genetics: beyond brca, reem saadeh-haddad, md
TRANSCRIPT
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 [email protected]