Ashish Sharma
PGY-4 GI fellow
Grand Rounds
12/11/14
Mentor- Milena Gould, MD
Case Presentation
• 31 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
Maternal
GM
Maternal GF
Uncle 1
Uncle 2
Aunt 1
Mother 54
Aunt 2
Colon Ca
Cousins
Cousins
Cousin
Father 55
Cousin
Paternal GF
Unknown
Paternal
GM
Patient 31
Sister 38
LS
LS
Brother –in-law
Amsterdam II
criteria met
Nephew 12
Brain cancer
Niece
Niece
Cousins
Case presentation
• Patient’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 Family
Mutation (KFM), and tested positive. He was
diagnosed with LS.
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 present
• EXT: No edema
• NEURO: Grossly intact and non focal
• Skin: No lesions
Procedures• Colonoscopy – sigmoid diverticulosis, no polyps detected
• EGD - Normal
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
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.
Background
• Approximately 3% of Colorectal
Cancers (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.
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.
Background – Definitions
•
•
•
•
Lynch like syndrome
Familial Colorectal Cancer Type X (FCRCTX)
Muir Torre syndrome
Turcot syndrome
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
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
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.
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
EPCAM
• Universal testing and Traditional testing
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.
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.
Universal Testing
• Definition – 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.2014
3. Recommendations from EGAPP Working Group 2009
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
MSI/IHC Testing – Interpretation
NCCN Clinical Practice Guidelines in
Oncology. Version I.2014
Universal Testing Algorithm
May be more cost
effective to perform
IHC testing only
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
Traditional testing in affected
individual or at risk family memberMutation Known
Our patient was diagnosed using this approach.
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
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
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
Colorectal cancer risk assessment toolUseful 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 .
Outcomes of effective implementation
of Universal Testing in safety net
hospital
Key points –
1. Role of genetic
team
2. Participation
rate of at risk
family
members
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
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
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
Evidence supporting colorectal cancer
surveillance
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
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
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.
Chemoprevention – CAPP2 2012
 918 LS patients from 43 centers
 Long-term follow-up report on randomized, placebocontrolled, 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.
Chemoprevention – CAPP2 2011
 861 LS patients from 43 centers
 Long-term follow-up report on randomized, placebocontrolled, 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.
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.
Back to our patient
• Colonoscopy 1-2 yrs
• EGD 2-3 yrs (possibly every 5 yrs), check for H
pylori; treat and eradicate if positive
• UA every year
• No aspirin for chemoprevention at this time
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 genetics
• Refer to US Multi-Society Task Force Guidelines,
2014 for cancer surveillance/management in LS
• Await results of CAPP3 trial before routine aspirin
use for chemoprevention in LS
Questions?