Consultas de Alto Riesgo de Cáncer Colorrectal

Dr. Antoni CastellsHospital Clínic, Barcelona

(castells@clinic.cat)

69%

2%27%

1%1%

Riesgo medio(esporádico)

Poliposis adenomatosafamiliar

CCHNP

Enfermedad inflamatoriaintestinal

CCR familiar

Epidemiología del cáncer colorrectal

Grupo de Oncología Digestiva-AEG. Eur J Gastroent Hepatol 2004

Factores de riesgo personal

y/o familiar

No

Edad

< 50 años 50 años

AbstenciónCribado

Si

Factor de riesgo personal

Adenoma Enfermedad inflamatoria

intestinal

Vigilancia Vigilancia

Factor de riesgo familiar

PAF CCHNP CCRfamiliar

Cribado

Cribado

Cribado

Clasificación del riesgo de CCR

Atención a la población de alto riesgo

• Diversas neoplasias• Centralizado• Pacientes referidos• Hereditario

• No integración del tratamiento y seguimiento

Modelo tradicional• Cáncer colorrectal• Descentralizado (red)• Enfoque poblacional• Hereditario y familiar, y

premaligno (adenoma)• Integración del tratamiento

y seguimiento

CAR-CCR

Familial adenomatous polyposis (FAP)

• Autosomal dominant disorder• One in 15,000 live births• More than 100 polyps• Diffuse distribution• Onset: 15-20 year-old• Extracolonic manifestations: upper

GI adenomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and dental anomalies (Gardner syndrome), brain tumor (Turcot syndrome)

• Overall CRC risk ~100% by age 40-50• APC gene mutations (truncanting)

Germline APC gene testing

2934_2935delAA (frameshift at codon 978, termination at codon 983)

• Autosomal dominant disorder• Early onset CRC: <45 years of age• Location in proximal colon• Histology: undifferenciated, signet-ring cell type• Multiple CRC (synchronous, metachronous)• Multiple neoplasms (endometrial, gastric, small

bowel, renal, ovarian, and skin)• Life-time risk of developing CRC: 60-80%• Benefit from periodic colonoscopy examination

(every 1-2 years)

Lynch syndrome – Hereditary non-polyposis colorectal cancer (HNPCC)

DNA mismatch repair (MMR) system

MSH6MSH2

MSH6

MSH2

MSH6

MSH2MLH1 PMS2

Lynch syndrome: pathogenesis

Normalmucosa

Carcinoma

MSH2, MLH1, MSH6, PMS2(germline mutation)

TGF--RII, BAX, IGFIIR

Microsatellite instability

Second hitLoss of protein

expression

N

T

N

T

• 3 relatives with CRC*: one relative should be first-degree relative of the other two, and

• 2 successive generations should be affected, and• 1 tumor should be diagnosed before age 50

• Familial adenomatous polyposis should be excluded

• Tumors should be verified by histopathologicalexamination

Vasen et al. Dis Colon Rectum 1991

Amsterdam criteria

*Vasen et al. Gastroenterology 1999

*Amsterdam II: CRC and/or HNPCC-related neoplasia (endometrial, small bowel, ureter or renal pelvis)

Lynch syndrome identification: limitations

DNA MMRdeficiency

60%

0%20%40%60%80%

100%

Fulfillment ofAmsterdam criteria

Lindor et al. JAMA 2005Llor et al. Clin Cancer Res 2005

Fulfillment of Amsterdam criteria

70%

0%20%40%60%80%

100%

Presence of MMRmutation

Aaltonen et al. N Engl J Med 1998

1. CRC diagnosed <50 yrs.

2. Synchronous CRC, metachronous CRC, or other HNPCC-related cancer (CRC, endometrial, ovarian, gastric, pancreas, biliary tract, small bowel, ureter or renal pelvis, brain), regardless of age.

3. CRC with presence of tumor infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern, diagnosed <60 yrs.

4. One or more first-degree relatives with an HNPCC-related tumor diagnosed <50 yrs.

5. Two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age.

Umar et al. J Natl Cancer Inst 2004

Identification of individuals who should be tested for MSI analysis:

Revised Bethesda guidelines

Performance of selective vs. universal molecular screening

*p<0.001 (McNemar test)

*

Piñol et al. JAMA 2005

*

0% 20% 40% 60% 80% 100%

Overall accuracy

NPV

PPV

Specificity

Sensitivity

Universal (IHC) Rev. Beth. + IHC Rev. Beth. + MSIRevised BethedaMSI Revised BethesdaIHC Universal (IHC)

Jerusalem recommendations1. All patients diagnosed with colorectal cancer before

the age of 70 years should be submitted to MMR testing

2. MMR testing can be done by immunostaining and/or MSI analysis

3. Colorectal cancers exhibiting loss of MLH1 expression should evaluated by means of BRAF (V600E) or MLH1 promoter methylation analysesbefore undergoing germline MLH1 gene testing

Shike y Boland. Gastroenterology 2010

University of Helsinki (n=1,042)

EPICOLON(n=1,222)

C-CFR(n=9,371)

The Ohio State University(n=1,516)

13,151 unrelated CRC probands

10,206 informative, unrelated CRC probands

MMR deficiency(n=1,386)

Mutation (n=289)

No mutation (n=779)

Mutation (n=12)

No mutation (n=1,383)

Lynch(n=312)

No Lynch(n=9,576)

2,945 excludeda

MMR proficiency(n=8,633)

No mutation (n=176)

Mutation (n=11)

Tumor MMR testing (n=10,019

Direct germline MMR gene analysis (n=187)

No germline MMR gene analysis

(n=318)

Germline MMR gene analysis

(n=1,068)

Germline MMR gene analysis

(n=1,395)

No germline MMR gene analysis

(n=7,238)

Moreira et al. JAMA 2012

Diagnostic yield of strategies for Lynch syndrome identification

1,96% 1,90%2,12%

2,23%

0,0%

0,5%

1,0%

1,5%

2,0%

2,5%

Bethesda Jerusalem Selective* Universal

*Selective strategy: tumor MMR testing of CRC patients diagnosed 70 years-old, and in older patients fulfilling the Bethesda guidelines

∆↓ 4.9%

∆↓ 14.6%

∆↓ 12.2%

Moreira et al. JAMA 2012

Cumulative distribution of MMR gene mutations according to the age at CRC diagnosis

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85

Age at CRC diagnosis (years)

Moreira et al. JAMA 2012

Diagnostic yield of strategies for Lynch syndrome identification

1,96% 1,90%2,12%

2,23%

0,0%

0,5%

1,0%

1,5%

2,0%

2,5%

Bethesda Jerusalem Selective* Universal

*Selective strategy: tumor MMR testing of CRC patients diagnosed 70 years-old, and in older patients fulfilling the Bethesda guidelines

∆↓ 4.9%

∆↓ 14.6%

∆↓ 12.2%

Moreira et al. JAMA 2012

Strategies for the identification of Lynch syndrome

4,4% 5,1%6,5%

9,1%

0%

2%

4%

6%

8%

10%

Germline MMR gene analysis

27,0%

57,8%65,2%

100%

0%

20%

40%

60%

80%

100%

Tumor MMR testing

Bethesda Jerusalem Selective* Universal

∆↓ 35% ∆↓ 29%

Moreira et al. JAMA 2012

Serrated polyposis(hyperplastic polyposis syndrome)

Definition (WHO 2010) >5 proximal serrated polyps (at

least, 2 polyps >10 mm), or >20 serrated polyps (any size,

any location), or any serrated polyp in a person

with one FDR with serrated polyposis

Prevalence: 1 in 3,000 screening sigmoidoscopies

Heterogeneous disease: Type 1: multiple SSA (large size and proximal) Type 2: multiple hyperplastic polyps (any location)

Normal mucosa

ACF

MVHP

SSA

SSA-HGD

CRC

Proximal tumors Mutated BRAF CIMP-H MSI-H (MSS) MLH1 loss

Sessile serrated pathway

Goel and Balaguer. Curr CRC Rep 2011

BRAF mutation

p16, IGFBP7, others? methylation

Apoptosis inhibition

Molecular changes

Morphologic changes

MSI-H tumors MSS tumors

MCC / APC methylation and/or

p53, 18q LOH…

MLH1methylation

Endoscopic surveillance in 77 patients with serrated polyposis Multicenter observational study, 1982-2008 27 (35%) patients developed CRC (22 at baseline examination)

Boparai et al. Gut 2010

Serrated polyposis and CRC risk

Cumulative risk: 7% at 5 years

Mucosacolónica

Adenoma Carcinoma

Prevención 3aria o vigilanciaPrevención 1aria

Prevención 2ariao cribado

Prevención del CCR en población de alto riesgo

High-Risk CRC Clinic Community-based center Primary care physician

Community-based screeningof hereditary CRC

Consultas de Alto Riesgo de Cáncer Colorrectal

Dr. Antoni CastellsHospital Clínic, Barcelona

(castells@clinic.cat)