Date

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