Jill Stopfer, MS, CGC

Abramson Cancer Center

University of Pennsylvania

Aging

Family history

Early menarche

Late menopause

Nulliparity

Estrogen / Progesterone use after menopause

More than two alcoholic beverages per day

Protective Factors for Breast Cancer • At least four or more hours a week of exercise • Breastfeeding • Maintaining ideal body weight (especially after menopause) • Having children prior to age 30

Sporadic

Family clusters

Hereditary

Ovarian Cancer Breast Cancer

5%–10% 5%–10%

15%-20%

Can find genetic risk in some families Can sort out who does, and who does not, have

genetic risk for cancer Can tailor health care to lower cancer risk and

maximize chances for cure Can spare those without genetic risk for cancer

from unnecessary procedures and worry

Hereditary Cancer Syndromes ◦ One important gene associated with major cancer risk ◦ Clear pattern of inheritance ◦ Genetic testing often available ◦ 5-10% of breast and ovarian cancer cases overall ◦ Certain features of the family history can suggest this

Moderate Risk Genes ◦ Each gene may increase risk, but less dramatically ◦ It may require a set of genes, or genetic profile, to

significantly raise risk

Multifactorial Inheritance ◦ Genes, environment, lifestyle risk factors, random cell

errors

Multiple generations of

cancer

Young age at diagnosis

More than one cancer in

the same person

Cancers that run together

such as breast / ovarian,

or colon / uterine

Rare cancers BR 35

OV 72 OV 53 Brain 50

BR 29

BR 51

Family history may guide: ◦ Screening recommendations

◦ Diagnosis of hereditary cancer condition

◦ Suggestions for genetic testing

◦ Potentially life saving interventions

Specific cancer types and ages at diagnoses

Every detail need not be shared

Multiple cases of early onset breast cancer (<50)

Ovarian cancer (with family history of breast or ovarian cancer)

Breast and ovarian cancer in the same woman

Bilateral breast cancer

Ashkenazi - Eastern European Jewish heritage

Male breast cancer

Increased risk of other cancers:

Male breast cancer: 1-5%

Pancreatic 2-3%

Breast cancer 60%-70%

Second primary breast cancer 40%-50%

Ovarian cancer 30-45%

Other increased risks:

Prostate: 15-25% Earlier ages

Pancreatic: 3-5%

Melanoma: 3-5%

breast cancer

(60%-80%)

ovarian cancer

(10%-20%)

male breast cancer

(5-10%)

An estimated 1 in 40 Ashkenazi Jews

carries a BRCA1 or BRCA2 mutation

185delAG

Prevalence = ~1%

5382insC

Prevalence = ~0.15%

6174delT

Prevalence = ~1.5%

BRCA1

BRCA2

Contrast enhanced MRI using Gadolinium ◦ Rapid enhancement of tumor relative to normal tissue

Data suggests improved sensitivity ◦ Picks up smaller cancers

◦ Sensitivity 83-100%

Decreased specificity ◦ Specificity ranges from 37-96%

◦ False positives are a major concern

Surveillance Options for Ovarian Cancer

• No proven methodology

• Annually or semiannually, starting at 30–35

– Transvaginal ultrasound w/color Doppler imaging

– CA-125

Chemoprevention of Breast Cancer

• Limited data are available for BRCA-mutation carriers

• Participation in ongoing studies is critical

• Other options… (Raloxifene, Aromatase Inhibitors)

Tamoxifen

49% reduction of breast cancer incidence in

high-risk women (mean follow-up of 4 years)

Fisher, JNCI, 1998

Chemoprevention of Ovarian Cancer

Oral Contraceptives

In general population, OCs reduce risk of ovarian

cancer 40% to 50% after 3 years cumulative use

Prophylactic Mastectomy

• Removes most but not all breast tissue

• Reduces breast cancer risk in women with a family history by 90%

• Total (simple) mastectomy removes more breast tissue than subcutaneous mastectomy

Prophylactic Oophorectomy

• Eliminates risk of primary ovarian cancer; however, peritoneal carcinomatosis may still occur

• Laparoscopic oophorectomy reduces postsurgical morbidity

• Induces surgical menopause

• In BRCA-mutation positive women – >85% risk reduction

• Also reduces risk of breast cancer by 50-70%

Can do…. ◦ Annual Endoscopic ultrasound

◦ Magnetic cholangiopancreatography (MRCP)

If suspicious findings noted, can do ERCP

Tissue biopsy

Pancreatic resection

Offered to those with BRCA2 + Fam hx Panc CA

2 or more cases pancreatic ca in close relatives

Peutz Jeghers syndrome

Endogenous damage

BER repair intermediates

SSB

PARP SSB repair

BER

PARP inhibitors

DNA replication BRCA1/2

Rad51

BRCA1/2

Rad51 strand invasion

HR

BRCA1/2 deficiency

Replication fork collapse

Cytotoxicity

Error prone repair

NHEJ or SSA

Treatment selection:

PARP inhibitors in BRCA1/2 carriers

BR 35

BR 58

Liver 72 Stom 53 Brain 50

BR 29

BR 51

BR 35

BR 58

OV 72 OV 53 Brain 50

BR 29

BR 51

BR 35

BR 58

OV 72 OV 53 Brain 50

BR 29

BR 51

B1

B1

Neg Neg

Neg Neg Neg

B1

B1 B1 Neg

B1 Neg

Colon 68

40y 43y 46y 38y 31y

Breast 61 Renal cell 55 Breast 40

Lung 70 Prostate 60

Colon 60

Ovary 30 Ovary 36 Ovary 51

40y 43y 46y 38y 31y

Breast 61 Renal cell 55 Breast 40

Lung 70 Prostate 60

Colon 60

Ovary 30 Ovary 36 Ovary 51

B1

40y 43y 46y 38y 31y

Breast 61 Renal cell 55 Breast 40

Lung 70 Prostate 60

Colon 60

Ovary 30 Ovary 36 Ovary 51

B1 B1

B1 B1

Colon 68

40y 46y 38y 31y

Breast 61 Renal cell 55 Breast 40

Lung 70 Prostate 60

Colon 60

Ovary 30 Ovary 36 Ovary 51

B1

40y 46y 38y 31y

Breast 61 Renal cell 55 Breast 40

Lung 70 Prostate 60

Colon 60

Ovary 30 Ovary 36 Ovary 51

B1 B1

B1 B1

BSO

BSO

Stage IV Ovary 46

Colon 68

Not all mutations can be seen using current lab

methods

Most breast and ovarian cancer risk is not due

to a mutation in a single gene like BRCA1/2

Pros ◦ More extensive searching

◦ Could find mutation in gene not suspected based on family history

◦ More economical

Cons ◦ Many genes on panels not well characterized

◦ Uncertain medical management of findings

◦ More testing but possibly increased uncertainty

Payment for testing

Confidentiality

Discrimination – Health and Life Insurance

Legislation – HIPAA and GINA

Pre-test genetic counseling ◦ Family history assessment – at least three generations ◦ Collection and review of medical records ◦ Determination of best person in the family to initiate

testing ◦ Explanation of natural history of condition to test ◦ Explanation of inheritance, and who else may be at risk ◦ Explanation of opportunities for intervention to lower risk

Genetic testing ◦ Typically a blood test or swish and spit kit ◦ Insurance pre-authorization

Result Disclosure ◦ Positive, Negative, Variant of Uncertain Significance ◦ Medical Recommendations