Rafael CATANE [Uyumluluk Modu]

Hereditary Cancers:
assessment of risk and
genetic counseling
Raphael Catane, M. D.
Sheba Medical Center
Tel Hashomer, Israel
Istanbul, Feb 5, 2010
Cancer is the result of
a series of changes in
the cell genome
Genomic Changes
• Can be Hereditary “GERMLINE”
• Can be new “SOMATIC” (caused during
life, usually from environmental changes,
or from “wear and tear”)
Cancers in which Heredity or germline
genomic are a major Factor
• Occur at a younger age
• Multiple tumors
• Family history
Most cancers are not inherited
10-15% familial
5-10% hereditary
75-85%
% sporadic
Genetic testing should be offered:
• Patient has characteristics of
hereditary cancer [young, multiple,
family]
• Adequate test
• Results will improve management
Introduction to
Genetic
Counseling in
breast and colon
cancer
Breast Cancer
n
8
Causes of Hereditary Breast
Cancer [5-10%
% of all breast cancers]
Gene
Contribution to Hereditary
Breast Cancer
BRCA1
BRCA
1
20%
20
%–40
40%
%
BRCA2
BRCA
2
10%
10
%–30
30%
%
TP53
TP
53 (Li Fraumeni)
<1%
PTEN (Cowden)
<1%
Other and undiscovered
genes
20%
20
%–50
50%
%
Hereditary Breast-Ovarian
Breast
Cancer
Syndrome
• BRCA1 on chromosome 17q21
(discovered 1994)
• BRCA2 on chromosome 13q12-13
(discovered 1995)
RAD51, BRCA1 and BRCA2 in
DNA Damage Repair
From: Welsch PL, Owens KN, King MC. Trends in Genet 2000, 16:69-74.
BRCA1-Associated
Associated Cancers: Risk
by age 70
Breast cancer 50-85
85% (often early age at onset)
Second primary breast cancer 20%-60%
Ovarian cancer 15-45
45%
Possible increased risk of other
cancers (e.g., prostate)
BRCA2-Associated
Associated Cancers: Risk
by age 70
breast cancer
(40-85%)
ovarian cancer
(10-30%)
male breast cancer
(6%)
Increased risk of prostate,
laryngeal, and pancreatic cancers
(magnitude unknown)
Cancer site effect: Risk in BRCA1
BRCA carriers
Carrier relatives of ovarian
cancer index cases (n=133)
Cancer risk
Cancer risk
Carrier relatives of breast
cancer index cases (n=334)
Simchoni
imchoni et al, Proc Natl Acad Sci, USA; March 2006
Cancer site effect: Risk in BRCA2
BRCA carriers
Carrier relatives of ovarian
cancer index cases (n=71)
Cancer risk
Cancer risk
Carrier relatives of breast
cancer index cases (n=132)
Simchoni
imchoni et al, Proc Natl Acad Sci, USA; March 2006
The BRCA mutations
are inherited with
autosomal dominant
genetics
BRCA -mutation
mutation positive family
Breast, dx 40
d. 43
d. 83
Ovary, dx 45
d. 47
Unaffected
Prostate, dx 58
Mutation carrier
38
Breast, dx 33
42
35
Affected with
cancer
BRCA1 and BRCA2
BRCA are
Tumor Suppressor
Genes
Women in Whom Genetic Testing
for BRCA Should be Considered
•
Early onset breast cancer
•
Bilateral breast cancer
•
Breast and ovarian cancer
•
Suggestive family histories
What can be Gained by Performing
BRCA Genetic Testing
•
For a patient with breast cancer
•
For a healthy woman
For Healthy Woman at High Risk
•
Alleviate fear if not carrier
•
Increase intensity of follow-up
follow
[MRI]
•
Prophylactic oophorectomy.
•
Prophylactic mastectomy?
•
Chemoprevention??
For a Patient with Breast Cancer
•
Oophorectomy ASAP
- Prevents ovarian cancer
- Improves outcome of breast cancer
•
Mastectomy instead of lumpectomy?
•
Bilateral mastectomy?
Testing for BRCA
For
Against
• Relief if negative
• Oophorectomy will
prevent ovarian
cancer and reduce
risk of breast cancer
• Other preventive
measures and close
follow-up [MRI]
• Clear knowledge of
situation
• Increased anxiety if
positive
• Family distress and
insurance problems
• Workplace
discrimination
• Cost
• Possibility of
inconclusive results
Olaparib
A novel, orally active PARP inhibitor
A phase I trial identified olaparib (AZD2281;; KU-0059436)
KU
•
400 mg bid as the maximum tolerated dose1 with a signal of efficacy
in BRCA-mutated ovarian cancer2
• Most common toxicities: CTCAE
grade 1 and 2 nausea and fatigue
• Significant PARP inhibition and tumor
response at olaparib doses 100–400
mg bid
1. Yap T et al. J Clin Oncol 2007;25(18S):abst 3529; 2. Fong P et al. J Clin Oncol 2008;26(15S):abst 5510.
Sporadic colorectal cancer
---------------------------------------------------------------------------------------Estimated lifetime risk of developing colorectal cancer (CRC)
FAMILY HISTORY
LIFETIME RISK OF CRC
---------------------------------------------------------------------------------------No family history of colorectal cancer
3%
One affected first degree relative(a)
6%
One affected first degree relative and two
affected second degree relatives
8%
One first degree relative affected under age 45
10%
Two affected first degree relatives
17%
HNPCC (mutation carrier)
70%
FAP (mutation carrier)
100%
FAMILIAL ADENOMATOUS
POLYPOSIS (FAP)
• Up to thousands of adenomatous polyps
in the colon
• Start at 10 to 20 years of age
• Symptoms at 20-40 years of age
• Risk of colon cancer – 100%
• Treatment: prophylactic colectomy
Adenomatous polyposis
Familial Adenomatous Polyposis
Genetic testing (APC) will help decide
earlier who need intensive monitoring, and
eventually might need colectomy
FAP, Extra-Colonic
Colonic Cancers
Hepatoblastoma
CNS
G astric
Thyroid
Pancreatic
Periampullary
Life-time Risk
(%)
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
LYNCH syndrome = HNPCC
• Hereditary non-polyposis
polyposis colorectal cancer
• The most common form of hereditary CRC
• Lynch 1:: Tumors exclusively located in colon
• Lynch 2:: Extracolonic tumors
0
Small bow el
CNS
B iliary
R enal cell
tract
U rinary
Gastric
Ovarian
L ife tim e ris k
(%)
Endometrial
HNPCC, Extra-Colonic
Colonic Cancers
40
35
30
25
20
15
10
5
DNA mismatch repair genes
A gene family that is responsible for
maintaining the integrity of the human
genome by making sure that DNA
mismatches during DNA replication are
corrected
Genotype =
MMR gene mutation
Phenotype =
Microsatellite instability
MICROSATELLITE INSTABILITY
Microsatellites = Very short
nucleotide sequences repeated
tandemly
[for example -AC-AC-AC
AC-AC-]
Microsatellite Instability (MSI)
•
No MSI
N: -CCTG(AC)nTTAGT: -CCTG(AC)nTTAGN=normal tissue
•
Yes MSI
N: -CCTG(AC)nTTAGT: -CCTG(AC)n+xTTAGT=tumor
3, 4, 6 No MSI; 1, 2, 5, 7 Yes MSI
CLINICAL SIGNIFICANCE OF MSI
• All HNPCC [germ line mutation]
• 15% of sporadic CRC [somatic methylation]
- Proximal
- Good prognosis
- Response to chemotherapy?
TREATMENT of Affected Patient
• Subtotal colectomy
• Chemoprevention? [NSAIDS]
• Surveillance by colonoscopy & biopsies
Time interval from Polyp to
Carcinoma
• Normal
8-10 years
• HNPCC
2-3 years
• Thus colonoscopy should be performed
every 5-10 years in normal (hi-risk)
(hi
individuals, and every 1-3 years in HNPCC
SCREENING RECOMMENDATIONS
• Complete colonoscopy every 1-3 years
• Should start at an age 10 years younger
than the earliest colonic cancer case in
the family
• Screening should be tailored according to
additional cancers running in the family
Summary: Who should be tested
• For APC: Young family members of
carriers
• If positive: yearly colonoscopy.
• When polyposis becomes evident:
Subtotal colectomy with annual
endoscopy of the remaining rectum
Summary: Who should be tested
• For HNPCC: All family member of known
carriers, those with a young age of onset
of colon ca. and/or familial cases of colon
ca. without adenomas
Practical Management for
Suspected HNPCC
• If known family member affected, check
for the known mutation
• If no known mutation:
1.. Assess Microsatellite Instability
2.. If positive, check for mutations in
MSH2 and MLH1 (=70
70% of HNPCC)
When Should Genetic Testing Be
Considered?
• Genetic testing should always be
performed in the context of genetic
counseling
– Discuss all medical and social concerns
– Provide psychosocial support
• It is easier to review the implications of
testing prior to obtaining results