HEREDITARY CANCER SYNDROMES: Identifying and Managing Patients at Risk

L. BRENT HAFEN, MS; LCGC

DISCLOSURES:

-Nothing to disclose

OBJECTIVES:

Upon completion, participants will be able to: Recognize primary clinical features of hereditary cancer syndromes

Identify appropriate genetic testing for at risk patients

Manage affected/at risk patients according to national guidelines

Utilize appropriate support resources

Intermountain Cancer Genetic Counseling Referrals 2016

SPECIALTY % of REFERRALS

Surgery 28%

OB/GYN 24%

Oncology 21%

Family Practice 16% Self Referred 11%

Cancer Risk Factors: RISK FACTOR CASES (%)

Diet 35

Tobacco use 30

Hereditary factors 5-10 Occupational exposures 5

Radiation 1-2

Viruses 1-2

Miscellaneous 16-23

Offit, K 1998. Clinical Cancer genetics

Importance of Checking Family History:

540 female, internal medicine pts surveyed 51 (9.4%) reported FHx of breast/ovarian cancer 32 (6%) reported significant FHx

(The Breast Journal, vol 9, no , 2003, 19-25)

2056 screening mammography patients 6.2% determined high risk by screening tool

(Genetics in Medicine, vol 11, no 11, 2009)

Signs of Hereditary Cancers:

Diagnosis before age 45 to 50

Cancer in paired organs (breasts, kidneys, eyes)

Multiple generations with related* cancers (*breast/ovarian & colon/endometrial most common)

Rare cancers (ovarian, male breast cancer)

One person with multiple cancers

BREAST & OVARIAN CANCERS

Breast Cancer: • Most prevalent cancer type in women (10-12%

lifetime risk)

• 2nd leading cause of cancer death in the US

• New cases in 2015: 231,840 (American Cancer Society)

• Deaths in 2015: 40,290 (American Cancer Society)

Ovarian Cancer:

• 1-2% lifetime risk

• 4.6x RR if mother affected; 1.6x RR if sister [Ziogas et al., 2009]

• 22,000 new diagnoses annually

• ~45% 5-year survival rate

Genes Associated With Hereditary Breast/Ovarian Cancer:

GENE CONTRIBUTION

BRCA1/2 30-70%

ATM 4%

CHD1 <1%

CHEK2 <1%

PALB2 <1%

PTEN <1%

RAD51C/D <1%

TP53 <1%

BRCA1/2: • Frequency: 1:300 (BRCA1) to 1:800 (BRCA2); Ashkenazi Jewish (1:40)

• More likely to be high-grade tumors and lymph node positive

• Invasive carcinoma most common but may occur with DCIS

• Triple negative (ER, PR, HER2) carcinomas more likely with BRCA1

• >90% ovarian serous adenocarcinoma

BRCA1/2 Cancer Risks:

Cancer Type Population Risk BRCA1 BRCA2

breast 10-12% 50-80% 40-70%

second primary 3.5% within 5 yrs 27% within 5 yrs 12% within 5 yrs

ovarian 1-2% 24-40% 11-18%

male breast 0.1% 1-2% 5-10%

prostate 15% Increased Up to 39%

pancreatic 0.5% 1-3% 2-7%

Van der Kolk et al. Breast Cancer Res Treat 2010;124:643-51

Indications of Possible BRCA1/2:

• Breast cancer diagnosed <50 years old

• Triple negative breast cancer (BRCA1 mutations in up to 28%)

• Two breast cancer primaries/bilateral cancer

• Male breast cancer

• Ashkenazi Jewish ancestry

• Breast cancer at any age and… – ≥1 close relative* with breast cancer <50 years old – ≥1 close relative* with epithelial ovarian cancer at any age

NCCN Guidelines: Genetic/Familial High-Risk Assessment: Breast and Ovarian *Includes third degree relatives

BRCA1/2 Management:

Women:

• Age 25+: Clinical breast exam, every 6-12 months

• Age 25-30: yearly breast MRI

• Age: 30-75: yearly mammogram and breast MRI

• Consideration of risk reducing, bilateral mastectomy • Risk reducing, bilateral salpingo-oophorectomy at age 45-40 years (or upon

completion of childbearing) • Consider pelvic ultrasound and/or CA-125 screening for women who

decline RRSO

BRCA1/2 Management:

Men:

• Age 35: Clinical breast exam, every 12 months; self breast exam training • Age 45: prostate cancer screening for BRCA2 carriers (consider for BRCA1

carriers) Women & Men:

• Education regarding risk for additional BRCA related cancers

• Recommend genetic testing for at risk family members • Discussion of pre-implantation genetic diagnosis for individuals of

reproductive age

PTEN (Cowden Syndrome) Cancer Risk: Cancer Type Population Risk PTEN

Overall cancer risk 20% 85-89%

breast (women) 10-12% 77-85%

Endometrial 1.6% 19-28%

Thyroid (non-medullary) 0.8% 21-38%

Colorectal 3-4% 9-16%

Renal 0.8% 15-34%

Melanoma 1.1% up to 6%

Pilarski R. Cowden Syndrome: A Critical Review of the Clinical Literature. J Genet Couns 2009; 18:13-27

PTEN (Cowden Syndrome) Additional Features:

Facial trichilemmomas

Oral papillomas

PTEN (Cowden Syndrome) Management:

TP53 (Li Fraumeni syndrome) Cancer Risk: Cancer Type Population Risk PTEN

Overall cancer risk: -sarcomas -brain tumors -adrenocortical carcinoma -GI cancers -GU cancers -leukemia/lymphoma

20% 50% (by age 30) 90% (by age 60)

breast (women) 10-12% 56% (by age 45)

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.

TP53 (Li Fraumeni syndrome) Management:

ATM Cancer Risk/Management: Cancer Type Population Risk ATM

Breast 10-12% 17-52%

Pancreatic 1% increased

Ahmed M, Rahman N. ATM and breast cancer susceptibility. Oncogene. 2006 25:5906-11 Thompson D, et al. Cancer Risks and Mortality in Heterozygous ATM Mutation Carriers. J Natl Cancer Inst. 2005 97:813-22

CDH1 Cancer Risk/Management: Cancer Type Population Risk CDH1

breast 10-12% 39-52%

gastric 0.6% 67-70% (male) 56-83% (female)

colorectal 3-4% Possible increase

Pharoah PD, et al. International Gastric Cancer Linkage Consortium. Incidence of Gastric Cancer and Breast Cancer in CDH1 Mutation Carriers from Hereditary Diffuse Gastric Cancer Families. Gastroenterology. 2001 121:1348-53

CHEK2 Cancer Risk/Management: Cancer Type Population Risk CDH1

breast (women) 10-12% 23-48%

breast (men) 0.1% 1%

colorectal 3-4% increased

Xiang HP, et al. Meta-analysis of CHEK2 1100delC variant and Colorectal Cancer Susceptibility. European Journal of Cancer 2011; 47: 2546-2551

PALB2 Cancer Risk/Managment: Cancer Type Population Risk PALB2

breast (women) 10-12% 17-58%

breast (men) 0.1% increased

pancreatic 1% increased

Antoniou AC, et al. Breast Cancer Risk in Families With Mutations in PALB2. N Engl J Med. 2014; 371-497-506

GASTROINTESTINAL CANCERS

Colorectal Cancer: • 4th most common cancer diagnosis in US

• Lifetime risk: 1/21 (men); 1/23 (women)

• new cases expected in 2016: 143,490

• Expected deaths due to CRC: 49,190

• Death rate is declining – early detection and prevention

Endometrial Cancer • lifetime risk: 2.5%

• new cases expected in 2016: 60,050

• 10,470 estimated deaths in 2016

• Most common heritable form is Lynch syndrome (2-3% of cases)

• May also be related to Cowden (PTEN Hamartoma Tumor syndrome)

and Peutz-Jeghers

Genes Associated with Hereditary Colorectal Cancer:

GENE CONTRIBUTION

MMR (Lynch Syndrome) 2-3%

APC 1%

MUTYH 1%

STK11 1%

Lynch Syndrome: • Incidence: 1 in 440

• Accounts for: – 2-10% of all CRC – 2% of ovarian cancers – 2-5% of endometrial

• Multiple genes (MLH1, MSH2, MSH6, PMS2, EPCAM)

Lynch Syndrome- Cancer Risks: Cancer Type Population Risk MLH1/MSH2 MSH6 PMS2

Colorectal 4% 52-82% 10-22% 15-20%

Gastric <1% 6-13% 3% increased

Endometrial 2.7% 25-60% 16-26% 15%

Ovarian 1-2% 4-12% 1-11% increased

Hepatobililary <1% 1-4% increased increased

Urinary tract <1% 1-4% increased increased

Small bowel <1% 3-6% increased increased

brain <1% 1-3% increased increased

Lynch Syndrome- Clinical Diagnosis

• 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 50 yrs

Used to make a clinical diagnosis of Lynch syndrome and does not take into account all possible Lynch syndrome-related tumors

Lynch Syndrome- Clinical Diagnosis: • 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 & IHC testing • 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 Syndrome- MSI & IHC:

Lynch- MSI/IHC Caveats:

• 90% of inherited tumors are MSI-high • MSI-high can be caused by many somatic (not inherited)

events, most notably BRAF & MLH1 promoter methylation • Some Lynch syndrome patients will have MSI-low or MSI-

stable testing • Absence of MLH1 and PMS2 on IHC indicative of an MLH1

promoter mutation

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

0

20

40

60

80

100

FAP: Age Related Adenomas and CRC Risk

% of patients with neoplasia

Age Bussey HJR. Familial Polyposis Coli, 1975 Petersen GM et al. Gastro 100:1658, 1991

20 40 60 80

FAP

General population

Adenomas

CRC

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

STK11 (Peutz-Jeghers Syndrome) • Prevalence: 1 in 25-280,000 • 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

Genetic Counseling / Genetic Testing

Genetic Counseling- A Multistep Process • Detailed and extensive family history • Medical records review • Determine best family member to test • Insurance and insurability questions • Pre- and post-test counseling • Test result interpretation • Facilitate informing at risk family members • Ongoing psychosocial support

Insurance Issues: Genetic counseling and genetic testing are separate services: Most insurance companies cover both services Select Health, DMBA, CIGNA, UHC require genetic counseling for cancer gene testing Genetic testing

Each insurance has testing criteria, most follow Medicare or NCCN guidelines Laboratories/Genetic Counselors handle insurance prior-authorization Options for self pay and limited insurance coverage Cost of testing ranges ($250-$4500)

Cancer Genetic Counseling Services (Utah): • Huntsman Cancer Institute: Salt Lake City: 801-587-9555

• Intermountain Healthcare: DRMC: 435-688-4175 IMED: 801-507-3900 Logan Regional Hospital: 435-716-6400 McKay-Dee Hospital: 801-387-3900 UVRMC: 801-357-7575

• MountainStar Healthcare: ORMC: 801-479-2848 St. Mark’s: 801-743-6509

• VA Medical Center: Salt Lake City: 801-582-1565 x4896

THANK YOU!