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Hereditary GI Cancer-a Primer for Medical Oncologists

Hereditary GI Cancer-a Primer for Medical Oncologists. Ophira Ginsburg , MD, MSc, FRCPC Clinical Lead, Cancer Prevention & Screening Director Familial Oncology Central East Regional Cancer Program March, 2009. Objectives. HNPCC review

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Hereditary GI Cancer-a Primer for Medical Oncologists

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  1. Hereditary GI Cancer-a Primer for Medical Oncologists Ophira Ginsburg, MD, MSc, FRCPC Clinical Lead, Cancer Prevention & Screening Director Familial Oncology Central East Regional Cancer Program March, 2009

  2. Objectives • HNPCC review Diagnosis, genetic testing, cancer risks, risk reduction strategies • Other Hereditary GI syndromes: FAP, AFAP/MAP, HDGC • Criteria for referral to Familial Oncology Programs

  3. Hereditary GI Cancer Examples [gene] • HNPCC[MLH1, MSH2, MSH6, PMS2] • FAP[APC] • AFAP [APC, MUTYH1] • FHDG [CDH1]

  4. Why do genetic testing? • To confirm there is a genetic predisposition to cancer • To predict which family members are at increased risk of cancer • To prevent cancer or detect it early

  5. GENETICS SERVICE

  6. Genetic Counselling Process Standard Timeframe 6-8 months Seen <2wks if urgent Courtesy of Lori Van Manen, 2008

  7. What Happens During a Genetic Counselling Session? • Risk Assessment • Review of hereditary cancer • Discussions regarding testing: Cons Inconclusive results (often) Feelings of guilt or anxiety Family tensions Ethical issues Insurance issues Decreased compliance with screening • Pros • Obtain information about personal risk • Provide incentives for surveillance • Clarifies uncertainty • Patient empowerment • Assists ongoing research

  8. History of Familial Oncology Programs • 1995: counselling and genetic testing became available through research in 1995. • 2001: Ministry of Health established recommended referral and testing criteria, and began funding BRCA1/2 testing. • Since 2001: HNPCC counselling/testing funded BUT. Local estimates of uptake/referrals given 5-10% CRC caused by HNPCC, ~ 20-25% CRC incident cases *should* be referred. Est: 10% capture so far

  9. CRC

  10. Lynch Syndrome in Family “G” • Dr. Aldred Scott Warthin, MD, PhD described “Family G” in a 1913 publication based on records ascertained from the University of Michigan hospitals between 1895 and 1913. “Of the 48 descendants of the cancerous grandfather, 17 have died or been operated on for cancer. The preponderance of carcinoma of the uterus (ten cases) and of the stomach (seven cases) is very striking in the 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

  11. Why HNPCC is important • HNPCC/Lynch syndrome- 3 to 5 times more common than FAP • Harder to diagnose: many non CRC tumours, families with more “other tumours” than colorectal • potential for 1 or 2 prevention of other HNCC cancers: endometrial, urothelial, ovarian?

  12. HNPCC -CRC Unique Features Colorectal cancer: • 70% right sided distribution • Synchronous, metachronous primaries • Pathology: mucinous, poorly differentiated, peri-tumoural lymphocytic infiltration • Prognosis: ? • Response to chemo?

  13. 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

  14. Type of Cancer MLH1 MSH2 MSH6 CRC Female 71 39 Lower than MLH1/MSH2 Male 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 Other Extracolonic- 11 Extracolonic -48 specific risk unknown Cancer risk (%) by age 70

  15. Family History in HNPCC-more than meets the eye Lynch and de la Chapelle

  16. Revised Amsterdam(ICG-HNPCC, 1999) 3 relatives with CRC or assoc ca (uterine, small bowel, ureter, renal pelvis) 1st degree of the other 2 2 successive generations 1 before age 50 Histological verification Revised Bethesda(Umar et al, 2004) CRC in pt under 50 Synch/metachronous, or other associated ca CRC with MSI under 60 CRC with one or more 1st degree relative (under 50) CRC with 2 or more 1st/ 2nd degree relative (any age) HNPCC-criteria for testing-beyond Amsterdam* 50% by mutation analysis 15% by mutation analysis *R/O FAP

  17. 2 main classes of CRC: different models of tumourigenesis • Chromosomal instability: 85% distal; aneuploid; APC, p53 K-Ras mutations; more aggressive; prototype FAP “APC= the gatekeeper of CRC” • Microsatellite instability: 15% proximal: diploid; MSI, MMR mutations; less aggressive?, prototype HNPCC “MMR genes = caretakers of CRC”

  18. Genetic Testing in HNPCC • MSI- microsatellite instability (tumour) • IHC- immunohistochemistry (tumour) • Germ-line DNA for mutations in one of 3 genes (MLH1, MSH2, MSH6) PMS2 Amsterdam or research lab

  19. Microsatellite instability • hallmark of tumours in HNPCC • Microsatellites: genomic regions with repetitive short DNA sequences (often single nucleotides) • prone to mutation during DNA replication • Results in elongation or contraction = instability

  20. Microsatellite Instability • When DNA polymerase inserts the wrong bases in newly synthesized DNA, the “mismatch repair” enzymes repair the mistake • Defects in mismatch repair genes (MLH1, MSH2, MLH6) lead to the mutator phenotype: high frequency microsatellite instability or “MSI-H”

  21. Gryfe et al, NEJM 2000

  22. NEJM May 5,2005 Hampel et al

  23. HNPCC: Risk Reduction OptionsColorectal • Unaffected: colonoscopy to cecum q 1-2 years • Affected w CRC: consider subtotal colectomy at 1st diagnosis d/t risk of 2nd primaries http://www.nccn.org/professionals/physician_gls/PDF/colorectal_screening.pdf Seminars in Oncology, Oct 2007

  24. HNPCC: Risk Reduction Gynecological Cancers Screening for ovarian ca: CA125 + TVUS jury still out- Lancet Oncology online Mar 09 Screening for endometrial ca: annual TVUS + random endometrial bx (age 30+) few studies: review Lindor et al, JAMA 2006 See also current NCCN guidelines

  25. Surgical Options for Gyne Ca Prophylactic BSO Ovarian/FT risk reduction > 80-90% nb/ primary peritoneal carcinomatosis ~5-7%) Prophylactic TAH/BSO -less studied but likely >90% RR for endometrial ca in HNPCC mutation carriers Recent meta-analysis for HBOC (BRCA carriers) : J Natl Cancer Inst.  2009;101(2):80-87

  26. HNPCC Colorectal Ca Prognosis • many studies: stage-for-stage survival advantage in HNPCC-CRC landmark paper: Gryfe (NEJM 2000): • 607 consecutive cases CRC <age 50 • 17% had MSI-H • Multivariate analysis showed a sigificant survival advantage for MSI-H patients versus MSS, independent of ALL other prognostic factors.

  27. The “atypical family history” • Families w multiple cases of non-CRC HNPCC- associated cancers • *GU-TCC renal pelvis, bladder, ovarian, squamous cell endometrial, no colorectal cancer in “line of fire” + mutation MSH2 • Are the carriers at risk of colorectal ca? YES, and should be screened appropriately

  28. FAP- prototype for hereditary cancer • 100s to 1000s of adenomatous polyps throughout colon & rectum • 100% penetrance without surgery • Very early age of onset (polyposis by 20’s most ca by 40s) • APC gene chromosome 5

  29. Risk-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 review:

  30. FAP- Desmoids 12-17% of FAP patients • Intra-abdominal 80%, small bowel mesentery >50% (present w SBO) • Genotype: APC mutation b/w codons 1310-2011 • Tend to occur AFTER surgery, high RR, high morbidity • Rx: sx for small, well defined desmoids; Tamoxifen, chemo: vinblastine, MTX (RR 40-50%) or for rapidly progressive desmoids per sarcoma protocol (adriamycin, dacarbazine)

  31. FAP-other tumours Upper GI tumours • 80-90% FAP mutation carriers have duodenal or periampullary polyps, of which • 36% will develop advanced polyposis • 3-5% will develop invasive carcinoma • Surveillance: side-viewing endoscopy + bx suspicious polyps @ 25-30 yrs • Polypectomy for high-grade dysplasia, villous changes, ulceration, > 1 cm size

  32. chemoprevention? • NSAIDS: level 1 evidence sulindac, celecoxib, rofecoxib shown to reduce # polyps in FAP, but not proven to reduce cancer incidence or mortality ** long term use as an alternative to sx is NOT recommended + adverse effects • Calcium • HRT

  33. FAP: natural history—revised Due to improved diagnosis, and prevention/screening for CRC, periampullary cancer and desmoids have become the leading causes of death for FAP(APC) mutation carriers

  34. Other Polyposis Syndromes • AFAP-attenuated familial polyposis 10-100 polyps, proximal location, later age of onset (1307K allele ~ 6% Ashkenazi Jews, 2x CRC risk) • MUTYH1 mutations: “MAP” recessive inheritance -7.5 % of pts w classical phenotype but APC - J. Jass. Pathology Res & Practice (2008) 204: 431-447

  35. Attenuated FAP

  36. “MAP” MYH-associated polyposis coli Nielsen et al, Journal of Medical Genetics 2005

  37. Hereditary Diffuse Gastric Cancer • E-cadherin CDH1 gene • 70% risk of diffuse gastric ca • 40% risk of lobular breast ca • Prophylactic total gastrectomy • ?screening chromoendoscopy Lynch et al, Cancer 2008 Jun 15;112(12):2655-63

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