Oncologic Genetic Syndromes and Screening Brad T Tinkle, MD PhD Director of AMG Genetics 6th Annual Trends in Hematology/Oncology March 2, 2013

Disclosures No financial disclosures

Objectives Review the role of genetic susceptibility in various cancer types Discuss the genetic syndromes and testing options of various cancer types Describe the role that genetics health professionals offer

Genetics in Cancer 5-10% of all malignancies are due to highly penetrant hereditary cancer predisposition syndromes [Ballinger, 2012] Over 400 cancer-related genes have been identified May account for many familial cancers Caution! Current clinical testing may include some of these genes of lower-risk http://www.sanger.ac.uk/genetics/GCP/Census

Breast Cancer Most prevalent type of cancer in women 2nd leading cause of cancer death in the US New cases in 2012: 229,060 (estimated) Deaths in 2012: 39,920 (estimated) 15%-20% Sporadic Family clusters Hereditary 5%–10%

Ovarian Cancer 22,000 newly diagnosed in the US annually 1.4% lifetime risk ~45% 5-year survival rate 4.6x RR if mother had ovarian cancer and 1.6x RR is sister [Ziogas et al., 2009] Sporadic Hereditary 5%–10%

Endometrial Cancer 47,130 newly diagnosed in 2012 (estimated) Lifetime risk is estimated to be 2.5% 8,010 estimated deaths in 2012 Most common heritable form is Lynch syndrome (a.k.a. hereditary non-polyposis coli) which represents 2-3% of all cases May also be related to Cowden (PTEN Hamartoma Tumor syndrome) and Peutz-Jeghers

Colorectal Cancer 4th most common cancer diagnosis in US 1 in 20 Americans will develop CRC In 2012, expected number of new cases: 143,460 Expected deaths due to CRC: 51,690 Death rate is declining – early detection and prevention 20 40 60 80 100 General population Personal h/o CRC Inflammatory bowel disease HNPCC mutation FAP 5% 15%-20% 15%–40% 70%–80% >95% Lifetime risk (%)

Gastric Cancer Estimated 21,320 new diagnoses in the US (2012) Estimated 10,540 deaths in the US (2012) 4th leading cause of cancer deaths worldwide 5 year survival of 20% 3-10% are hereditary Hereditary diffuse gastric cancer Hereditary breast/ovarian cancer Lynch syndrome Li-Fraumeni syndrome Familial Adenomatous Polyposis Juvenile polyposis Peutz-Jeghers

Pancreatic Cancer Estimated 43,920 new diagnoses in the US (2012) 4th leading cause of cancer-related deaths in the US Estimated deaths 37,390 in 2012 5-10% are hereditary Associated with familial forms of pancreatitis Breast-ovarian cancer syndrome (BRCA2 and PALB2) Familial multiple melanoma with 0.6-31% lifetime risk Higher risk if first-degree relative with pancreatic ca. Lynch syndrome 0.4-4% lifetime risk Peutz-Jeghers 8-36% risk Solomon S et al. Cancer J 2012;18:485-91. Bartsch DK, et al. Nat Rev Gastroenterol Hepatol 2012;9:445-54.

Melanoma 76,250 new cases in the US in 2012 (estimated) 9,180 estimated attributable deaths in 2012 ~10% hereditary Familial atypical mole-melanoma syndrome Accounts 5-7% of all melanoma May be associated with HBOCS (BRCA2)

Prostate Cancer Most frequently diagnosed cancer in US men - 36% of all cancers Lifetime risk for men in US: 15-20% 241,000 new cases diagnosed in 2012 (estimated) 5-10% is heritable ~40% under 55y Higher in families with breast/ovarian cancer 5-10%

Cancer Syndromes

Genetic Syndromes There are those with dysmorphic or characteristic features that also have a tumor predisposition Beckwith-Wiedemann syndrome Bloom syndrome Diamond-Blackfan Down syndrome Fanconi anemia Neurofibromatosis type I and II Gorlin syndrome (basal cell nevus syndrome) Rothmund-Thomson syndrome Tuberous sclerosis Werner syndrome

Hereditary Breast Cancer Syndromes Hereditary breast-ovarian cancer (5% of all breast cancer) Li-Fraumeni (~1%) PTEN hamartoma (<1%) Peutz-Jeghers (<1%) Hereditary diffuse gastric cancer syndrome Also: Autoimmune lymphoproliferative (ALPS) Ataxia telangiectasia Bloom syndrome Familial melanoma Werner syndrome Xeroderma pigmentosa

Heritable Ovarian Cancer Lifetime risk varies from 12-60% Often earlier than those of the general population 6-15% breast/ovarian cancer syndrome Also includes: Lynch syndrome Peutz-Jeghers syndrome

Hereditary CRC Syndromes Accounts for 5-10% of all CRC cases Polyposis types: Adenomatous Familial adenomatous polyposis (<1%) MYH-associated polyposis (<1%) Hamartomatous Juvenile polyposis (<1%) Peutz-Jeghers Cowden (PTEN) Lynch syndrome (2-3%) Often not polyps but can have and still increased cancer risk Seldom in: Bloom, hereditary diffuse gastric cancer syndrome, and Li-Fraumeni

Breast/Ovarian Cancer Syndrome Primarily BRCA1 and BRCA2 Frequency of carriers 1 in 300 (BRCA1) to 1 in 800 (BRCA2) Ashkenazi Jewish (1 in 40) Accounts for >90% of families with breast and ovarian cancers

Breast-Ovarian Cancer Syndrome Of those with BRCA1 mutations: 50-80% risk of invasive breast carcinoma-females ~1% risk for males Up to 60% risk of serous ovarian carcinoma Up to 30% risk of prostate cancer 1-3% risk of pancreatic Of those with BRCA2 mutations: 40-85% risk of invasive breast carcinoma-females 6-7% risk for males Up to 35% risk of serous ovarian carcinoma Up to 39% risk of prostate cancer 2-7% risk of pancreatic Van der Kolk et al. Breast Cancer Res Treat 2010;124:643-51.

HBOCS- Tumor Characteristics Breast tumor often originates from breast epithelia cells Basal keratin positive More commonly a/w with invasive lobular and ductal carcinoma as well as DCIS More likely to be high-grade malignancies and lymph node positive Estrogen receptor negative Progesterone receptor negative Her2/neu negative >90% ovarian serous adenocarcinoma

Li-Fraumeni Syndrome Prevalence: Up to 1 in 20,000 Inheritance: Autosomal dominant Gene: TP53 Lifetime risk of cancer: 50% by age 30-35y 90% by 60y Female lifetime risk is 90% Male lifetime risk is 70% 57% risk of a second primary

LFS- Diagnostic Criteria Proband with sarcoma <45yoa First-degree relative with any cancer <45yoa First- or second-degree relative with any cancer <45yoa or sarcoma at any age LFS-related cancers include: Breast cancer Most common LFS-related cancer Lifetime risk 49% <1% overall of total breast cancers; however, more likely with diagnosis <30yoa (up to 7%) More likely to be triple positive Soft tissue and bone sarcomas Brain tumors Choroid plexus tumors Adrenocortical carcinoma LFS accounts for 80% of childhood ACC Leukemia Bronchoalveolar cancer NCCN 1.2012 Guidelines: Genetic/Familial High-Risk Assessment: Breast and Ovarian Masciari S et al. Breast Cancer Res Treat 2012;133:1125-30.

Li-Fraumeni Syndrome Noncarrier Affected with cancer TP53-carrier Bilateral Breast, 40 50 Breast, 40 Osteosarcoma, 42 Leukemia, 33 Breast, 35 Brain tumor, 32 Soft tissue sarcoma, 7 Leukemia, 6 ASCO

PTEN Hamartoma Syndrome A.k.a Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome Prevalence: 1 in 200-250,000 Inheritance: Autosomal dominant Gene: PTEN Planchon S M et al. J Cell Sci 2008;121:249-253

PTEN Hamartomatous Syndrome 25-85% lifetime risk of breast cancer <1% overall of all breast cancer Average age of diagnosis 38-46y 5-28% lifetime risk of endometrial cancer 3-35% lifetime risk of non-medullary thyroid (follicular) cancer 40-93% lifetime risk of polyps (hamartomatous) 9% lifetime risk of CRC Ganglioneuroma 13% of PTEN mutation-associated Cowden syndrome patients developed CRC <50yoa Strongly a/w Lhermitte-Duclos (dysplastic gangliocytoma) May also be associated with renal cancer and melanoma

PTEN Physical Features Macrocephaly Facial papules (trichilemmomas) ≥2 pathognomic? Oral mucosal papillomatosis 99% incidence Acral keratoses Macrocephalic No unusual skin lesions or pigmentation BrCa at 42yoa

Breast Cancer- When to Refer Breast cancer <50yoa Triple negative breast cancer 11-28% have BRCA1 mutations Two breast cancer primaries in a single individual ~30% risk of second primary in 10 years for BRCA1/2 Breast or ovarian cancer at any age in those of Ashkenazi Jewish ancestry Breast cancer at any age and… ≥1 close relative* with breast cancer <50yoa ≥1 close relative* with epithelial ovarian cancer at any age ≥2 close relatives* with breast cancer and/or pancreatic cancer at any age NCCN Guidelines: Genetic/Familial High-Risk Assessment: Breast and Ovarian *Includes third degree relatives

When to Refer (2) A combination of breast cancer with one or more of the following in close relatives: Thyroid cancer Sarcoma Endometrial cancer Pancreatic cancer Brain tumors Diffuse gastric cancer Dermatologic manifestations and/or macrocephaly Leukemia/lymphoma Ovarian cancer with a family history of breast and/or ovarian cancer Male breast cancer 4-14% due to BRCA2 NCCN Guidelines: Genetic/Familial High-Risk Assessment: Breast and Ovarian

Lynch Syndrome A.k.a. hereditary nonpolyposis colorectal cancer; includes Muir-Torre (sebaceous adenomas) Incidence: 1 in 440 Accounts for: 2-10% of all CRC 2% of ovarian cancers 2-5% of endometrial 9-20% of those <50y Autosomal dominant Multiple genes (MLH1, MSH2, MSH6, MSH3, PMS1, PMS2, TACS (EPCAM), TD1) Chr 2 MSH2 PMS1 MSH6

Lynch Syndrome- Cancer Risks 22-92% lifetime risk of CRC Mean age of 44yo (MLH1 or MSH2) 6-19% lifetime risk of gastric cancer More common in Japan 20-70% risk of endometrial cancer MSI-IHC testing recommended 4-12% risk of ovarian cancer 18% hepatobiliary 5-10% urinary tract cancers May also develop: Small bowel, pancreatic cancer Skin: (sebaceous carcinomas, keratocanthomas, and epitheliomas) Brain tumors, especially glioblastoma

Lynch Syndrome- Amsterdam II Amsterdam II criteria (all have to be met): ≥3 family members, one of whom is a first-degree relative of the other two, with HNPCC-related cancers (CRC, endometrial, stomach, small bowel, hepatobiliary, renal pelvic, or ureteral cancer) Two successive generations One or more HNPCC-related cancer diagnosed before 50yoa Used to make a clinical diagnosis of Lynch syndrome and does not take into account all possible Lynch syndrome-related tumors

Lynch Syndrome- Bethesda Modified Bethesda criteria (any of the following): CRC diagnosed <50yoa Presence of synchronous or metachronus CRC, or other HNPCC-related tumors (CRC, endometrial, gastric, ovarian, pancreatic, ureteral, biliary tract and brain tumor) regardless of age CRC with microsatellite instability-high <60yoa CRC in ≥1 first-degree relatives with HNPCC-related tumor with one cancer <50yoa CRC in ≥2 first- or second-degree relatives at any age Used to guide additional testing such as MSI/IHC

Lynch Syndrome- MSI Microsatellite instability Microsatellites are highly-repetitive DNA sequence Susceptible to dynamic changes if not for the mismatch repair genes MSI-high= instability >30% of cells MSI-low= instability <30% of cells MSI stable= no evidence of MSI

Lynch- MSI Caveats 90% of inherited tumors are MSI-high MSI-high can be caused by many somatic (not inherited) events, most notably BRAF methylation/mutation Some Lynch syndrome patients will have MSI-low or MSI-stable testing Immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6, PMS1, PMS2) recommended as adjunctive analysis

Lynch- Genetic Testing If met Amsterdam II criteria, recommend genetic testing If met Bethesda, testing of the tumor sample by MSI/IHC recommended initially with consideration of genetic testing If MSI-high and IHC positive (i.e. absence of one of the proteins) the probability of Lynch is high therefore genetic testing recommended

Familial Adenomatous Polyposis A.k.a Turcot or Gardner syndromes 1 in 6-20,000 live births Due to genetic defect in APC If negative, consider MYH testing Accounts for <1% of all CRC Hallmark is the adenomatous polyposis 20-100% penetrance in the duodenum 100% lifetime risk of CRC with average age of cancer diagnosis of 39y

FAP: Age and Development of Adenomas and CRC % of patients with neoplasia CRC General population 20 40 60 80 Bussey HJR. Familial Polyposis Coli, 1975 Petersen GM et al. Gastro 100:1658, 1991 Age 11

FAP- Associated Risks 4-12% lifetime risk of other intestinal cancers 0.5-2% gastric 5% duodenal 1-2% risk of pancreatic and non-medullary thyroid 0.6% risk of hepatoblastoma before 6yoa with 1-2% lifetime 10-30% lifetime risk of desmoid tumors Also a/w medulloblastoma as well as gliomas and ependymoma CHRPE- congenital hypertrophy of the retinal pigmented epithelium

Peutz-Jeghers Syndrome Prevalence: 1 in 25-280,000 Inheritance: Autosomal dominant Gene: STK11 Hamartomatous and adenomatous polyposis especially of the small intestine 37-93% lifetime risk of cancer 38-66% risk of gastrointestinal 2-39% CRC 29% gastric 11-36% pancreatic 30-54% risk of breast cancer Lifetime uterine cancer risk is 9-21% Lung 15% lifetime risk Includes ovarian and sex cord tumors Labial and oral mucosal hyperpigmentation- may fade with time

Letterman’s Top 10 Genetic Cancers Adrenocortical carcinoma (LiFraumeni and BWS) Carcinoid tumors (MEN I) Diffuse gastric cancer (Hereditary Diffuse Gastric Cancer) Fallopian tube (HBOCS) Leiomyosarcoma (HLRCC, Lynch, Rb) Medullary thyroid carcinoma (MEN 2) Paraganglioma/pheo (MEN 2, VHL, NF1, PGL) Renal cell carcinoma- chromophobe, hybrid oncocytotic, oncocytoma histology (Britt-Hogg-Dube) Sebaceous carcinoma (Lynch) Sex cord tumor with annular tubule (PJS) Banks et al. Familial Cancer 2013;12:1-18.

Genetic Services

When to Suspect Hereditary Cancer Syndrome Cancer in 2 or more close relatives Early age at diagnosis Multiple primary tumors Bilateral or multiple cancers Constellation of tumors consistent with specific cancer syndrome (e.g. breast and ovary) Evidence of autosomal dominant transmission

Genetic Counseling- A Multistep Process Detailed and extensive family history Ethnic-risk evaluation Cancer cluster recognition Breast-ovarian-pancreatic Macrocephaly-skin lesions-breast cancer Gather necessary medical records Determine who best to test Insurance and insurability questions Test selection Pre- and post-test counseling Psychosocial support Test result interpretation Help with informing family members of risk

Taking a Cancer Family History Obtain at least a three-generation pedigree Ask about all individuals in the family and record: Age at cancer diagnosis, age at and cause of death Primary vs metastatic cancer Precursor lesions, bilateral cancer Physical features Birth defects Other diagnoses Record ethnicity and race

Clarify Family History Verbally reported pedigree Revised pedigree based on pathology reports Stomach Ca Prostate Ca Bone Ca d. 59 Breast Ca dx 45 Ovarian Ca dx 43, d. 49 BPH dx 54

Testing The More Appropriate Person in the Family Colon Ca, 42 Test first, if possible Colon Ca, 38 d.45 Colon Ca, 45 Person seeking counseling (proband) If a mutation is found in an affected person, testing will be more informative for other family members

ASCO- Genetic testing A personal or family history suggesting genetic cancer susceptibility Test can be adequately interpreted and put into clinical context Results will aid in the diagnosis OR influence the management of the patient/family

Informed Consent: Benefits of Genetic Testing Improved cancer risk management Relief from uncertainty and anxiety about cancer risk Information for individual and family members Lifestyle decision making

Informed Consent: Potential Risks of Genetic Testing Psychological distress Anxiety/fear Guilt Depression Grief Loss of privacy Discrimination by employers and insurers Change in family dynamics False sense of security

Informed Consent: Limitations of Genetic Testing Not all mutations are detectable Uncertain significance of some mutations Negative result is fully informative only if mutation has been identified in family Results indicate probability, not certainty, of developing cancer Unproven efficacy of most interventions ASCO

Possible Testing Results: Beyond Positive or Negative Variants of Uncertain Significance (VUS) Amino acid substitutions Frequency 11% at Myriad, > in African American Determine significance several ways: Observed with deleterious mutation Population studies (frequency >1%) Biochemical, evolutionary models Linkage in large families ASCO

Implications For The Entire Family Consider the impact of testing on all family members Ultimately, testing is the individual’s choice ASCO

THANK YOU!

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