Clinical Utility of BRCA Testing

Mark Robson, MDSeptember 7, 2012

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Pharoah PD et al. N Engl J Med 2008;358:2796-2803.2

Risk Factors

• Not modifiable– Age– Gender– Age menarche– Age menopause– Histologic RF (eg ADH)– Mammo density

• Potentially modifiable– Age FFTP– Breast feeding– Obesity– Alcohol– HRT– Radiation exposure

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Importance of family history

Pharoah et al, Int J Cancer 1997; 71: 800 4

Mechanisms of familial risk

• Chance

• Shared socio-cultural risk factors

• Shared environmental exposures

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Dx 45d. 89

92 86

73 68 Dx 59d. 62

Dx 72

Dx 36 36

71

* **

* *

*

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Causes of Hereditary Breast Cancer

• BRCA1 & BRCA2• PTEN• TP53• CDH1• LKB1/STK11

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BRCA1 and BRCA2 mutations in BCKurian et al, CEBP 2009;18:1084-91

Category A Category B

Category A: BC <35, B/L BC with first before 50, prior OC, 1+ FDR with BC or OC

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BRCA1 and BRCA2 mutations in OC

Zhang et al, Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselectedpatients with invasive ovarian cancer. Gynecol Oncol 2011;121:353

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NCCN Criteria for BRCA testing

Personal History of BC • Dx ≤ 45• Dx ≤ 50 with:

– 1 or more relative with BC ≤ 50 or– 1 or more relative with OC

• Bilateral with first ≤ 50• TNBC ≤ 60• Any age with 2+ relatives with breast

or ovary any age• Any age with 2+ relatives with

pancreas• Any age with relative with male BC• Any age if Ashkenazi

No Personal History of BC• Epithelial ovarian cancer• Male BC• Pancreas with 2+ relatives with

breast, ovary, or pancreas cancer• Unaffected with FDR or SDR meeting

criteria

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Impact on management of affected

• Choice of local therapy

• Choice of systemic therapy

• Surgical prevention of second primaries

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Risks to unaffected carriersChen & Parmigiani JCO 2007;25:1329

Breast Ovary

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Management of breast cancer risk 14

Author N cancers/ N screened % detected by modality

MMG US MRI

Kriege 45/1909 40% 71%

Warner 22/236 36% 33% 77%

Kuhl 43/529 33% 39% 91%

Lehman 4/367 25% 100%

Leach 33/649 40% 77%

Lehman 6/171 33% 17% 100%

Sardanelli 18/278 59% 65% 94%

MRI surveillance in women at risk

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Diagnostic yield of surveillance strategies

Kuhl et al, J Clin Oncol 2010;28:1450

True positive diagnoses per 1000 screens

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Management of ovarian cancer risk 17

Risk-Reducing Salpingo-Oophorectomy

•Peritoneal cancers may occur

•Unexpected cancers in ~4%

•Also ↓ breast cancer risk

•Survival benefit

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Risk-Reducing Salpingo-Oophorectomy

•Peritoneal cancers may occur

•Unexpected cancers in ~4%

•Also ↓ breast cancer risk

•Survival benefit

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Impact of RRSO

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Potential impact of intervention

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Potential impact of intervention

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