Dr. Mark Robson, Clinic Director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, presents a medical update regarding the latest developments in genetic testing as it relates to breast and ovarian cancer. Topics include non-BRCA mutations, including both high-penetrance and so-called moderate penetrance mutations, and a framework for management of these. Presented in collaboration with FORCE.

1. Inherited Risk for Breast
and Ovarian Cancer: 2016
Update
2016-07-19
Mark Robson, MD
Attending, Clinical Genetics and Breast Medicine Services
@MarkRobsonMD

3. Reasons for familial aggregations
• Chance
• Shared environmental factors
• Shared socio-cultural risk factors
• Shared genetic factors

5. • Early onset
• Bilateral disease
• Male = female transmission
• Incomplete penetrance
• Gender-variable expression
Autosomal Dominant Predisposition

7. • Most common cause of autosomal dominant
predisposition to breast (and ovarian) cancer
• How common are BRCA1/2 mutations?
– About 1 in 200 individuals of European ancestry
• About 1 in 300 (Finns) to 1 in 600 (African-American) non-AJ
• About 1 in 40 Ashkenazi Jewish ancestry

8. Cancers and Interventions for BRCA
Cancer Risk (to age 80) Intervention
Breast 50-80%
Breast MRI
Preventive mastectomy
Ovarian 15-60%
RRSO +/- hysterectomy
? Salpingectomy
Prostate 25-30% DRE/PSA
Male breast 3-8%
Awareness
?Mammogram
Pancreas 3-5% (mainly B2) Investigational screening
?Colon Uncertain Early colonoscopy

9. Risk modifiers for BRCA1/2 risk?
• Impact of traditional RF on risk unclear
– Age at start/stop periods, age of first childbirth,
number of children, etc
• No clear environmental modifiers
• Genetic background factors are influential

10. Non-surgical interventions for BRCA
risks
• Oral contraceptives decrease OC risk
– Effect on BC risk unclear but likely limited
• Early menopause may decrease BC risk
– B2> B1, new data suggests more limited
benefit
• Impact of tamoxifen, raloxifene,AIs unclear

11. Breast Cancer Linkage Consortium
(Breast only)
BRCA1
28%
BRCA2
37%
BRCAx
35%
Ford et al, Am J Hum Genet 1998

12. Cowden Syndrome
PTEN

13. Peutz-Jegher’s Syndrome
STK11/LKB1
Yoo et al, BMC Genetics 2008

14. Li-Fraumeni Syndrome
TP53
Bilateral breast, 40
Leukemia,
33
Brain tumor, 32
Breast, 40
Osteosarcoma, 42
Breast,
35
Soft tissue
sarcoma, 7
Leukemia, 6
50

15. Hereditary Diffuse Gastric Cancer
CDH1

16. High-penetrance
P53, PTEN, CDH1, STK11
• Rare, recognizable syndromes
• Multi-site cancer predispositions
• “True negative” results meaningful

17. Genetic architecture of breast cancer riskAlleleFrequency
Relative Risk
Common variants
(GWAS)
1 2 5 ≥10
Rare variants
(moderate)
Rare variants
(high penetrance)

18. ”Moderate penetrance” genes
• ATM
• BRIP1
• BARD1
• BLM
• CHEK2
• MRE11
• NBN
• PALB2
• RAD50
• RAD51C
• RAD51D
• XRCC2
• SLX4
Found in ~3% of BRCA-negative families undergoing testing

20. Results of Multigene Testing
0.00%
0.10%
0.20%
0.30%
0.40%
0.50%
0.60%
0.70%
0.80%
0.90%
1.00%
CHEK2 ATM PALB2 BRIP1 NBN BARD1 RAD51C RAD51D
Percentage of cases with mutations (n=91,216)

21. Results of Multigene Testing
CHEK2
29%
ATM
22%
PALB2
19%
BRIP1
10%
NBN
6%
BARD1
5%
RAD51C
5%
RAD51D
2%
RAD50
1%MRE11
1%

22. Average Risks of Moderate
Penetrance Genes
Gene Breast Cancer (by 80) Ovarian Cancer (by 80) Other cancers
CHEK2 25-30% Not increased ?Colon
ATM ~30% Not increased ?Pancreas
PALB2 ~44% Not clearly increased ?Pancreas
BRIP1 Not clearly increased 10-15%
NBN ~30% Not clearly increased
BARD1 Undefined Undefined
RAD51C Not clearly increased 5-10%
RAD51D Not clearly increased 10-15%
Risks may be different for different mutations (e.g. CHEK2, ATM)
Risks are not currently well-defined for some genes
Risks are likely to be significantly modified by other factors
Some families appear to be at much higher than average risk, others lower

23. Complexities in working with
moderate penetrance mutations
• These are NOT BRCA1/2
– Risks are lower (in general)
– Breast cancer genes not clearly linked to OC
– OC genes not clearly linked to BC
• Risks in younger women generally less than
BRCA1/2 (but modified by family history)
• Individuals testing negative for family
mutations may remain at significant risk

24. Summary suggestions
Gene
Mammogram
CBE
Breast MRI RRSO Colonoscopy
Pancreas
Screening
ATM Annual starting at 40* No FH Clinical trial
CHEK2 (truncating) Annual starting at 40* No ?Discuss at 40
NBN Annual starting at 40* No FH
PALB2 Annual starting at 30 No (for now) FH Clinical trial
BRIP1/RAD51C/RAD51D FH Around 50 yrs FH
Individuals with mutations of uncertain clinical validity (presently including BARD1,
CHEK2 p.I157T and possibly p.S428F, MRE11A, RAD50/51B, SLX4, and XRCC2) should be
managed as indicated by family history.
*Start surveillance at 35 if significant FH of breast cancer (FDR with early onset) or if
targeting lower threshold (e.g. population 40 year-old risk)
Breast MRI for BRIP1/RAD51C/D only if FH model CLTR>20%
RRSO for ATM, CHEK2, NBN, PALB2 only if indicated by family history, not mutation alone
Consider RRSO for BRIP1/RAD51C/D earlier than 50 if close relatives with OC