Hereditary Breast & Ovarian Cancer

Debbie Terespolsky

Clinical Geneticist

Common question

“There is cancer in my family. Am I at increased risk of getting cancer?” Pattern of cancer in family Type of cancer Age at diagnosis of cancer

Discuss screening Referral to genetics if appropriate

Objectives

Overview of role of genetics in cancer

Known hereditary breast/ovarian cancer syndrome genes BRCA1/BRCA2

Genetics clinic

All cancer is genetic Genetic code controls all cell growth

Cell cycle Several classes of genes

Promote growth Suppress growth Repair damaged DNA

Series of checks and balances to maintain the rate of new cell growth and cell death

Mutations causing cancer

Activating gain-of-function mutations of one allele of a proto-oncogene (RET – MEN2)

Loss of function of both alleles of a tumour-suppressor gene

Chromosomal translocations that cause misexpression of genes or create chimeric genes (CML)

Tumour suppressor genes

BRCA1 and BRCA2 Contribute to cancer through loss

of function of both alleles of the gene

Involved in sporadic and hereditary breast cancer

Sporadic cancer

At birth

30 – 50 years

50 – 70 years

2-hit hypothesis

At birth

30 – 50 years

50 – 70 years

2-hit hypothesis

Germline mutation exists in all tissues

Second hit can cause a tumour whenever it occurs in one of the numerous cells of a tissue Initial tumour may arise at multiple

sites

Tumour suppressor genes

Highly heterogeneous “gate-keepers” – directly regulate

cell growth (RB1) “caretakers” – repair DNA damage

and maintain cell integrity (BRCA1/2)

BRCA1 and BRCA2

Proteins interact with RAD51 protein in cell cycle

Functions in repair of damaged DNA

Regulate activities of other genes

Critical role in embryo development

sporadic

familial

Breast and ovarian Cancer

Breast cancer

Most common cancer amongst Canadian women

1 in 9 women In 2006:

22,300 women diagnosed5,300 women will die160 men, 45 will die

Ovarian Cancer

1 in 70 women 2,300 new cases in 2006

Familial clustering

~15% Common environment exposures Common lifestyle Chance Hereditary

Hereditary cancer

unknown

other known genes

BRCA1/2

Hereditary susceptibility to breast cancer

GENE % CONTRIBUTION

BRCA1 20 - 40

BRCA2 10 - 30

TP53 <1

CHEK2

PTEN <1

UNDISCOVERED 30 - 70

BRCA1

Discovered 1994 Chromosome 17q21 > 600 mutations

Missense Nonsense Frameshift – insertion/deletion

BRCA1

Increased risk of Breast Ovarian Prostate Colorectal

BRCA2

Discovered 1996 Chromosome 13q12.3 ~ 450 mutations

Insertions deletions

BRCA2

Fanconi anaemia Increased risk of

Breast Ovarian Prostate Pancreas

Mutations in midsection of gene Increased ovarian cancer Decreased prostate cancer

BRCA1 and BRCA2

Autosomal dominant Ethnic specific mutations

Ashkenazi Jewish 185 – 2 bp deletion BRCA1 5382 – 1 bp insertion BRCA1 6174 – 1 bp deletion BRCA2

BRCA1 and BRCA2

Up to an 85% chance for a woman to develop breast cancer up to age 70 years

Average age mid-40’s For affected patients, the risk of

second primary is 40-60% Increased risk male breast

cancer (6-10%)

BRCA1

16-44% lifetime risk to develop ovarian cancer (serous invasive ca most common); includes fallopian tubes

Increased risk of prostate cancer (8-16%) and male breast cancer

Other possible associated cancers Pancreas Colorectal

BRCA2

Increased risk of ovarian cancer (10-25%)

Increased risk for prostate (8-16%) and male breast cancer

Pancreas

Other

Likelihood of BRCA1 Mutation

No family history: 0.13% Br ca <40: 6% 2 br ca <40: 37% Br ca <50 & ov ca <50: 46% 2 ov ca <50: 61% 2 br ca & 2 ov ca: 91%

adapted from Cole et al., 1998

Clinical relevance

Importance of ovarian cancer and BRCA1/2

Serous ovarian cancer most likely to be due to BRCA1/2 mutation

Clinical characteristics of individuals with BRCA1/2 mutations

No br <50; no ov 3.9% Br <50 4.4% More than 1 Br <50 11% Ov any age; no br <50 3.9% More than 1 ov; no br 8.5% Br <50 and ov any age 16.4%

Frank et al, 2002

Clinical characteristics of individuals with BRCA1/2 mutations

Proband with br <40: No br <50; no ov 13.2% Br <50 29.7% More than 1 Br <50 50.7% Ov any age; no br <50 24.1% More than 1 ov; no br 23.5% Br <50 and ov any age 56.3%

Frank et al, 2002

Clinical characteristics of individuals with BRCA1/2 mutations

Importance of ovarian cancer history regardless of age

Insufficient evidence to merit testing BRCA1/2 based on dx of DCIS

Importance of both BRCA1 and BRCA2 in male breast cancer

Ductal carcinoma in-situ

DCIS is a part of the breast/ovarian cancer syndromes defined by BRCA1 and BRCA2

Mutation rates similar to those found for invasive breast cancer.

Screen patients with breast cancer with an appropriate personal or family history of breast and/or ovarian cancer according to high-risk protocols, regardless of whether they are diagnosed with in situ or invasive breast cancer.

Referral to Genetics

Guidelines available Detailed family history Confirmation of pathology Risk assessment Surveillance Genetic testing

Issues for patients and families

Right to know or NOT to know Sharing of information Privacy Reproduction decision making Testing of minors

Who is eligible for testing

Breast cancer < 35 Two breast cancer < 50 > 2 breast cancer Serous ovarian cancer Breast and ovarian Bilateral breast cancer – one < 50 Male breast cancer

Best testable

Affected individual If no affected, unaffected with >

10% risk of having BRCA1/2 mutation

Genetic testing

Protein truncation testing (PTT) Sequencing MLPA (multiplex ligation probe

amplification) DHPLC (denaturing high

performance liquid chromatography)

Genetic testing

Turn-around-time New tests more efficient Myriad in USA

Results

Mutation detected Mutation not detected

Missed Involves another gene Individual’s cancer is not

hereditary True negative result

Population risk

Management for BRCA carriers

Enhanced surveillance Mammogram, CBE, Transvaginal u/s, CA-125

Chemoprevention Prophylactic surgery

Bilateral mastectomy BSO/TAH

Risk reduction

Bilateral prophylactic mastectomy 90% decrease in breast ca

BSO + TAH 50% decrease in breast ca (<50

yrs) >50% decrease in ovarian ca

Cancer

Br @ 33,35

Br @68, 69

2

ovarian

3

Br, died at 33

63

40

Cancer

Br @62

2

Br @46

2

Stroke @82

2

Ov Abd

MI @76

63

40

Cancer

Br @62

2

Br @51

2

Stroke @82

2

cervical stomach

MI @76

22

2

dx34

2

5

3

3

40

42 40

35

dx57dx40’s

38

3

65

69

2

65

62

Multidisciplinary team

Family physician Oncologist Surgeon Gynaecologist Geneticist Psychologist/social worker

Family physician’s role

Family history Assess likelihood of inherited breast

cancer Offer referral if appropriate Pre-referral discussion of what to

expect at genetics appointment Post-referral counselling Implementation of

surveillance/treatment plans

Perspective

20% women have a family history of breast cancer

<5% of women are at high risk for a genetic predisposition

Management: general population

Annual CBE not later than age 30. If family history, begin 10 years earlier than youngest age at diagnosis of affected relative

Annual or bi-annual mammogram starting from age 40-50, or 10 years earlier than youngest age at diagnosis of affected relative

BSE

The Future

Education of population Risk assessment surveillance

New surveillance New treatments Genotype phenotype correlation BRCA3/4