Transcript Center for Cancer Risk Assessment

Evidence-based detection and management of
hereditary breast cancer syndromes
Kristen Mahoney Shannon, MS, CGC
Program Manager/Sr. Genetic Counselor
Date
MGH Center
for Cancer Risk Assessment
April 13, 2012
Lecture Overview
Detection
• Identifying Risk
• Personal / Family history
• Genetic Testing
• Syndromes
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



Hereditary Breast/Ovary Cancer Syndrome (HBOC)
Li-Fraumeni Syndrome (LFS)
Cowden Syndrome
Hereditary Diffuse Gastric Cancer (HDGC)
Peutz-Jeghers Syndrome (PJS)
Management
• Cancer Screening
• Cancer Risk Reducing Surgeries
• Psychosocial Management
Relative Risk
of Developing Cancer
Association between population frequency
and relative risk for breast cancer
Frequency in the Population (Percent)
Foulkes W. N Engl J Med 2008;359:2143-2153
Detection of At-Risk Individuals
Comprehensive Risk Assessment
A Classic Hereditary Breast/Ovarian
Family
CancerHistory
Kindred
Breast, 49
73
Breast, 38
55
Breast, 29
Ovary, 42
d 45
Breast, 32
Personal Medical History
Non-familial Risk Factors
•Early menarche/late menopause
• Nulliparity or late pregnancy
• OCP use/hormonal exposures
• Breast irradiation (during puberty)
• Breast density
• High BMI/Obesity
• Atypical hyperplasia/ Lobular
Carcinoma in Situ
80
Breast, 49
57
62
29
Physical Exam
Genetic Testing
Single Gene
Testing
Gene Panel
Testing
Hereditary Breast/Ovarian Cancer (HBOC)
A Classic Hereditary Breast/Ovarian
BRCA1 and BRCA2
Cancer Kindred
Breast, 49
73
Breast, 38
55
Breast, 29
Ovary, 42
d 45
Breast, 32
80
Breast, 49
57
29
62
BRCA1 and BRCA2 phenotype
Breast Cancers
• BRCA1 – 80% are triple negative
• BRCA2 – garden variety
Ovarian Cancers
• Endometriod, serous (BRCA1 and BRCA2)
• Serous papillary (BRCA1)
• NOT borderline tumors
Identifying BRCA carriers
HBOC Cancer Risks
Breast Cancer Risk
BRCA1: 50-80%
BRCA2: 40-70%
Ovarian Cancer Risk
BRCA1: 40-60%
BRCA2: 15-20%
Other Cancer Risk
Male Breast: <6-7%
Pancreatic: 1.3-7%
Prostate:
<30-40%
HBOC Cancer Risks Can Be Modified
•
•
•
•
Lifestyle factors
Location in the gene
“Modifier” gene allelotypes
Hormonal Interventions
Breast Cancer Incidence (Penetrance)
Non-carrier
Chance of Remaining Cancer Free
(Opposite Breast)
In Different BRCA1 and BRCA2 Carrier Populations
Metcalfe K et al JCO 22:2328, 2004
Li-Fraumeni Syndrome (TP53 gene)
Component Tumors:
•Sarcoma
•Breast Cancer
•Brain tumors
•Leukemia (childhood)
•Adrenal cortical
carcinoma
Identifying LFS
Table 1: Clinical Criteria for Classic Li-Fraumeni Syndrome
Li-Fraumeni Like Syndrome, and Chompret Criteria
Classic Li-Fraumeni syndrome (LFS) criteria
Proband diagnosed with a sarcoma before 45 years of age; and
A first degree relative with cancer diagnosed before 45 years of age; and
A first of second degree relative on the same side of the family with cancer diagnosed before 45
years of age OR a sarcoma at any age
Li-Fraumeni Syndrome-Like (LFL) criteria
Proband with any childhood cancer or sarcoma, brain tumor, or adrenocortical carcinoma diagnosed
before 45 years of age; and
First or second degree relative with a component LFS cancer (sarcoma, breast cancer, brain tumor,
leukemia, or adrenocortical carcinoma) diagnosed at any age and;
One first or second degree relative on the same side of the family with any cancer diagnosed under
age 60
Chompret criteria
Proband diagnosed with a narrow spectrum cancer (sarcoma, brain tumor, breast cancer, or
adrenocortical carcinoma) before age 36 years, and at least one first or second degree relative
affected by a narrow spectrum tumor (other than breast cancer if the proband was affected by breast
cancer) before 46 years or a relative with multiple primary tumors at any age
A proband with multiple primary tumors, two of which belong to the narrow spectrum and the first
of which occurred before 36 years, regardless of family history
A proband with adrenocortical carcinoma, regardless of age at diagnosis or family history
*First degree relative is defined as parent, sibling, or child;
*Second degree relative is defined as grandparent, aunt, uncle, niece, nephew, or grandchild
LFS Cancer Risks
~75% of tumors are classic
component tumors
Risk of cancer
100
80
60
40
20
0
15-
40-
20y
45y
50y
80y
Nichols, K.E., et al., Cancer Epidemiol Biomarkers Prev, 2001. 10(2): p. 83-7
Hwang, S.J., et al., Am J Hum Genet, 2003. 72(4): p. 975-83. .
Chompret, A., et al., Br J Cancer, 2000. 82(12): p. 1932-7.
Le Bihan, C., et al.,. Genet Epidemiol, 1995. 12(1): p. 13-25.
Other tumors:
Colorectal cancer
Endometrial cancer
Esophageal cancer
Gonadal germ cell tumor
Hematopoietic malignancies (leukemias
and lymphomas)
Lung cancer
Melanoma and non-melanoma skin cancer
Neuroblastoma
Ovarian cancer
Pancreatic cancer
Prostate cancer
Stomach cancer
Thyroid cancer
Wilms’ tumor and other kidney cancers
57% risk of 2nd primary
38% risk of 3rd primary
Cowden Syndrome (PTEN gene)
91 yr
70 yr
32 yr
67 yr
42 yr
94 yr
lung cancer
75 yr
65 yr
colon polyps
head circumference 62 cm
oral mucosal papillomatosis
40 yr
33 yr
cancer, unspecified
65 yr
35 yr
enlarged thyroid
56 yr
37 yr
recurrent goiter since 16 yr
DCIS, 35
oral mucosal papillomatosis
head circumference 60 cm
Courtesy of G. Chan-Smutko, MGH
Cowden Syndrome (PTEN gene)
Cutaneous features (90-100%)




(Oral) mucosal papillomas  coalesce into “cobblestone” surface
Trichilemmomas (facial)
Acral keratoses (palmar/plantar)
Papillomatous lesions
trichilemmoma
Images referenced from:
Gene reviews: http://www.ncbi.nlm.nih.gov/books/NBK1488/
Emedicine: http://emedicine.medscape.com/article/1059940-overview
Identifying Cowden Syndrome
http://www.lerner.ccf.org/gmi/ccscore/
Cowden Syndrome Cancer Risks
Tumor Site
Risk
Pilarski R. JGC.2009;18:13-27
Risk
Tan et al. Clin Can Res. 2012;18(2):400-7
Breast
25-50%
85%
Thyroid
3-10%
35%
Endometrial
5-10%
28%
Renal Cell
Unknown
34%
Melanoma
Unknown
6%
Colon
Unknown
9%
Hereditary Diffuse Gastric Cancer
CDH1 gene
75
65
24
80
58
BR 56
49
47
45
?CA
69
33
STO 32
35
THY 29
39
73
BR 66
86
BR 75
65
OV
51
STO 50
70
40
81
BR 77
60
78
57
66
BR 58
BR 66
STO 67
32
2
6
5
3
Courtesy of D. Patel, MGH
Identifying HDGC
The International Gastric Cancer Linkage Consortium (IGCLC)
criteria:
• Two gastric cancer (GC) cases in family, one individual under age
50 years with confirmed diffuse gastric cancer (DGC)
• Three confirmed DGC cases in first- or second-degree relatives
independent of age
• Simplex case (i.e., a single occurrence in a family) of DGC
occurring before age 40 years
• Personal or family history of DGC and lobular breast cancer, one
diagnosed before age 50 years
Fitzgerald et al, 2010
HDGC Cancer Risks
Diffuse Gastric Cancer Risk in
CDH1 carriers by Age
90
Lobular Breast
Cancer Risk =
39-51%
80
70
60
50
Women
40
Men
30
20
10
0
30years
50 years
Lifetime
Peutz-Jeghers Syndrome (PJS)
STK11 gene
Melanotic macules, intestinal polyps, increased cancer risk
Identifying PJS
Clinical Diagnosis
• Two or more histologically confirmed PJ polyps
• Any number of PJ polyps detected in one individual
who has a family history of PJS in close relative(s)
• Characteristic mucocutaneous pigmentation in an
individual who has a family history of PJS in close
relative(s)
• Any number of PJ polyps in an individual who also has
characteristic mucocutaneous pigmentation
Beggs, et al (2010)
PJS Cancer Risks
Cancer Risks:
Pancreas
Liver
Lungs
Breast
Ovaries
Uterus
Testicles
other
Low-Moderate Penetrant Genes
Description
Genes functionally related to
BRCA1 and BRCA2
Genes
ATM
BARD1
CHEK2
MRE11A
NBN
RAD50
RAD51C
(other) Genes in the Fanconi
Anemia Pathway
BRIP1
PALB2
Genes involved in hereditary
colorectal cancer
MLH1
MSH2
MSH6
PMS2
MYH
2-4x RR
of breast
cancer
Managing Breast Cancer Risk
For BRCA carriers:
•
Breast self-exam training and education and
regular monthly BSE starting at age 18y
•
Semiannual clinical breast exam starting at age
25y
•
Annual mammogram and MRI screening starting
at age 25
•
Discuss option of prophylactic mastectomy on
case-by-case basis
•
Consider chemoprevention options for breast and
ovarian cancer
•
Consider investigational imaging and screening
studies
High-Risk Patient With MRI detected Breast Cancer:
Normal Mammogram
Courtesy of Dr. Phoebe Freer, MGH
MRI Detects an Apparent Cancer
Courtesy of Dr. Phoebe Freer, MGH
Risk Reducing Mastectomy
•
Bilateral prophylactic mastectomy decreases risk breast cancer ~90%
•
Prophylactic contralateral mastectomy decreases risk second breast cancer ~90%
Hartmann L NEJM 2001; Seynaeve C ASCO abs #102962 2002; Rebbeck T JNCI 1999; NEJM 2002;
Kauff N NEJM 2002
•
•
•
Uptake ~50%
More often in women w/ sister or mother w/ breast ca
Less when mom or sister had ovarian cancer
Skytte et al, Clin Genet 2010; Metcalfe et al Clin Genet 2008
Managing Ovarian Cancer Risk
• Recommend ovary/fallopian tube removal,
ideally between 35 and 40 y, or upon
completion of child-bearing
• For those who have not elected
ovary/fallopian tube removal, consider
concurrent ultrasound + Ca-125 every 6 mo
starting at age 35y or 5-10 y earlier than the
earliest age of first diagnosis of ovarian
cancer in the family
• Consider chemoprevention options for breast
and ovarian cancer
• Consider investigational imaging and
screening studies
Risk Reducing Oophorectomy
• Decreases risk of breast cancer ~50%
• Decreases risk of ovarian cancer ~90%
Hartmann L NEJM 2001; Seynaeve
C ASCO abs #102962 2002;
Rebbeck T JNCI 1999; NEJM 2002;
Kauff N NEJM 2002
• Uptake ~90%
• More often in women w/ mom or sister
with ov cancer
• BRCA2 carriers less
Skytte et al, Clin Genet 2010; Metcalfe et al Clin Genet 2008
Management – Other cancers
Gene
BRCA1/2
LFS
Cancer Risk
Screening
Begin at age
Frequency
Surgery
Prostate
PSA/DRE
As directed
annual
Not
discussed
Pancreatic
Investigational
(EUS/MRI)
10 years
earlier than
panc dx
annual
Not
discussed
Male Breast
BSE
CBE
Consider mammo
35
35
40
Monthly
Q 6mo
annual
Not
discussed
Brain
Investigational (MRI)
childhood
Annual
n/a
Sarcoma
Investigational (whole
body MRI)
childhood
annual
n/a
Leukemia
Investigational
Bloodwork
childhood
annual
n/a
Adrenal
Investigational MRI
childhood
annual
n/a
Colon
Consider Colonoscopy
25
2-5y
Per clinical
findings
Others
As directed
Management – Other cancers (cont.)
Gene
Cowden
HDGC
PJS
Cancer Risk
Screening
Begin at age
Frequency
Surgery
Thyroid
U/S & bloodwork
18
Consider
annual
Not discussed
Endometrial
Education
n/a
n/a
Consider
Renal Cell
Urinalysis
18
annual
Not discussed
Colon
Consider colonoscopy
35 (50?)
5-10y
Per clinical
findings
Melanoma
Consider derm exam
18
Annual
n/a
Stomach
Upper endoscopy w/ random
biopsies
20?
Q 6mo
Recommended
Colon
Consider colonoscopy
10 years younger
than youngest dx
or 35y
3-5
Not discussed
Colon
Colonoscopy
18
Annual
Per clinical
findings
Ovary / Uterus
Education
n/a
n/a
Consider
Testicular
Exam & u/s
Childhood
Annual
Not discussed
Small bowel
Upper endoscopy plus small
bowel examination (MR or CT
enterography, wireless capsule
endoscopy
8y
annual
Not discussed
Other Management Issues
• Education about signs and symptoms of cancer
• Education about heritability /
encourage family testing
• Education about prenatal diagnosis /
assisted reproduction
• Psychosocial Management
Summary
• Detection & Management
not straightforward
• Multidisciplinary effort
• Genetic Counselors /
Specialists
Acknowledgements
MGH Center for Cancer Risk Assessment
Breast/Ovarian Cancer Genetics Program
Leif Ellisen, MD, PhD, Director
Gayun Chan Smutko, MS, CGC
Devanshi Patel, MS, CGC
Michele Jacobs Gabree, MS, CGC
Janette Lawrence, MS, CGC
Erica Blouch, MS, CGC
Meredeth Seidel, MS, CGC