COLON CANCER & VERMONT COLORECTAL CANCER SUMMIT NOVEMBER 15, 2014 WENDY MCKINNON, MS, CGC ... Early

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Text of COLON CANCER & VERMONT COLORECTAL CANCER SUMMIT NOVEMBER 15, 2014 WENDY MCKINNON, MS, CGC ......

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    COLON CANCER &

    GENETICS VERMONT COLORECTAL CANCER

    SUMMIT

    NOVEMBER 15, 2014

    WENDY MCKINNON, MS, CGC

    CERTIFIED GENETIC COUNSELOR

    FAMILIAL CANCER PROGRAM

    UNIVERSITY OF VERMONT MEDICAL CENTER

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    � Multiple relatives with colorectal cancer on same side of the family (maternal or paternal lineage)

    � Early age at diagnosis of colon cancer (

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    � Peutz-Jegher syndrome (PJS)

    �Gene: STK11

    � Juvenile Polyposis (JP)

    �Genes: SMAD4, BMPR1A

    �Mutations in SMAD4 also associated with HHT

    � Cowden syndrome (CS)

    �Variant: Bannayan-Ruvalcaba-Riley (BRR)

    �Gene: PTEN

    INHERITED CRC: HAMARTOMATOUS

    * All are autosomal dominant

    �Accounts for at least 3% all colon

    cancers

    �Characteristics:

    �Early age onset

    �Proximal tumors

    �Pathologic characteristics

    �Extra-colonic cancers

    � LS accounts for at least 3% all endometrial cancers

    � Gastric, small intestine, urinary tract, ovarian, hepatobiliary,

    sebaceous skin tumors, and glioblastomas

    LYNCH SYNDROME

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    LIFETIME CANCER RISKS FOR LS

    Cancer siteCancer siteCancer siteCancer site MLH1MLH1MLH1MLH1 MSH2MSH2MSH2MSH2 MSH6MSH6MSH6MSH6 PMS2PMS2PMS2PMS2

    Any Lynch

    cancer

    44-79% 38-78% 25-65% 16-53%

    ColorectalColorectalColorectalColorectal MenMenMenMen

    WomenWomenWomenWomen

    58585858----65%65%65%65%

    50505050----53%53%53%53%

    54545454----63%63%63%63%

    39393939----68%68%68%68%

    36363636----69%69%69%69%

    18181818----30%30%30%30%

    20%20%20%20%

    15%15%15%15%

    Endometrial 57-66% 21% 17-44%

    15%

    Lynch syndrome Surveillance Options

    Lindor et al, 2006; Vasen et al, 2007; Lu 2007

    Intervention Recommendation

    Colonoscopy Every 1-2 y beginning at age 20-25 (MLH1

    & MSH2), or age 30 (MSH6 & PMS2).

    Annual after age 40.

    Endometrial sampling

    Transvaginal US

    Upper endoscopy

    Annual beginning at age 30-35

    Consideration of TAH/BSO

    Urinalysis Every 1-2 y beginning at age 25-35

    History & Exam w/

    review of systems

    Annual beginning at age 21

    Periodic

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    �Family history / clinical criteria

    �Tumor based testing

    �Molecular / DNA based testing

    �Multi-gene panels

    �Tumor genomics

    APPROACHES TO DIAGNOSING LYNCH

    SYNDROME

    THE FAMILY HISTORY AND

    DIAGNOSING LYNCH SYNDROME

    CRC dx 50s

    CRC dx 45

    CRC dx 61

    CRC dx 75

    Ovarian Ca, dx

    64

    CRC dx 48

    CRC dx 52

    Endometrial Ca, dx 59

    CRC dx 42

    45

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    �Many families do not meet current clinical criteria for Lynch syndrome

    �Amsterdam Criteria I and II

    �Bethesda Criteria, original and revised

    �Hampel, et al NEJM, 2005

    �Screened 1500 CRC; 44 LS mutation carriers

    �50% CRC diagnosed after age 50

    �25% did not meet AC or BC

    CLINICAL CRITERIA

    � Genes belong to DNA mismatch repair (MMR)

    family

    � Mutations in MMR genes lead to microsatellite

    instability (repetitive sequences of DNA)

    � MMR proteins are missing in the tumor tissue

    GENETIC FEATURES OF LYNCH

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    � Identify MMR proteins normally present

    � If protein is absent, gene is not being expressed (mutation or methylation)

    � Helps direct gene testing by predicting likely involved gene

    IMMUNOHISTOCHEMISTRY

    MSH2MLH1

    MSH6PMS2

    ABNORMAL – MLH1 & PMS2 ABSENT

    �15% of the

    time

    �80% acquired

    methylation of

    MLH1

    �20% will be LS

    MLH1 MSH2

    MSH6 PMS2

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    ABNORMAL – MSH2 & MSH6 ABSENT

    �3% of the time

    �Most likely LS due to either MSH2 or MSH6 gene mutation

    �Refer to Genetics for GC and GT

    MLH1 MSH2

    PMS2MSH6

    ABNORMAL – MSH6 OR PMS2 ABSENT

    �2% of the time

    �Most likely LS due to an MSH6 or PMS2 gene mutation

    �Refer to Genetics for GC and GT

    MLH1 MSH2

    MSH6 PMS2

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    � Columbus-area HNPCC studies ◦ NEJM 2005;352:1851-60; J Clin Oncol 2008;26:5783-88

    � EGAPP Recommendations ◦ All CRC be screened for LS; Genet Med, 2009,11:35-41

    � Cost-effectiveness evaluations ◦ Genet Med, 2010, 12:93-104; Ann Int Med, 2011, 155:69-79

    � Healthy People 2020; www.healthypeople.gov

    � Institutions adopting universal screening ◦ 71% NCI Cancer Centers

    ◦ 28% COC Accredited Cancer Centers

    ◦ 15% Community Cancer Centers

    EVIDENCE FOR UNIVERSAL SCREENING

    POTENTIAL IMPACT

    �146,970 new cases of CRC in the US

    �4,115 have Lynch syndrome (2.8%)

    �12,345 of their relatives have LS (~3 per

    proband)

    �Total of 16,460 individuals who could be

    diagnosed with LS by universal screening on

    colon cancers

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    �For cancer patient with LS diagnosis:

    � Increased risk of second primary cancer

    � 50% after 20 years

    �Guidelines differ for cancer patients with/without LS

    �For relatives:

    � Individualize screening for relatives with/without LS

    �Early diagnosis / prevention

    IMPLICATIONS OF DIAGNOSIS OF LYNCH

    SYNDROME

    �2010-11, a targeted approach was used

    �Jan 2012, all colon cancers tested for Lynch

    syndrome

    �colon resections

    �biopsies under age 50

    �September 2014, switched to testing all

    biopsies containing cancer regardless of age

    � IHC is screening tool used

    UNIVERSAL SCREENING FOR LYNCH

    SYNDROME AT FAHC/UVMC

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    IHC LETTER

    �Genetic Counselor notified by pathology of all

    results

    �For abnormal results, GC asks permission of

    ordering physician to contact patient

    �Patient contacted and GC appointment

    scheduled

    �All results entered into database housed in

    the EMR

    �All patients with normal results sent letter

    COMMUNICATION OF RESULTS

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    PRISM (EPIC) Document Flowsheet

    NORMAL IHC RESULT LETTER

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    Established Guidelines

    � MLH1

    � MSH2

    � MSH6

    � EPCAM

    � PMS2

    � APC

    � MUTYH

    � SMAD4

    � BMPR1A

    � TP53

    � STK11

    Newer genes; no

    established guidelines

    � CHEK2

    � GREM1

    � GALNT12

    � POLE

    � POLD1

    GENES ASSOCIATED WITH INCREASED COLON

    CANCER RISK

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    � Family history is key component

    � Thanksgiving is National Family History Day

    � Access the My Family Health Portrait Web

    tool at https://familyhistory.hhs.gov/

    FAMILY HISTORY

    Contact Information:

    Familial Cancer Program

    (802) 847-4495

    wendy.mckinnon@vtmednet.org

    THANK YOU!