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Hereditary Cancer Syndromes: Implications for Improved Medical Management and Cancer Prevention Objectives Recognize who to refer Review hereditary cancer syndromes Discuss genetic testing available for pediatric and adult cancer as well as genetic research opportunities Provide the latest medical management recommendations for cancer prevention and early detection in carriers of a genetic predisposition for cancer Debbie Pencarinha, M.S., C.G.C. Li Licensed d Genetic G ti Counselor C l Kingsport Hematology and Oncology 15th Annual Primary Care Conference March 30, 2011 Audience Demographics 1. Family practice 2. Internal medicine 3 Ob/ 3. Ob/gyn 4. Pediatrics 5. Specialist 6. Other Personal Identification with Cancer 1. Personal history of cancer 2. Personal and family history 3. One 1st or 2nd degree relative 4. 2 or more 1st or 2nd degree relatives 5. Distant or no family history of cancer Hereditary cancer genes can lead to cancer risks as high as 100%! BRCA1 or BRCA2 = 85% MLH1/MSH2 = 80% APC = 100%!!! P53 90 % Percentage of Cancer that is Hereditary Are cancer genes REALLY rare? 1. 1-2% Tri-Cities population > 500,000 2. 5-10% 1 3. 15-20% 4. 25-30% in 400 carry BRCA = 1,250 1 in 1000 carry Lynch syndrome = 500 1 in 20,000 carry Li Fraumeni = 25 (previously thought 400 worldwide!) All cancer is genetic … but not all cancer is hereditary! “An ounce of prevention is worth a pound of cure” Germline mutations Parent All cells affected in offspring Mutation in egg or sperm Somatic mutations Child Present in egg or sperm Are heritable Cause cancer family syndromes Somatic mutation (eg, (eg breast) Occur in nongermline tissues Are nonheritable ASCO Hereditary Breast and Ovarian Cancer (HBOC) Mutations in Specific Genes are Responsible for Hereditary Cancer Risk •~ MYH 180,510 new cases in 2007 • ~10,614 due to a BRCA mutation MSH2 MSH6 MLH1 • ~22,430 new cases in 2007 • ~2,243 due to a BRCA mutation VHL APC 15% 15% 20% PMS2 CDKN2A RET PTEN BRCA2 RB1 CDH1 PALB2 ATM TP53 BRCA1 5%– 5% –10% 5%– 5% –10% TP53 MLH1 Breast Cancer Ovarian Cancer Sporadic Family clusters Hereditary STK11 Cancer Statistics, 2007, American Cancer Society ASCO Cancer Susceptibility Genes and DNA Repair BRCA1 Endogenous DNA damage hydrolysis Exogenous DNA damage ROS, RNS UV rad. ionizing rad. chemicals 4 Avg cell repairs 10 SSB each day Exon 2 17q12 (22 exons) Tumor suppressor Dominant Inheritance Up to 87% risk for BC Up to 44% risk for OC Tumors tend to be ER-, PR-, HER2- 185delAG Low penetrance Med. onset br=55y br=55y Exon 11 Exon 13 4184delTCAA Duplication British mutation Med. onset br=41y br= 41y Med. onset br=47y br=47y Refer women diagnosed <50 with triple negative breast cancer… Venkitaraman A. NEJM 2003;348:1917-1919 Chen Y, Lee WH et al., J Cell Physiol. 1999;181:385-92. Family with Hereditary Risk of Breast and Ovarian Cancer BRCA Mutation: Other Cancer Risks BRCA1 BRCA2 Increased 6% 16-30% 19-34% Cancer Male Breast Cancer Prostate Pancreas 2 to 3-fold increase Melanoma GI cancers: Stomach, colon Breast ca d.49 5% ovarian ca dx 49; d. 52 < 5% 2-fold increase 57 60 No increase breast ca dx 38 Liede A, Karlan B, Narod S. JCO 2004;22(4):735-742 At risk? 36 45 43 28 35 39 Hereditary Breast and Ovarian Cancer Syndrome After Mutation is Identified, Risk of Individual Family Members is Clarified Cancer Breast ca d.49 Red-flags (Individuals at increased risk for hereditary cancer) High risk Population risk ovarian ca dx 49; d. 52 57 60 breast ca dx 38 36 45 43 28 35 As more of these features are present in the family, the chance of a BRCA1 or BRCA2 mutation increases 39 NCCN Guidelines: High Risk Screening And Hereditary Breast/Ovarian Women BSE: Begin at age 18 CBE: Every 6 months b i att age 25 begin Annual mammogram & breast MRI: begin age 25 (or individualized) Consider chemoprevention Breast cancer before age 50 Ovarian cancer at any age Bilateral breast cancer Both breast cancer and ovarian cancer diagnosed in the same individual Male breast cancer Ashkenazi Jewish ancestry Men BSE education, monthly BSE CBE semiannually CBE, i ll Baseline mammogram • Annual if gynecomastia or parenchymal/glandular breast density on baseline study Strict adherence to prostate cancer screening Sensitivity of Screenings Mammography: detects 36% of cancers Ultrasound: detects 33% of cancers MRI: detects 77% of cancers Sensitivity i i i up to 95% with i h Mammography, h Ultrasound, MRI and clinical breast exam. Sensitivity and specificity: dependent upon radiologic experience and follow-up capabilities Warner, et al, 2004. JAMA, 292(11):1317-1325. Prophylactic Mastectomy Total Mastectomy Risk Reducing SalpingoSalpingo-Oophorectomy 95-99% removal of breast tissue S b Subcutaneous or nipple i l sparing mastectomy risk of GYN and breast cancer Pathologic evaluation of specimen after BSO Thin skin flaps 2-3mm thick nipple-areolar flap Awareness of spectrum of lesions Metcalfe KA et al., Lancet Oncol 2005; 6:431-4; Fatouros M. et al., Annals of Surg Oncol 2007;15(1)21-33 Kauff et al., Atlas Of Cancer, 2008; Weber et al., Zaloudek et al, Am J Surg Pathol 2009;33(8)1125-36 Tamoxifen Impact on Mortality? BRCA1 53% BRCA2 71% Absolute Survival Gain BRCA1 Absolute Survival Gain BRCA2 Mammo + MRI only 6% 4% PM at age 25y 13% 8% PM at 25y & PO at 40y 26% 12% PM at age 40y 11% 7% PO at age 40y 15% 6% With no intervention survival to age 70 = First drug approved by FDA to reduce the risk of developing a cancer. 20 mg day for 5 years Estimated that 2 million women in US could benefit from Tamoxifen Risk reduction of up to 49% (NSABP P-1) Common side effects: Overall survival to age 70 in the general US population = 84% Survival Analysis of Cancer Risk Reduction Strategies for BRCA1/2 Mutation Carriers . Plevritis SK, et al., JCO 2010;28(2):222-31. 2-10% BRCA carriers have occult cancers 2-3mm interval sections Hot flashes Vaginal discharge or vaginal dryness Fluid retention Fracture risk reduction Lowering of cholesterol levels Reduced incidence of benign breast disease and fewer biopsies Rare: endometrial cancer, thromboembolic events, cataracts Contraindications: history of DVT, PE, stroke, TIA, pregnancy Fisher, et al, 1998. Journal of the National Cancer Institute, 90(18):1371-1388. PARP Inhibitors Hinder Alternative DNA Repair in BRCA Deficient Cells Leading to Cell Death Effects of delaying prevention on survival 6 Survival benefit inyears 5 4 3 Tamoxifen 2 Oophorectomy 1 Tamoxifen and oophorectomy 0 30 35 40 45 50 55 Age at initiating preventive measure © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. Underhill C et al. Ann Oncol 2010;annonc.mdq322 Case I -- 32 yo female is diagnosed with breast cancer after stereotactic biopsy. She had a prior history of adrenocortical carcinoma at age 2 Lumpectomy and radiation vs. mastectomy if genetic test was positive “No other history of breast or ovarian cancer but there are lots of relatives with cancer” Patient did not want chemotherapy, strongly desired to have a child with her new partner Olufunmilayo I. Olopade, M.B.,B.S. University of Chicago Medical Center 60 Mastectomy Mastectomy and oophorectomy LFS Cancer Risks Li--Fraumeni Syndrome: Li Incidence— Incidence —1 / 20,000 Breast cancer (early-onset 25.5%) Soft tissue sarcoma (14.3%) Adrenocortical carcinoma (13.1%) (13 1%) Brain tumor (11.9%) Osteosarcoma (11.0%) Hematological (3.4%) Other: melanoma, colon, pancreatic, lung, stomach, ovarian, head and neck, renal Petitjean, et al (2007) Hum Mutat Radiation exposure and cancer risk in LFS patients has been documented: Available surveillance guidelines for LFS: are these sufficient? • Recommended surveillance for children – Annual physical examination, CBC, urinalysis – Annual abdominal ultrasound – Additional organ based screening depending on family history • Recommended surveillance for adults – Annual physical examination (with skin and neuro evaluation) – Annual CBC, urinalysis – For women: clinical breast exam q6 months at 20-25 yrs – For women: annual mammogram at 20-25 yrs – Consideration of annual rapid full body MRI or PET scan—NEW (found ca in 20% of asymptomatic carriers when screening--soon to be published by Schiffman et. al.) Slide Courtesy of Kowalski --CHOP http://www.nccn.org http://www.genetests.org Cancer risk by age: 50% by age 30 (vs. 1% pop risk) 90% by age 70 Age-specific cancer risk: 42% from 0-16 years 38% from 17-45 years 63% after age 45 Lifetime risk of cancer: 90%- 100% for women 70% for men Heyn R, et al. J Clin Oncol 1993 Several cases of soft tissue sarcoma occurred in previous radiotherapy fields Hisada M, et al. J Natl Cancer Instit. 1998 Radiotherapy led to 8 subsequent solid tumors in six patients and one patient with acute leukemia Salmon A, et al. Clinical Oncology 2007. Case report of a LFS patient who developed a second and third primary in the irradiation field. Clinical Features of Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Case Report II A 58-year old male is diagnosed with three separate primary colon cancers. He has a partial colectomy. colectomy He is referred to genetics for testing despite a negative family history. He tests positive for Lynch syndrome. Early but variable age at CRC diagnosis (~45 years)years)- ~ 80% Lifetime risk for cancer: 90% ---males, males, 70% 70%--females Tumor site in proximal colon predominates Extracolonic cancers: endometrium - Up to 60% risk ovary – 9-12% risk stomach – 11 11--19% risk urinary tract – 4-5% risk small bowel – 1-4% bile ducts – 2-7% brain/CNS – 1-3% Colonoscopy Improves Survival of GeneticallyGeneticallyConfirmed Lynch Syndrome Surveillance No surveillance Survival 100 92.2% 80 73.9% 60 40 0 5 10 15 Follow--up time (years) Follow Gastroenterology 2000;118:829 2000;118:829--34 NCCN guidelines for management of 1.2011--10/4/10) 10/4/10) Lynch Syndrome (version 1.2011-- NCCN guidelines (cont.) Colonoscopy beginning at 20-25, every 1-2 years Consider EGD with extended duodenoscopy and polypectomy every 2-3 yrs. at age 30-35. Consider prophylactic TAH-BSO after childbearing Preliminary data suggests baseline gastric biopsies Educate re: prompt response to endometrial ca symptoms Consider capsule endoscopy for small bowel cancer every 2-3 yrs beginning at 30-35. Consider annual urinalysis. Annual endometrial sampling may be appropriate in select patients Annual physical exam with a high index of suspicion for associated cancers. Transvaginal u/s may be considered Accumulating evidence for “anticipation” in Lynch syndrome families… Clinical Characteristics of Classic Familial Adenomatous Polyposis (FAP) Hereditary Susceptibility to CRC Clinically defined as: • at least 100 adenomatous polyps • often thousands of polyps • present throughout the colon • with early age of onset ~16 yrs, range 8-34 yrs autosomal dominant near 100% penetrance 20-30% de novo mutation rate1 (eg., no prior family history) Sporadic (65%– (65% –85%) Familial (10%– (10% –30%) Rare CRC syndromes (<0.1%) Lynch Syndrome (aka Hereditary nonpolyposis colorectal cancer) (5%) Familial adenomatous polyposis (FAP) (1%) Adapted from Burt RW et al. Prevention and Early Detection of CRC, CRC, 1996 Pediatric Management of FAP Endoscopic Surveillance or Management Infancy to 5 years (for known mutation carriers) • Twice yearly physical exam & serum AFP • Annual abdominal ultrasound (hepatoblastoma) Childhood • Evaluation of GI symptoms (changes in stool number/consistency, mucous or blood, abdominal/back pain) (?early indicators of CRC) 10-12 Years • Genetic counseling • First screening colonoscopy (adenoma development) 1Bisgaard, ASCO Other Cancer Risks and Management for Older Individuals with FAP •UpperGI malignancies --duodenal ampullary carcinomas, gastric ca Screening: EGD every 1-3 years •Non-intestinal cancers = HB (1-2%), desmoid tumors (10-20%), pancreatic ca (2%), thyroid ca (1-2%), medulloblastoma (1-2%), benign adrenal adenomas or other adrenal masses (7-13%) Screening: periodic EUS (no data), annual thyroid exam • Colorectal polyps and cancer Screening: Sigmoidoscopy or colonoscopy q 1-2 years, starting at 10 12 yrs or 10 years before earliest cancer diagnosis in the family • Total Vasen HF, et al. GUT 2008, Aretz S, Dtsch Arztebl Int 2010, www.NCCN.org V.I.2010 Hum Mutation 1994; 3:1213:121-125 Colectomy after initial polyps are identified EJ Groen et al. Annals of Surgical Oncology 2008; 15(9):2439-2450 Attenuated FAP (AFAP) Colorectal Cancer in FAP is Inevitable without Intervention Fewer polyps than classic FAP ~20-100 colon polyps Polyps generally begin at an older age (~44) generally ll right-sided i ht id d colon l polyps l Cancer risk approaches 80-100% Extra-intestinal manifestations may be present later colorectal cancer onset (~50 yr) Probability of cancer (%) 100 FAP HNPCC Population Risk 30 Age (Years) Risk Factors for Renal Cancer Male:Female (2:1) Non--hereditary factors Non smoking end stage renal disease (30X) cystic diseases of the kidney hypertension analgesic use Hereditary (~4(~4-5% of all cases) Multiple tumors Bilateral disease Young age at onset 50 70 Bussey, Familial Polyposis Coli 1975 Petersen, Gastroenterology 1991; 100:1658 Hereditary Renal Cancer Syndromes Syndrome Gene / Locus von Hippel-Lindau (VHL) VHL / 3p26-p25 Familial Non-VHL clear cell RCC H dit P Hereditary Papillary ill R Renall C Carcinoma i (HPRCC) Chromosome 3 translocations-all different c-MET MET / 7q31.1-34 7 31 1 34 Birt Hogg Dube (BHD) FLCN / 17p11.2 Hereditary Leiomyomatosis & Renal Cell Carcinoma (HLRCC) ? Familial Renal Oncocytoma (FRO) FH / 1q42.1 ? Low Penetrant susceptibility genes VHL Clinical Manifestations & Incidence Retinal 45-60% Angioma Endolymphatic sac tumor 10% Pancreatic cysts 90%; islet cell tumors; cystadenomas Epididymal cystadenomas 20-26% VHL: CNS Hemangioblastoma (benign) Cerebellar HB 65% Spine HB 13-60% Pheochromocytoma 15% Clear cell renal cancer 35% - 45% Cysts 60-80% Broad Ligament cystadenomas Slide from Lindsay Middelton, RN, CGC; Urology Oncology Branch, NCI Birt‐‐Hogg Birt Hogg‐‐Dube (BHD): Fibrofolliculomas Benign tumor hair follicle Frequency Frequency ~84% 84% Distribution primarily face & neck Slide from Lindsay Middelton, RN, CGC; Urology Oncology Branch, NCI Slide from Lindsay Middelton, RN, CGC; Urology Oncology Branch, NCI BHD: Pulmonary Cysts 84% one or more pulmonary cyst 38% history of pneumothorax Can be recurrent Bilateral Slide from Lindsay Middelton, RN, CGC; Urology Oncology Branch, NCI Preventative Measures for Mutation Carriers– Carriers– MEN2A, 2B Screen for pheochromocytoma first! Totall Thyroidectomy h id < 6 yo for MEN2A At birth for MEN2B The Genetic Influence on Prostate Cancer Risk Genome-wide Association Studies Genomeand Prostate Cancer Prostate cancer has the largest number of susceptibility loci identified of any cancer to date At l least 25 SNPs (single ( i l nucleotide l id polymorphisms) l hi ) are commercially available Limitations of SNP testing Hereditary Prostate Cancer Panel applies only to Caucasians Other risk factors not included in calculation (Hopkins Criteria) Does not account for HPC or other genetic risk • Potential for false reassurance At least one of the following: 1. Three or more first degree relatives New technology • Validity, clinical utility 2. Three successive generations on one side of the family There are no standard SNP panels 3. At least two relatives affected at age 55 or younger No consensus guidelines for medical management (Carter –1993 J. Urol.) Finasteride Putative HPC Genes HPC1/RNASEL (1q24-p25) Associated with younger and more aggressive HPC (inconsistent results) HPC2/ELAC2 (17p11) 2 missense mutations identified (linkage not replicated elsewhere) MSR1 (8p22-p23) Associated with later onset HPC (confirmed in some but not all studies) PCAP (1q42.2-q43) Linked to early onset PC (not confirmed by most studies) HPCX (Xq27-q28) X-linked HPC (conflicting data) HPC20 (20q13) Associated with PC in men over 65; less than 5 affected men/family, no male to male transmission (conflicting data) CAPB (1p36) Linked to prostate and brain cancer in 12 families (inconsistent results) New guidelines: Healthy men with PSA of 3.0 or lower should consider taking a 5-alpha reductase inhibitor (Finasteride) to prevent prostate cancer American Urological Association American Society of Clinical Oncologists Applies to men who plan to get yearly PSA or regular prostate cancer screenings and h have no signs i off prostate t t cancer Prostate Cancer Prevention Trial found an overall 25% relative risk reduction for prostate cancer in men who took Finasteride for 1-7 years Reduction of about 50% in PSA by 12 months expected Decision aid tool: www.asco.org/guidelines Patient guide: www.cancer.net Kramer, et al. (2009). (http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2008.16.9599) X Germ cell & trophoblastic tumors & neoplasms of gonads 3% XI Other malignant epithelial neoplasms and melanomas 4% XII Other and unspecified malignant neoplasms 0% Pediatric Cancers Ages 0-14 Not classified by ICCC 0% IX Soft tissue and other extraosseous sarcomas 7% Leukemia (includes MDS) 31% VIII Malignant bone tumors 4% VII Hepatic tumors 2% VI Renal tumors 5% V Retinoblastoma 3% IV Neuroblastoma and other peripheral nervous cell tumor 6% III CNS and misc intracranial and intraspinal neoplasms (2004+ only) 25% Pediatric Cancers that Merit Genetics Referral Lymphomas and reticuloendothelial neoplasms 10% Age-Adjusted and Age-Specific SEER Cancer Incidence Rates, 2003-2007 Retinoblastoma (RB1) Bilateral Wilms Tumor (WT1) Adrenocortical carcinoma (p53) Choroid Plexus Tumor (p53) Rhabdomyosarcoma < 3 yo (p53) Osteosarcoma < 10 yo (p53) Medullary thyroid cancer (RET) Hepatoblastoma (APC) Pediatric Cancers for Genetics Referral (cont.) Pheochromocytoma / paraganglioma (VHL, NF1, RET,SDHB, SDHC, SDHD) Retinal/cerebellar hemangioblastoma (VHL) Endolymphatic sac tumors (VHL) Optic pathway tumor (NF1) Acoustic or vestibular schwannomas (NF2) Atypical teratoid and malignant rhabdoid tumor (INI1/SNF5) Cancer risk and screening in hereditary retinoblastoma (RB) • 40% of RB patients have hereditary disease • RB1 gene (13q14) p intracranial tumors • 0.5 - 15% develop • Increased life-long risk of 2nd cancers – Bone, soft tissue sarcomas – Brain, nasal cavity cancer – Melanoma, lung, GI, bladder – Commonly in irradiated sites C-L Yu et al. JNCI 2009; 101:581-591. C Eng et al. JNCI 1993; 85:1121-1128. R Kleinerman et al. JCO 2005; 23:2272-2279. Idiopathic hemihypertrophy (Beckwith Beckwith-Wiedemann syndrome) and associated cancer risks Leukemias/Lymphomas •Overgrowth syndromes most commonly due to defects in methylation of genes at 11p15 •7-14% risk of developing embryonal tumors Wilms tumor, hepatoblastoma (2:1 ratio) Adrenocortical carcinoma Case reports of neuroblastoma, rhabdomyosarcoma • Screening: Abd U/S q 3 months until age 4 yrs Serum AFP q 6-12 weeks until 4 yrs At 4 yrs, renal U/S until age 8-10 yrs Not typically hereditary Risk for 1st and 2nd degree relatives (1.5-4.5%) RARE families have a hematologic malignancy syndrome Higher risk for leukemia can be seen with other genetic syndromes Genetics Challenge #1 Genetics Challenge #2 Which patient does NOT need a genetics referral? A patient tells you that her mother carries a BRCA mutation. She has not been tested. What is her approximate risk for breast cancer? 1. Male with breast cancer diagnosed at age 55 2. Twenty-year-old with medullary thyroid carcinoma 3. Sixty-year-old female with a sister diagnosed with breast cancer at age 55. No other family history. 1. 2. 3. 4. 4. Fifty-year-old male diagnosed with colon cancer with no family history Last Challenge Choose the FALSE statement: 1. Skin lesions are as important as cancer in making some genetic diagnoses 2. BRCA mutations can be associated with Fanconi anemia 3. Breast cancer is not inherited from the father 4. Do genetic testing on the person with cancer first 50% 50% x 87% = 45% 100% 25% x 87% = 22% HOW DO WE IDENTIFY INDIVIDUALS AT RISK? Early diagnosis of cancer Bilateral or multiple primaries of the same type Two different, associated p primary y cancers (breast and ovarian, colon and endometrial, medullary thyroid and pheochromocytoma) FAMILY HISTORY Rare cancer—male breast ca, sarcoma, ACC Polyposis Genetic Information NonNon-discrimination Act (GINA) BOTTOM LINE Signed May 21, 2008 KNOWLEDGE IS POWER Many have concerns about potential adverse effects to employability p y y and health insurability GENETIC DIAGNOSIS ALLOWS FOR: Protects individuals from genetic information discrimination in health insurance and employment Earlier, more frequent, most appropriate screening for cancer Surgical options for cancer prevention Chemoprevention Avoidance of risk factors (ie. radiation) Research opportunities Information for family members Avoidance of unnecessary screening and anxiety Genetic Testing is here to stay Where should you go for information? www.genetests.org NCCN Guidelines™ & Clinical Resources http://www.nccn.org/index.asp Genetics Home Reference http://ghr.nlm.nih.gov/ Thank You! Debbie Pencarinha, M.S., CGC Genetic Counselor Kingsport Hematology and Oncology 423--224 423 224--3736