Grand Rounds 121114 Mentor Milena Gould MD Case Presentation 31 yo 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 ID: 779953
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Slide1
Ashish SharmaPGY-4 GI fellow
Grand Rounds
12/11/14
Mentor- Milena Gould, MD
Slide2Case 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
Slide3Amsterdam II criteria met
Slide4Case 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.
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
Slide6Clinical 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
Slide7Background
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.
Slide8Background
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.
Slide9Background - 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.
Slide10Background – 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
Slide11Background- 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
Slide12Background-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.
Slide13Diagnostic 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
Slide14Diagnostic 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.
Slide15Diagnostic 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.
Slide16Universal 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
Slide17Traditional 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
Slide18MSI/IHC Testing – Interpretation
NCCN Clinical Practice Guidelines
in Oncology
. Version I.2014
Slide19Universal 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
Slide20Traditional 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
.
Slide21Traditional 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
Slide22Diagnostic 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
Slide23Colorectal 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 .
Slide24Outcomes 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
Slide25Clinical 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
Slide26Cancer 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
Slide27Evidence supporting colorectal cancer surveillance
Slide28Evidence 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
Slide29Clinical 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
Slide30Chemoprevention- 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.
Slide31Chemoprevention – 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.
Slide32Chemoprevention – 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.
Slide33Conclusion 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.
Slide34Back 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
Slide35Take 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
Slide36Questions?