.82)

Schoen R, et al. N Engl J Med 2012;366:2345-57

CT Colonoscopy

• NIH funded multi-center trial, CTC vs Colonoscopy

• 2531 participants, 15 US centers

• Highly selected radiologists

• Asymptomatic outpatients

> 5 mm > 6 mm > 7 mm > 8 mm > 9 mm > 10 mm

Sensitivity 65% 78% 84% 87% 90% 90%

Specificity 89% 88% 87% 87% 86% 86%

Johnson D, et al. NEJM 2008, 359:1207-1217

Stool DNA vs gFOBTfor CRC detection

0

10

20

30

40

50

60

% CRC detected

gFOBT

sDNA

• 2507 average risk subjects undergoing colonoscopy

• Comparison of gFOBT and stool DNA

Imperiale T, et al. N Engl J Med 2004;351:2704

Colon Capsule vs Colonoscopy

Colon Capsule Endoscopy-1 (N=328)

Lesion Sensitivity Specificity

Polyp 64% 84%

Advanced Adenoma 73% 79%

CRC 74% 74%

Van Gossum A, et al. N Engl J Med 2009;361:264

Spada C, et al. GIE 2011;74:581

Colon Capsule Endoscopy-2 (N=109)

Lesion Sensitivity Specificity

Polyp > 6 mm 84% 64%

Polyp > 10 mm 88% 95%

4 frames/sec; 156°FOV

35 frames/sec; 172°FOV

Lakoff et. al. CGH 2008;6:1117-1121

• Manitoba

• >110,000 pts with negative colonoscopy vs. Ontario population

Screening Colonoscopy & CRC Risk

Cancer Location RR (95% CI) Year of Benefit

Distal 0.21 (0.05–0.36) 1 to 14

Proximal 0.23 0.03–0.44 > 7 to 14

CRC

Incidence

Years after negative baseline colonosopy

0.5 1 2 5 10

Observed 73 58 38 12 0

Expected 150 134 105 49 9

SIR 0.49(0.38-0.62)

0.43 (0.33-0.57)

0.36 (0.26-0.49)

0.24 (0.12-0.42)

0

Sing H, et al. JAMA 2006;295:2366

1993

Colonoscopy and removal of adenomas reduces CRC incidence by 76-90%

Winawer, et al, N Engl J Med 1993;329:1977-1981

Colonoscopy and CRC Incidence

o 2915 pts undergoing polypectomy

o FU 4 years

o SIR CRC = 0.98 (0.63-1.54)

o 19 CRC :

o 3.79 CRC /1000 person-yrs <1 yr exam

– 0.96 CRC/1000 person-yrs > yr 1 exam

Robertson DJ, et al. Gastroenterology 2005;129:34

Baxter NN et. al. Ann Int Med 2009;150:1-8

Colonoscopy and CRC Mortality

o 10,292 CRC vs 51,460 controls

o Colonoscopy associated with less CRC death

o L sided OR 0.33 (0.28 to 0.39)

o R-sided OR 0.99 (0.86-1.14)

o Technical limitations of exam

o Incomplete removal of polyp

o Missed adenoma/cancer

o Inadequate bowel preparation

o Biologic variation in CRC precursor lesions

Why is colonoscopy less effective in proximal CRC prevention?

Screening Colonoscopy

• 45,026 participants followed 5 years

• 42 interval cancers

– 39 (93%) in individuals with normal baseline exam

– Median time to detection 2.2 yrs (0.5-4.7 yrs)

Kaminski MF, N Engl J Med 2010;362:1795-803

ADR and Risk Interval CRC

Kaminski MF, N Engl J Med 2010;362:1795-803

Withdrawal Time and ADR

Barclay, et al. N Engl J Med 2006;355:2533

Variable < 6 mins > 6 mins P value

Adenoma Detection Rate (ADR) 12% 28% <0.001

Advanced ADR 2.6% 6.4% 0.005

Hyperplastic polyp Detection Rate 10% 27% 0.03

ADR and Time of Day

Sanaka M, et al. Am J Gastro 2009;104:1659

Colonoscopy Technique Matters

• 11 gastroenterologists

• Grouped by ADR – Low: < 21%

– Moderate: 21-42%

– High: > 42%

• Comparison of WD time and technique on ADR

• Blinded video review

• Technique Scored

• Points: 0 (worst) -5 (best)

– Looking behind folds, adequate cleansing, adequate distension

– 5 colon locations (cecum, asc, transverse, desc, r-s)

Lee R, et al. GIE 2011;74:128

Colonoscopy Technique Matters

Lee R, et al. GIE 2011;74:128

Quality Indicators Screening Colonoscopy

• Cecal intubation: 95%

– Photodocumentation of landmarks

• Adenoma Detection Rate:

– > 25% men and >15% women

• Withdrawal time: > 6 minutes

• Description of bowel preparation

Rex D, et al. Am J Gastro 2002;97:1296

Interval Cancers

• Occurs in 9% who had colonoscopy in past 5 yrs

• Proximal

• Microsatellite Instability-High

• CpG Island Methylation (CIMP)

Molecular Features of CRC Neoplasia

BRAF CIMP MLH-1

TA 0% 44% 15%

SSP 83% 76% 72%

CRC 82% 90% 50%

O’Brien M, et al. Am J Surg Path 2006

Classification of Serrated Polyps

• Hyperplastic Polyp

• Sessile Serrated Polyp – Also known as sessile serrated adenoma

• Traditional Serrated Adenoma

Snover D, et al. WHO 2010

Serrated Pathway of MSI-H CRC

Snover DC. Human Pathology 2011;42:1-10

Sessile Serrated Adenomas/Polyps

• Proximal

• Subtle, Flat

• Covered with mucus

• Associated with smoking

• Not completely removed

Huang CS, et al. Am J Gastroenterology;106:229

Prevalence of Serrated Colon Polyps

All Adenoma HP SSA

No. patients 7192 1595 844 46

No. polyps 4535 2513 1279 61

Prevalence -- 22.2% 11.7% 0.6%

Hetzel, et al. Am J Gastroenterology 2010;105:2656-64

No. patients = 3337 ADR SSADR

Overall 25 ± 10.5% 1.7 ± 2.3%

Proximal 15.5 ± 7.9% 1.2 ± 1.8%

Distal 12.9 ± 5.9% 0.5 ± 1.1%

P value 0.011 0.003

Sanaka, et al. Gastrointestinal Endoscopy 2011; 73:AB138

Variation in Polyp Detection Rate

Adenoma HP SSA/P

Proximal 19% 3.6% 0.9%

Distal 12% 10% 0.1%

Detection Variability 13-36% 8-31% 0.3-2.2%

P value <0.001 <0.001 0.020

13 endoscopists, 184-1463 screening colonoscopies/endoscopist

Hetzel J, et al. Am J Gastro 2010; 105:2656-64

Variation in Polyp Diagnosis Pathologist

Adenoma HP SSA/P

Detection Variability 55-75% 20-37% 0.3-4%

P value 0.264 0.062 <0.001

12 pathologists, 8-498 screening cases/pathologist

Hetzel J, et al. Am J Gastro 2010; 105:2656-64

Post Polypectomy Surveillance

Colonoscopy Surveillance and CRC Mortality

Zauber A, et al. NEJM 2012;366:687

53%Reduction

Question

62 year old woman. Colonoscopy to cecum. Prep good. Flat 8 mm TVA with HGD in tranverse colon and removed with snare, o/w normal.

When should next colonoscopy be performed?

1. 3-6 months

2. 1 year

3. 3 years

4. 5 years

Polyp Characteristic Advanced Neoplasia

OR (95% CI)

Number of Adenomas 1.32 (1.25-1.40)

Large Adenoma 1.56 (1.39-1.74)

Villous Histology 1.40 (1.17-1.68)

HGD 1.08 (0.82-1.41)

Proximal Location 1.68 (1.39-2.02)

Baseline Characteristics Predict Recurrence

Martinez et al, Gastroenterology 2009;136:832–841

Risk Status at Baseline Advanced Adenoma CRC

Low Risk 6.9% 0.5%

High Risk 15.5 % 0.8%

USMTF Surveillance RecommendationsRisk Factor Interval Yrs

Adenomatous Lesions

1-2, < 1cm, TA 5-10

3-10, or > 1 cm, or TVA/VA/HGD 3

> 10 adenomas 1 exam < 3

Serrated Lesions

< 10 mm, recto-sigmoid hyperplastic polyps 10

SSP < 10 mm 5

SSP > 10 mm or SSP with dysplasia or TSA 3

Serrated Polyposis Syndrome 1

Lieberman D, et al. Gastro 2012;143:844

SPS: > 5 serrated polyps proximal sigmoid with > 2 being > 10 mmAny serrated polyp proximal sigmoid with FHX SPS> 20 serrated polyps throughout the colon

Family History and CRC Risk

• 2.25x increase if a FDR has CRC

• Increases with # affected relatives

– 1.85 (One FDR)

– 8.52 (> 3 FDR)

• Increases as age of affected relative decreases

– 2.18 (FDR > 50 yrs)

– 3.55 (FDR < 50 yrs)

Butterworth A, Eur J Cancer 2006;42:216–227

CRC Screening: Family History

Family History Age to Begin

Method

CRC or adenoma in FDR < 60 yr or > 2 FDR at any age

40* Colonoscopy

Q 5 yrs

CRC or adenoma in FDR > 60 yr or 2 SDR w/ CRC

50 Colonoscopy Preferred

Rex D, et al. Am J Gastroenterology 2009;104:739

* Or 10 yrs younger than youngest relative affected

Hereditary Non Polyposis Colon Cancer

= unaffected

= affected

• > 3 relatives with CRC

• 1 FDR to other 2

• > 2 successive generations

• 1 CRC diagnosed < 50 yrs

Mutations found in 50%

Amsterdam Criteria I

Vasen HF et al, Dis Colon Rectum 1991

CRC in Lynch Syndrome• Lifetime Risk: Varies by genotype

• Median age: 45 years

• Location: Usually right sided

• Pathology: Distinctive

• Recurrence: 40% at 20 yrs

Bonadona V et al. JAMA 2011;2304

Lynch SyndromeExtra-Colonic Cancer Risks

Koornstra JJ et al. Lancet Oncology 2009;10:400-408

Cancer RiskLynch Syndrome vs Type X

Site of Cancer SIR (95% CI) P value

Lynch (MSI or MMR) (N=1855)

Type X (No MSI)(N=1567)

Colorectum 6.1* 2.3* <0.001

Uterus 4.1* 0.8 <0.001

Stomach 4.6* 1.4 .008

Kidney 2.6* 0.9 .04

Ovary 2.0* 1.5 .60

Small Intestine 7.6* 1.6 .10

Ureter 9.0* 2.9 .29

161 AC-1 families

* Compared to SEERLindor N, JAMA. 2005;293:1979-1985

Hereditary Non Polyposis Colon Cancer

Evaluation of Genomic Applications in Practice and Prevention

• Launched 2004: CDC Office of Public Health Genomics

– To establish and evaluate a systematic, evidence-based process for assessing genetic tests and other applications of genomic technology in transition from research to clinical and public health practice

Recommendation All pts with CRC should be tested for Lynch syndrome

Genet Med 2009:11(1):35–41

Universal CRC Testing for LS• 1066 patients

– 2.2% LS

• 19.5% had MSI– 11% LS

• Phenotype:– 43% diagnosed > 50 years

– 22% did not Amsterdam II or revised Bethesda guidelines

Hampel H et al. NEJM 2005;352;18

Germline Testing Results In 21 Proband’s Relatives

Relationship Tested Positive Negative

First degree 54 25 29

Second degree 22 10 12

> Third degree 41 17 24

Total 117 52 65

Surveillance in Lynch Syndrome

IntervalInterval Age to beginAge to begin EvidenceEvidence

ColonoscopyColonoscopy 11--2 yrs2 yrs 2020--25 yrs25 yrs StrongStrong

Endometrial Bx, TVUSEndometrial Bx, TVUS 1 yr1 yr 3030--35 yrs35 yrs InsufficientInsufficient

EGDEGD--Push/Capsule Push/Capsule

endoscopyendoscopy22--3 yrs3 yrs 3030--35 yrs35 yrs InsufficientInsufficient

UAUA 1 yr1 yr 2525--3030 No commentNo comment

Hysterectomy/BSOHysterectomy/BSO After childbearingAfter childbearing FairFair

Or 2-5 yrs earlier if relative was < 25 years

NCCN 2012 www.nccn.org

Optimal operationin Lynch Syndrome

Surgery No. Pts CRC

Extensive 50 0

Segmental 332 22%

CRC Risk Segmental Surgery Cohort

Parry S, et al Gut 2011;60:950-957

Screening and Surveillance 2012

• Screening and surveillance saves lives

• Adherence and technique imperative

• New guidelines include recommendations for patients with serrated lesions