유방암의 Genetic Screening

영남의대 병리학교실배 영 경

Breast cancer

Breast cancer susceptibility genes

Syndrome Gene Inheritance (%)*

Cancers

Breast/ovarian cancer syndrome

BRCA1 AD (60-80) Breast, ovary, colon

BRCA2 AD (60-85) Breast, ovary, prostate, pancreas

Li-Fraumeni syndrome TP53 AD (100) Breast, brain, sarcoma, leukemia, adrenocortical carcinoma

Cowden disease PTEN AD (20-30) Breast, ovary, thyroid, colon

Peutz-Jegher syndrome

STK11/LKB1 AD

(RR: 20.3 folds)

GIT, breast

Ataxia-telangiectasia ATM AD Breast

Site-specific CHEK2 AD Breast

Muir-Torre/HNPCC MSH2/MLH1 AD Colorectal, breast

*Breast cancer penetrance in mutation carriers

Problems in genetic screening of breast cancer

• No unifying molecular alteration in sporadic breast cancer (genetically heterogeneous)

• Low incidence of BRCA1/BRCA2 mutation in breast cancer

• Large size of BRCA1/BRCA2 genes• No specific loci of mutation on BRCA1/BRCA2 genes • High cost: not covered by insurance• No domestic data of penetrance/cancer risk for BRCA1

/BRCA2 mutation carriers

Germline mutation of BRCA1 & BRCA2

15-20% of familial breast cancer

5% of breast cancer overall

BRCA1

• Lifetime breast cancer risk: 60-80%

• Lifetime ovarian cacner risk: 20-40%

• Increased risk for prostate and colon cancer

• Cell cycling, DNA-damage response

BRCA2• Lifetime breast cancer

risk: 60-85%• Lifetime ovarian cancer

risk: 10-20%• Lifetime male breast

cancer risk: 6%• Increased risk for colon,

prostate, pancreas, GB, bile duct, stomach cancer and malignant melanoma

• Maintenance of chromosome integrity

Cancer risk in women with germline BRCA1 mutations

Nature Med 7: 552-6, 2001

Incidence of BRCA1/BRCA2 mutation

• Non-cancer populationAshkenazi Jews: BRCA1: 1%, BRCA2: 1%

General population: BRCA1: 0.06%

• Breast cancer patientsUnselected groups: BRCA1: 1.4%, BRCA2: 1.2%

Early onset breast cancer patients (<45 yrs)

BRCA1: 6-13% , BRCA2: 4-5%

• Families with both breast and ovarian cancer BRCA1 &BRCA2: 55%

• Families with both breast and ovarian cancer in the same individual

BRCA1 &BRCA2: 75%

Incidence of BRCA1/BRCA2 mutation in Korean Breast Cancer

BRCA1 (%) BRCA2 (%) Total (%)

Unselected

Kim et al. 1.4 1.2

Ahn et al. 1.8 1.0 2.8

Selected

Ahn et al.* 8.7 4.0 12.7

Choi et al.# 10 8.7 15

*: High-risk patients with family history of breast or first-degree ovarian cancer, bilateral breast cancer, male breast cancer, multiple organ cancer, earlier age of onset(<35 yr).

#: Early onset breast cancer patients: <40 yr

• ER-negative• PR-negative• Cyclin D1-negative• HER-2/neu-negative• P53-positive• High nuclear and histologic grade

BRCA mutation carriers’ tumors

F-CSGE or DHPLC Direct sequencing

Analysis of BRCA1/BRCA2 mutation

BRCA1-exon24‘ATTGGGCA’ deletion

Limitation of widespread BRCA1/BRCA2 testing

• Expensive cost

• Uncertain clinical value of a positive test result

• Fear of loss of health

Cost of genetic screening

• 한국요양급여비용의 100 분의 100 을 본인이 부담하는 항목돌연변이검사 ( 확진 )

121 다 .

유전성유방암 / 난소암 BRCA1, BRCA2 305,740원

• 미국$ 2400 – 2975 for both BRCA1 and BRCA2

• Expensive screening test

• Uncertain clinical value of a positive test result

• Fear of loss of health

Limitation of widespread BRCA1/BRCA2 testing

Results of mutation analysis

1) Over 800 different mutations are found throughout the entire gene sequence

2) Nonsense or frame shift mutations

protein truncation

Missense mutation

undetermined clinical significance

3) No founder mutations in Korean

e.g.) Ashkenazi Jew, Iceland

4) No domestic data for penetrance of BRCA mutation

Cumulative risk of breast cancer by age in women from families with cancer-predisposing mutations

Age

Age Cumulative Risk

BRCA1 BRCA2

30 yrs 3.2% 4.6%

40 yrs 19.1% 12%

50 yrs 50.8% 46%

60 yrs 54.2% 61%

70 yrs 85% 86%

Easton et al., 1995 and 1997

Limitation of widespread BRCA1/BRCA2 testing

• Expensive cost

• Uncertain clinical value of a positive test result

• Fear of loss of health

Advantages to testing for BRCA mutations

• Women may feel relieved knowing for certain whether or not they are at a higher risk for breast cancer.

• Women with breast cancer may have better responses to certain treatments that are specifically designed for BRCA positive patients.

• Women may take preventive measures to help reduce their risk of breast cancer if they are positive for BRCA mutations.

• Other family members may decide if they wish to be tested for BRCA mutations based on the results of a woman’s test.

Disadvantages to testing for BRCA mutations

• Women may become worried, panicked, or stressed if they discover they have a higher than average risk for breast cancer.

• Women who test positive for BRCA mutations are faced with the difficulty of telling family members

• Women who test negative for BRCA mutations may falsely believe they will never get breast cancer.

Genetic Screening

• Who to screen

• Who may not need screen

• How reducing the incidence and morbidity of breast cancer

• How reducing health care cost

• How benefiting women, their families, and society

Models for prediction of BRCA1/BRCA2 mutations (by NCI)

• Personal characteristics• Breast cancer diagnosed at an early age• Bilateral breast cancer• A history of both breast and ovarian cancer• The presence of breast cancer in 1 or more male family

members

• Family characteristics• Multiple cases of breast cancer in the family• Both breast and ovarian cancer in the family• One or more family members with 2 primary cancers• Ashkenazi Jewish background

Recommendation for BRCA mutation analysis

High-risk patients with

1) family history of breast or first-degree ovarian cancer

2) bilateral breast cancer

3) male breast cancer

4) multiple organ cancer including breast cancer

5) earlier age of onset (<35 yr)

Ahn et al. J Korean Med Sci 19: 269-74, 2004

Risk assessment of patients with a family history of breast cancer

Warner E, et al. Canadian Family Physician 45: 105-112, 1999.

One FDR > 50yr, orMore distant relative

One FDR < 50yr, two FDRs or male relative

Patient requests gene testing

Inherited risk education orGenetic counseling

No genetic risk or patient does not want gene testing

Patient desires further gene testing

Test for mutations in affected relatives

positive

Test for mutations in patient

positive

Routine breast cancer surveillance

negative

negative

Begin early surveillance programAge 18: monthly breast self-examinationsAge 25: monthly breast self-examinations annual clinical examinations annual mammograms Prophylactic mastectomy after childbearing?For those with BRCA1 mutation, annual CA-125 and pelvic ultrasound examinations prophylactic oophorectomy after age 40?

positive

Suggested algorithm for genetic screening based on recommendations by the National Institutes of Health and the National Human Genome Research Institute.

The Johns Hopkins Breast and Ovarian Surveillance Service (BOSS)

• review family history and other risk factors • provide individualized risk assessment • perform a clinical breast exam and instruct patients in

breast self-exam • discuss and offer genetic testing to evaluate inherited

cancer susceptibility • provide individualized cancer prevention and

screening information • discuss the benefits and risks of hormone

replacement therapy • provide information about chemoprevention of breast

cancer in high risk women

What to do?

• Select high-risk family• Genetic counselor• Give information for genetic testing• Explore the clinical significance of unverified

mutations • Develop standardized protocol for genetic

testing and follow-up of mutation carriers• Support the cost of genetic testing for the

high-risk family