Download Identifying and Managing Hereditary Cancer Syndromes

Identifying and Managing
Hereditary Cancer Syndromes
Monica Trout, MS
Genetic Counselor / Regional Medical Specialist
Myriad Genetic Laboratories
© 2005 Myriad Genetic Laboratories, Inc.
Learning Objectives
At the conclusion of this presentation
participants should understand the following:
• Features of hereditary breast/ovarian cancer, colon
cancer and melanoma
• Cancer risks associated with mutations
• Use of genetic test results in medical management
• Relevant health insurance issues
© 2006 Myriad Genetic Laboratories, Inc.
Impact of Hereditary Cancer
in Your Practice
• Hereditary cancer is more common than previously
thought
– Approximately 20% of breast cancer and colorectal cancer
patients are at-risk for a hereditary cancer syndrome
• Mutations in genes associated with hereditary cancer
dramatically increase the risks for cancer development
• Specific medical management options are available to
reduce cancer risks
Cancer. 2005 Dec 15;104(12):2807-16
Cancer Res 2006; 66(15): 7810-7)
J Clin Oncol. 2003;21(23):4364-70
Cancer. 2002 Jan 15;94(2):305-1
Cancer. 2005 Nov ;104(9):1849-53
The Development of
Hereditary Cancer
2 normal genes
Tumor
develops
1 damaged gene 2 damaged genes
1 normal gene
In hereditary cancer, one damaged gene is inherited.
1 damaged gene 2 damaged genes
1 normal gene
Tumor
develops
© 2006 Myriad Genetic Laboratories, Inc.
Hereditary Breast and Ovarian
Cancer
Most cases caused by a BRCA1 or BRCA2
mutation
Other16%
genes
BRCA1
52%
BRCA2
32%
7-10%
Sporadic
Hereditary
AJHG 1998;62:676-89
JCO 2002;20:1480-149
“Red Flags” for Hereditary
Breast and Ovarian Cancer
•
•
•
•
•
•
Breast cancer before age 50
Ovarian cancer at any age
Male breast cancer at any age
Multiple primary cancers
Ashkenazi Jewish ancestry
Relatives of a BRCA mutation carrier
Science 2003;302: 643-6
www.nccn.org
A BRCA Mutation Increases Breast
and Ovarian Cancer Risks
Up to
87%
Risk of Cancer (%)
100
General Population
BRCA Mutation
80
Up to
50%
60
Up to
44%
40
20
2%
8%
<1%
Breast cancer Breast cancer Ovarian cancer
by age 70
by age 50
by age 70
Lancet 1994;343:692-695
NEJM 1997;336:1401-1408
AJHG 2003;72:1117-1130
AJHG 1995;56:265-271
Science 2003: 643-646
JCO 2005 23 (8): 1656-63
NCI 2005
A BRCA Mutation Increases Risk
of Second Breast Cancer
Up to
64%
Risk of Cancer (%)
60
General Population
BRCA Mutation
40
Up to
27%
20
Up to
3.5%
0
Breast Cancer
after 5 years
Up to
11%
Breast Cancer
by age 70
Ca Epi Biomarkers Prev. 1999;8(10):855-61
JNCI 1999;15:1310-6
JCO 1998;16:2417-25
Lancet 1998;351:316-21
JCO 2004;22:2328-35
Lancet 1994;3343:692-5
Gynecol Oncol. 2005 Jan;96(1):222-6
Ovarian Cancer AFTER Breast
Cancer in BRCA carriers
• 10-fold increased risk compared to noncarriers
– No effective ovarian cancer screening
– Prophylactic bilateral salpingo-oophorectomy
recommended (NCCN)
J Clin Oncol. 1998 16:2417-242
Gynecol Oncol. 2005 Jan;96(1):222-6
www.nccn.org
Risks in Men With a BRCA Mutation
Risk of Cancer (%)
25
20%
20
General Population
BRCA Mutation*
15%
15
10
7%
5
<1%
Breast Cancer
by age 80
Prostate Cancer
by age 80
*Risks refer to BRCA2 mutation carriers.
Risks for male BRCA1 mutation carriers are less characterized
JCO 2004;22: 735-42
NCI 2005
Medical Management Options for
Hereditary Breast and Ovarian
Cancer
• Increased Surveillance
• Breast- Self exam, clinical exams, mammograms, MRI
• Ovary- CA-125, pelvic exam, transvaginal ultrasound
• Chemoprevention
• Breast- Tamoxifen
• Ovary- Oral Contraceptives
• Prophylactic surgery
• Bilateral Mastectomy
• Bilateral Salpingo-oophorectomy
JAMA 2000; 283:617-24
Surveillance for Breast Cancer
Procedure
Age to begin
Frequency
Breast self-exam
18 yrs
Monthly
Clinical breast
exam
25 yrs
Twice a year
Mammography
25 yrs
Yearly
MRI
25 yrs
Yearly
www.nccn.org
Cancer 2004;100:479-89
NEJM 2004;351:427-37
Chemoprevention of Breast Cancer
Tamoxifen
• Affected BRCA carriers: 50% decrease for
contralateral breast cancer
• Unaffected BRCA2 carriers: 62% decrease
• Unaffected high-risk: 45% decrease
• Aromatase inhibitors are currently under investigation
Int J Cancer. 2006;118(9):2281-4
Lancet 2000;356:1876-81
JAMA 2001;286:2251-6
JNCI 1998; 90:1371-88
Chemoprevention of Ovarian Cancer
Oral Contraceptives
• Up to 60% risk reduction for ovarian cancer
• Current literature supports there is no evidence
that current low-dose oral contraceptive formulations
increase the risk of early onset breast cancer for
mutation positive individuals
NEJM 1998; 339:424-8
NEJM 2001;345:235-40
JNCI 2002;94:1773-9
Ca Epi Biomarkers Prev. 2005 Feb;14(2):350-6
Prophylactic Mastectomy
Greater than 90% breast cancer risk reduction in BRCA carriers
• Total (simple) mastectomy more effective than
subcutaneous mastectomy
NEJM 2001;345:159-64
JNCI 2001;93:1633-7
JCO 2004;22:1055-62
BJC 93(3):287-92
Prophylactic Oophorectomy
Recommend bilateral salpingo-oophorectomy (BSO)
at age 35 or after childbearing is complete
• ~96% ovarian cancer risk reduction in BRCA
carriers
• Can reduce breast cancer risk by up to 68% for
both BRCA1 and BRCA2 mutation carriers
JAMA. 2006;296:185-92
Clin Oncol. 2005 Mar 10;23(8):1656-63
NEJM 2002;346:1609-15
www.nccn.org
Managing Hereditary vs Sporadic
Breast and Ovarian Cancer
Breast Cancer Patient
Sporadic
BRCA1/BRCA2
2nd Primary (after Br Ca)
• Breast Cancer
• Ovarian Cancer
2-11%
1-2%
50-64%
10x increase
Surveillance
• Annual Mammography
• Annual MRI
• TV US, Pelvic, CA-125
Yes
Not Indicated
Not Indicated
Yes
Yes
Yes
↓ Contralateral br ca 50%
Chemoprevention
• Tamoxifen
Dependant on
ER/PR status
Surgical Options
• Mastectomy
• Oophorectomy (BSO)
Based on tumor ↓ Br ca >90%
Not Indicated ↓ Ov ca 96%, ↓ Br ca 68%
Interpreting Test Results
d.82
Diabetes
80
d.71
MI
d.65
Breast
ca 47
47
Prostate
ca 60
Prostate
cancer
Breast
cancer
55
45
Breast ca 49
BRCA1 +
25
23
22
Interpreting Test Results
d.82
Diabetes
80
d.65
d.71
Breast
ca 47
MI
47
Prostate
ca 60
Prostate
cancer
Breast
cancer
55
45
Breast ca 49
BRCA negative
25
23
22
Positive vs. Negative Result
Positive BRCA1/2
Negative BRCA1/2
Patient
2nd breast ca
•27% within 5 years
•1% per year
Patient
ovarian cancer
10-fold increase over
general population
Not significantly
increased
Management
considerations
BSO; bilateral
Consider mammo for
mastectomy; use of
relatives at younger
MRI if breast conserved age
Relatives’ risk
High – breast and
ovarian cancer, offer
genetic testing
Moderately increased
for breast cancer only
Epidemiology of Colorectal Cancer
Sporadic
(~60%)
Familial
(~30%)
Rare
FAP (~1%)
Syndromes
MAP (~1%)
(~4%)
HNPCC
(3-5%)
Cancer 1996;78:1149-67
Am J Med 1999;107:68-77
Gastroenterology 2000;119:837-53
Am J Path 2003;162:1545-8
Hereditary Colorectal
Cancer (CRC) Syndromes
Nonpolyposis (few to no adenomas)
HNPCC – CRC and/or endometrial cancer (EC)
Polyposis (multiple adenomas)
FAP – Severe colonic polyposis +/- CRC
AFAP – Less severe colonic polyposis +/- CRC
MAP – Varying degrees of colonic polyposis +/- CRC
Hereditary Nonpolyposis
Colorectal Cancer (HNPCC)
HNPCC
(3-5%)
MLH1
Other
MSH6
MSH2
Cancer 1996;78:1149-67
J Clin Oncol 2003;21:1174-9
J Clin Oncol 2004;22:4486-94
“Red Flags” for
HNPCC/Lynch Syndrome
• Early onset colorectal cancer (<50y)
• Early onset endometrial cancer (<50y)
• Two or more HNPCC cancers in an individual
or family*
*HNPCC cancers: colorectal, endometrial, gastric, ovarian,
ureter/renal pelvis, biliary tract, small bowel, pancreas, brain,
sebaceous adenoma
HNPCC Increases Lifetime
Cancer Risk
100
General Population
HNPCC
Up to 80%
Risk of Cancer (%)
80
Up to 71%
*Ureter/renal pelvis
*Biliary tract
*Small bowel
*Pancreas
*Brain
*Sebaceous adenoma
60
40
20
13%
12%
7%
1.5%
2%
0
CRC
Endometrial
Ovarian
Gastroenterology 1996;110:1020-7; Int J Cancer 1999;81:214-8;
Gastroenterology 2004;127:17-25; Gastroenterology 1996;110:1020-7;
Int J Cancer 1999;81:214-8
<1%
Gastric
<1%
<5%
Other*
HNPCC Increases
Risk of Second Cancer
General Population
HNPCC
60
Risk of Cancer (%)
50%
40
30%
20
3.5%
5%
0
Within 10 yrs
Within 15 yrs
Cancer 1977;40:1849
Dis Colon Rectum 1986;29:160
Cancer 1993;36:388-93
Hereditary vs Sporadic
Colorectal Cancer
Colon Cancer Patient
Sporadic
HNPCC/Lynch
2nd HNPCC cancer
(**colorectal/endometrial)
5%/1.5%
50%
<1%
N/A
annual
•TV US, Pelvic, CA-125
1 yr, then
every 2-3yr
Not Indicated
25-35y
Surgical Options
•Colectomy
• TAH-BSO
Not Indicated
Not Indicated
Consider at CRC diagnosis
↓ Endo ca 100%,↓ Ov ca 95%
Ovarian Cancer
Surveillance
• Colonoscopy
Rationale for Frequent Colonoscopy
• Accelerated progression from adenoma to cancer
– HNPCC, 1-3 years
– General population, 5-10 years
• Adenomas/cancers are often right-sided in HNPCC
• Reduces CRC risk by more than 50%, overall mortality
reduced by 65%
Gastroenterology 1993;104:1535-49
Am J Med 1999;107:68-77
Gastroenterology 2000;118:829-34
HNPCC Surgical Guidelines
• Colorectal cancer or more than one advanced adenoma
– 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
Hereditary Colorectal Cancer
Adenomatous Polyposis Syndromes
• The majority of colonic adenomatous polyposis
is caused by mutations in one of two genes
– APC
– MYH
• The conditions associated with mutations in
these genes include:
– Familial Adenomatous Polyposis (FAP)
– Attenuated Familial Adenomatous Polyposis (AFAP)
– MYH-Associated Polyposis (MAP)
Am J Gastroenterol 2006;101(2):385-98.
Various Presentations of
Adenomatous Polyposis Syndromes
Condition:
FAP
AFAP
MAP
Gene:
APC
APC
MYH
Inheritance
Pattern:
Autosomal
Dominant
Autosomal
Dominant
Autosomal
Recessive
Polyp
Number:
100 or more
Less than 100
0 - 1000
Additional
Information
20-30% of cases will be first
affected individual in family
• Variable presentation and clinical overlap
necessitates testing for all three conditions
Am J Gastroenterol 2006;101(2):385-98.
Hereditary Melanoma
Other genes:
CDK4, p14ARF
(~2%)
~10%
p16
(20%-40%)
Unknown
Genes
(~ 60%)
Sporadic
Hereditary
© 2006 Myriad Genetic Laboratories, Inc.
“Red Flags” for
Hereditary Melanoma
• ≥ 2 melanomas in an individual or family
• Melanoma and pancreatic cancer in the same
individual or family
• Relatives of individuals with a known p16 mutation
© 2006 Myriad Genetic Laboratories, Inc.
A p16 Mutation Increases
Melanoma Risk
*US population
J Natl Cancer Inst 2002;94:894-903
Int J Cancer 2000;87:809-11
American Society of Clinical Oncology
Guidelines for Genetic Testing
• Personal or family history features suggestive of
a genetic cancer susceptibility condition
• Test can be adequately interpreted
• Test results will aid in diagnosis or influence
medical management of the patient and/or
family
JCO 2003; 21:2397-2406
Societal Standards and Guidelines
• ACCC- Association of Community Cancer Centers
• AMA- American Medical Association
• ASBS- American Society of Breast Surgeons
• ASCO- American Society of Clinical Oncology
• NCCN- National Comprehensive Cancer Network
• ONS- Oncology Nurses Society
• SGO- Society of Gynecologic Oncologists
• SSO- Society of Surgical Oncology
• USPSTF- U.S. Preventive Services Task Force
Genetic Testing
• Benefits
– Allows for individualized medical management
– Accurate risk assessment
– Alleviates uncertainty and anxiety
• Limitations
– Positives and true negatives are most
informative results
– Genetic testing does not identify all causes of
hereditary cancer
© 2006 Myriad Genetic Laboratories, Inc.
Insurance Coverage of
Genetic Testing
• All major carriers provide coverage for
genetic testing
• Established guidelines
– Medicare
– Most major carriers
© 2007 Myriad Genetic Laboratories, Inc.
Genetic Discrimination
Myth versus Reality
• Federal and state laws prohibit the use of genetic
information as a ‘pre-existing condition’
– Federal HIPAA legislation
– The majority of states have additional laws
• Over 175,000 clinical tests performed to date
• No documented cases of genetic discrimination
AJHG 2000;66:293-307
In Summary:
Screen for “Red Flags”
1.
•
•
•
•
•
Cancer <50 (Breast, Colorectal, Endometrial)
Multiple primaries
Constellation of specific cancers
Family history
Jewish ancestry
2.
Discuss genetic testing options
3.
Establish appropriate medical management plan