Hereditary Breast/Ovarian Cancer

The Genetics Education ProjectThe Genetics Education Project

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 2006

The Genetics Education Project The Genetics Education Project

Acknowledgments Reviewed by:

– Members of The Genetics Education Project– Clinical subcommittee of the Ontario Cancer

Genetics Steering Committee

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 many factors: 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

EnvironmentalUndiscovered gene mutation ChanceGenerally not eligible for genetic testing

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

cancerVariety of cancer syndromesAbout 2/3 of these - BRCA 1 or BRCA 2 mutationsMay 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’ Model

Inherited Cancer

Birth: Two 2 non-mutated copies of the BRCA1 gene

One mutation in one BRCA1 gene; One non-mutated copy

SECOND HIT

Two mutations - one in each BRCA1 gene

CANCER

Born with one hit(hit = mutation)


Compared to sporadic cancer, people with hereditary cancer have…

A higher risk of developing cancer A younger age of onset of cancer

– Generally < 50 years of age

Multiple 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

– ~1/800 in general (Caucasian) population

– 1/40 - 1/50 in Ashkenazi Jewish people3 common mutations in Ashkenazi Jews

– Unique French Canadian mutations


bb Bb

Bb bb Bb bb

Breast Cancer

Affected withbreast cancer

Autosomal Dominant Inheritance

Population Risk

Population Risk

SusceptibleBRCA gene

Unaffected

Legend

B: BRCA gene with mutation

b: normal BRCA 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 death–Uncontrolled growth, cancer


Consequences of having a BRCA mutationEstimated Risk in BRCA Mutation

Carriers – by Age 70

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% <1%


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

Multiple cases of breast and/or ovarian cancer in family– closely related relatives– more than one generation– Breast cancer diagnosed at < age 50

Breast cancer diagnosed at age < 35 Family member with both breast and ovarian cancers Ashkenazi Jewish + relatives with breast or ovarian

cancer


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

Family member with primary cancer in both breasts Family member with invasive

serous ovarian cancer Male breast cancer Family member with an identified with

a 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 old– Concerned about her risk for cancer– Family 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 Psychological assessment


…A genetics consultation involves: Assessment of eligibility for genetic testing

– Estimated risk of a mutation must be ≥10%

– Availability of living affected relative to be tested first

Discussion of risks, benefits & limitations of test

Testing and disclosure of genetic test results– May be months before results are available

Determining patient’s thoughts about breast cancer– Motivations for testing

Screening/management recommendations


Genetic Testing Available at regional genetic centres

– Familial cancer clinics

Covered by OHIP if criteria are met: Ontario US Privative Lab

Full gene testing $1,200CDN $2,975US

Ashkenazi Panel $325 $415

Familial mutation $250 $350

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

October 2005


Results from Genetic Testing

Positive– Deleterious mutation identified

Negative– Interpretation differs if a mutation has previously been

identified in the familyMutation known – true negativeMutation 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: ? reported previously


Risks/Benefits/Limitations of genetic testingPositive test result

Potential 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 inventions

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 BRCA1/2 mutation carriers:

–Breast surveillance – “I” recommendation USPSTF 2005

Monthly BSE – unproven

CBE q6 months starting when carrier status identified

Annual mammography starting at age 30

MRI and U/S if surveillance required before age 30

MRI may have higher sensitivity for surveillance of breast cancer among BRCA mutation carriers

– Studies ongoing




Recommendations for BRCA1/2 mutation carriers:– Ovarian surveillance

Consider…– PV exam– transvaginal ultrasound – serum CA-125

» q6 months starting age 30-35Symptom recognition


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 breast cancer after 3 years in 76 with risk-reducing

mastectomy compared with 8 cases of breast cancer in 63 who chose surveillance


Management of Mutation Carriers – Surgical options: risk reduction salpingo-oophorectomy

(SO)

Kauff et al. NEJM 2002 – 170 women with BRCA1 or BRCA2 mutations

– Proportion free from br ca or ovarian ca at 5 years

94% (SO group) vs 69% p=0.006

– Hazard ratio for either cancer after SO: 0.25 (95% CI 0.08-0.74)

Rebbeck et al. NEJM 2002– Breast cancer in 21% of SO group / 42% of control (hazard ratio

0.47)

– Hazard ratio for cancer of the coelomic epithelium after SO was 0.04


Management of Mutation Carriers – Surgical options: risk reduction salpingo-

oophorectomy (SO)

Eisen et al. J Clin Oncol 2005– Study of BRCA carriers who had SO and developed

breast cancer within 15 years– Breast cancer in 51/1388 (3.5%) SO group / 115/1751

(6.2%) control group– BRCA1: 56% reduction in breast cancer (OR 0.43, p =

0.00006)– BRCA2: 46% reduction in breast cancer (OR 0.57, p =

0.11) Summary: Consider for mutation carriers

before age 40


Management of Mutation Carriers - Chemoprevention

Tamoxifen– 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

– Tamoxifen Prevention Trial 2005

– May show promise in estrogen +ve tumours associated with BRCA2

Raloxifene– Shows promise - conflicting data

Aromatase inhibitors – ExCel trial– Exemestane vs. placebo (Ca Info Service – 1-888-939-3333)


Management of Mutation Carriers Consider…

Psychological support to assist with:– Adjusting to new information– Making decisions regarding management– Addressing family issues, self concept– Dealing with future concerns i.e. child bearing,

surgical menopause after oophorectomy

Stress management Support groups


Management of Mutation Carriers Consider…

Additional psychosocial support for those with:– History of depression/anxiety – Poor coping skills– Multiple losses in the family– Loss of parent at a young age– Recent loss– Multiple surgical procedures


Important messages to share with women

Most women will not develop breast cancer– Of those who do – most will not have a known FH

For most women – increasing age is the greatest risk factor

Great majority of women with FH of breast cancer do not fall into a high-risk category and do not develop breast cancer and are not eligible for genetic testing

Women at increased risk of breast cancer should be “breast aware”

The Genetics Education ProjectThe Genetics Education Project

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 1Answer :

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

family with breast cancer <age 70 or ovarian cancer at any age

Management:– CBE and mammogram q1 years starting at 40

– Discuss lifestyle changes

– Consider enrollment in chemoprevention clinical trials


Case 2

Alz -75

A&W A&W ↑Chol Migraines

Stroke -83

A&W


Accident MI 85

IDDM

Breast

Legend

Br Ca Dx 41


Case 2

Breast

Legend


Case 2Answer:

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 trials


Case 3

Alz -75

A&W OvCa Dx 52 Prost Ca 65 ↑ Chol

Bilateral Breast Ca Dx 49

died 53 Aneurysm

A&W


Accident BrCa Dx 75

IDDM

Legend

Prostate

Breast

Ovarian


Case 3

Legend

Prostate

Breast

Ovarian


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

with breast cancer <50 or ovarian cancer (any age)

One 1st/2nd degree relative with breast cancer:– <35 years– Bilateral, first before age 50– Breast and ovarian cancer (any age)– Male breast cancer


Case 3Answer: High risk Management:

– Offer genetics or familial cancer clinic referral

Pt. agrees: Familial Cancer Clinic will suggest management

Pt. declines: Discuss management with familial cancer clinic or manage as moderate risk

Consider chemoprevention, i.e. Tamoxifen 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 50– Discuss lifestyle changes


Case 5Legend

Prostate

Breast

Ovarian

Nt Causes -75

A&W Schizophrenic MI 65 ↑ Chol

Died 81 stroke

IDDM


OvCa Dx 52

Prost Ca Dx 80

Died 81

BrCa Dx 55

IDDM BrCa Dx 45

Eastern Europe

Ashkenazi JewishIrish / German

Christian


Case 5

Legend

Prostate

Breast

Ovarian


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

ovarian cancer 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 Consider chemoprevention i.e.Tamoxifen 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


Accident MI-84

Diabetes

Bladder

Breast

Head & Neck

Legend


Case 6

Bladder

Breast

Head & Neck

Legend


Case 6Answer: 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 cancers– Shoe manufacturers have an increase risk of nasal

cavity cancers– The 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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Hereditary Breast/Ovarian Cancer