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Evidence-based detection and management of hereditary breast cancer syndromes
Kristen Mahoney Shannon, MS, CGCProgram Manager/Sr. Genetic CounselorMGH Center for Cancer Risk AssessmentApril 13, 2012
Lecture Overview
Detection• Identifying Risk• Personal / Family history• Genetic Testing• Syndromes
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
Association between population frequencyand relative risk for breast cancer
Foulkes W. N Engl J Med 2008;359:2143-2153
Rel
ativ
e R
isk
of D
evel
opin
g C
ance
r
Frequency in the Population (Percent)
Detection of At-Risk Individuals
Comprehensive Risk AssessmentA Classic Hereditary Breast/Ovarian A Classic Hereditary Breast/Ovarian
Cancer KindredCancer Kindred
Breast, 49Breast, 497373
Breast, 38Breast, 385555
Breast, 29Breast, 29Ovary, 42Ovary, 42
d 45d 45
6262
2929
Breast, 49Breast, 495757
8080
Breast, 32Breast, 32
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
Family HistoryFamily History
Physical ExamPhysical Exam
Personal Medical HistoryPersonal Medical History
Genetic Testing
Gene Panel Gene Panel TestingTesting
Single Gene Single Gene TestingTesting
Hereditary Breast/Ovarian Cancer (HBOC)
A Classic Hereditary Breast/Ovarian A Classic Hereditary Breast/Ovarian Cancer KindredCancer Kindred
Breast, 49Breast, 497373
Breast, 38Breast, 385555
Breast, 29Breast, 29Ovary, 42Ovary, 42
d 45d 45
6262
2929
Breast, 49Breast, 495757
8080
Breast, 32Breast, 32
BRCA1 and BRCA2
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
Non-carrier
Breast Cancer Incidence (Penetrance)
In Different BRCA1 and BRCA2 Carrier Populations
Non-carrierNon-carrier
Breast Cancer Incidence (Penetrance)
In Different BRCA1 and BRCA2 Carrier Populations
• Lifestyle factors• Location in the gene• “Modifier” gene allelotypes• Hormonal Interventions
Cha
nce
of
Re
ma
inin
g C
ance
r F
ree
(Op
po
site
Bre
ast)
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) criteriaProband diagnosed with a sarcoma before 45 years of age; andA first degree relative with cancer diagnosed before 45 years of age; andA 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) criteriaProband with any childhood cancer or sarcoma, brain tumor, or adrenocortical carcinoma diagnosed before 45 years of age; andFirst 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 criteriaProband 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 ageA 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 historyA 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
0
20
40
60
80
100
15-
20y
40-
45y
50y 80y
Ris
k of
can
cer
Nichols, K.E., et al., Cancer Epidemiol Biomarkers Prev, 2001. 10(2): p. 83-7Hwang, 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.
57% risk of 2nd primary38% risk of 3rd primary
Other tumors:Colorectal cancer Endometrial cancerEsophageal cancerGonadal germ cell tumorHematopoietic malignancies (leukemias and lymphomas) Lung cancerMelanoma and non-melanoma skin cancerNeuroblastomaOvarian cancerPancreatic cancerProstate cancerStomach cancerThyroid cancer Wilms’ tumor and other kidney cancers
Cowden Syndrome (PTEN gene)
37 yrrecurrent goiter since 16 yrDCIS, 35oral mucosal papillomatosishead circumference 60 cm
33 yr 35 yr enlarged thyroid
65 yr 56 yr
65 yrcolon polyps
head circumference 62 cmoral mucosal papillomatosis
70 yr 67 yr
32 yr 42 yr 40 yr
91 yr 94 yr lung cancer 75 yr cancer, unspecified
Courtesy of G. Chan-Smutko, MGH
Cowden Syndrome (PTEN gene)
Images referenced from:
Gene reviews: http://www.ncbi.nlm.nih.gov/books/NBK1488/
Emedicine: http://emedicine.medscape.com/article/1059940-overview
Cutaneous features (90-100%) (Oral) mucosal papillomas coalesce into “cobblestone” surface Trichilemmomas (facial) Acral keratoses (palmar/plantar) Papillomatous lesions
trichilemmoma
Identifying Cowden Syndrome
http://www.lerner.ccf.org/gmi/ccscore/
Cowden Syndrome Cancer Risks
Tumor Site RiskPilarski R. JGC.2009;18:13-27
RiskTan 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
39 4035THY 29
69 33STO 32
70 60 57 66BR 58BR 66
STO 67
51STO 50
81BR 77
7873BR 66
65OV
75 86BR 75
45?CA
32
56 3
58BR 56
24
65 80
4749
2
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
0
10
20
30
40
50
60
70
80
90
30years 50 years Lifetime
Women
Men
Diffuse Gastric Cancer Risk in CDH1 carriers by Age
Lobular Breast Cancer Risk =
39-51%
Peutz-Jeghers Syndrome (PJS)
STK11 gene
Melanotic macules, intestinal polyps, increased cancer risk
Identifying PJS
• 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
Clinical Diagnosis
Beggs, et al (2010)
PJS Cancer Risks
Cancer Risks:
Pancreas
Liver
Lungs
Breast
Ovaries
Uterus
Testicles
other
Low-Moderate Penetrant Genes
Description Genes
Genes functionally related to BRCA1 and BRCA2
ATMBARD1CHEK2
MRE11ANBN
RAD50RAD51C
(other) Genes in the Fanconi Anemia Pathway
BRIP1PALB2
Genes involved in hereditary colorectal cancer
MLH1MSH2MSH6PMS2MYH
2-4x RR of breast cancer
Managing Breast Cancer Risk
• 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
For BRCA carriers:
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
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
• Decreases risk of breast cancer ~50%• Decreases risk of ovarian cancer ~90%
Management – Other cancers
Gene Cancer Risk Screening Begin at age Frequency Surgery
BRCA1/2 Prostate PSA/DRE As directed annual Not discussed
Pancreatic Investigational (EUS/MRI)
10 years earlier than panc dx
annual Not discussed
Male Breast BSECBEConsider mammo
353540
MonthlyQ 6moannual
Not discussed
LFS 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 Cancer Risk Screening Begin at age Frequency Surgery
Cowden Thyroid U/S & bloodwork 18 Considerannual
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
HDGC 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
PJS 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 AssessmentBreast/Ovarian Cancer Genetics Program
Leif Ellisen, MD, PhD, DirectorGayun Chan Smutko, MS, CGCDevanshi Patel, MS, CGCMichele Jacobs Gabree, MS, CGCJanette Lawrence, MS, CGCErica Blouch, MS, CGCMeredeth Seidel, MS, CGC
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