This document summarizes a presentation on genetic testing for cancer risk. The presentation covered: - The role of genetic cancer risk assessment in identifying inherited cancer risk. - Common hereditary cancer syndromes like BRCA1/2 and Lynch syndrome and their associated cancer risks. - Guidelines for cancer screening and management based on genetic test results. - The benefits and limitations of multi-gene cancer panels. - How to interpret genetic test results and provide appropriate risk management recommendations to patients.

1. FLASCO Fall Session, Orlando FL
Saturday, November 5th, 2016
Kathleen R. Blazer, EdD, MS, LCGC
Division of Clinical Cancer Genomics
City of Hope
Duarte, CA
Genetic Testing for Cancer Risk:
What you need to know

2. Disclosures
• I do not have any financial arrangements or affiliations with
any corporate organization relating to the topic being
presented

3. Genetic Cancer Risk Assessment
(GCRA)
• Interdisciplinary specialty practice that
uses genetic and genomic information to
– Identify individuals with inherited cancer risk
– Prescribe high-risk screening, preventive
care, targeted treatment
• Increasing demands for GCRA services in
community settings
• Guidelines/resources needed to help
community-based clinicians
• Recognize and refer patients
• Provide GCRA services
• Manage patients and families with cancer
predisposition

6. Learning Objectives
After this presentation, the participant should be able to:
• Identify patients with potential hereditary cancer risk
• Recognize the strategies and possible outcomes of genetic
testing for hereditary cancers
• Incorporate National Comprehensive Cancer Network (NCCN)
guidelines for cancer predisposition testing, high-risk cancer
screening and management into clinical practice

7. Sporadic, Familial, and
Strongly Hereditary Cancer
• 5% to 10% of cancers due to
high-penetrant hereditary
predisposition
• >50 single-gene syndromes
identified
• 15-20% ‘familial’ cancer clusters
• Shared environment
• Growing number of
low/moderate risk genes

8. Who Is at Risk for Hereditary Cancer?
Only a small proportion
of all cancers
heritable
Why do we want
to know who’s at
risk?

9. BRCA1- and BRCA2-Associated Cancers:
Lifetime Risk
Breast cancer 50%-85% (often early age at onset)
Second primary breast cancer 40%-60%
Ovarian cancer 15%-45%
Absolute risk >10%
- Prostate cancer
Absolute risk <10%
- Male breast cancer
- Pancreatic cancer
Proven risk reduction and early detection

10. Lynch Syndrome Cancers: Lifetime Risks
• Autosomal dominant
• DNA mismatch repair (MMR)
genes: MLH1, MSH2, MSH6,
PMS2, EPCAM/TACSTD1
Proven risk reduction and early detection
Lifetime Cancer Risks:
• Colorectal 40-80%
• Endometrial 25-60%
• Ovary 4-24%
• Stomach 1-13%
Up to 10% Risk for:
• Sebaceous neoplasm,
• Urinary tract, Small bowel,
• Pancreatic, Hepatobiliary

11. Young age at diagnosis
Rare tumor
Multiple Primary Cancers
When to Suspect Hereditary Cancer
Family History Syndromic Pattern

12. Document the Patient and Family History

13. Most Cancer Susceptibility Syndromes Are
Dominant With Incomplete Penetrance
Who in the family has cancer?
What is the primary cancer site?
What was their age at diagnosis?
Is there a pattern suggesting inherited risk?
• Individuals inherit susceptibility, not cancer
• May appear to ‘skip’ generations
• Different cancer types may be related to a single syndrome

14. Important to Verify Family History
Breast Ca
dx 45
d. 59, lung
mets
Revised based on pathology
reports
Ovarian Ca
dx 43, d. 50
Colon
polyps,
54
Breast and
Lung Ca
d. 59
Verbally reported pedigree
Colon
Ca, 54
Stomach Ca, 50
Engage the patient to help verify family history

15. Family Structure May Limit Risk
Assessment
Adequate Structure
60
Br 45
57 65
85
60 5358
8788 73
64 5562
Limited Structure
Br 45
57 60
85
60 59
8788 43
56 55 d.28
Accide
nt
Weitzel et al. 2007. Limited Family Structure and BRCA Gene Mutation
Status in Single Cases of Breast Cancer. JAMA. Vol. 297(23).

16. Case1: When to Test
Ana is a 51 year-old woman
with stage III, ER/PR/Her2 -
(triple negative) breast cancer
• Undergoing neoadjuvant
chemotherapy
• Family history of breast cancer
25
Breast 51
78
Breast 62
30 28
5557
80
48
30
76 70D. 48
Breast 40
D. 55
2
Would you recommend
genetic testing for this
patient?
42
Breast 35

17. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#genetics_screening
Triple negative histology
BC any age & family hx
BC and/or OVCa

18. BRCA1/BRCA2 full-gene
sequence analysis reveals a
deleterious BRCA1 mutation
(IVS18-1G>A)
Ana has breast cancer, and no
surgical treatment yet
BRCA1 IVS18-1G>A
25
Breast 51
78
Breast 62
30 28
5557
80
48
30
76 70D. 48
Breast 40
D. 55
2
Case 1: High-Risk Management
Does the BRCA1 mutation change
options for Ana’s treatment and/or risk
management?
42
Breast 35
How?

19. Hereditary Breast-Ovarian Cancer Syndrome
Risk Management
Management outcomes for women with BRCA1/2 mutations
Breast
Screening Annual mammograms and breast MRI
beginning at age 25
Chemoprevention Tamoxifen use for 5 years may reduce risk
by 50%
Risk reducing mastectomy Reduces risk by 90%
Ovarian
Risk reducing oophorectomy Oophorectomy recommended between 35-
40 years of age or at completion of
childbearing, reduces risk by ~90%
Chemoprevention Use of oral contraceptives for five years
reduces risk by 50%
Screening CA-125 blood test/transvaginal US every 6
months
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#genetics_screening

20. Case 1: What about family members?
Pos Neg
BRCA1
IVS18-1G>A
25
Breast 51
78
Breast 62
30 28
5557
80
30
76 70D. 55D. 48
Breast 40
48
Neg
NegPos
2
For Carriers Consider:
• Medical history (eg. Cancer, surgeries,
co-morbidities)
• Age
- Life stage/Quality of life
- Lifetime cancer risks
For Non-carriers:
• Population screening guidelines, BUT
• Consider other cancer patterns (ddx;
other side of family) What side of the family carries
the mutation?
42
Breast 35
• Perceived risk/Preferences
Who else would you test?

21. 25
Breast 51
78
Breast 62
30 28
5557
80
30
76 70D. 55D. 48
Breast 40
48
2
42
Breast 35
• What test was done?
– Recommend BRCA
arearrangement analysis if only
sequenced
• Could Ana’s breast cancer be
a phenocopy?
• Would you test anyone else?
What if Ana’s Result was Uninformative ?
Negative
What test would you order and
on who?

22. Lifetime Risk for Breast or Ovarian Cancer & Screening Guidelines
10-12%
(to age 80-90)
50 %
85 %
Average Risk
Moderate
Increased Risk
High Risk
(BRCA1/ BRCA2)
1.6%
BRCA2
20 %
50 %
Range of
risk
Ovarian
Cancer
Risk
Ovarian
Cancer
Risk
BRCA1
or
BRCA2
Gail: 5 yr 3.7%; Lifetime 23.7%
Tyrer-Cusik: 10 yr 10.9%; Lifetime 29.9 %
56 %
BRCA1
or
BRCA2
BRCA1
or
BRCA2
Range of
risk
40 %
60 %
BRCA1
Refs: 1American Cancer Society; 2 National Comprehensive Cancer Network;3 Gail et al. (1989)J Natl Cancer Inst 81:1879-1886; 4 Claus, et al.
(1994).Cancer. 73(3), 643-651
Breast
Cancer
Risk
Empiric breast cancer risk
for Ana’s unaffected sisters:
Breast
Cancer
Risk
New Primary
Breast
Cancer
Risk
Risk Recommendations:
• BSE monthly
• Clinical breast exam q 6 mos
• Annual Mammogram
• Annual breast MRI
• Option: Chemoprevention
*or 5-10 years before earliest breast
cancer in family
11%
40%
Counseled empiric
BC risk: 25-30%

23. Fatima is a 45-year-old woman
with a Stage IIIc ovarian cancer
s/p TAH/BSO w optimal debulking,
Chemo (CTx6)
Family history multiple cancers
Case 2: What Test to Order
Would you recommend
genetic testing for this patient?
What test? 20
d. 56
Br 49
Uterine 54
30
d. 57
Ca NOS
d. 52
CRC 48
59
36CRC 40
8075
OvCa
45

24. Multi-Gene Panels
Clinically available
•Supreme Court
ruling against
Myriad’s patent on
BRCA genes
•Rapid advances in
NGS technologies
Spectrum of Panels
Pan-cancer
Cancer-specific
Genes
included
in an
Ovarian-
Cancer
Panel

25. Cancer Multigene Panel Testing
Levels of Information

26. Fatima is a 45-year-old woman
with a Stage IIIc ovarian cancer
s/p TAH/BSO w optimal debulking,
Chemo (CTx6)
Family history multiple cancers
Case 2: What Test to Order
Multigene Panel Ordered (25 genes
associated with breast, ovary, GI,
other cancers) 20
d. 56
Br 49
Uterine 54
30
d. 57
Ca NOS
d. 52
CRC 48
59
36CRC 40
8075
OvCa
45
Results:
MSH2: del 1-9 (deleterious)

27. • Colonoscopy every 1-2 ys starting age 20-25 or 2-5 yrs before the earliest CRC
• Consider risk-reducing TAH/BSO between ages 35-40 or at completion of child bearing;
annual transvaginal ultrasound and endometrial sampling
• Consider upper endoscopy every 2-3 years beginning at 30-35; annual urinalysis
20%
Lifetime Risk for Colorectal Cancer to Age 80
5-6%
60%
80%
Average
(sporadic)
Moderate
(familial)
High
Lynch Syndrome
60%
Endometrial
Cancer
~50%
(2% per
year)
For
second
CRC
Ovarian
Cancer
9-12%
Lifetime Risks for Other
Lynch Syndrome Cancers
1-7%
Other
Cancers
(Renal
pelvis,
small bowel,
brain,
hepato-
biliary,
pancreatic)
40% 40%
20%
Gastric
Cancer
11-19%
*All recommendations are based on the NCCN Guidelines
Colorectal and Lynch Syndrome Screening & Risk Management Guidelines

28. 20
d. 56
Br 49
Uterine 54
30
d. 57
Ca NOS
d. 52
CRC 48
59
36CRC 40
7055
BRCA2 : K2950N (asparagine
for lysine @ a.a. 2950) VUS
Case 2: Additionlal Results
OvCa
45
Fatima’s multigene panel test
also had the following result:
How would you interpret this
result for the patient?
Would you test other family
members for this mutation?

29. Interpreting Variants of Uncertain Significance
(VUSs)
Classification Should other at-risk
relatives be tested?
Management
recommendations
Deleterious Yes High risk management
Likely deleterious Yes High risk management
Variant of uncertain
significance
Only for research purposes Empiric risk management
based on individual/family
risk factors
Variant favor
polymorphism
Only for research purposes Empiric risk management
based on individual/family
risk factors
Lindor NM et al. Human Mutation 2012

30. Summary
• Genetic cancer risk assessment requires recognition of patient
characteristics, family history, knowledge about genetic test options and
testing strategies
• Proper selection and interpretation of genetic test results essential to
providing appropriate personalized risk management recommendations
• Use of multi-gene panel tests have benefits and limitations
– Can order one test to assess risk for multiple cancers/syndromes
– Interpreting test results more challenging
• VUSs , mutations in less well-characterized genes, incidental findings require
careful interpretation, counseling, investigation
• Patient recontact, follow up

31. Resources
• National Comprehensive Cancer Network (NCCN)
http://www.nccn.org/index.asp
• National Society of Genetic Counselors (NSGC)
http://www.nsgc.org/
• Genetic Testing Registry (NCBI)
http://www.ncbi.nlm.nih.gov/sites/GeneTests/
• National Cancer Institute Physician’s Data Query (NCI
PDQ) http://www.cancer.gov/cancertopics/pdq/genetics
• City of Hope Division of Clinical Cancer Genetics
http://www.cancergenetics.net

32. CCGCoP Contact
• For Information: Clinical Cancer Genetics Community of Practice:
http://www.cancergenetics.net
• or contact Dr. Kathleen Blazer: kblazer@coh.org