The Cancer Pedigree

BRCA What?

Outline• Introduction: Understanding the weight of genetics in Ovarian Breast

Cancer

• BRCA 1 and BRCA 2 Genes– Function– Incidence– Cancer Risk– Who should get tested?– Family History

• Genetic Testing• A positive result

– What does it mean?– What are your options?

Understanding the weight of genetics in Ovarian Breast Cancer

• Association of Cancer with Germline mutations– Less than 10 percent of all breast cancers – less than 15 percent of ovarian cancers – The majority of hereditary breast and ovarian

cancers are associated with mutations in two genes: breast cancer type 1 and 2 susceptibility genes (BRCA1 and BRCA2) (table 1).

Percent of Population

Percent of All Cases

Average Risk to age 70

Positive Family History of Breast cancer

10 15-20 10-13

Positive BRCA 1 or 2 mutation 0.1 5-6 50-85

General Population without positive family history or BRCA mutation

90 80-85 7

COMPARISON OF RISK BETWEEN FAMILY HISTORY, GENETIC MUTATION CARRIERS and THE GENERAL POPULATION

BRCA 1 and BRCA 2

• Why are they so important?– BRCA 1 and 2 are tumor suppressor genes– Role:

• Maintenance of genome integrity• Repair of double strand DNA breaks• Control of cell cycle check point responses• Chromosomal segregation

– GERM LINE Mutations:• loss of one wild type one functional allele vs two• those with tumors usually demonstrate loss of other wild

type through somatic mutation or loss of heterozygosity

Genetics: Random mutation rate: 1 per 106 cell divisions• Probability of two acquired gene mutations,

same locus: 1 x 1012

• Hereditary cancers occur because one inherited gene copy is already damaged at birth

• Shifts prevalence and age incidence for hereditary cancers

Cell Cycle: Made Easy

DNA Repair Genes:

BRCA1BRCA2

Cell cycle image

INCIDENCE

• Estimated at 1/800- 1/1000 per gene– Higher prevalence in individuals with personal or

family history of breast or ovarian cancer– Usually younger onset

• Geographic/ Ethnic Variation– Ashkenazi Jews: up to 2 %– Also Netherlands, Sweden, Hungary, Iceland,

French Canada

Cancer Risk in Positive Individuals

• Autosomal Dominance• High Penetrance• Women– Lifetime risk:

• Breast: 50-85%• Ovarian: 15-40%

• Males (BRCA 2 data)– Lifetime risk:

• Breast : 10%• Prostate: 5-7 fold increase

Genetics: Random mutation rate: 1 per 106 cell divisions• Probability of two acquired gene mutations,

same locus: 1 x 1012

• Hereditary cancers occur because one inherited gene copy is already damaged at birth

• Shifts prevalence and age incidence for hereditary cancers

Should I get tested?

Non Jewish FamiliesHigh risk Breast- ovarian: any one of the following

One case of breast cancer < 40 years old in first or second degree relative

One first or second degree relative with both breast and ovarian cancer

Two cases of breast cancer in first or second degree relative if one is diagnosed <50 years of age or is bilateral

One first or second-degree relative with breast cancer diagnosed at ≤50-years-old or bilateral and one first or second-degree relative with ovarian cancer

Three cases of breast and ovarian cancer (at least one case of ovarian cancer) in first or second-degree relatives

Two cases of ovarian cancer in first or second-degree relative

One case of male breast cancer in a first or second-degree relative if another first or second degree relative has (male or female) breast or ovarian cancer

Moderate risk* breast; any of the following:

Two first-degree relatives if both diagnosed between 51 and 60 years of age

One first degree and one second-degree relative (mother or sister and maternal aunt or maternal grandmother), if the sum of their ages is ≤118-years-old

Moderate risk ovarian:

One first-degree relative with ovarian cancer

Jewish FamiliesHigh risk* breast-ovarian; any of the following:One case of breast cancer ≤50-years-old in a first or second-degree relative

One case of ovarian cancer at any age in a first or second-degree relative

A first or second degree relative with breast cancer at any age if another first or second degree relative has breast and/or ovarian cancer at any ageOne case of male breast cancer in a first or second-degree relative

High Risk: this means you have a family history suggestive of hereditary cancer susceptibility syndrome and may benefit from referral to a cancer genetics professional and increased surveillance.Note: Those women with family history and known BRCA mutation should follow different guidelinesModerate risk: family history not diagnostic for increased risk, but still with increased risk for cancer and requiring increased surveillance.

General Information about the BRCA genetic testing

• Should be done by an expert.• Expensive test roughly $3000.00• www.genetests.org• Insurance Reimbursement: most insurance companies

cover roughly 90%– May need letter of medical necessity

• Do the results affect my health or life insurance?– You are protected by a federal law known as the “Genetic

Information Nondiscrimination Act (GINA)– This prohibits health insurers and employers from using your

genetic information

What Your Result Means

• If you test positive:– This means a deleterious mutation was identified in

BRCA1 or BRCA2– This mutation is known to be associated with

increased risk for cancer• If you test negative:– If you have a family history of familial BRCA mutation,

this means your risk of developing cancer is lower– Chances of false negative results exist, should still

undergo surveillance if coming from high risk family

What a positive test means for Cancer

• Your lifetime risk of breast cancer is:– 55-85% for BRCA1– 50-85% for BRCA 2

• Your lifetime risk of ovarian cancer is:– 35-46 % for BRCA1– 13-23% for BRCA2

You tested positive: What are your options?

• Screening– Starting at 18 years of age:

• Monthly Breast Self Exam: table with instructions

– Starting at 25 years of age:• Professional Breast Exam every 6 months• Yearly mammogram• Yearly MRI

– Ovarian: less accurate than breast• Includes blood test and pelvic ultrasound every 6 months beginning at age 35 or 5-10 years before youngest known

cancer case

• Surgical Intervention: preventative– Mastectomy: both breasts removed “bilateral prophylactic mastectomy), decreases development of breast

cancer by 90%– Removal of ovaries:: “prophylactic bilateral salpingo-oopherectomy”. Reduces risk of cancer development

in the pelvis by 80-90 % and breast cancer by 50-60%• Medical Management:

– Tamoxifen Therapy: reduces risk of breast cancer in women who have a BRCA mutation– Hormonal birth control: decrease risk of ovarian cancer (however concerns regarding risk of increased

breast cancer risk)• Combination of all 3

Bilateral Mastectomy

Robotic Surgery: TOH BOS

Ovarian Cancer Paradigm of Illness: Future Shift

Trimodal Survival Distribution

Cured Chr Disease Term Phase

35% 50% 15%