Inherited Risk for Breast and Ovarian Cancer: 2016 Update

2016-07-19Mark Robson, MDAttending, Clinical Genetics and Breast Medicine Services@MarkRobsonMD

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

• Early onset

• Bilateral disease

• Male = female transmission

• Incomplete penetrance

• Gender-variable expression

Autosomal Dominant Predisposition

• 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

Cancers and Interventions for BRCACancer Risk (to age

80) Intervention

Breast 50-80%Breast MRIPreventive 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

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

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

Breast Cancer Linkage Consortium (Breast only)

BRCA128%

BRCA237%

BRCAx35%

Ford et al, Am J Hum Genet 1998

Cowden SyndromePTEN

Peutz-Jegher’s SyndromeSTK11/LKB1

Yoo et al, BMC Genetics 2008

Li-Fraumeni Syndrome TP53

Bilateral breast, 40

Leukemia, 33

Brain tumor, 32

Breast, 40Osteosarcoma, 42

Breast, 35

Soft tissue sarcoma, 7

Leukemia, 6

50

Hereditary Diffuse Gastric CancerCDH1

High-penetranceP53, PTEN, CDH1, STK11

• Rare, recognizable syndromes

• Multi-site cancer predispositions

• “True negative” results meaningful

Genetic architecture of breast cancer risk

Alle

le F

requ

ency

Relative Risk

Common variants (GWAS)

1 2 5 ≥10

Rare variants (moderate)

Rare variants (high penetrance)

”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

Results of Multigene Testing

CHEK2 ATM PALB2 BRIP1 NBN BARD1 RAD51C RAD51D0.00%

0.10%

0.20%

0.30%

0.40%

0.50%

0.60%

0.70%

0.80%

0.90%

1.00%

Percentage of cases with mutations (n=91,216)

Results of Multigene Testing

CHEK229%

ATM22%

PALB219%

BRIP110%

NBN6%

BARD15%

RAD51C5%

RAD51D2%

RAD501%

MRE111%

Average Risks of Moderate Penetrance GenesGene 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 genesRisks are likely to be significantly modified by other factorsSome families appear to be at much higher than average risk, others lower

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

Summary suggestions

Gene

MammogramCBE

Breast MRI RRSO ColonoscopyPancreas 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 aloneConsider RRSO for BRIP1/RAD51C/D earlier than 50 if close relatives with OC