All in the Family: Using Family Health History to Identify and Support Women at Risk

for Hereditary Cancer2/15/12

Peter Hulick, MD MMSc

Center for Medical Genetics

NorthShore University HeathSystem

1. Understand the genetic consultation process

2. Examine genetic contribution to breast cancer

3. Identify suggestive family history patterns and risk estimation

4. Influence of genetic testing on management

Objectives

1. Family history of a medical condition• Cancer, heart disease, Huntington disease, connective

tissue disease, hearing/visual disorder

2. At risk for a hereditary disorder• Thalassemia, Tay-Sachs disease

3. Unusual presentation or history• Unexplained/early cardiomyopathy, early onset of cancer

4. Exploring recurrence risks for future pregnancies

5. Diagnostic evaluation for known syndromes• Klinefelter, Down syndrome

Reasons for a Genetics Consultation

• Busiest adult genetic clinic in Midwest– Vying for busiest in US

• Patient visits FY2011– 658 New– 1134 Total

• Focus– Hereditary cancer– Breadth of adult genetics diagnoses– Expanding to pediatrics and more non-cancer

NorthShore Clinical Genetics Practice

What occurs at an initial genetics consultation?– Meet with a genetic counselor and a geneticist– Personal and family medical history reviewed– Targeted physical exam when appropriate– Discussion of genetic concepts, risks, and testing

options– Patient has option to decline or proceed with genetics

testing if indicated– Disclosure appointment scheduled if decision to test– Typical initial appointment lasts 1.5 hours

The Consultation Appointment

• Using a questionnaire as a guide, the patient gathers detailed information on their personal/family history– Current ages– Ages at death– Causes of death– Site that cancer originated? (i.e. uterine vs ovarian cancer?)– Other questions, depending on reason for referral

» Who has had colonoscopies?» Number and type of polyps on colonoscopy?» Have the women had hysterectomies?» Skin biopsies –what was found?

Genetic Counseling Process

Genetic Counseling Process – Information Gathering

Costs of genetic testing

• Genetic counseling and genetic testing fees are separate– Both are usually covered

• About 95% of patients use their insurance for consultation and genetic testing– Coverage is typically 70-100%– Medicare often covers consultation and genetic testing fees

• Federal law signed into law May 21st, 2008– Went into effect in May/Nov of 2009

• Prohibits genetic discrimination by health insurance companies and employers

• Defines genetic information as predictive genetic tests, family members’ genetic tests, and family history information

• Applies to both group and individual health insurance markets

• Prohibits the use of genetic information in underwriting

• Prohibits insurers and employers from requiring genetic testing

Genetic Information Non-discrimination Act (GINA)

Facilitate Decision-making

Not a simple decision …– Should I have testing?– What would I do differently if I

were to test positive?– Will it help my family

members?– Now that I have tested

positive, should I do high risk screening or do I go onto preventative surgery?

– Is a negative test a true negative?

The disclosure appointment:– Scheduled based on anticipated time of results

» BRCA1/2 testing 2-3 weeks» LQT syndrome 2-3 months

– Everyone scheduled for a return disclosure appt.» Patient not “positive” just because they are returning» Risk implications/adjustments in setting of negative test» Recommendations for treatment/screening» Emotional support» Assistance with appropriate referrals» Implications for family members – duty to warn

Genetic Counseling Process – Disclosing Results

About 5-10% of breast and ovarian cancer is hereditary—caused by single, strong, dominant genes

Ovarian CancerOvarian CancerBreast CancerBreast Cancer

5%5%––10%10% 5%5%––10%10%

15%15% 20% 20%

SporadicSporadic

Family clustersFamily clusters

HereditaryHereditary

Hereditary piece of the pie: BRCA1, BRCA2, TP53, PTEN, ATM, and other genes

Ovarian CancerOvarian CancerBreast CancerBreast Cancer

5%5%––10%10% 5%5%––10%10%

15%15% 20% 20%

SporadicSporadic

Family clustersFamily clusters

HereditaryHereditary

SporadicSporadic

Family clustersFamily clusters

HereditaryHereditary

Hereditary piece of the pie: BRCA1, BRCA2, TP53, PTEN, ATM, and other genes

Hereditary piece of the pie: BRCA1, BRCA2, TP53, PTEN, ATM, and other genes

BRCA1/2 contribution to breast cancer …

• Woman with breast cancer - ~5%– Of Ashkenazi Jewish ancestry - ~10%

• Diagnosed w/ breast cancer <45 yrs - ~ 10%– >45 yrs - ~2%– < 45 yrs and AJ - ~26%

• Woman and FHx Br Ca <45 - ~20%– Of AJ ancestry – ~30%

Cancer Res 2006; 66(16): 8297-308

General population Ashkenazi Jewish

1 in 401 in 300

3 Founder Mutations

BRCA1 187delAG 5382insC

BRCA2 6174delT

Frequency of BRCA1 & BRCA2 mutations

Clinical Case

• 53 year old woman diagnosed with breast cancer

• Underwent bilateral mastectomy with reconstruction, chemotherapy, hormonal therapy

• Eager to get back to work so that she could focus on matters other than her health

• Significant family history of breast cancer

• Surgeon told her about the link between breast and ovarian cancer and referred her for genetics consultation

Significant family history of breast cancer:• Mother BC age 40• 4 paternal relatives with BC • Young-onset BC (35) in cousin, linked through father w/ colon & prostate CA

Risk assessment and genetic testing

• Her motivations for genetic testing:– determine her risk of ovarian cancer– ‘put all this behind her’– clarify her sister’s risk of breast cancer

• Calculated 43% chance of having a positive gene test (i.e. a mutation)

Use the right model to get the right answer

Modified From: Rubinstein WS, O’Neill SM: Quantitative Risk Assessment. In: Singletary SE, Robb GL, Hortobagyi GN (eds): Advanced Therapy of Breast Disease, Second Edition. BC Decker, Inc., 2nd Edition, pp. 97-112, 2004.

Levels of BRCA1 and BRCA2 testing

• Multi-site analysis– AJ Founder mutations – 80-90%– BRCA1 187delAG and 5385insC– BRCA2 6174delT

• Comprehensive– “spell-check” of the genes – sequencing– 5-site rearrangement panel of BRCA1

• BART– Rearrangements in BRCA1 and 2– Adds 1-3% detection in high risk families

Costs of genetic consultation and testing

• Genetic counseling and genetic testing fees are separate– Both are usually covered

• Genetic testing– ~$400 to ~$3000

» Lower costs apply when familial mutation is known– We help patients obtain preauthorization and write letters of

medical necessity

• ~95% of patients use their insurance for consultation and genetic testing

» Coverage is typically 70-100%» Medicare often covers consultation and genetic testing fees

Risk assessment and genetic testing

• Her motivations for genetic testing:– determine her risk of ovarian cancer– ‘put all this behind her’– clarify her sister’s risk of breast cancer

• Calculated 43% chance of having a positive gene test (i.e. a mutation)

• Testing covered by insurance– she said she would get testing regardless of coverage

• Results: BRCA2 886delGT mutation

Increased risk of pancreatic, fallopian tube, other cancers

Breast cancer (+ early age at onset) (50-85%)

Second primary breast cancer (40-60%)

Ovarian cancer(20%-40%)

Male breast cancer(5-6%)

Prostate cancer(30-40%)

BRCA1 and BRCA2 lifetime cancer risks

Cancer screening and prevention:the patient

• Evidence-based medicine– ovarian cancer lifetime risk 20-40%– preventive removal of ovaries and fallopian tubes reduces ovarian

cancer risk by 96%

• Patient referred by geneticist to gynecologic oncologist

• Laparoscopic removal of ovaries and fallopian tubes shortly after finishing chemotherapy for breast cancer

• Pathology revealed ovarian cancer– stage 1-C: caught very early, 90% cure rate– underwent 6 cycles of chemotherapy

• Patient remains free of evident disease and is probably cured– “natural presentation” is late-stage with poor survival rates

In genetics, the family is the patient

In genetics, the family is the patient

Genetic testing, cancer screeningand prevention: the sister

• Sister underwent genetic testing, also a BRCA2 886delGT mutation carrier

• Breast and ovarian cancer screening was negative• Underwent preventive removal of ovaries and

fallopian tubes and prophylactic mastectomy• Stage 1 breast cancer diagnosed

“I’d have been here sooner if it hadn’t been for early detection.”

Increased risk of pancreatic, fallopian tube, other cancers

Breast cancer (+ early age at onset) (50-85%)

Second primary breast cancer (40-60%)

Ovarian cancer(20%-40%)

Male breast cancer(5-6%)

Prostate cancer(30-40%)

BRCA1 and BRCA2 lifetime cancer risks

Cancer Risk Management in BRCA1/2 carriers

Breast cancer – Screening • Annual mammography/MRI start age 20-25• Clinical breast exam every 6 months• Monthly self breast exam

Breast cancer – Prevention• Tamoxifen chemoprevention (50% effective)• Prophylactic mastectomy (90-95% effective)• Prophylactic oophorectomy (40% effective against breast cancer)

Ovarian cancer – Screening• Transvaginal ultrasound + Ca-125 every 6-12 months limited efficacy

Ovarian cancer – Prevention• PBSO after childbearing complete (80-96% effective) strongly recommended• Consider oral contraceptives

Other Cancers with BRCA1/2

• Male Breast• Prostate• Pancreatic• Stomach• Melanoma of the skin and eye• Colon cancer: inconsistently observed

Recognition of Hereditary Cancer Syndromes

When to Suspect Hereditary Cancer Syndrome

• Cancer in 2 or more close relatives (on same side of family)

• Early age at diagnosis

• Multiple primary tumors

• Bilateral or multiple rare cancers

• Constellation of tumors c/w specific cancer syndrome breast + ovary = HBOC colon + endometrial = HNPCCcolon + adenomatous polyposis = FAP

melanoma + pancreatic = p16

• Evidence of autosomal dominant transmission

• Penetrance is often incomplete• May appear to “skip” generations • Individuals inherit altered cancer susceptibility gene,

not cancer • Paternal family history matters!

Normal

Susceptible Carrier

Carrier, affected with cancer

Sporadic cancer

Most Cancer Susceptibility Genes are Dominant with Incomplete Penetrance

Features of hereditary breast-ovarian cancer (BRCA1 and BRCA2)

• Early age of breast cancer onset• Ovarian cancer at any age• Bilateral breast cancer, or more than once• An individual with both ovarian and breast cancer• Many relatives affected; multiple generations• Male breast cancer• Other cancers in the family, e.g. pancreas• Ashkenazi Jewish ancestry• Medullary breast cancer (BRCA1)• ER/PR/Her2 neg (triple negative) breast cancer (BRCA1)

“Family History is Negative for Breast Cancer”

Need more information to pick the right gene

• Ovarian cancer, male breast cancer, pancreatic, prostate cancer: BRCA1, BRCA2

• Sarcoma, childhood leukemia/lymphoma, others: TP53 (Li-Fraumeni syndrome)

• Thyroid, endometrial, trichilemmomas, hamartomas:PTEN (Cowden syndrome)

• Diffuse gastric cancer, lobular breast cancer: CDH1 (Hereditary diffuse gastric cancer)

• Ovarian (granulosa), testicular, pancreatic, uterine, GI; intestinal hamartomatous polyps, mucocutaneous pigmentation: STK11 (Peutz-Jeghers)

• Young breast cancer (most common cancer)• Adrenocortical carcinoma• Sarcoma• Leukemia

Li-Fraumeni syndrome

J Clin Oncol 27:1250-1256.

Pathognomonic mucocutaneous features of Cowden syndrome

(a) Trichilemmomas on the nape of the neck

(b) Palmar keratoses(c) Perioral papillomatous

papules (arrow head) and nasal polyposis

(d) Gastric hamartomas as seen by endoscopy

European Journal of Human Genetics (2008) 16, 1289–1300

What if genetic testing in a family with significant breast cancer history is negative?

• BRCA1/2 testing ~90% sensitive

• Risk models for lifetime risk calculation– Tyrer-Cusick– Gail

• Addition of MRIs?• Tamoxifen?

Breast MRI Surveillance

• Higher sensitivity for detection of invasive breast cancers

• Mammography has higher sensitivity for ductal carcinoma in situ (DCIS)

• Reserved for screening high risk patients

Who is considered high risk?

ACS Recommendations for Breast MRI Screening as an Adjunct to Mammography

Saslow D et al. (2007) CA Cancer J Clin 2007; 57:75-89

Continue to follow-up …

• Family history changes– New information– New cancer diagnosed in family (missed 10% families,

different syndrome to consider?)

• Genetic testing– BART relatively recent – New gene(s) clinically available for testing

• New Screening guidelines– MRI for women with 20-25% lifetime risk of developing

breast cancer

PROSE Study of BRCA1 and BRCA2 Mutation Carriers– How do lifestyles, habits, exposures, hormones, preventive

surgery and other interacting genes influence cancer risk?

Pancreatic Cancer Family Registry (PCFR)– Database for families affected by pancreatic cancer in hopes of

learning the causes of familial pancreatic cancer

IMPACT Study– Evaluation of usefulness of prostate cancer screening methods

for screening high risk BRCA positive men

SIFT Registry– Families with history of breast cancer but negative genetic testing

for breast cancer susceptibility genes

NorthShore Center for Medical GeneticsClinical Research

The Center for Medical GeneticsNorthShore University HealthSystem

• Peter Hulick, MD, MMSc

Medical Geneticist

• Genetic CounselorsScott Weissman, MS, CGC

Anna Newlin, MS, CGC

Kristen Vogel, MS, CGC

Shelly Weiss, MS, CGC

• Research CoordinatorTina Selkirk, MS