Ashish Sharma PGY-4 GI fellow - PowerPoint Presentation

Slide1

Ashish SharmaPGY-4 GI fellow

Grand Rounds

12/11/14

Mentor- Milena Gould, MD

Slide2

Case Presentation31 y/o Hispanic male was seen in GI clinic as a referral for colonoscopy and EGD.

Patient referred by Genetics Clinic due to family history of hereditary colon cancer.

Denied

hematochezia, melena

, hematemesis,

constipation, diarrhea, abdominal pain, weight loss

.

PMH - GERD, asthma, obesity

PSH - None

SH – denies smoking, ETOH use, IVDA

Slide3

Amsterdam II criteria met

Slide4

Case presentationPatient’s mother underwent tumor testing and germline testing, and was found to have MLH1 MMR gene deleterious mutation consistent with Lynch Syndrome (LS).

Our patient was tested for the Known

F

amily

M

utation (KFM), and tested positive. He was diagnosed with LS.

Slide5

Case presentation

GEN: No acute distress, alert and oriented

HEENT: An-icteric, oropharynx clear, PERRLA, EOMI

NECK: No lymphadenopathy

CV: Regular rate and rhythm S1, S2  ,no m/r/g

CHEST: Clear to auscultation bilaterally

ABD: Obese, soft, non tender, no hepatosplenomegaly, bowel sounds presentEXT: No edema

NEURO: Grossly intact and non focalSkin: No lesionsProcedures-Colonoscopy – sigmoid diverticulosis,

no polyps detectedEGD - Normal

Slide6

Clinical Questions

1

.

Diagnostic strategies in LS, and effectiveness of implementation of Universal Testing in LS

2. GI cancer surveillance in LS

3. Role of chemoprevention in LS

Slide7

Background

Henry T.

Lynch , characterized

the syndrome in

1966

and called it “cancer family syndrome”. The term "Lynch syndrome" was coined in 1984 by other authors; Lynch named the condition

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) in 1985. HNPCC is no longer used; Lynch syndrome is the preferred term.

Douglas et. al. History and Molecular Genetics of Lynch Syndrome in Family G:  A Century Later

JAMA. 2005;294(17):2195-2202.

Slide8

Background

Approximately

3% of

Colorectal

C

ancers

(CRCs) are due to LS.

LS is caused by autosomal dominantly inherited mutations in the Mismatch Repair (MMR) genes MLH1, MSH2,

MSH6 ,PMS2 and/or EPCAM gene. First-degree relatives of individuals identified with a

LS gene mutation have a 50% chance to carry the mutation.

Douglas et. al.

History and Molecular Genetics of Lynch Syndrome in Family G:  A Century Later

JAMA.

2005;294(17

):2195-2202.

Slide9

Background - Definitions

What is ImmunoHistochemistry (IHC) testing?

–Detects presence or absence of the protein products of MMR genes (protein carries same name as MMR gene). A missing protein suggests a mutation in gene that codes for that protein.

What is Micro Satellite Instability (MSI) testing?

-

Detects abnormal number of microsatellite repeats, which indicates that the cancer more likely arose from cells with defective MMR genes.

Umar et

al. (2004). Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite

instability. J Natl Cancer Inst, 96(4

), 261–268.

Slide10

Background – Definitions

Lynch like syndrome

Familial Colorectal

C

ancer Type X (FCRCTX)

Muir Torre syndrome

Turcot syndrome

Giardiello et al. Guidelines on Genetic Evaluation and Management ofLynch Syndrome: A Consensus Statement by the

US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol advance online publication, 29 July 2014

Slide11

Background- Colon cancer risk in LS

Bonadona

et al.

Cancer risks associated

with germline

mutations in

MLH1, MSH2

, and

MSH6

genes in Lynch syndrome . AMA 2011 ; 30 : 2304 – 10

Slide12

Background-Extracolonic cancers in LS

Lynch et al

.

Genetics

, natural history,

tumor spectrum

, and pathology of hereditary

nonpolyposis

colorectal cancer:

an update review. Gastroenterology 1993; 104:1535

–

49.

Slide13

Diagnostic tools

Clinical criteria –

Amsterdam II, Revised Bethesda Guidelines

Clinical prediction models – MMRpredict, MMRpro, PREMM (>5% cut off)

Colorectal cancer risk assessment tool

Tumor testing – MSI, IHC

Genetic testing – MLH1, MSH2, MSH6, PMS2 and EPCAMUniversal testing and Traditional testing

Slide14

Diagnostic tool -Amsterdam Criteria

Vasen

et al. 1999. New

clinical criteria for hereditary

nonpolyposis

colorectal cancer (

HNPCC,Lynch

syndrome) proposed by the International Collaborative Group on HNPCC.

Gastroenterology

, 116(6), 1453–1456.

Slide15

Diagnostic tool – Revised Bethesda Guidelines

Umar et al. (2004). Revised Bethesda Guidelines for hereditary

nonpolyposis

colorectal cancer (Lynch syndrome) and microsatellite instability.

J

Natl

Cancer

Inst

, 96(4), 261–268.

Slide16

Universal TestingDefinition – Tumor testing all CRCs diagnosed

<70/=

yrs

or CRCs diagnosed in individuals > 70 yrs if they meet Revised Bethesda Guidelines. (NCCN guideline)

EGAPP working group endorses tumor testing all CRCs diagnosed.

1.

Ladabaum et. Al.Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness

analysis. Ann Intern Med. 2011 Jul 19;155(2):69-79

2. NCCN Clinical Practice Guidelines in Oncology. Version I.20143. Recommendations from EGAPP Working Group 2009

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Traditional Testing

Selective tumor and/or germline testing. This is particularly useful when no tumor is available for testing.

Giardiello et al. Guidelines on Genetic Evaluation and Management

of Lynch

Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.

Am J Gastroenterol

advance online publication, 29 July 2014

Slide18

MSI/IHC Testing – Interpretation

NCCN Clinical Practice Guidelines

in Oncology

. Version I.2014

Slide19

Universal Testing Algorithm

Giardiello et al. Guidelines on Genetic Evaluation and Management of

Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.

Am J Gastroenterol

advance online publication, 29 July 2014

May be more cost effective to perform IHC testing only

Slide20

Traditional testing in affected individual or at risk family member- Mutation Known

Giardiello et al. Guidelines on Genetic Evaluation and Management of

Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.

Am J Gastroenterol

advance online publication, 29 July 2014

Our patient was diagnosed using this approach

.

Slide21

Traditional Testing in at risk family member- Mutation Unknown

Giardiello et al. Guidelines on Genetic Evaluation and Management

of Lynch

Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.

Am J Gastroenterol

advance online publication, 29 July 2014

Slide22

Diagnostic tools in LS- Diagnostic Accuracy

Giardiello et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.

Am J Gastroenterol

advance online publication, 29 July 2014

Slide23

Colorectal cancer risk assessment tool- Useful for routine use in GI clinic

Kastrinos

et

al.

Development and validation

of a

colon cancer risk assessment tool for patients undergoing colonoscopy

.Am

J Gastroenterol 2009 ; 104 : 1508 – 18 .

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Outcomes of effective implementation of Universal Testing in safety net hospital

1. Beamer et al. Reflex

Immunohistochemistry and Microsatellite Instability Testing of Colorectal Tumors for Lynch Syndrome Among US Cancer Programs and Follow-Up of Abnormal

Results.

JCO April 1, 2012 vol. 30 no. 10 1058-1063

2. Marquez et al.

Implementation of routine screening for Lynch

syndrome in

university and safety-net health system settings:

successes and challenges.

Genetics in Medicine (2013) Volume: 15, Pages:925–932

Key points

–

Role of genetic team

Participation rate of at risk family members

Slide25

Clinical Questions

1

.

Diagnostic strategies in LS, and effectiveness of implementation of Universal testing in LS

2. GI cancer surveillance in LS

3. Role of chemoprevention in LS

Slide26

Cancer surveillance in LS

TAH-BSO by 40 years

Giardiello et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.

Am J Gastroenterol

advance online publication, 29 July 2014

Slide27

Evidence supporting colorectal cancer surveillance

Slide28

Evidence supporting gastric cancer surveillance

Majority of gastric cancers in LS are Intestinal type

However, there is no difference in the frequency of premalignant lesion in the stomach on biopsy in MMR positive versus MMR negative patients

Mallorca group strategy

Slide29

Clinical Questions

1

.

Diagnostic strategies in LS, and effectiveness of implementation of Universal testing in LS

2. GI cancer surveillance in LS

3. Role of chemoprevention in LS

Slide30

Chemoprevention- CAPP2 2008

1071

LS

patients from 43

centers

Randomized

, placebo-controlled, 2 × 2 design

727 randomized to resistant starch (30 g / d)

or placebo; 693 randomized to aspirin (600 mg / d) or no aspirin

No effect on incidence of colorectal adenoma /cancer by starch or aspirin or both at

mean follow-up of 29 months

Burn

et al

.

Effect

of aspirin or resistant

starch on

colorectal neoplasia in the Lynch

syndrome. N

Engl

J Med

2008; 359:2567

–

78.

Slide31

Chemoprevention – CAPP2 2012

918

LS

patients from

43

centers

Long-term follow-up report on

randomized, placebo-controlled, 2 × 2 design

463 randomized to resistant-starch; 455 randomized to placebo

No effect on incidence of CRC by starch at median follow-up of 52.7 months

Mathers

et

al.

Long-term

eff

ect

of

resistant starch

on cancer risk in carriers of hereditary colorectal cancer: an

analysis from

the

CAPP2 randomized

controlled

trial.Lancet

Oncol

2012;13:1242–9.

Slide32

Chemoprevention – CAPP2 2011

861

LS

patients from

43

centers

Long-term

follow-up report on randomized, placebo-controlled, 2 × 2 design

427 randomized to aspirin (600 mg / d); 434 randomized to placebo

600 mg aspirin / d for mean of 25 months reduced cancer incidence after 55.7 months

Time to first CRC hazard ratio (HR) by per protocol

analysis, 0.41 (95 % CI: 0.19 –

0.86;

P

=0.02);intention-to treat analysis of all

LS cancers

, HR=0.65; 95 % CI: 0.42 – 1.00;

P

=0.05)

Burn

et al.

Gerdes

AM ,

Macrae

F

et al.

Long-term

effect

of aspirin on

cancer risk

in carriers of hereditary colorectal cancer: an analysis from

the CAPP2

randomized controlled

trial. Lancet

2011 ; 378 : 2081 –

7.

Slide33

Conclusion of Chemoprevention in LS

Mortality benefits in CRC in

LS patients can be

seen from

longer

use

of aspirin (2-4 yrs), and after longer term (5-10

yrs) follow up.Patients with cardiovascular problems benefit the most with aspirin use.

Optimal dose of aspirin for CRC prevention in LS not clear from current trials.CAPP3 study underway to assess optimal dose and duration of aspirin to prevent CRC in LS.

Rothwell

et al. Effect

of daily aspirin on

long term risk

of death due to cancer: analysis of individual patient data

from randomized

trials.Lancet

2011;377:31

–

41.

Slide34

Back to our patient

Colonoscopy 1-2 yrs

EGD 2-3

yrs

(possibly every 5 yrs

), check for H pylori; treat and eradicate if positiveUA every yearNo aspirin for chemoprevention at this time

Slide35

Take home points

Use colorectal cancer risk assessment tool in

clinics/endoscopy lab routinely

to identify possible LS patients

Universal testing of all

colorectal cancers in patients

< 70 yrs of age. If the MSI/IHC is positive on tumor testing, refer to geneticsRefer to US Multi-Society T

ask Force Guidelines, 2014 for cancer surveillance/management in LSAwait results of CAPP3 trial before routine aspirin use for chemoprevention in LS

Slide36

Questions?