Universal Screening for Lynch Syndrome

Cecelia Bellcross, PhD, MS, CGCEmory University School of Medicine

Department of Human Genetics

Genetics of CRC

Sporadic (65%–85%)

Familial (10%–30%)

Lynch syndrome (aka Hereditary

nonpolyposis colorectal cancer -

HNPCC) (3%)Familial adenomatous polyposis (FAP) (1%)

Rare CRC syndromes

(<0.1%)

MYH associated polyposis (MAP) (1%)

Clinical Features of Lynch/HNPCC• Early but variable age at

CRC diagnosis (~45 years)

• Tumor site in proximal colon predominates

• Metachronous/synchronous CRCs

• Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile duct, pancreatic, sebaceous skin tumors; brain tumors

A Classic HNPCC/Lynch Family

CRCdx 50s

CRCdx 45

CRCdx 61

CRCdx 75

OvarianCa, dx 64

CRCdx 48

CRCdx 52

EndometrialCa, dx 59

CRCdx 42

45

Other Features of Lynch Syndrome

• Autosomal dominant inheritance• Genes belong to DNA mismatch repair

(MMR) family • Genetic heterogeneity (MLH1, MSH2,

MSH6, PMS2)• CRC lifetime risk 30-80%• Endometrial cancer lifetime risk 30-60%

18-29 30-39 40-49 50-59 60-69 70-790

102030405060708090

100

Male MLH1Male MSH2Female MLH1

Age (years)

Cum

ulat

ive

Ris

k C

olor

ecta

l Can

cer

(%)

CRC RISK

*Barrow, Clin Genet 2008

Extra-colonic/Extra EndometrialLifetime Cumulative Incidence to age 70 yo:• Urologic tract (8.4% overall)

– MLH1: female =1.1%, Male = 3.7% – MSH2: female =11.9%, Male = 27.8%

• Ovary = 6.7%• Gastric = 5.8%• Small Bowel = 4.3%• Biliary/Pancreatic = 4.1%

Watson, Int. J. Cancer, 2008

Cancer Site Surveillance/ Prevention Frequency Begin Age:

Colon Rectum

Colonoscopy Every 1-2 years 20-25 (30)(Colectomy)

Uterus Transvaginal Ultrasound / Endometrial Biopsy

Every year 30-35

Hysterectomy 30+Ovary Transvaginal Ultrasound / CA-125 Every year 30-35

Oral contraceptives > 5 yearsOophorectomy 30+

Stomach Small Bowel

Upper Endoscopy Every 2 years 30-35

Pancreas Biliary

Liver function tests & Abdominal Ultrasound

Every year 30-35

Urinary Tract Urinalysis cytology Every year 30-35Renal Ultrasound Every 1-2 years 30-35

Skin Lesions Dermatology Exam Every year 20-25

Surveillance/Prevention Options for Lynch syndrome (Lindor JAMA, 2006;296:1507)

Impact of Screening

Incidence Mortality05

1015202530354045 Screened Group

(n=44)Control Group (n=46)

Perc

ent

Jarvinen, Gastroent, 2000

Jarvinen, JCO, 2009: 242 mutation +, 367 mutation - : >95% screening compliance, no difference in cancer or all cause mortality rates

Amsterdam II Criteria 3 or more relatives with verified HNPCC

associated tumor (CRC, endometrial, ovarian, gastric, small bowel, urinary tract) in family

One case a first-degree relative of the other two

Two or more generations involved One or more cancer diagnosed by age 50 FAP excluded

Failure to meet these criteria does not exclude HNPCC

Revised Bethesda Guidelines:• CRC < age 50• Patient with 2 HNPCC related tumors• Patient with CRC < age 60 with MSI-H

histology• Patient with CRC with 1st degree relative with

HNPCC related cancer; one of the cancers at < 50 years

• Patient with CRC and 2 or more relatives with HNPCC-related cancer regardless of age

Umar, JNCI, 2004

Microsatellite Instability

-CG--CGCGCGCG

-CG--CGCGCGCG

-CG--CGCGCGCG

-CG

-CGCGCGCG-

-CG-

-CGCGCGCGCG--CG-

-CGCGCG-

-CG-

-CGCG-

-CG--CGCG-

-CGCGCG--CGCGCGCGCG-

Normal Cells

Tumor Cells

Microsatellite Instability

Normal Microsatellites

Abnormal or missing MSH2 protein

Immunohistochemistry

Abnormal Gene (MSH2)

MSH2-Lack of MSH2 expression, negative IHC staining for MSH2 protein

Normal tissue Tumor tissue

MSH2+

Testing for Lynch/HNPCCFamily/Medical history meets screening criteria

Amsterdam/Bethesda

MSI/IHCon tumor tissue MSI normal

IHC normal

No further testingRisks & screeningbased on history

MSI-High IHC – loss of protein expression

Genetic Testingon blood

Mutation Identified

No mutation Identified

1. Consider additional genetic testing2. Risks & screening based on test results and family/medical history

Lynch/HNPCC screening & managementFamily members offered testing

Rationale for HNPCC/Lynch Syndrome Screening of Newly Diagnosed CRC

• Common: ~ 3% of all CRC• Age/screening criteria miss up to 25%• Accurate methods (MSI/IHC) using easily

accessible tumor tissue• Benefits of medical intervention

– Cascade testing of family members– Surveillance/prevention– CRC treatment decisions

• Evidence of cost-effectiveness

EGAPP Lynch RecommendationGenetics in Medicine January 2009

May, 2007www.ahrq.gov/downloads/pub/evidence/pdf/hnpcc/hnpcc.pdf

GIM, 2009;1:42

GIM, 2009;1:35

Summary Statement

“The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer (CRC) to reduce morbidity and mortality in relatives.

We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.”

2.8% of CRC probands with deleterious mutations (n=44)

• Age at diagnosis – 51.4 (range 23-87)• 50% diagnosed over age 50• 25% did not meet either Amsterdam or Bethesda criteria• Mutations

– 20.5% MLH1 – 52.3% MSH2– 13.6% MSH6– 13.6% PMS2

Columbus-area HNPCC study (1999-2005)

Hampel et al. New Engl J Med 2005; 352:1851 Hampel et al. J Clin Oncol 2008; 26:5783

35 CRC probands have had genetic counseling

Degree of Kinship Tested PositiveFirst 99 52Second 64 28> Second 86 29Total 249 109

Family Studies of 35/44 CRC Probands

Hampel et al. NEJM 2005;352:1851-60.; Hampel et al. JCO 2008.

Theoretical Population

Health Benefit

Bellcross, Genet Med, 2012

Healthy People 2020 Approved Genomics Objective

(Developmental)

“Increase the proportion of persons with newly diagnosed colorectal cancer who receive genetic testing to identify

Lynch syndrome”

Endometrial cancer

Hampel H et al. Cancer Res. 2006; 66:7810 Hampel H et al. Cancer Res. 2007;67:9603

• Age at diagnosis – 54.1 (range 39-69)• 65% diagnosed over age 50• 65% did not meet either Amsterdam or Bethesda

criteria• Mutations

– 14.3% MLH1 – 21.4% MSH2– 64.3% MSH6– No PMS2

2.5 % with deleterious mutations (n=14)

12/14 EC probands have had genetic counseling

Degree of Kinship Tested PositiveFirst 28 16Second 12 3> Second 8 2 Total 48 21

Columbus HNPCC study Family studies of 14 EC probands

EGAPP Data Interpretation Concerns

• “To reduce morbidity and mortality in relatives”– Implies no benefit to proband

• Increasing evidence of impact on CRC management – chemotherapy, surgery

• Known increased risk for 2nd primary colorectal cancers and other tumors impacts medical management

• Does not take into account current practice and insurance coverage (including Medicare)

Potential Impact on CRC treatment

• MSI-H tumors– Better prognosis (Popat, JCO 2005;23:609) – Lack of impact of 5FU on RFS/OS (DesGuetz, Eur J

Cancer 2009;45:1890)• Surgical (Gut 2011;60:950 – 382 LS gene mutation carriers

– Extensive colectomy – 0/50 metachronous tumors vs. Segmental resection – 74/322 (22%)

– Cumulative risk of metachronous CRC at 10, 20, & 30 yrs = 16%, 41% & 62% respectively

Cost effectiveness Data

Mvundura M, et al. Genet Med. 2010;12:93-104

Targeting screening only to CRCs < age 50 would miss over 50% of LS cases

Business Analysis by a Healthcare System

• Evidence review & computerized simulation models – Intermountain Healthcare

• Cost of screening all (unselected) CRC patients for Lynch syndrome <$25,000/LYS

• IHC with methylation studies, reflexing to BRAF most efficient

Gudgeon, Am J Managed Care, 2011;17:e288

Universal IHC screening for CRC: OSU experience

• Began March 1, 2006• 270 cases of CRC in first 2 years

– 57 (21.1%) absent for one or two MMR proteins– 54 contacted by genetics with physician

consent• 5 deceased, reported to next of kin• 7 prisoners

– 34 appropriate for consultation– 18 scheduled appointment/9 completed appt– 7/9 tested

• 2 confirmed Lynch, 3 with MLH1 methylation

South et al, Genet Med 2009; 11:812-817

Challenges to Implementation

Lack of provider knowledge of Lynch syndrome and testing issues

Question of informed consent Availability of genetic services Cost and coverage Psychosocial impact Informing relatives – who is responsible? Patient and provider compliance Infrastructure needs Testing limitations (e.g. IHC accuracy by site)

It takes a teamSurgeryPathologyOncologyGastroenterologyGeneticsGynecologyPatientsFamiliesHealthcare system

http://www.lynchscreening.net

LSSN Vision and Mission• LSSN Vision:

– to reduce the cancer burden associated with Lynch syndrome.

• LSSN Mission:

– to promote universal Lynch syndrome screening on all newly diagnosed colorectal and endometrial cancers; to facilitate the ability of institutions to implement appropriate screening by sharing resources, protocols and data through network collaboration; and to investigate universal screening for other Lynch syndrome related malignancies

Membership Data

Emory LS Screening TeamN. Volkan Adsay, MD PathologyCecelia A. Bellcross PhD, MS, CGC GeneticsAmanda Eppolito, MS, CGC GeneticsAlton B. Farris, III, MD PathologyNatalyn N. Hawk, MD Hem/OncIra R. Horowitz, MD Gyn/OncJohn Kauh, MD Hem/OncNamita Khanna, MD Gyn/OncDana M. Meaney-Delman, MD High Risk Gyn Virginia O. Shaffer, MD Colorectal SurgeryChristine Stanislaw, MS, CGC GeneticsPatrick S. Sullivan, MD Colorectal Surgery

Miranda Chergosky – GC Student Focus Intern

Emory LS Screening Protocol

IHC Result InterpretationIHC Result Frequency Implications Follow-up

MLH1 & PMS2 Absent

15%

80% acquired

20% LS due to MLH1 mutation

BRAF (V600E +) and/or MLH1 hypermethylation Genetics referral & MLH1 DNA analysis

MSH2 & MSH6 Absent

3% Most LS due to MSH2 mutation

Genetics referral & MSH2 DNA analysis

MSH6 or PMS2 Absent

2% Most LS due to MSH6 or PMS2 mutation

Genetics referral & MSH6/PMS2 DNA analysis

Genetics Follow-up• Access to CoPath – automatic search for all

CRC specimens– Monitor if IHC being done – interface with GI

path fellows– Review IHC/BRAF results

• Enter into LSSN database• Abnormal IHC results

• Follow-up letter to MD via EMR• Coordination with RN staff to ensure genetics referral• Subset of IHC positive screens to be seen at point of

care (post-op or oncology appt)• Enter follow-up/outcome data into LSSN db

What Is Cancer Genetic Counseling?

• Cancer genetic counseling is NOT genetic testing!

• It is a process of information gathering, risk assessment and education.

• The goal of cancer genetic counseling is to provide the individual, family and their health care providers with accurate cancer risk information to facilitate personal management decisions.

Initial Genetic Counseling Visit

• Review medical history and family history• Assess risk for hereditary cancer• Discuss cancer biology and genetics• Discuss genetic testing options and/or referrals

for additional evaluation if appropriate• Discuss implications of testing for the patient

and their family• Coordinate testing including review of

insurance issues

Informed Consent:Potential Benefits of Genetic Testing

• Improved cancer risk management– Prevention– Early detection– Avoidance of unnecessary and costly screening and

surgery

• Relief from uncertainty and anxiety about cancer risk

• Information for individual and family members• Lifestyle decision making

Informed Consent:Limitations of Genetic Testing

• Not all mutations are detectable• Uncertain significance of some mutations • Negative result is fully informative only if

mutation has been identified in family • Results indicate probability, not certainty, of

developing cancer • Management/screening strategies continually

evolving as new data collected

Ideally, Begin Testing With an Affected Person

If a mutation is found in an affected person, testing will be more informative for other family members.

Colon Ca, 42

Colon Ca, 38d.45

Colon Ca, 45 Person seeking

counseling (proband)

Test first, if possible

Understanding Possible Test Results

Positive

Negative

Uncertain Variant

Increased Cancer Risk

Has a mutation been found in the

family?

Y

N

NO Increased Cancer Risk

Cancer Risk Not Altered

(individualized empiric risk based on family

history)

Impact of Genetic TestingFamily with known mutation

True negative: no increased risk beyond general population

Colon Ca, 52

Endometrial Ca, 47

Colon Ca, 45

MSH2 +37

MSH2 -

d. 50MSH2?

*30

MSH2+

Mutation Positive: initiate screening

Informed Consent:Potential Risks of Genetic Testing

• False sense of security if test negative• Psychological distress• Change in family dynamics• ?? Insurance discrimination

The Myth of Genetic Discrimination• No well-documented cases of health

insurance loss, denial, or rate increase based on cancer genetic testing • State and Federal laws exist which address health insurance and employment• GINA – Genetic Information Non-

discrimination Act (May, 2008)• Life/disability/long-term care not

protected

Result Disclosure and Post-test Counseling

• Assess cancer risk based on test results• Discuss any additional testing recommendations• Review of implications for family members• Present screening and management options• Discuss risk reduction strategies• Explore psychosocial adjustment to cancer risk and/or

genetic risk

QuestionsCommentsThoughts

Suggestions

?Thank You