Transcript 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 A
t 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 1 damaged gene 1 normal gene 2 damaged genes
Tumor develops
In hereditary cancer, one damaged gene is inherited.
1 damaged gene 1 normal gene 2 damaged genes
Tumor develops
© 2006 Myriad Genetic Laboratories, Inc.
Hereditary Breast and Ovarian Cancer
Most cases caused by a BRCA1 or BRCA2 mutation
Other genes
BRCA1
52%
BRCA2
32% 7-10% Sporadic Hereditary
AJHG
1998;62:676-89
JCO
2002;20:1480-1490
“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
100 80 60 40 20 Up to 50% Up to 87% General Population
BRCA
Mutation Up to 44% 8% 2% <1% Breast cancer by age 50 Breast cancer by age 70 Ovarian cancer by age 70
Lancet NEJM
1994;343:692-695 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% General Population
BRCA
Mutation 60 40 Up to 27% 20 Up to 3.5% Up to 11% 0 Breast Cancer after 5 years 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
25 20% 20 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 General Population
BRCA
Mutation*
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 Breast self-exam Clinical breast exam Mammography MRI Age to begin 18 yrs 25 yrs 25 yrs 25 yrs Frequency Monthly Twice a year Yearly Yearly
www.nccn.or
g
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 JNCI
2001;345:235-40 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
both
BRCA1
and cancer risk by up to 68% for
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 2 nd Primary (after Br Ca) • Breast Cancer • Ovarian Cancer Surveillance • Annual Mammography • Annual MRI • TV US, Pelvic, CA-125 Chemoprevention • Tamoxifen Surgical Options • Mastectomy • Oophorectomy (BSO) Sporadic 2-11% 1-2% Yes Not Indicated Not Indicated Dependant on ER/PR status
BRCA1/BRCA2
50-64% 10x increase Yes Yes Yes ↓ Contralateral br ca 50% Based on tumor Not Indicated ↓ Br ca >90% ↓ Ov ca 96%, ↓ Br ca 68%
Interpreting Test Results d.82
Diabetes Prostate ca 60 Prostate cancer Breast cancer 80 55 25 MI d.71
Breast d.65
ca 47 Breast ca 49
BRCA1 +
23 47 45 22
Interpreting Test Results d.82
Diabetes Prostate ca 60 Prostate cancer Breast cancer 80 55 25 MI d.71
Breast d.65
ca 47 47 Breast ca 49
BRCA negative
23 45 22
Positive vs. Negative Result Patient 2 nd breast ca Patient ovarian cancer Management considerations Relatives’ risk Positive BRCA1/2 •27% within 5 years Negative BRCA1/2 •1% per year 10-fold increase over general population Not significantly increased BSO; bilateral mastectomy; use of MRI if breast conserved High – breast and ovarian cancer, offer genetic testing Consider mammo for relatives at younger age Moderately increased for breast cancer only
Epidemiology of Colorectal Cancer
Sporadic (~60%) Familial (~30%) Rare Syndromes (~4%) FAP (~1%) MAP (~1%) 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%) Other MSH6 MLH1 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
100
HNPCC Increases Lifetime Cancer Risk
General Population HNPCC Up to 80% 80 Up to 71% 60 40 *Ureter/renal pelvis *Biliary tract *Small bowel *Pancreas *Brain *Sebaceous adenoma 20 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 13% <1%
Gastric
<1% <5%
Other*
60
HNPCC Increases Risk of Second Cancer
General Population HNPCC 50%
40
30%
20 0
3.5%
Within 10 yrs
5%
Within 15 yrs
Cancer
1977;40:1849
Dis Colon Rectum Cancer
1986;29:160 1993;36:388-93
Hereditary vs Sporadic Colorectal Cancer
Colon Cancer Patient 2 nd HNPCC cancer (**colorectal/endometrial) Ovarian Cancer Surveillance • Colonoscopy •TV US, Pelvic, CA-125 Surgical Options •Colectomy • TAH-BSO Sporadic 5%/1.5% <1% 1 yr, then every 2-3yr Not Indicated Not Indicated Not Indicated HNPCC/Lynch 50% N/A annual 25-35y Consider at CRC diagnosis ↓ Endo ca 100%,↓ Ov ca 95%
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: Gene: Inheritance Pattern: Polyp Number: Additional Information FAP
APC Autosomal Dominant 100 or more
AFAP
APC Autosomal Dominant Less than 100 20-30% of cases will be first affected individual in family
MAP
MYH Autosomal Recessive 0 - 1000 • 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%)
p16
(20%-40%) Unknown Genes (~ 60%) ~10%
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:
1.
• • • • • Screen for “Red Flags” 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