Hereditary Breast/Ovarian Cancer

Prepared by: June C Carroll MD, CCFP, FCFPSydney G. Frankfort Chair in Family MedicineMount Sinai Hospital, University of Toronto

Andrea Rideout MS, CGC, CCGCCertified Genetic CounsellorProject Manager – The Genetics Education

Project

Funded by: Ontario Women’s Health Council

Version: March 2009

Acknowledgments Reviewed by:

Members of The Genetics Education Project

Funded by: The Ontario Women’s Health Council

as part of its funding to

The Genetics Education Project

* Health care providers must use their own clinical judgment in addition to the information presented herein. The authors assume no responsibility or liability resulting from the use of information in this presentation.

Outline

Sporadic versus familial cancer Hereditary breast cancer syndromes Referral guidelines Benefits, risks and limitations of genetic

testing Management Cases

CancerAll cancer involves changes in genes….

Threshold effect: During mitosis & DNA replication

mutations occur in the cell’s genetic code Mutations are normally corrected by DNA repair

mechanisms If repair mechanism or cell cycle regulation

damaged Cell accumulates too many mutations

→ reaches ‘threshold’→ tumor development

Sporadic Cancer All cancer arises from changes in genes….

But NOT all cancer is inherited Most breast cancer is sporadic ~ 80%

Due to mutations acquired over a person’s lifetime:

Cause unknown – multifactorial Interaction of: age environment, lifestyle (obesity,

alcohol), chance, unknown factors

Sporadic cancer generally has a later onset

Clustering of Cancer in Families 11% lifetime risk of developing breast cancer

~20% of women with breast cancer have a family history:

10 -15% of breast cancer is familial: Due to some factor in the family

Environmental Undiscovered gene mutation Chance Generally not eligible for genetic testing

5-10% of breast cancer is hereditary: Caused by an inherited gene mutation which causes increased risk

for cancer Variety of cancer syndromes About 2/3 of these - BRCA 1 or BRCA 2 mutations May be eligible for genetic testing

Proportion of Hereditary Breast Cancer

Sporadic 80%

Familial 10-15%

Hereditary 5-10%

Knudson ‘two-hit’ Model

Sporadic Cancer

Birth: Two non-mutated copies of the gene

One mutation in one gene; Second gene non-mutated

ONE HIT

(hit=mutation)

SECOND HIT

Two mutations - one in each gene

CANCER

Knudson ‘two-hit’ ModelHereditary Cancer

Birth: Two non-mutated copies of the gene

One mutation in one gene; Second gene non-mutated

ONE HIT

(hit=mutation)

SECOND HIT

Two mutations - one in each gene

CANCER

Compared to sporadic cancer, people with hereditary cancer have…A higher risk of developing cancerA younger age of onset of cancer

Generally < 50 years of ageMultiple primary cancers

Hereditary cancer is less common in the general population than sporadic cancer

Genes involved in hereditary breast/ovarian cancer > 2,600 mutations in:

BRCA1- chromosome 17 BRCA2 - chromosome 13

Autosomal dominant transmission Carrier frequency of BRCA1& 2 mutations

~1/500 – 1/1,000 in general (Caucasian) population 1/40 - 1/50 in Ashkenazi Jewish people

3 common mutations in Ashkenazi Jews

Unique French Canadian mutations

bb Bb

Bb bb Bb bb

BRCA mutation

Autosomal Dominant Inheritance

Population Risk

Population Risk

SusceptibleBRCA gene

Normal BRCA genes

Legend

B: BRCA gene with mutation

b: normal BRCA gene

SusceptibleBRCA gene

BRCA1 and BRCA2What happens when their function is compromised ? Both genes are tumor suppressors:

Regulation of cell growth Maintenance of cell cycle

Mutation leads to: Inability to regulate cell deathUncontrolled growth, cancer

Consequences of having a BRCA mutation:

Estimated cancer risk by age 70

BRCA Mutation Carriers

In General Population

Breast Cancer ♀BRCA1 & BRCA2

50-85% 11%

Ovarian CancerBRCA1

40-60% 1-2%

Ovarian CancerBRCA2

10-20% 1-2%

Breast Cancer ♂BRCA2

≤6% Rare

Who should be offered referral for genetic counselling and/or genetic testing?.... Multiple cases of breast or ovarian cancer on same side

of family, especially in closely related relatives in more than one generation when breast cancer is diagnosed

before age 50 A family member with breast cancer

diagnosed before age 35 A family member with both breast and ovarian cancers An Ashkenazi Jewish heritage, particularly with relatives

with breast or ovarian cancer

…Who should be offered referral for genetic counselling and/or genetic testing?

A family member with primary cancer in both breasts(especially if before age 50)

A family member with ovarian cancer A family member with male breast cancer A family member with an identified

BRCA1 or BRCA2 mutation

USPSTF 2005 recommends referral for genetic counselling and evaluation for BRCA testing to women with family history indicating increased risk of BRCA mutations

Case: Rachel

Rachel - healthy 40 year oldConcerned about her risk for cancerFamily history of both breast & ovarian

cancer

Case: Rachel’s family historyLEGEND

Breast cancer

Ovarian cancer

Br Ca

Dx 30

Br Ca

Dx 38

Ov Ca

Dx 40

Ov Ca

Died 48

RACHEL

age 40

Rachel was referred to genetics…A genetics consultation involves: Detailed family history information Pedigree documentation

Confirmation of cancer history: pathology reports/death certificates

Medical & exposure history Empiric risk assessment Hereditary cancer / genetic risk

assessment Psychosocial assessment

Psychological Aspects to Consider Motivation for genetic testing:

Reduce uncertainty

Learn about risk for children

Childbearing/marital decisions

Explore further surveillance/treatment options

Perceived risk

Expectations of genetic testing

Psychological well-being – current & past prior experiences with cancer

prior loss/ disruptions associated with cancer approaching age of parent’s diagnosis or

death from cancer

A genetics consultation involves: Assessment of eligibility for genetic testing

Estimated risk of a mutation must be ≥10%

for most provincial programs Most appropriate family member to test first

Discussion of risks, benefits & limitations of test Testing and disclosure of genetic test results

Will be months before results are available

Discussion of types of results and what they mean

Screening/management recommendations

Genetic Testing Available at regional genetic centres and familial cancer

clinics Covered by provincial insurance plans (i.e. OHIP) if criteria

are met: Ontario US Privative Lab

Full gene testing $1,400CDN $3,120 USD

Ashkenazi Panel $350 $535

Familial mutation $250 $440

Testing is only offered if the risk of mutation is ≥10% Test highest risk affected individual first Only in exceptional circumstances will testing be offered

to unaffected individuals

February 2009

Results from Genetic Testing Positive

Deleterious mutation identified Negative

Interpretation differs if a mutation has previously been identified in the family

Mutation known – true negative Mutation unknown – uninformative

Variant of unknown significance Significance will depend on how variant tracks through

family - i.e. is variant present in people with disease? Can use software to predict functional significance Check with lab to see if reported previously

Risks/Benefits/Limitations of genetic testingPositive test resultPotential Benefits: Clinical intervention may

improve outcome Family members at risk

can be identified Positive health behaviour

can be reinforced Reduction of uncertainty

Potential Risks: Adverse psychological

reaction Family issues/distress Uncertainty -incomplete

penetrance Insurance/job discrimination Confidentiality issues Intervention carries risk

Risks/Benefits/Limitations of genetic testing? Negative test result

Potential Benefits: Avoidance of

unnecessary clinical interventions

Emotional - relief Children can be

reassured Avoidance of higher

insurance premiums

Potential Risks: Adverse psychological

reaction (i.e. survivor guilt) Dysfunctional family

dynamics Complacent attitude to

health

Risks/Benefits/Limitations of genetic testing?Uninformative test result

Potential Benefits: Future research may

clarify test results Positive health behaviour

can be reinforced Some relief Higher insurance

premiums may be avoided

Potential Risks: Continue clinical interventions

which may carry risks Complacent attitude to health Uncertainty Continued anxiety Higher insurance premiums

may not be reduced

Normal

Mutation

Case: Rachel’s test results….

Rachel

BRCA1 185delAG

Legend

Breast cancer

Ovarian cancer

What is the benefit of having genetic testing?

Can anything be done to change risk/outcome?

Recommendations for BRCA1 and BRCA2 mutation carriers:Lifestyle

Reduce dietary fat Avoid obesity Reduce alcohol consumption Regular exercise

WeakEvidence

Recommendations for BRCA1 and BRCA2 mutation carriers

Breast cancer surveillance- Recommendations from Canadian Hereditary

Cancer Task Force, JOGC 2007BSE – not recommendedCBE – part of surveillance program including imaging Mammography & MRI (if available) q12 months age ≥30MRI (possibly + U/S) if surveillance required before age 30MRI may have higher sensitivity for surveillance of breast

cancer among BRCA1/2 carriers 2008 Meta-analysis: combined mammography and MRI screening

had a 94% sensitivity, 77% specificity (95% CI; p=0.01)

Recommendations for BRCA1 and BRCA2 mutation carriers Ovarian cancer surveillance

- Recommendations from Canadian Hereditary Cancer Task Force, JOGC 2007 Surveillance not routinely recommended Women should be counselled on the limitations of

current screening for ovarian cancer If woman chooses surveillance, then consider the

following q6 months starting at age 30-35: pelvic exam transvaginal ultrasound serum CA-125

Symptom recognition

Recommendations from Canadian Hereditary Cancer Task Force, JOGC 2007

Potential benefits should be raised with all women with a known mutation.

Multidisciplinary team that includes at least: genetics professional, breast surgeon, plastic surgeon.

Women should have access to: Written and oral information Support services Adequate time for reflection

Breast reconstruction options should be discussed in advance

Management of Mutation Carriers – Surgical options: Risk reduction mastectomy

Management of Mutation Carriers –Surgical options: Risk reduction mastectomy Hartmann et al. NEJM 1999

Retrospective study of 639 women with FH of breast cancer who had bilateral mastectomy (mutation status unknown)

Expected 37 br ca in 425 women at mod risk (Gail model) Observed 4 (90% risk reduction) 3 br ca in 214 high risk women with mastectomy (1.4%) 156 br ca in 403 sisters without mastectomy – 38.7% (90% risk

reduction)

Meijers-Heijboer et al. NEJM 2001 139 BRCA1 and BRCA2 mutation carriers No br ca after 3 years in 76 ♀♀ with risk-reducing mastectomy

compared with 8 cases of br ca in 63 who chose surveillance

Management of Mutation Carriers –Surgical options: risk reduction salpingo-oophorectomy (SO)Recommendations from Canadian Hereditary Cancer

Task Force, JOGC 2007 The potential benefits of risk reduction SO should be

discussed with women. Management by multidisciplinary team that includes a

genetics professional 2009 meta-analysis Rebbeck et al.

80% reduction in risk of BRCA 1/2 -associated ovarian/fallopian tube cancer

Hazard ratio 0.21 (95% CI = 0.12-0.39) 50% reduction in risk of breast cancer in BRCA 1/2 mutation

carriers Hazard ratio 0.49 (95% CI = 0.37-0.65)

Optimal age of SO – more study needed

Management of Mutation Carriers - Chemoprevention Tamoxifen Prevention Trial 2005

Invasive breast ca reduced from 42.5/1000 in placebo group to 24.8/1000 in Tamoxifen group in women at increased risk of breast cancer

Preliminary data suggest benefit for BRCA2 but not BRCA1 carriers

Raloxifene Shows promise No data for mutation carriers

Aromatase inhibitors – ExCel trial Exemestane vs. placebo (Ca Info Service – 1-888-939-3333) No data for mutation carriers

2007 Canadian Hereditary Cancer Task Force Recommendations: women choosing chemoprevention should be enrolled in a clinical trial

Management of Mutation Carriers Consider… Psychosocial support to assist with:

Adjusting to new information most adjust within 3-6 months subset remain psychologically distressed (16-25% anxiety

and/or depression)

Making decisions regarding management“to inflict surgery is a hard decision to make… when I don’t have the disease and feel healthy”

Addressing family issues, self concept, body image Dealing with future concerns i.e. child bearing,

surgical menopause after oophorectomy

Referral to support groups

Management of Mutation Carriers Consider…

Additional psychosocial support may be needed for high risk individuals such as those with: History of depression/anxiety

Poor coping skills

Inadequate social support / conflict in the family

Multiple losses in the family

Loss of parent at a young age

Recent loss

Multiple surgical procedures

Testing children for BRCA1 and BRCA2 mutations

Benefits and non-harm No medical benefit from genetic testing for children < 18 Potential harm from this information – psychological, insurability, etc.

Autonomy Consider the child’s autonomy and ability to provide informed

consent Parents are not always the decision maker for a child

Privacy/confidentiality Results are available to the parent who may or may not share these

with the child Equity & justice

Access to resources if the genetic status is known vs unknown

Despite focus on hereditary cancers… Most women will not develop breast cancer

Of those who do, most will not have a known family history

Increasing age is the greatest risk factor

Most women with family history of breast ca: do not fall into a high-risk category do not develop breast cancer are not eligible for genetic testing

All women should be “breast aware” and contact their health care providers if any lumps or breast changes are noted.

Cases

Assessing the Risk of Hereditary Breast CancerUsing the Canadian Cancer Society triage card (below), what category of risk do the following family histories fit into?

Case 1

Alz -75

A&W A&W ↑Chol BrCa Dx 61

Colon Ca Dx 76

died 85Aneurysm

A&W

AsthmaA&WYour Patient

Accident MI 80

BrCa Dx 68

Colon

Breast

Legend

Case 1

Colon

Breast

Legend

Case 1 Answer:

Moderate risk for hereditary breast cancer Two 1st/2nd degree relatives on the

same side of the family with breast cancer < age 70

Management:CBE and mammogram q1 years starting at 40Discuss lifestyle changes Consider enrollment in chemoprevention

clinical trial

Case 2

Alz -75

A&W A&W ↑Chol Migraines

Stroke -83

A&W

AsthmaA&WYour Patient

Accident MI 85

IDDMBr Ca Dx 41

Breast

Legend

Case 2

Breast

Legend

Case 2 Answer:

Moderate risk for hereditary breast cancer

One 1st/2nd degree relative with breast cancer at 35-49 years

Management: CBE and mammogram q1 years staring at 40 Discuss lifestyle changes Consider enrollment in chemoprevention clinical trial

Case 3

Alz -75

A&W OvCa Dx 52 Prost Ca 65 ↑ Chol

Bilateral Breast Ca Dx 49

died 53 Aneurysm

A&W

AsthmaA&WYour Patient

Accident BrCa Dx 75

IDDM

Legend

Prostate

Breast

Ovarian

Case 3

Legend

Prostate

Breast

Ovarian

Case 3 Answer:

High risk for hereditary breast/ovarian cancer

One 1st/2nd degree relative with:bilateral breast cancer, first one before

age 50ovarian cancer (any age)

Case 3 Answer: High risk Management:

Offer genetics or familial cancer clinic referralPt. agrees: Familial Cancer Clinic will suggest

managementPt. declines: Discuss management with familial

cancer clinic or manage as moderate risk Referral to psychologist and/or support

group Discuss: lifestyle changes, enrollment in

chemoprevention clinical trials

Case 4

Alz -75

A&W A&W ↑Chol BrCa Dx 71

Colon Ca Dx 76

died 85Aneurysm

A&W

↑CholA&WYour Patient

Accident Breast Ca 85

MI 69

Colon

Breast

Legend

Case 4

Colon

Breast

Legend

Case 4 Answer:

Low risk for hereditary breast cancer Meets none of the high or moderate risk

criteria

Management:Clinical breast exam & mammogram q 1-2

years beginning at age 50Discuss lifestyle changes

Case 5

Nt Causes -75

A&W Schizophrenic MI 65 ↑ Chol

Died 81 stroke

IDDM

AsthmaA&WYour Patient

OvCa Dx 52

Prost Ca Dx 80

Died 81

BrCa Dx 55

IDDM BrCa Dx 45

Eastern Europe

Ashkenazi JewishIrish / German

Christian

Legend

Prostate

Breast

Ovarian

Case 5

Legend

Prostate

Breast

Ovarian

Case 5 Answer: High risk for hereditary breast/ovarian cancer 3 relatives on the same side of the family with

breast or ovarian cancer at any age

Management: Offer genetics or familial cancer clinic referral

Agrees: Familial Cancer Clinic will suggest management

Declines: Discuss management with familial cancer clinic or manage as moderate risk

Referral to psychologist and/or support group Discuss: lifestyle changes, enrollment in

chemoprevention clinical trials

Case 6

Neck CA

Dx 70

Bladder CA Dx55

A&WHead CA

Dx 65BrCa Dx 61

Bladder CA Dx 58

died 62

A&W

AsthmaA&WYour Patient

Accident MI-84

Diabetes

Bladder

Breast

Head & Neck

Legend

Case 6

Bladder

Breast

Head & Neck

Legend

Case 6 Answer: Low risk for hereditary breast cancer

Meets none of the high or moderate criteria Patient’s family worked in a tannery and

shoe factory.Aromatic amines (dyes) increase the risk of

bladder cancersShoe manufacturers have an increase risk of

nasal cavity cancersThe high incidence of cancer is due to

common environment exposures.

Resources The National Cancer Institute:

http://cancernet.nci.nih.gov/ Detailed information on cancer for patients and

physicians including causes, treatments, clinical trials & more

Canadian Cancer Society: www.cancer.ca FORCE: www.facingourrisk.org www.hereditarybreastcancer.cancer.ca

Patient information aid Gene Clinics: www.Genetests.org

See Gene Reviews for clinical summaries Where to find a genetics centre:

www.cagc-accg.ca/centre1.html

The Genetics Education Project Committee June Carroll MD CCFP Judith Allanson MD FRCP

FRCP(C) FCCMG FABMG Sean Blaine MD CCFP Mary Jane Esplen PhD RN Sandra Farrell MD FRCPC

FCCMG Judy Fiddes Gail Graham MD FRCPC

FCCMG Jennifer MacKenzie MD

FRCPC FAAP FCCMG

Wendy Meschino MD FRCPC FCCMG

Joanne Miyazaki Andrea Rideout MS CGC

CCGC Cheryl Shuman MS CGC Anne Summers MD

FCCMG FRCPC Sherry Taylor PhD FCCMG Brenda Wilson BSc MB

ChB MSc MRCP(UK) FFPH

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