Reem Saadeh, MDClinical Geneticist

The Johns Hopkins Medicine Family Sibley Memorial Hospital colleagues and

friends

Ambry Genetic slides Myriad Genetic slides

Lifetime risk in the general population for sporadic cancer:

◦ Ovarian cancer: 1-2%◦ Breast cancer:

8-12% for women <1% for men

Additional Genes:

Cause and age at death or current age Significant illnesses, physical findings

that can be seen with other cancer syndromes

Cancer screening and prophylactic or treatment surgical procedures that may decrease risk of another cancer

Types of cancer-abdominal cancer, did that mean ovarian.

2nd cancers, primary vs metastasis

Frank (Myriad) model◦ Relies on information

regarding if and at what age first or second degree relatives with breast and/or ovarian cancer diagnosed

◦ Takes into consideration Ashkenazi Jewish heritage

◦ Does not take into consideration other cancers that can be associated with BRCA1/2 mutations

◦ www.brcacalculator.com

BRCA-Pro◦ Computer model that

requires manual entry of each individual’s: History of cancer or risk

reducing procedures ex. Oophorectomy

Causes of death Age or age at death Ashkenazi Jewish heritage Genetic testing Gives other risk factors

such as Gail risk if applicable

◦ http://www8utsouthwestern.edu/utsw/cda/dept47829/files/65844.html

AJHG 1995;56:265-271Science 2003: 643-646

JCO 2005 23 (8): 1656-63NCI 2005

20

40

60

80

100

Breast cancerby age 50

Breast cancerby age 70

Ovarian cancerby age 70

2%

Up to 50%

8%

Up to 85%

Ris

k of

Can

cer

(%)

<1%

Up to 50%

General PopulationBRCA Mutation

Lancet 1994;343:692-695 NEJM 1997;336:1401-1408

AJHG 2003;72:1117-1130

Lancet 1998;351:316-21JCO 2004;22:2328-35

Lancet 1994;3343:692-5Gynecol Oncol. 2005 Jan;96(1):222-6

0

20

40

60

Breast Cancerafter 5 years

Breast Cancer by age 70

Up to 3.5%

Up to 27%

Up to 11%

Up to 65%

Ris

k of

Can

cer (

%)

General PopulationBRCA Mutation

Ca Epi Biomarkers Prev. 1999;8(10):855-61JNCI 1999;15:1310-6

JCO 1998;16:2417-25

JCO 2004;22: 735-42NCI 2005

Breast Cancerby age 80

Prostate Cancerby age 80

General PopulationBRCA Mutation*

5

10

15

20

25

<1%

7%

15%

20%

Ris

k of

Can

cer (

%)

*Risks refer to BRCA2 mutation carriers.

Risks for male BRCA1 mutation carriers are less characterized

JNCI 1999;15:1310-1316 JNCI 2002;94 1365-72

J Med Genet. 2005 Sep;42(9):711-9

Pancreatic cancerby age 80

General PopulationBRCA Mutation

5

15

20

25

<1%

2-4%Ris

k of

Can

cer (

%)

10

Melanoma by age 80

1%

2-4%

• Improved outcomes with proven medical interventions

Surveillance Chemoprevention Prophylactic surgery

• Treatment of manifestations in individuals with BRCA1 or BRCA2 related tumors is similar to that of sporadic forms of these cancers.

JAMA 2000;283:617-24

◦ Surveillance: Self breast exam q 1 mo (starting at age 18yr) Physician breast exam 4 times a year Mammograms once a year Breast MRI once a year

◦ Chemoprevention: Tamoxifen use has been associated with a reduction Tamoxifen use has been associated with a reduction

of 53% in the risk of a second primary breast cancer of 53% in the risk of a second primary breast cancer in contralateral cancersin contralateral cancers

◦ Prophylactic Surgery: Bilateral mastectomy reduces risk by >90%

Surveillance:◦ Ovarian transvaginal u/s every 6-12 mo◦ CA-125 –blood marker of ovarian ca every 6-12 mo

Chemoprevention:◦ Oral contraceptives, Oral contraceptives,

when taken for 6 or when taken for 6 or more years, have been more years, have been associated with a associated with a reduction of up to 60% reduction of up to 60% in the risk of ovarian in the risk of ovarian cancer.cancer.

◦ Prophylactic Surgery Prophylactic

oopherectomies reduces ovarian cancer risk by >95%

Recommended after child bearing or 35-40 years.

Removal of adjacent fallopian tubes is recommended as well and pathologic investigation of both at time of surgery

Also has been shown to reduce the risk of breast cancer in mutation carriers.

Breast:◦ Breast self exam—monthly◦ Clinician breast exam—yearly ◦ Mammogram based on clinical findings

Prostate◦ Prostate specific antigen—yearly◦ Digital rectal examination—yearly◦ Begins same age as general population

Additional Genes:

Majority risk here is for HNPCC: HereditaryNon polyposis CRC (HNPCC)

Due to mutations in:◦ MLH1◦ MSH2◦ MSH6◦ PMS2◦ EPCAM

Autosomal Dominant Inheritance

0

20

40

60

80

100

CRC by age50

CRC by age70

EC by age 50 EC by age 70

General PopulationHNPCC

Ris

k of

Can

cer (

%)

0.2%

>25%

2%

Up to 80%

0.2%

20%

1.5%

Up to 71%

Gastroenterology 1996;110:1020-7Int J Cancer 1999;81:214-8Gastroenterology 2004;127:17-25

0

4

8

12

16

Ovarian Cancer Gastric Cancer

General PopulationHNPCC

Ris

k of

Can

cer (

%)

Int J Cancer 1999;81:214-8Stat Med 2003;22:1837-48

2%

12%

<1%

13%

Additional cancers that have a lifetime risk of <5%

◦ Ureter/renal pelvis◦ Biliary tract◦ Small bowel◦ Pancreas◦ Brain◦ Sebaceous adenoma

Gastroenterology 1996;110:1020-7Int J Cancer 1999;81:214-8

0

20

40

60

Within 10 yrs Within 15 yrs

General PopulationHNPCC

Ris

k of

Can

cer (

%)

Cancer 1977;40:1849Dis Colon Rectum 1986;29:160Cancer 1993;36:388-93

3.5%

30%

5%

50%

Improved outcomes with proven medical interventions

Surveillance

Surgery

Gastroenterology 2000;118:829-34Gastroenterology 2001;121:195-7Dis Colon Rectum 2002;45:1588-94

Site Procedure Age to Begin

Interval

Colon Colonoscopy20-25 1-2 years

40 Annually

Endometrium & Ovaries

Endometrial aspirationTransvaginal ultrasoundCA-125

25-35 1-2 years

JAMA 1997;277:915-19Gastroenterology 2000;119:837-53Gastroenterology 2001;121:198-213Gastroenterology 2003;124:544-60

Colorectal cancer or more than one advanced adenoma◦ Total Colectomy

With ileorectal anastomosis (IRA) May be considered for patients unable/unwilling to undergo

frequent colonoscopies◦ Hemicolectomy

With yearly colonoscopy

Endometrial/Ovarian cancer◦ Hysterectomy/salpingo-oophorectomy

Option for HNPCC patients at time of any intra-abdominal surgery Option after childbearing is complete

JAMA 1997;277:915-19Gastroenterology 2001;121:198-213Dis Colon Rectum 2003;46:1001-12

Additional Genes:

Majority risk here is for HNPCC: HereditaryNon polyposis CRC (HNPCC)

It is important to remember that if a mutation is identified in the individual, then the following individuals are at a 50% risk of inheriting the same mutation:

◦ Each child of the individual◦ Each sibling of the individual◦ Each parent of the individual◦ Extended relatives may be at risk◦ All individuals should be made aware that a mutation has

been identified in an individual in the family

Why get tested:◦ Increased knowledge◦ Health care decisions

regarding ovarian cancer treatment and prevention

◦ Information for relatives

◦ Emotional benefits

Why not get tested:◦ Emotional implications◦ Difficulties interpreting

test results◦ Test results may not

change management guidelines.

Thank you! Reem Saadeh, MDSibley Memorial Hospital5255 Loughboro Road, NWWashington DC 20016 202-370-6546 rsaadeh1@jhmi.edu