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BRCA1 and BRCA2 Mutations and Breast Cancer:. An Integrated Approach Using Four Epidemiologic Parameters. Monica McClain, PhD. Assistant Director, Biometry and Epidemiology Foundation for Blood Research Scarborough, Maine  Email: [email protected]

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brca1 and brca2 mutations and breast cancer
BRCA1 and BRCA2 Mutations and Breast Cancer:

An Integrated Approach Using Four Epidemiologic Parameters

Monica McClain, PhD.Assistant Director, Biometry and Epidemiology

Foundation for Blood Research Scarborough, Maine 

Email: [email protected]

cumulative incidence

Cumulative Incidence

Proportion of women that will develop breast cancer by a given age

DevCan: Probability of developing or dying of cancer software. Version 5.1: Statistical Research and Application Branch, National Cancer Institute; 2003.

clinical sensitivity

Clinical Sensitivity

Proportion of women with breast cancer by a given age carrying a BRCA1/2 mutation

penetrance

Penetrance

Proportion of women with a BRCA1/2 mutation that develops breast cancer by a given age

Anglian Breast Cancer Study Group. Br J Cancer. 2000; Easton et al. Am J Hum Genet. 1995; Antoniou et al. Am J Hum Genet. 2003; Antoniou et al. Br J Cancer. 2002; Antoniou et al. Genet Epidemiol. 2000; Brose et al. J Natl Cancer Inst. 2002; Ford et al. Am J Hum Genet. 1998; Schubert et al. Am J Hum Genet. 1997.

carrier rate

Carrier Rate

The rate of BRCA1/2 mutation carriers in the

general population

Anglian Breast Cancer Study Group. Br J Cancer. 2000; Antoniou et al. Br J Cancer. 2002; Antoniou et al. Genet Epidemiol. 2000; Ford et al. Am J Hum Genet. 1995; Peto et al. J Natl Cancer Inst. 1999; Whittemore et al. Am J Hum Genet. Mar 1997.

slide7
Meta-analysis for each parameter to calculate a point estimate

but

  • Heterogeneity
  • Wide ranges, broad confidence intervals
  • Not internally consistent
integrated approach

Integrated Approach

1

CR

=

(( CI * CS ) / P ) / 1,000,000

CR= Carrier Rate (1 in N)

CI = Cumulative incidence (N out of 1,000,000)

CS = Clinical sensitivity (%)

P = Penetrance (%)

integrated approach9

Integrated Approach:

C l i n i c a l S e n s i t i v i t y

Results By Age 70

(assuming a cumulative incidence of 9.67%)

Yellow indicates plausible combinations

applying the integrated approach to a hypothetical cohort of 1 000 000 women
Applying the integrated approach to a hypothetical cohort of 1,000,000 women

1,000,000 followed from age 20 to age 70

96,700 will develop breast cancer

1,000,000

*

9.67 %

Apply Cumulative Incidence of 9.67 %

con t
Con’t

1,000,000 followed age 20 to age 70

96,700 will develop breast cancer

903,300 will not develop breast cancer

1,000,000

-

96,700

Calculate those that will not develop breast cancer

con t12
Con’t

1,000,000 followed age 20 to age 70

96,700 will develop breast cancer

903,300 will not develop breast cancer

1,450 BRCA1/2+

96,700

1.5 %

*

Apply clinical sensitivity of 1.5 %

con t13
Con’t

1,000,000 followed age 20 to age 70

96,700 will develop breast cancer

903,300 will not develop breast cancer

1,450 BRCA1/2+

95,250 BRCA1/2 -

96,700

1,450

-

Calculate non-BRCA1/2 mutation carriers

in women with breast cancer

con t14
Con’t

1,000,000 followed age 20 to age 70

96,700 will develop breast cancer

903,300 will not develop breast cancer

1,450 BRCA1/2+

95,250 BRCA1/2 -

1,186 BRCA1/2 +

(1,450 / 0.55) – 1,450

Calculate BRCA1/2 mutation carriers

in women without breast cancer (penetrance = 55%)

con t15
Con’t

1,000,000 followed age 20 to age 70

96,700 will develop breast cancer

903,300 will not develop breast cancer

1,450 BRCA1/2+

95,250 BRCA1/2 -

1,186 BRCA1/2 +

902,114 BRCA1/2 -

Calculate non-BRCA1/2 mutation carriers

in women without breast cancer

con t16
Con’t

1,000,000 followed age 20 to age 70

96,700 will develop breast cancer

903,300 will not develop breast cancer

1,450 BRCA1/2+

95,250 BRCA1/2 -

1,186 BRCA1/2 +

902,114 BRCA1/2 -

Carrier Rate: 2,636 / 1,000,000 or 1 in 380

a comparison among commonly used information sources
A Comparison Among Commonly Used Information Sources

www.myriad.com www.ama-assn.org www.cancer.gov/cancerinfo/pdq www.genetests.org

calculated parameters using our integrated approach
Calculated parameters using our integrated approach

Each epidemiologic parameter is calculated by setting the other three parameters

listed by the same information source as constants in our integrated approach

what s next
What’s next?

Expand the approach to incorporate family history

epidemiologic parameters needed when family history is used as a screening test
Epidemiologic parameters needed when family history is used as a screening test

Lancet. Oct 27 2001

Pharoah et al. Int J Cancer. 1997

* value fixed by the first three variables

** risk ratio computed using the other 6 variables

slide21

Relationship Between Strong Family History, Breast Cancer and BRCA1/2 Mutation Status

1,000,000 Women followed from age 20 to 70

Strong Family History

10,000 Positive

990,000 Negative

Develops Breast Cancer

3000 Yes

7000 No

93,700 Yes

896,300 No

BRCA1/2 Mutation Present

2100 No

900

Yes

300 Yes

6700 No

550 Yes

93,150 No

750 Yes

895,550 No

what s next22
What’s next?
  • Expanded approaches
    • Family history
    • Ovarian cancer
    • Breast and ovarian cancer
    • Race/ethnicity (Ashkenazi Jewish)
    • Mutation location (BRCA1, BRCA2, OCCR)
  • Other conditions with a genetic component
slide23

AcknowledgmentSupport for this study was provided by a cooperative agreement (UR/CCU319352) with the Centers for Disease Control and Prevention, Office of Genomics and Disease Prevention.

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