Risks of breast or ovarian cancer in BRCA1 or BRCA2 predictive test

negatives: findings from the EMBRACE study.

Authors:

Fabio Girardi MD, Daniel R. Barnes PhD, Daniel Barrowdale BSc, Debra Frost ONC,

Angela F. Brady FRCP PhD, Claire Miller RN BA, Alex Henderson PhD, Alan

Donaldson MD, Alex Murray MD, Carole Brewer MD, Caroline Pottinger MD, D.

Gareth Evans MD PhD, Diana Eccles MD, EMBRACE, Fiona Lalloo MD, Helen

Gregory MD, Jackie Cook MD, Jacqueline Eason MD, Julian Adlard MD PhD, Julian

Barwell MD, Kai-ren Ong MD, Lisa Walker PhD, Louise Izatt PhD, Lucy E. Side MD,

M. John Kennedy MB, Marc Tischkowitz MD PhD, Mark T. Rogers MD, Mary E.

Porteous MD, Patrick J. Morrison MD, Ros Eeles MD PhD, Rosemarie Davidson MD,

Katie Snape MD, Douglas F. Easton PhD, Antonis C. Antoniou PhD

List of elements:

Generation of the eligible set

Supplemental figure 1

Supplemental figure 2

Supplemental figure 3

Sensitivity analyses

Supplemental table 1

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Generation of the eligible set

The initial dataset included 2,111 women without BRCA1 and BRCA2 mutations.

Seventy six individuals recruited in Northern Ireland and in the Republic of Ireland were

excluded because record linkage was not possible. We also excluded 122 individuals with

personal history of cancer, other than NMSC, at baseline. For the invasive BC analysis, we

excluded a further 18 individuals who had reported a prior bilateral mastectomy, leaving a

cohort of 1,895 women for analysis. For the EOC analysis we excluded 176 individuals

with prior bilateral salpingo-oophorectomy and one individual with prior bilateral

salpingectomy, resulting in a final cohort of 1,736 women (supplemental figure 1).

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Supplemental figure 1. Generation of the eligible set for the invasive BC analysis. 1:

NMSC, non-melanoma skin cancer.

Supplemental figure 2. Generation of the eligible set for the EOC analysis. 1: NMSC,

non-melanoma skin cancer.

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Supplemental figure 3. Kaplan Meier plot for the risk of invasive BC, separately for

relatives of BRCA1 mutation carriers and relatives of BRCA2 mutation carriers.

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Sensitivity analyses

After excluding 135 non-carriers with history of bilateral oophorectomy or bilateral

salpingectomy at ages <50 years (prior to ascertainment), the SIR for invasive BC was

estimated to be 0.91 (95% CI 0.58-1.40) in the overall samples, 0.81 (95% CI 0.44-1.51)

for relatives of BRCA1 mutation carriers and 1.03 (95% CI 0.56-1.92) for relatives of

BRCA2 mutation carriers.

The SIR for EOC was re-estimated after retaining 45 women with history of breast

cancer and the SIR was estimated to be 0.76 (95% CI 0.19-3.03) in the overall sample and

1.68 (95% 0.42-6.73) for relatives of BRCA2 mutation carriers.

In a separate analysis, women with less than one year of follow-up were excluded

to ensure that none of the participants had pre-existing cancers at the time of recruitment.

After excluding 128 non-carriers, the SIR for invasive BC was similar: 0.81 (95% CI 0.52-

1.25) in the overall samples, 0.78 (95%CI 0.43-1.41) for relatives of BRCA1 mutation

carriers and 0.85 (95% 0.44-1.63) for relatives of BRCA2 mutation carriers. After excluding

116 women included in the ovarian cancer risk estimation, the SIR for EOC was 0.40 (95%

CI 0.06-2.82) in the overall sample and 0.87 (95% CI 0.12-6.21) for relatives of BRCA2

mutation carriers.

In the main analysis only incident invasive BCs were included. In this prospective

cohort three DCISs and one LCIS also occurred. As an exploratory analysis we repeated

the analysis considering all breast cancers. Separate population incidence estimates for

DCIS and LCIS were available only until 2009. Therefore we considered only in situ breast

cancer, irrespective of subtype. With 27 prospective breast cancers overall, the crude

incidence rate was estimated to be 2.01 per 1000 person years (95% CI 1.40-3.01). The

overall SIR was estimated to be 0.95 (95% CI 0.65-1.39), 0.93 (95% CI 0.56-1.55) for

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members of BRCA1 families and 0.98 (95% CI 0.56-1.73) for relatives of BRCA2 mutation

carriers (supplemental table 1).

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Supplemental table 1. Invasive BC and DCIS/LCIS combined analysis: summary of the estimated parameters.

overall sample relatives of BRCA1 mutation carriers relatives of BRCA2 mutation carriers

py1 incident

breast

cancers

IR2 per

1000 py1

(95%CI)

SIR3

(95%CI)

cumula-

tive risk

(95%CI)

py1 incident

breast

cancers

IR2 per

1000 py1

(95%CI)

SIR3

(95% CI)

cumula-

tive risk

(95%CI)

py1 incident

breast

cancers

IR2 per

1000 py1

(95%CI)

SIR3

(95% CI)

overall 13398.1 27 2.01

(1.4-3.01)

0.95

(0.65-

1.39)

NA4 7738.7 15 1.94

(1.19-3.39)

0.93

(0.56-1.55)

NA4 5632.4 12 2.13

(1.24-4)

0.98

(0.56-

1.73)

agegroup

18-<25 187.5 0 0 0 0 116.1 0 0 0 0 68.8 0 0 0

25-<35 1556.4 0 0 0 0 904.8 0 0 0 0 646.1 0 0 0

35-<45 3426.1 1 0.29

(-)

0.32

(0.04-

2.26)

0.3%

(0-1.8)

2114.1 0 0 0 0 1312 1 0.76

(-)

0.83

(0.12-

5.9)

45-<55 3908.9 13 3.33

(1.97-6.08)

1.32

(0.76-

2.27)

3.5%

(2.1-5.9)

2157.6 6 2.78

(1.27-7.33)

1.11

(0.5-2.46)

2.7%

(1.2-5.9)

1751.2 7 4

(1.96-9.52)

1.58

(0.75-

3.31)

55-<65 2574.4 7 2.72

(1.32-6.54)

0.84

(0.4-

1.77)

6.3%

(4.1-9.7)

1437.3 3 2.09

(0.65-10.2)

0.64

(0.21-1.99)

4.8%

(2.4-9.1)

1137.1 4 3.52

(1.32-12.6)

1.1

(0.41-

2.93)

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overall sample relatives of BRCA1 mutation carriers relatives of BRCA2 mutation carriers

py1 incident

breast

cancers

IR2 per

1000 py1

(95%CI)

SIR3

(95%CI)

cumula-

tive risk

(95%CI)

py1 incident

breast

cancers

IR2 per

1000 py1

(95%CI)

SIR3

(95% CI)

cumula-

tive risk

(95%CI)

py1 incident

breast

cancers

IR2 per

1000 py1

(95%CI)

SIR3

(95% CI)

agegroup

65-<75 1316 5 3.8

(1.6-11.3)

0.98

(0.41-

2.36)

9.8%

(6.4-15)

754.7 5 6.62

(2.79-19.6)

1.73

(0.72-4.15)

11%

(6.1-19)

555.1 0 0 0

75-<85 428.8 1 2.33

(-)

0.61

(0.09-

4.26)

11%

(7.2-17)

253.9 1 3.94

(-)

1.04

(0.15-7.35)

13%

(7.3-22)

162 0 0 0

European

Ancestry

13184.4 27 2.05

(1.42-3.06)

0.97

(0.66-

1.41)

NA4 7587.7 15 1.98

(1.21-3.46)

0.95

(0.58-1.58)

NA4 5569.6 12 2.15

(1.25-4.04)

0.99

(0.56-

1.75)

1: py, person years; 2: IR, incidence rate; 3: SIR, standardised incidence ratio; 4: NA, not applicable.

* In 4 individuals family identification number and family mutation were missing.

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