Hereditary GI Cancer-a Primer Hereditary GI Cancer-a Primer for Medical Oncologistsfor Medical Oncologists

Ophira GinsburgOphira Ginsburg, MD, MSc, FRCPC, MD, MSc, FRCPC

Clinical Lead, Cancer Prevention & ScreeningClinical Lead, Cancer Prevention & Screening

Director Familial OncologyDirector Familial Oncology

Central East Regional Cancer ProgramCentral East Regional Cancer Program

March, 2009March, 2009

ObjectivesObjectives

1.1. HNPCC reviewHNPCC review

Diagnosis, genetic testing, cancer risks, risk Diagnosis, genetic testing, cancer risks, risk reduction strategiesreduction strategies

2.2. Other Hereditary GI syndromes: Other Hereditary GI syndromes:

FAP, AFAP/MAP, HDGCFAP, AFAP/MAP, HDGC

3.3. Criteria for referral to Familial Oncology ProgramsCriteria for referral to Familial Oncology Programs

Hereditary GI CancerHereditary GI Cancer

Examples [gene]Examples [gene]

• HNPCCHNPCC [[MLH1, MSH2, MSH6, PMS2]]

• FAPFAP [[APC]]

• AFAP AFAP [APC, MUTYH1][APC, MUTYH1]

• FHDG FHDG [CDH1][CDH1]

Why do genetic testing?Why do genetic testing?

To To confirmconfirm there is a genetic there is a genetic predisposition to cancer predisposition to cancer

To To predictpredict which family which family members are at increased members are at increased risk of cancerrisk of cancer

To To preventprevent cancer or detect cancer or detect it earlyit early

GENETICS SERVICE

Genetic Counselling Genetic Counselling ProcessProcess

REFERRAL•Triage

•Family hx forms

Chart Prep•Forms received•Pedigree drawn

•Pathology verification

Case conference/Counselling +

Testing (if indicated/accepted)

Result session

•Follow-up apptsarranged

Standard Timeframe6-8 months

Seen <2wksif urgent

Courtesy of Lori Van Manen, 2008

What Happens During a Genetic What Happens During a Genetic Counselling Session?Counselling Session?

Risk AssessmentRisk Assessment Review of hereditary cancerReview of hereditary cancer

Discussions regarding testing:Discussions regarding testing:ProsObtain information about personal riskProvide incentives for surveillanceClarifies uncertaintyPatient empowermentAssists ongoing research

Cons

Inconclusive results (often)

Feelings of guilt or anxiety

Family tensions

Ethical issues

Insurance issues

Decreased compliance with screening

History of Familial Oncology History of Familial Oncology ProgramsPrograms

1995: counselling and genetic testing became 1995: counselling and genetic testing became available through research in 1995available through research in 1995 . .

2001: Ministry of Health established recommended 2001: Ministry of Health established recommended referral and testing criteria, and began funding referral and testing criteria, and began funding BRCA1/2 testing.BRCA1/2 testing.

Since 2001: HNPCC counselling/testing fundedSince 2001: HNPCC counselling/testing funded BUT. Local estimates of uptake/referrals given 5-10% CRC BUT. Local estimates of uptake/referrals given 5-10% CRC caused by HNPCC, ~ 20-25% CRC incident cases *should* caused by HNPCC, ~ 20-25% CRC incident cases *should* be referred. Est: 10% capture so farbe referred. Est: 10% capture so far

CRCCRC

Lynch Syndrome in Lynch Syndrome in Family “G”Family “G”

Dr. Aldred Scott Warthin, MD, PhD described Dr. Aldred Scott Warthin, MD, PhD described “Family G” in a 1913 publication based on “Family G” in a 1913 publication based on records ascertained from the University of records ascertained from the University of Michigan hospitals between 1895 and 1913.Michigan hospitals between 1895 and 1913.

““Of the 48 descendants of the cancerous Of the 48 descendants of the cancerous grandfather, 17 have died or been operated grandfather, 17 have died or been operated on for cancer. The preponderance of on for cancer. The preponderance of carcinoma of the uterus (ten cases) and of the carcinoma of the uterus (ten cases) and of the stomach (seven cases) is very striking in the stomach (seven cases) is very striking in the family history” Dr. Warthin, 1913.family history” Dr. Warthin, 1913.

Douglas et al. (2005) History of Molecular Genetics of Lynch Syndrome in Family G; JAMA; Vol. 294 (17), 2195-2202

Progenitorsite unknown

d. 60y

B

d. 64yStomach

H

d. 60yStomach

F

d. 55yColon, NOS

G

d. 42yRectum

A

d. 47ySite Unknown

C

d. 84y

E

d. 63y

I

d. 55yUterus, NOS

D

d. 26y

Why HNPCC is importantWhy HNPCC is important

HNPCC/Lynch syndrome- 3 to 5 times HNPCC/Lynch syndrome- 3 to 5 times more common than FAPmore common than FAP

Harder to diagnose: many non CRC Harder to diagnose: many non CRC tumours, families with more “other tumours, families with more “other tumours” than colorectaltumours” than colorectal

potential for 1potential for 1 or 2 or 2 prevention of prevention of other HNCC cancers: endometrial, other HNCC cancers: endometrial, urothelial, ovarian?urothelial, ovarian?

HNPCC -CRC Unique HNPCC -CRC Unique FeaturesFeatures

Colorectal cancer: Colorectal cancer: • 70% right sided distribution70% right sided distribution• Synchronous, metachronous Synchronous, metachronous

primariesprimaries• Pathology: mucinous, poorly Pathology: mucinous, poorly

differentiated, peri-tumoural differentiated, peri-tumoural lymphocytic infiltrationlymphocytic infiltration

• Prognosis: ?Prognosis: ?• Response to chemo?Response to chemo?

Cancer General Population Risk

HNPCC

Risks Mean Age of Onset

Colon 5.5% 80% 44 years

Endometrium 2.7% 20-60% 46 years

Stomach < 1% 11-19% 56 years

Ovary 1.6% 9-12% 42.5 years

Hepatobiliary tract < 1% 2-7% Not reported

Urinary tract < 1% 4-5% ~ 55 years

Small bowel < 1% 1-4% 49 years

Brain/central nervous system < 1% 1-3% ~ 50 years

Cancer risk (%) by age 70

Type of Cancer MLH1 MSH2 MSH6

CRC

Female

71

39Lower than

MLH1/MSH2Male 96

Endometrium 42 61 Higher than MLH1/MSH2

Ovary 3.4 10.4 specific risk unknown

Stomach 2.1 4.3 specific risk unknown

Small bowel 7.2 4.5 specific risk unknown

Urinary Tract 1.3 12 specific risk unknown

OtherExtracolonic- 11 Extracolonic -48

specific risk unknown

Family History in HNPCC-Family History in HNPCC-more than meets the eyemore than meets the eye

Lynch and de la Chapelle

HNPCC-criteria for testing-HNPCC-criteria for testing-beyondbeyond Amsterdam* Amsterdam*

Revised AmsterdamRevised Amsterdam (ICG-HNPCC, (ICG-HNPCC, 1999)1999)

o 3 relatives with CRC or assoc 3 relatives with CRC or assoc ca (uterine, small bowel, ca (uterine, small bowel, ureter, renal pelvis)ureter, renal pelvis)

o 11stst degree of the other 2 degree of the other 2o 2 successive generations2 successive generationso 1 before age 501 before age 50o Histological verificationHistological verification

Revised BethesdaRevised Bethesda (Umar et al, (Umar et al, 2004)2004)

o CRC in pt under 50CRC in pt under 50o Synch/metachronous, or Synch/metachronous, or

other associated caother associated cao CRC with MSI under 60CRC with MSI under 60o CRC with one or more 1CRC with one or more 1stst

degree relative (under 50)degree relative (under 50)o CRC with 2 or more 1CRC with 2 or more 1stst/ 2nd / 2nd

degree relative (any age)degree relative (any age)

50% by mutation analysis 15% by mutation analysis*R/O *R/O FAPFAP

2 main classes of CRC: 2 main classes of CRC: different models of different models of

tumourigenesistumourigenesis Chromosomal instability: 85% distal; Chromosomal instability: 85% distal;

aneuploid; APC, p53 K-Ras mutations; aneuploid; APC, p53 K-Ras mutations; more aggressive; prototype FAPmore aggressive; prototype FAP““APC= the gatekeeper of CRC”APC= the gatekeeper of CRC”

Microsatellite instability: 15%Microsatellite instability: 15% proximal: diploid; MSI, MMR proximal: diploid; MSI, MMR

mutations; mutations; less aggressive?, prototype HNPCCless aggressive?, prototype HNPCC

““MMR genes = caretakers of CRC” MMR genes = caretakers of CRC”

Genetic Testing in Genetic Testing in HNPCCHNPCC

MSI- microsatellite instability MSI- microsatellite instability (tumour)(tumour)

IHC- immunohistochemistry (tumour)IHC- immunohistochemistry (tumour)

Germ-line DNA for mutations in one of Germ-line DNA for mutations in one of 3 genes (MLH1, MSH2, MSH6) PMS2 3 genes (MLH1, MSH2, MSH6) PMS2 Amsterdam or research labAmsterdam or research lab

Microsatellite instabilityMicrosatellite instability

hallmark of tumours in HNPCChallmark of tumours in HNPCC Microsatellites: genomic regions Microsatellites: genomic regions

with repetitive short DNA sequences with repetitive short DNA sequences (often single nucleotides) (often single nucleotides)

prone to mutation during DNA prone to mutation during DNA replicationreplication

Results in elongation or contraction Results in elongation or contraction = instability= instability

Microsatellite InstabilityMicrosatellite Instability

• When DNA polymerase inserts the When DNA polymerase inserts the wrong bases in newly synthesized wrong bases in newly synthesized DNA, the “mismatch repair” DNA, the “mismatch repair” enzymes repair the mistakeenzymes repair the mistake

• Defects in mismatch repair genes Defects in mismatch repair genes (MLH1, MSH2, MLH6) lead to the (MLH1, MSH2, MLH6) lead to the mutator phenotype: high frequency mutator phenotype: high frequency microsatellite instability or “MSI-H”microsatellite instability or “MSI-H”

Gryfe et al, NEJM 2000

NEJM May 5,2005 Hampel et al

HNPCC: Risk Reduction HNPCC: Risk Reduction OptionsOptions

ColorectalColorectal Unaffected: colonoscopy to cecum q Unaffected: colonoscopy to cecum q

1-2 years1-2 years Affected w CRC: consider subtotal Affected w CRC: consider subtotal

colectomy at 1colectomy at 1stst diagnosis d/t risk of diagnosis d/t risk of 22ndnd primaries primaries

http://www.nccn.org/professionals/physician_gls/PDF/colorectal_screening.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/colorectal_screening.pdf

Seminars in Oncology, Oct 2007

HNPCC: Risk Reduction HNPCC: Risk Reduction Gynecological CancersGynecological Cancers

Screening for ovarian caScreening for ovarian ca: CA125 + TVUS: CA125 + TVUS

jury still out- jury still out- Lancet Oncology online Mar 09Lancet Oncology online Mar 09

Screening for endometrial ca:Screening for endometrial ca:

annual TVUS + random endometrial bx (age annual TVUS + random endometrial bx (age 30+)30+)

few studies: review few studies: review Lindor et al, JAMA 2006Lindor et al, JAMA 2006

See also current NCCN guidelinesSee also current NCCN guidelines

Surgical Options for Gyne CaSurgical Options for Gyne Ca

Prophylactic BSOProphylactic BSO

Ovarian/FT risk reduction > 80-90% Ovarian/FT risk reduction > 80-90%

nb/ primary peritoneal carcinomatosis ~5-7%)nb/ primary peritoneal carcinomatosis ~5-7%)

Prophylactic TAH/BSOProphylactic TAH/BSO

-less studied but likely >90% RR for endometrial -less studied but likely >90% RR for endometrial ca in HNPCC mutation carriersca in HNPCC mutation carriers

Recent meta-analysis for HBOC (BRCA carriers) : J Natl Cancer Inst.  2009;101(2):80-87 

HNPCC Colorectal Ca HNPCC Colorectal Ca PrognosisPrognosis

many studies: stage-for-stage many studies: stage-for-stage survival advantage in HNPCC-CRCsurvival advantage in HNPCC-CRC

landmark paper: landmark paper: Gryfe (NEJM 2000):Gryfe (NEJM 2000):• 607 consecutive cases CRC <age 50607 consecutive cases CRC <age 50• 17% had MSI-H17% had MSI-H• Multivariate analysis showed a sigificant Multivariate analysis showed a sigificant

survival advantage for MSI-H patients survival advantage for MSI-H patients versus MSS, independent of ALL other versus MSS, independent of ALL other prognostic factors.prognostic factors.

The “atypical family The “atypical family history”history”

Families w multiple cases of non-CRC Families w multiple cases of non-CRC HNPCC- associated cancersHNPCC- associated cancers

*GU-TCC renal pelvis, bladder, ovarian, *GU-TCC renal pelvis, bladder, ovarian, squamous cell endometrial, no colorectal squamous cell endometrial, no colorectal cancer in “line of fire” + mutation MSH2cancer in “line of fire” + mutation MSH2

Are the carriers at Are the carriers at risk of colorectal ca?risk of colorectal ca?

YES, and should be screened appropriatelyYES, and should be screened appropriately

+1927

80TAH @ 41

transitional cell ca of Rt. ureter, dx. 60Stage 1C ovarian ca, dx. 67 - tx with BSO + adjuvant chemo

peritoneal recurrence - transitional cell ca dx 74

1925d. 59

colon cadx. 56

12/17/195254

+1945

60endometrial ca; dx. 52

MSI + IHC testing 2002 - unstable at BAT26DNA Sequencing 2004 - MSH2 mut. +ve

+1961

44squamous cell carcinoma

dx. 38Rt. shoulder

(Growing like keratoacanthoma)

1/16/1899d. 49

ovarian ca; dx. 46

12/1/193166

pancreatic cadx. 68

d. 33appendix ruptured

d. 84

27 31 34 10 8

34 36

5

no info bladder ca COD unknown

ca, type unknown

28

12/20/1899d. 49

PA

PA

PA

d. 82 d. 62colon ca dx. 55

uterine ca? or kidney ca?

d. 60colon ca dx. 59

d. 77colon ca dx. 77

d. stroke

+

d. 77uterine ca dx. ?

MSH2 +ve

n

4/5/1925 - ?d. 71

colorectal ca (3 sep primaries)dx. 55, 62, 69

?

195048

19

195642

MLH1 +ve

11/27/196038

1924 - ?d. 68

stroke

PApresumed MLH1 carrier

2

1921 - ?77

endometrial cadx. 53

colon cadx. 77

d. 45stroke

bowel problems

d. 64

colon cadx. 70-Toronto

80's 70-80

d. 48colon cadx. 45

MSI unstable at Bat26 locusIHC deficiency on MLH1

d. 33rectal cadx. 26

46France

44colonoscopy

4548 44

3

2

16-25 16-25

2

15-21

3

15-21

195642

MLH1 +ve

11/27/196038

11/10/199214

198719

3/12/199710

1924 - ?d. 68stroke

PA

PA

PA PA

presumed MLH1 carrier

FAP- prototype for FAP- prototype for hereditary cancerhereditary cancer

100s to 1000s of adenomatous 100s to 1000s of adenomatous polyps throughout colon & rectumpolyps throughout colon & rectum

100% penetrance without surgery100% penetrance without surgery Very early age of onset (polyposis by Very early age of onset (polyposis by

20’s most ca by 40s)20’s most ca by 40s) APC gene chromosome 5APC gene chromosome 5

Risk-reducing surgery in FAPRisk-reducing surgery in FAP

Sigmoidoscopy: q1-2 ~ age 10-12, genetic testing

Colonoscopy: once polyps + annually if colectomy is delayed more than one year

Prophylactic Colectomy: recommended- TPC, IRA, IPAA (ileal pouch)

Follow-up screening is necessary

JCO Oct 1, 2006 ASCO reviewJCO Oct 1, 2006 ASCO review::

FAP- DesmoidsFAP- Desmoids12-17% of FAP patients12-17% of FAP patients• Intra-abdominal 80%, small bowel mesentery Intra-abdominal 80%, small bowel mesentery

>50% (present w SBO)>50% (present w SBO)• Genotype: APC mutation b/w codons 1310-2011Genotype: APC mutation b/w codons 1310-2011• Tend to occur AFTER surgery, high RR, high Tend to occur AFTER surgery, high RR, high

morbiditymorbidity

• RxRx: : sxsx for small, well defined desmoids; for small, well defined desmoids; TamoxifenTamoxifen, , chemochemo: vinblastine, MTX (RR 40-: vinblastine, MTX (RR 40-50%) or for rapidly progressive desmoids per 50%) or for rapidly progressive desmoids per sarcoma protocol (adriamycin, dacarbazine)sarcoma protocol (adriamycin, dacarbazine)

Upper GI tumours Upper GI tumours • 80-90% FAP mutation carriers have 80-90% FAP mutation carriers have

duodenal or periampullary polyps, of duodenal or periampullary polyps, of whichwhich

• 36% will develop advanced polyposis36% will develop advanced polyposis• 3-5% will develop invasive carcinoma3-5% will develop invasive carcinoma• Surveillance: side-viewing endoscopy Surveillance: side-viewing endoscopy

+ bx suspicious polyps @ 25-30 yrs+ bx suspicious polyps @ 25-30 yrs• Polypectomy for high-grade dysplasia, Polypectomy for high-grade dysplasia,

villous changes, ulceration, > 1 cm villous changes, ulceration, > 1 cm sizesize

FAP-other tumoursFAP-other tumours

chemoprevention?chemoprevention?

• NSAIDS: level 1 evidenceNSAIDS: level 1 evidence

sulindac, celecoxib, rofecoxib shown to sulindac, celecoxib, rofecoxib shown to reduce # polyps in FAP, but not proven reduce # polyps in FAP, but not proven to reduce cancer incidence or mortalityto reduce cancer incidence or mortality

** long term use as an ** long term use as an alternative alternative to sx to sx is NOT recommended + adverse is NOT recommended + adverse effectseffects

• CalciumCalcium• HRTHRT

FAP: natural history—FAP: natural history—revisedrevised

Due to improved diagnosis, and Due to improved diagnosis, and prevention/screening for CRC, prevention/screening for CRC, periampullary cancer and desmoids periampullary cancer and desmoids have become the leading causes of have become the leading causes of death for FAP(APC) mutation death for FAP(APC) mutation carrierscarriers

Other Polyposis Other Polyposis SyndromesSyndromes

AFAP-attenuated familial polyposisAFAP-attenuated familial polyposis

10-100 polyps, proximal location, later age of onset 10-100 polyps, proximal location, later age of onset

((1307K allele ~ 6% Ashkenazi Jews, 2x CRC1307K allele ~ 6% Ashkenazi Jews, 2x CRC risk) risk)

MUTYH1 mutations: “MAP” recessive MUTYH1 mutations: “MAP” recessive inheritanceinheritance

-7.5 % of pts w classical phenotype -7.5 % of pts w classical phenotype but APC but APC --

J. Jass. Pathology Res & Practice (2008) 204: 431-447J. Jass. Pathology Res & Practice (2008) 204: 431-447

Attenuated FAPAttenuated FAP

““MAP” MYH-associated MAP” MYH-associated polyposis colipolyposis coli

Nielsen et al, Journal of Medical Genetics 2005

Hereditary Diffuse Gastric Hereditary Diffuse Gastric CancerCancer

E-cadherin CDH1 geneE-cadherin CDH1 gene 70% risk of diffuse gastric ca70% risk of diffuse gastric ca 40% risk of lobular breast ca40% risk of lobular breast ca Prophylactic total gastrectomyProphylactic total gastrectomy ?screening chromoendoscopy?screening chromoendoscopy

Lynch et al, Cancer 2008 Jun 15;112(12):2655-63Lynch et al, Cancer 2008 Jun 15;112(12):2655-63

ObjectivesObjectives

HNPCC reviewHNPCC review

Diagnosis, genetic testing, cancer risks, risk Diagnosis, genetic testing, cancer risks, risk reduction strategiesreduction strategies

Other Hereditary GI syndromes: Other Hereditary GI syndromes:

FAP, AFAP/MAP, HDGCFAP, AFAP/MAP, HDGC

Criteria for referral to Familial Oncology ProgramsCriteria for referral to Familial Oncology Programs