Presentation on theme: "Hereditary GI Cancer Syndromes: Keys to identify high risk patients"— Presentation transcript:
1Hereditary GI Cancer Syndromes: Keys to identify high risk patients Courtney Rice, MSCertified Genetic CounselorTriHealthMarch 24, 2012OSGNA Educational Conference
2ObjectivesRecognize the characteristics suggestive of hereditary cancer syndromes.Distinguish between various hereditary cancer syndromes based on family history.Become familiar with the management of hereditary cancer syndromes for the patient and their relatives.
3Why is this important?Knowledge about how genomics impacts cancer development, prevention, and treatment is rapidly increasing.Number of genetic tests continue to increaseIncreasing interest from patients and their families
4Why is this important for nurses? “Informed nurses can identify genetic cancer risk factors, educate patients about cancer risks and risk management/treatment strategies, and refer appropriate patients to a cancer genetics professional.”Aiello-Laws, L Seminars in Oncology Nurses; 27:13-20
5Genetics ReviewModified from ASCO education slides
6Gene mutations cause cancer A mutation is a change in the normal base pair sequence that affects the function of that gene’s proteinMany types of genes are important in the development of cancer including tumor suppressor genes, mismatch repair genes and oncogenes
7Gene mutations cause cancer All cancers arise from genetic alterationsModified from ASCO education slides
8Autosomal Dominant Inheritance Equally affects men and women50% chance offspring will inherit mutation
9Distribution of Cancer Etiology 5-10%10-15%75-80%
10When to suspect a Hereditary Cancer Syndrome Early onsetBilateral or multifocal diseaseMultiple primary cancers in one individualCluster of cancer in a familyCertain patterns of cancer in the family, usually multiple generations affectedRare cancersPrecursor lesions
11Family History Often the key to identifying a hereditary cancer family Allows for proper referral to genetics professional for risk assessment and appropriate management recommendations and follow up
12Family History At least 3 generations Both maternal and paternal lineagesLiving and deceasedAffected and unaffectedInfo to include for the patient :Current age, cancer history, precursor lesions/biopsy results, surveillance practices, cancer risk factors
13Family History Affected Relatives: Unaffected Relatives Current age & screening practicesAge at and date of diagnosis/deathType and location of primary cancer(s), stage and lateralitySecond cancer: metastasis or new primary?Environmental exposures (eg, smoking, sun, radiation)Other medical conditions associated with cancers (ulcerative colitis, pancreatitis, diabetes, etc.)Unaffected RelativesCurrent ageHealth status and history of significant illnessesPresence of other physical findings associated with cancer syndromes (benign tumors)Screening practicesIf deceased, cause of and age at death
14Family History Caveats Accuracy is keyFamily history is dynamic“No family history” is different than “negative family history”Adoption, small family, lack of females, estranged relativesHereditary cancer syndrome does not always lead to cancer in all relatives.
15Hereditary Gastric Cancer Hereditary Pancreatic Cancer GI Cancer SyndromesHereditary Gastric CancerHereditary Pancreatic CancerHereditary Colorectal CancerFamilial Adenomatous PolyposisLynch SyndromeThis list is no all inclusive, but covers some of the most common cancer syndromes you are likely to encounter in your practice
16Hereditary Gastric Cancer Genetic contributionMostly sporadic, some familial cases1-3% of gastric cancers are inheritedGastric cancers are part of many distinct hereditary cancer syndromes including Lynch syndrome, FAP, Peutz-Jeghers syndrome, Li FraumeniHereditary Diffuse Gastric CancerTwo major types of gastric cancer intestinal and diffuse. Instestinal type is more common in the general population and is more likely to be sporadic or related to environmental factors such as diet, smoking, alcohol use, H. pylori infection.
17Hereditary Diffuse Gastric Cancer Clinical Criteria:2 or more cases of DGC in first or second degree relatives, with at least one diagnosed before the age of 503 or more cases of documented DGC in first/second degree relatives, regardless of age of onset.Oliveira et al. Hum Mutat 2002;19:
18Hereditary Diffuse Gastric Cancer 25-50% of families that meet clinical criteria will have an identified mutationCDH1 gene, autosomal dominant inheritanceCancer RisksUp to 80% risk of gastric cancer, average age of dx 37 yrsUp to 60% risk of lobular breast cancerPossible risk for colorectal and prostate cancersCausative gene, CDH1, identified in the late Tumor suppressor gene-two hit hypothesisCDH1 codes for E-cadherin proteinCancer most often develops before age 40 (range 16-82); however, cases of teenage gastric cancer have been reported.Lifetime risks to age 80 for both gastric and lobular breast cancerGastric cancer rarely occurs before age 20.Fitzgerald et al. J Med Genet 2010;47:436-44
19Management of HDGCShould include families with confirmed CDH1 mutations and/or those that meet clinical criteria but have negative genetic testing.SurveillanceAnnual endoscopy with random biopsiesBiannual clinical breast examAnnual mammogramAnnual breast MRIProphylactic SurgeryConsider prophylactic gastrectomyBreast surveillence: the population is small and data is insufficient to prove the benefit of breast surveillence in this population, but other hereditary breast cancers set a precedence for increased screening including biannual clinical breast exams, mammograms and breast MRI starting at age is a pragmatic age
20HDGC Criteria for further evaluation Single case of DGC dx <40 yrs of age.Two cases of DGC, one diagnosed less than 50 years of age.Three cases of DGC dx at any age.Combination of DGC and lobular breast cancer, one dx <50 yrs
21Hereditary Pancreatic Cancer May account for 15% of pancreatic adenocarcinomasGenes responsible are largely unknownPrimarily autosomal dominantHereditary CausesHereditary cancer syndrome with PC as a feature along with other characteristics, usually other cancersHereditary pancreatitisFamilial pancreatic cancerFamilial pancreatic cancer—pancreatic cancer is the main or only cancer the an individual would inherit a predisposition for.
22Hereditary Syndromes and PC GeneRelative Risk for PCAdditional CancersBreast and Ovarian cancerBRCA1, BRCA23.5-10xBreast, ovarian, prostateFamilial Atypical Multiple Mole Melanoma Syndrome (FAMM)P1615-65xMelanomaPeutz-Jeghers syndromeSTK11130xEsophageal, stomach, sm bwl, colon, lung, breast, ovarianLynch syndromeMMR genes2-8xColon, endometrialHereditary PancreatitisPRSS1, SPINK150x__PALB2 related-cancerPALB2IncreasedBreastLifetime cancer risksFAMM:17-25%BRCA2 5-7%Lynch: 3.7%Hereditary pancreatitis: 30-40%Peutz-Jeghers syndrome: 11-32%
23Familial Pancreatic Cancer 2 or more FDR with pancreas cancer1 FDR with pancreas cancer, <50 yrs old2 or more second degree relatives with pancreas cancer, one at any early ageCancer risk for relativesfold increase depending on fam hxFamilial pancreatic cancer is a term reserved for family with primarily PC, no pancreatitis and not fitting the pattern of another hereditary cancer syndome.
24Screening high-risk population No standard screening protocolClinical trials underway to evaluate the use of EUS, CT and/or MRI with the goal of early detection in this high risk population.Who to screen?Individual having a >10 fold increased riskLifetime risk is >16%
25Pancreatic Cancer Criteria for Further Evaluation Sakorafas GH et al. Individuals at high-risk for pancreatic cancer development: Management options and the role of surgery. Surgical Oncology (2012). In press.Nurses are integral in identifying these high-risk groups through recognizing features of hereditary cancer syndromes, hereditary pancreatitis, and familial pancreatic cancer syndrome. Appropriate patient can be referred to genetic counseling to be educated on their personalized risk for cancer, the likelihood and appropriateness of genetic testing, and a discuss of risk reducing strategies (smoking cessation is particularly important). Based on the family history and the possible presence of a hereditary cancer syndrome screening recommendations would then be discussed with the individual. There is no standard screening protocol for high risk individuals, most recommendations are based on expert opinion, but clinical trials are underway to determine the most effective means of screening for pancreatic cancer. These authors from John Hopkins University propose annual screening with ______, starting years before the first diagnosis in the family.When screening is negative. It is generally agreed that pancreatectomyis not indicated even in high risk patients.In contract, if suspicious findings from screening surgery should be strongly considered. Surgery becomes theapeutic and not prophylactic at this point.Sakorafas GH et al. Individuals at high-risk for pancreatic cancer development: Management options and the role of surgery. Surgical Oncology (2012). In press.
26Causes of Hereditary CRC Modified from ASCO education slides
27Familial Adenomatous Polyposis (FAP) 1% of all colorectal cancersMain feature>100 polyps throughout entire colon, often thousandsAvg onset of polyps is 16 (range <10—30’s)Cancer risk is ~100% if left untreatedAverage age of colon cancer is 39 years.
29FAP: Other Cancer Risks Small bowel: 4%-12%Pancreas (adenocarcinoma): ~1%Thyroid (papillary): 1%-2%CNS (medulloblastoma): <1%Liver (hepatoblastoma): 1.6%Bile duct: <1%Stomach (adenocarcinoma): <1% in Western culturesGastric polyps present in 50% of individuals; 10% have gastric adenomasSmall bowel adenomas present in 50-90% of patients, can be obstructive.
30Attenuated FAP Fewer polyps Average of 30Cancer dx later onset compared to classic FAP (average age yrs)Can look like Lynch syndrome
31FAP Clinical Variants Turcot Syndrome Colon polyposis with CNS tumors, often medulloblastomasGardner SyndromeColon polyposisDesmoid tumors (10%)OsteomasDental anomaliesCongenital hypertrophy of the retinal pigment epithelium (CHRPE)Soft tissue skin tumorsDesmoid tumors –soft tissue tumor, often at the site of a surgery.Osteomas-bony growth in skull/jawDental anomalies—extra/missing teethCHRPE—thickening of the a pigmented layer of the retina, usually do not cause symptoms but found on routine eye exam.
32FAP Genetics APC gene; tumor suppressor Autosomal dominant inheritance 20-25% of individuals with FAP have no family history
33Management of FAP Individuals with known FAP or at risk but not tested Birth-5 years: serum AFP and abdominal U/S, 3-6 mo10-12 years: flexible sigmoidoscopy, 1-2 yUpper endoscopy by age 25, every 1-3 ySmall bowel imaging when duodenal adenomas are detected or prior to colectomy, 1-3 yPhysical palpation of thyroid annually, beginning late teensAnnual physical examNCCN. Colorectal Screening
34Management of FAP Once polyps/cancer is detected: Proctocolectomy or colectomyIf ileorectal anastomosis, then endoscopic rectum exam every 6-12 monthsIf ileal pouch or ileostomy, then endoscopic evaluation every 1-3 yearsDepending on disease burden in the rectum, may have ileorectal anastomosisNCCN. Colorectal Screening
35FAP: Criteria for further evaluation >10 cumulative colon polypsCRC dx <50 yrs, regardless of family historyCRC with a second primary (colon or non-colon)Presence of CRC and non-cancer features such as small bowel adenomas, desmoid tumors, osteomas, etc.
37Lynch Syndrome Cancer Risk Cancer TypeGeneral PopulationLifetime RiskColonAverage age of dx5%71 yrs54-74% (male)30-52% (female)42-61 yrsEndometrial2%62 yrs28-60%47-62 yrsModified from Weissman et al. J Genet Counsel 2011;20:5-19
38Lynch Syndrome Cancer Risk (Cont) Cancer typeGeneral PopulationLifetime Risk with Lynch SyndStomach<1%6-9%Ovarian1%6-7%Urinary tractRare3-8%Small bowel3-4%Brain/CNS2-3%Pancreatic1-4%HepatobiliarySebaceous skin1-9%Modified from Weissman et al. J Genet Counsel 2011;20:5-19
39Lynch Syndrome Cancer Risk (Cont) Second primary CRC30% after 10 years50% after 15 yearsMuir-Torre SyndromeLynch cancers AND sebaceous gland tumors or keratoacanthomasTurcot SyndromeLynch cancers AND CNS tumors (glioblastoma)
40Features of Lynch Syndrome Excess of right-sided tumorsHistopathologyMucinous/signet ring, poorly differentiated, medullary growth pattern, tumor infiltrating lymphocytes and Crohn’s like lymphocytic reactionProgression from polyp to cancer occurs more quicklyColonoscopy is recommended instead of sigmoidoscopy b/c more risk for left-sided CRCLynch syndrome progression can occur in 1-3 yrs versus 8-17 years with sporadic CRC.
41Lynch Syndrome Management SurveillanceInterventionOnset (age)Interval (years)Colonoscopy20-25*1-2Endometrial sampling30-35*AnnualTransvaginal USUrinalysis with cytology25-35*Physical exam21* Or 10 years prior to earliest diagnosis in the familyLindo et al. JAMA 2006;12:
42Lynch Syndrome Management SurveillanceAfter 15 years of follow-up:Surveillance decreased mortality by 65% (9 deaths in control group; 0 in case group)Decreased CRC by 63% (CRC rate 41% in controls, 18% in cases)Colonoscopy ever 1-3 years leads to earlier detection and improved survivalJarvinen et al. Gastroenterolgoy 2000;118:829-34Decreased deaths from CRC and overall deathsCases=screened=133; Controls=no screening=119
43Lynch Syndrome Management Prophylactic SurgeryColonLimited role for prophylactic colectomyUterus and ovariesConsider total abdominal hysterectomy and bilateral salpingo-oophorectomyTherapeutic SurgeryAdenoma—polypectomy, option of prophylactic colectomyCRC—consider subtotal colectomy instead of segmental resection
44Identifying patients at risk for Lynch syndrome Clinical criteria (Family History)Tumor StudiesImmunohistochemistry (IHC)Microsatellite Instability (MSI)
45Identifying patients at risk for Lynch syndrome Amsterdam Criteria II3 or more relatives with verified Lynch-associated cancerIncludes CRC, endometrial, small bowel, ureter or renal pelvisone is a first degree relative of the other two2 or more successive generations1 cancer dx <50 yrsFAP excludedCaveat: At least 50% of patients with Lynch syndrome will be missed by using this criteria.Vasen et al. Gastroenterology. 1999:116:1453.
46Challenges with a Family History Family sizes are getting smallerWider use of colonoscopies likely prevent many colon cancersSome gene mutations may have lower cancer risksInaccurate information: patient recall, poor communication, adoption, estrangement
47Identifying patients at risk for Lynch syndrome Tumor testingNot dependent on family historyTwo options for tumor testingMSI testingAbnormal in >90% with LSAbnormal in 10-15% of sporadic CRCAbnormal MMR genes allow mismatch errors during DNA replication variable lengths of DNA segments.IHCAbnormal in >90% of LSAbnormal in up to 20% of sporadic CRCAbsence of protein expression suggests a mutation in the respective gene.
49Revised Bethesda Criteria Guidelines Tumors from individuals should be tested for MSI in the following situationsCRC dx <50 years of agePresence of synchronous or metachronous CRC, or other Lynch related cancer, regardless of ageCRC with MSI-H histology diagnosed in a patient who is less than 60 years of ageCRC diagnosed in a patient with one or more first degree relative with Lynch related cancer, with one of the cancers being diagnosed under age 50 yearsCRC dx in a patient with 2 or more first/second degree relatives with Lynch related cancers, regardless of age.LS histology includes tumor infiltrating lymphocytes, Crohn’s-like lymphocytic reactin, muscinous/signet-ring differentiation, or medullary growth pattern.Assoc cancers includes CRC, endometrial, gastric, ovarian, pancreas, ureter, and renal pelvis, biliary tract, CNS, small bowel.Umar et al. J Natl Canc Inst 2004;96:
50Moving towards Universal Screening IHC and/or MSI screening of all colorectal cancers (and endometrial cancers), regardless of age of dx or family history has been implemented at some centers.Based on recommendations by the Evaluation of Genomic Applications in Prevention and Practice group from the CDC. EGAPP. Genet in Med 2009:11:35-41.Tumor screening has also been shown to be beneficial to patients and their at-risk relatives, and cost effective.∞ Family History is not the only tool to use in screening for high risk families.
51ConclusionsObtaining a family history is a crucial first step in identifying high-risk families.An accurate family history makes all the differenceEnhanced knowledge about the biology of hereditary cancers will allow for new and improved screening methods in the future.Appropriate identification of high-risk families can lead to prevention and early detection of cancer.