Hereditary breast and ovarian cancer

Who should be screened and How?

Symposium on Cancer

Waterloo Inn

October 31, 2007

Mala Bahl, MD, MSc

Objectives

• Describe genetic syndromes associated with breast and ovarian cancers

• Identify those at high risk for hereditary breast or ovarian cancer

• Review cancer screening and risk reduction measures relative to the general population

• Review referral opportunities for such patients

• This presentation contains no conflicts of interest

General population risk

• Breast cancer– 10.6% – 1 in 9 women

• Ovarian Cancer– 1.5% – 1 in 70 women

Breast Cancer Risk Factors

• Familial/genetic– 1st degree relatives at 1.5-3 x risk

• Age

• Reproductive/hormonal

• Lifestyle

• Environmental

• Previous breast diseaseThe majority of cases have no identifiable risk factor!

Contribution of Family History

• 15-20% have an affected 1st/2nd degree relative• ~5% -Family history suggests high-risk gene mutation• Majority are “sporadic”

75%

Sporadic

Familialclustering

Hereditary

5-10%5-10%

~15-20%~15-20%

Two hit hypothesis

Sporadic cancer

? age 30-50 ?age 50-70

Two hit hypothesis

Sporadic cancer

Hereditary cancer

? age 30-50 ?age 50-70

Familial Vs Hereditary

• Familial Clustering– 2 cases in a family– Not necessarily young cases (cases >60 years)– Not necessarily related cancers– No clear pattern seen

– Shared genetics– Shared environment– Shared lifestyle– Chance

Jean Cervical 39

Fred 41 Susan 37 Lori 33 Michael 30

John 65 Mary Breast 60

Charles 74Prostate 68

Louise d.62Colon 59

Agnes Breast 76

Familial Cancer

Familial Vs Hereditary

• Hereditary– Multiple generations with same cancer– Early onset– >1 cancer / individual especially in paired organs– Pattern fits with known cancer syndrome – Presence of rare cancers

• Most are autosomal dominant with incomplete penetrance (like BRCA1 and 2!)

Hereditary

ASCO

May appear to “skip” generations (penetrance)May appear to “skip” generations (penetrance) Inheritance of cancer susceptibilityInheritance of cancer susceptibility genes not cancergenes not cancer

Normal Normal

Carrier, affected Carrier, affected

Susceptible CarrierSusceptible Carrier

SporadicSporadic

Ovary, 40

Breast, 45

Colon, 67 Breast,50 Ovary 50

Breast, 35

Factors that Influence Phenotype

• Penetrance– Gender– Co-morbidites– Lifestyle– Environment– Modifier genes

– Risk-Reduction

ASCO

Causes of Hereditary Breast Cancer

GeneGene

BRCA1BRCA1

BRCA2BRCA2

TP53 Li-FraumenniTP53 Li-Fraumenni

PTEN Cowden’sPTEN Cowden’s

CHEK2CHEK2

Undiscovered genesUndiscovered genes

% of Hereditary % of Hereditary Breast CancerBreast Cancer

20%–40%20%–40%

10%–30%10%–30%

<1%<1%

<1%<1%

<1%<1%

30%–70%30%–70%

BOCSBOCS

Breast and Ovarian Cancer Syndrome

• Refers to BRCA1 or BRCA2• AD inheritance • Tumor Suppressors- a caretaker function• 1 in 800 women in the general population

• BRCA1 identified in 1994 – >600 mutations

• BRCA2 in 1995– ~ 450 mutations

Founder mutations

• 4 founder mutations among Ashkenazi Jews– Prevalence 1 in 40

• Other groups with BRCA!/2 mutation families– French-Canadian

– Mennonite

– Icelandic

– Scandinavian

– Irish

– British

– Dutch

– Japanese

– Pakistani

Hereditary Breast and Ovarian Cancer: BRCA1

• Breast ca risk by age 50: 50% • Risk for Male Breast Cancer UnclearRisk for Male Breast Cancer Unclear• Risk for Prostate Cancer if < 65Risk for Prostate Cancer if < 65

Breast cancer 85%Breast cancer 85%

Second primary breast cancer 40%-60%Second primary breast cancer 40%-60%

Ovarian cancer 20%-40%Ovarian cancer 20%-40%

Adapted from ASCO

Hereditary Breast and Ovarian Cancer: BRCA2

• prostate cancer(12-18%) prostate cancer(12-18%) • melanoma (melanoma (2.5x) 2.5x) • bile duct (5x), pancreas ca (~5%)bile duct (5x), pancreas ca (~5%)

breast cancer breast cancer (30%-85%)(30%-85%)

ovarian cancer ovarian cancer (10%-20%)(10%-20%)

male breast male breast cancercancer(6.7%)(6.7%)

Adapted from ASCO

Clues to Breast/Ovarian Ca Syndrome

• Breast Cancer < age 35

2 cases Breast ca before age 50

• Bilateral breast cancer, first <50

• Serous ovarian cancer

• Breast and ovarian cancer in the same woman

• Male breast cancer

• Ashkenazi Jewish heritage with breast cancerASCO

More Breast Cancer Syndromes (<1%)

• Cowden’s – 25-50% breast ca risk – Oral lesions, GI hamartomas, benign breast dz– Thyroid, uterine lesions or CA, macrocephaly

• Li-Fraumeni – breast ca < age 40 – Often childhood cancers– sarcoma, leukemia, brain adrenocortical CA

• Peutz-Jeghers - <1% – Childhood GI hamartomas, colon CA– Pigmentation of lips, buccal mucosa, hands/feet

Clinical Management Options

Screening and other interventions

Who needs what?

Family History

Assessment

Personalized prevention recommendations

Referral for genetic evaluation

Standard preventionrecommendations

Intervention

Average

Moderate(“Familial”)

High(Genetic)

Risk

Ontario Screening Guidelinesfor the general population

• Breast– Mammogram every 1-2 years from 50– Annual clinical breast exam for all women– Monthly breast self exam for all women– No guidelines for men

• Ovary– No gen population screening guidelines

Moderate Risk Families• Low risk of BRCA1/ 2 or other cancer syndromes

• Lifetime risk 10-30%

• Screening recommendations:

– BSE monthly; CBE once or twice a year

– Annual (digital) mammo from 40 or 5-10 yrs prior to youngest cancer

• Immediate biopsy of any suspicious findings

– Explore Chemoprevention

– Lifestyle modifications

Lifestyle Modification

• Good for all risk categories!

• Exercise – 30 min. or more most days

• Weight control

• Diet ??

– Less saturated/trans fat

– Less refined flour, sugar

– More fruits/vegetables, whole grains, legumes

• Alcohol: less than 1-2 drinks/day

• Breast feeding

Options for High Risk Patients

• Increased surveillance

• Prophylactic surgery

• Lifestyle changes

• Chemo prevention

Surveillance: BRCA1/2

• Breast– Annual mammogram from age 30 (digital)– Annual Breast MRI from 30– CBE q6-12mos from age 18– Monthly breast self exam from age 18

• Ovarian screening – significant limitations– Ca-125, TV ultrasound 1-2/yr- age 25-35– Suboptimal early detection– high false positive– Preferred in a research setting

Class I

Class B

Class E

Other

• Heightened male breast screening– Chest wall exams, visual

• Consider PSA at age 40

• Monitor skin and general health• Pancreatic screening research (BRCA2)

Challenges to Surveillance• CBE detects few cancers missed by above

– Promotes awareness no mortality

• Mammo – insensitive in younger patients 26-42%

• MRI – Sensitivity 83-100% – Lower specificity

• TV US– +FH, Sensitivity 92%, Specificity 97.8%– PPV 11%; if 2 cases, PPV=20%

• CA 125 Sensitivity 35-55%

Series of 3991 high-risk pts

• 155 cancers• 78% of cancers detected by MRI• 38% by mammo

– 18 (10 DCIS, 8 invasive) on mammo NOT MRI

• 42% by US (<1% detected by US only)• Interval cancer < 10% if MRI • Of MRI detected cancers

– 12-27% DCIS – if invasive ca 75-94% < 2 cm – Axillary node mets seen in 17-25%

Other Management Options BRCA1/2

• Mastectomy– Cohort shows 96% breast ca– Total Mastectomy, no node dissection– Path review- cancer found in 7%

• Oophorectomy ovarian ca 85% Breast ca by 50-66%

• Birth Control Pill• Tamoxifen

Your Role

• Detailed family history

– Cancer status in 1st and 2nd degree relatives

– Type of primary cancer(s) in each relative

– Age of disease onset

– Cancer status in both sides of the family

– Ethnic background on both sides

– Other medical findings – benign tumors, etc.

Referral opportunities

Referral forms available at our website

www.grandriverhospital.on.ca

follow links to GRRCC, then Treatments & Services then Genetic Counseling Service