Premenopausal risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers effectively reduces ovarian cancer risk, but also reduces breast cancer risk. Breast cancer risk reductions up to 50% have been reported for both BRCA1 and BRCA2 mutation carriers, but recent prospective studies were not able to reproduce this finding for BRCA1 mutation carriers.

Breast cancer incidence after RRSO was assessed in a consecutive series of 104 BRCA1 and 58 BRCA2 mutation carriers. On the basis of data from our own centre, and assuming a 50% risk reduction through RRSO at premenopausal age, we expected to find 8 breast cancers (range 6–10) in this population for the reported screening period (532 women-years).

In 162 carriers with a median age of 41 years at RRSO, 13 incident breast cancers were diagnosed. In BRCA1 mutation carriers, 12 incident breast cancers were found compared with 5 (range 3–6) expected and in BRCA2 mutation carriers 1 breast cancer was found compared with 3 (range 2–5) expected.

Breast cancer incidence after premenopausal RRSO is still high, especially in BRCA1 mutation carriers. Previously reported breast cancer risk reductions up to 50% were not confirmed. As a consequence, continued intensive screening for breast cancer is warranted in BRCA1 and BRCA2 mutation carriers after RRSO. Cancer Prev Res; 5(11); 1291–7. ©2012 AACR.

Women with a proven BRCA1 or BRCA2 mutation have a risk for developing breast cancer of 40% to 80% by the age of 70 (1, 2). Ovarian cancer risk by the age of 70 is 40% for BRCA1 and 18% for BRCA2 mutation carriers (1, 2) A study by van der Kolk and colleagues (3) conducted at our centre found cumulative risks of breast cancer of 71% [95% confidence interval (CI), 67%–82%) in BRCA1 and 88% (95% CI, 82%–93%) in BRCA2 mutation carriers by the age of 70. These risks were at the high end of the spectrum compared with other studies, especially for BRCA2 mutation carriers. The authors hypothesized that this could be due to skewing towards testing in women affected with cancer, competing risks of mortality from ovarian cancer in BRCA1 mutation carriers, or missing of BRCA2 mutation families with lower cancer penetrance that fail to meet the age-related criteria for mutation testing (3).

BRCA1 and BRCA2 mutation carriers are counseled on different risk-reducing strategies, either screening or prophylactic surgery. Breast cancer screening with clinical breast examination (CBE), mammography, and MRI is effective in detecting early-stage breast cancer in mutation carriers (4–8). For ovarian cancer, current screening protocols are ineffective in detecting early-stage ovarian cancer (9, 10). Risk-reducing salpingo-oophorectomy (RRSO) is effective in reducing the risk of ovarian cancer (HR, 0.21; 95% CI, 0.12–0.39) (11). After counseling, RRSO is chosen by almost all BRCA1 and BRCA2 mutation carriers at our centre.

Besides reducing ovarian cancer risk, RRSO has been shown to reduce breast cancer risk in mutation carriers. A large meta-analysis found risk reductions of 50% associated with RRSO in both BRCA1 and BRCA2 mutation carriers (BRCA1: HR, 0.47; 95% CI, 0.35–0.64; BRCA2: HR, 0.47; 95% CI, 0.26–0.84; ref. 11). The effect of RRSO on breast cancer risk was suggested to be stronger in women at premenopausal age, as greater risk reductions were found in women who had surgery before the age of 40 to 50 years (12, 13).

However, it has been suggested that the effect of RRSO differs between BRCA1 and BRCA2 mutation carriers (14, 15). In a study of Shah and colleagues (15), in 51 BRCA1 and 41 BRCA2 mutation carriers, 11 new breast cancers were found, all within BRCA1 mutation carriers. The percentage of women with RRSO was equal in women who did and did not develop breast cancer (87% vs. 82%, P = 0.754; ref. 15).

We aimed to study the incidence of breast cancer after RRSO at premenopausal age in BRCA1 and BRCA2 mutation carriers in the Northern Netherlands in a prospective cohort.

Study population

All women with 1 or 2 breasts in situ, who were 51 years old or younger (mean menopausal age in the Netherlands; ref. 16) at the time of RRSO, were consecutively selected from a prospective cohort of BRCA1/2 mutation carriers who were enrolled in the surveillance program for hereditary breast and ovarian cancer at the University Medical Center Groningen (UMCG; Groningen, The Netherlands) from September 1995 until January 2011. Women with previous breast cancer were included, when breast cancer screening continued on the remaining breast tissue. Women in whom ovarian cancer was found on the RRSO specimen were not included. Before this study, we analyzed a previous version of this database (data up until 30 September, 2009) to determine the effectiveness of breast cancer screening after RRSO (17).

RRSO protocol

RRSO is advised from the age of 35 to 40 years in BRCA1 mutation carriers and 40 to 45 years in BRCA2 mutation carriers (18). However, patients are counseled individually, and actual timing of RRSO depends on personal circumstances such as previous breast cancer, family history of cancer, previous or planned pregnancies, and mental acceptance of this definitive procedure. The operative procedure is conducted by laparoscopy (19).

Breast cancer screening

Breast cancer screening in BRCA1/2 mutation carriers was done according to the Dutch guidelines, with annual complete breast examination (CBE), and mammography and MRI alternating by 6 months since 2008 (18). Before 2008, CBE was conducted biannually and MRI was conducted in women participating in the MRISC trial (MRI screening for breast cancer in women with familiar or genetic predisposition, ref. 20).

Data collection

All BRCA1/2 mutation carriers who visit our Family Cancer Clinic are consecutively included in a prospective cohort. If these women met our inclusion criteria, we retrospectively retrieved relevant data from the patient files in the hospital. Physician's letters, pathology reports, and imaging reports were used for data collection.

Information on the type of mutation, date of birth, date of RRSO, and ever-use of hormonal replacement therapy after RRSO was collected. For previous breast cancers, age of diagnosis and conducted surgical procedure (breast-conserving therapy or mastectomy) were recorded. For breast cancers diagnosed after RRSO, age at diagnosis and pathologic features were recorded: tumor type according to the WHO classification, tumor size in millimeters, tumor grade (Elston–Ellis modification of Bloom–Richardson grading system), receptor status [estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor], presence of ductal carcinoma in situ (DCIS), and presence of lymph node metastases. Patient data were entered into an SPSS database. Protection of the patient's identity was guaranteed by a patient-specific number. Those numbers were only retraceable to individual women when entered in the password-protected hospital database, which is only accessible for hospital employees who have a personal account. Complying with Dutch law, no further Institutional Review Board approval was needed.

Statistical analysis

To present the study population and characteristics of breast cancers discovered after RRSO, contingency tables were used. Breast cancers detected after RRSO could be prevalent, possibly prevalent or incident. Prevalent breast cancers were defined as breast cancers detected within 6 months after RRSO. Possibly prevalent breast cancers were defined as breast cancers detected more than 6 months after RRSO that we considered prevalent because the time after RRSO was shorter than the estimated growing time of the breast cancer. For all the invasive breast cancers diagnosed more than 6 months after RRSO, we estimated the duration of time a breast cancer had been growing and compared this with the time interval between RRSO and detection of breast cancer. To estimate this time, we used the formula for estimating tumor-doubling time in mutation carriers based on age at tumor diagnosis as presented by Tilanus-Linthorst and colleagues (21): log2 [doubling time (years)] = −7.75 + 0.12 age. On the basis of the tumor-doubling time, we estimated the time a tumor was growing from the theoretical size at baseline of 5 mm (which is the assumed detection threshold for invasive breast cancer on MRI; refs. 22, 23) to the size at detection. If this estimated time period was longer than the time period between RRSO and tumor detection, we considered a breast cancer possibly prevalent. Incident breast cancers were defined as breast cancers detected more than 6 months after RRSO and not possibly prevalent.

Duration of follow-up was calculated for each woman from RRSO to diagnosis of incident breast cancer, to prophylactic mastectomy, to one year after the last screening visit, or to January 1, 2011. The analyses were conducted using the SPAW software package, version 18.0 for Windows (SPSS).

Breast cancers expected

To estimate the number of women who develop incident breast cancer after RRSO based on womens' ages at RRSO and their ages during follow-up, we used the penetrance curves for breast cancer in mutation carriers in our centre as published by Van der Kolk and colleagues (3) and a 50% risk reduction for breast cancer expected after RRSO [BRCA1/2: HR, 0.49; (95% CI, 0.37–0.65); BRCA1: HR, 0.47; (95% CI, 0.35–0.64) and BRCA2: HR, 0.47 (95% CI 0.26–0.84); ref. 11].

Population characteristics

We analyzed the data of 162 women, 104 BRCA1 mutation carriers and 58 BRCA2 mutation carriers (Table 1). At the time of RRSO, median age was 41 years (range 30–51) for BRCA1 mutation carriers and 42 years (range 33–51) for BRCA2 mutation carriers (P = 0.013). At the time of RRSO, 25% of the BRCA1 mutation carriers and 12% of the BRCA2 mutation carriers had a history of breast cancer (P = 0.066). After RRSO, hormonal replacement therapy was prescribed to 47% (68/146) of the women, all without previous breast cancer. Total follow-up in this study was 6,389 months (532 women-years); 4,309 months (359 women-years), and 2,080 months (173 women-years) for BRCA1 and BRCA2 mutation carriers, respectively.

Table 1.

Characteristics of the women at baseline (N = 162)

BRCA1 (N = 104)BRCA2 (N = 58)Total (N = 162)Statistics
Age at RRSO in years     
 Median (range) 40 (30–51) 42 (33–51) 41.0 (30–51) P = 0.013a 
 ≤40 years 50% (52/104) 28% (16/58) 42% (68/162) P = 0.006a 
Follow-up in months     
 Total 4,309 2,080 6,389  
 Median (range) 31 (3–228) 28 (2–159) 28 (2–228) P = 0.681 
Previous breast cancer     
 No 75% (78/104) 88% (51/58) 80% (129/162) P = 0.066 
 Yes unilateral 20% (21/104) 12% (7/58) 17% (28/162)  
 Yes bilateral 5% (5/104) 3% (5/162)  
Age at onset of first breast cancer in years (N = 33)     
 Median (range) 38 (29–49) 42 (32-50) 41.0 (29–50) P = 0.330 
Breast cancer therapy     
 BCT unilateral 39% (10/26) 71% (5/7) 46% (15/33) P = 0.403 
 Mast unilateral 42% (11/26) 29% (2/7) 39% (13/33)  
 BCT bilateral 15% (4/26) — 12% (4/33)  
 BCT and Mast 4% (1/26) — 3% (1/33)  
Hormonal replacement therapy use     
 No 53% (49/92) 54% (29/54) 53% (78/146) P = 0.959 
 Yes 47% (43/92) 46% (25/54) 47% (68/146)  
BRCA1 (N = 104)BRCA2 (N = 58)Total (N = 162)Statistics
Age at RRSO in years     
 Median (range) 40 (30–51) 42 (33–51) 41.0 (30–51) P = 0.013a 
 ≤40 years 50% (52/104) 28% (16/58) 42% (68/162) P = 0.006a 
Follow-up in months     
 Total 4,309 2,080 6,389  
 Median (range) 31 (3–228) 28 (2–159) 28 (2–228) P = 0.681 
Previous breast cancer     
 No 75% (78/104) 88% (51/58) 80% (129/162) P = 0.066 
 Yes unilateral 20% (21/104) 12% (7/58) 17% (28/162)  
 Yes bilateral 5% (5/104) 3% (5/162)  
Age at onset of first breast cancer in years (N = 33)     
 Median (range) 38 (29–49) 42 (32-50) 41.0 (29–50) P = 0.330 
Breast cancer therapy     
 BCT unilateral 39% (10/26) 71% (5/7) 46% (15/33) P = 0.403 
 Mast unilateral 42% (11/26) 29% (2/7) 39% (13/33)  
 BCT bilateral 15% (4/26) — 12% (4/33)  
 BCT and Mast 4% (1/26) — 3% (1/33)  
Hormonal replacement therapy use     
 No 53% (49/92) 54% (29/54) 53% (78/146) P = 0.959 
 Yes 47% (43/92) 46% (25/54) 47% (68/146)  

aP < 0.05 is significant. Mann–Whitney U test for continuous variables, Fisher exact test for proportions.

Abbreviations: BCT: Breast-conserving therapy; Mast, mastectomy; if noted as BCT and Mast, 1 breast is treated with BCT and 1 with Mast; after RRSO.

Breast cancers after RRSO

During the post-RRSO screening period, 18 breast cancers in 18 women were detected (34/1,000 women-years). Of these, 16 were found in BRCA1 mutation carriers (45/1,000 women-years) and 2 in BRCA2 mutation carriers (12/1,000 women-years).

Of the 18 breast cancers diagnosed after RRSO, 3 were found within 6 months after RRSO and were considered prevalent breast cancers. On the basis of tumor-doubling time calculations, we considered 2 breast cancers to be possibly prevalent (Table 2). Leaving out 3 prevalent breast cancers and 2 possibly prevalent breast cancers, there were at least 13 incident breast cancers (24/1,000 women-years) during the study period, 12 in BRCA1 mutation carriers (33/1,000 women-years) and 1 in a BRCA2 mutation carrier (6/1,000 women-years). Table 3 illustrates the number of women expected to develop breast cancer compared with the number observed. Table 4 illustrates the characteristics of women who did and did not develop incident breast cancer after RRSO.

Table 2.

Estimated growing time and time to diagnosis in individual breast cancers after RRSO (N = 15)a

MutationAge at detection of breast cancerWHO tumor classificationMax. diameter (in mm)Doubling time (in months)Time to diagnosis (in months)Estimated growing time (in months)
BRCA1 37 LC 1.2 54.8 1.8 
BRCA1 38 DCIS n.d. n.d. 14.8 n.d. 
BRCA1 45 IDC 25 2.4 27.4 19.1 
BRCA1 45 IDC 14 2.4 12.6 10.6 
BRCA1 43 IDC 2.0 7.2 -4.4 
BRCA2 52 IDC 11 4.2 19.8 14.4 
BRCA1 36 IDC 1.1 10.3 2.3 
BRCA1 41 DCIS 13 1.7 12.4 n.d. 
BRCA1 47 IDC 30 2.8 20.9 21.6b 
10 BRCA1 55 IDC 16 5.4 228.4 27.2 
11 BRCA1 42 IDC 1.8 42.5 4.7 
12 BRCA1 53 IDC 11 4.6 48.3 15.7 
13 BRCA1 52 GRCCC 11 4.2 95.5 14.4 
14 BRCA1 41 IDC 20 1.7 6.7 10.2b 
15 BRCA1 47 IDC 11 2.8 78.3 9.5 
MutationAge at detection of breast cancerWHO tumor classificationMax. diameter (in mm)Doubling time (in months)Time to diagnosis (in months)Estimated growing time (in months)
BRCA1 37 LC 1.2 54.8 1.8 
BRCA1 38 DCIS n.d. n.d. 14.8 n.d. 
BRCA1 45 IDC 25 2.4 27.4 19.1 
BRCA1 45 IDC 14 2.4 12.6 10.6 
BRCA1 43 IDC 2.0 7.2 -4.4 
BRCA2 52 IDC 11 4.2 19.8 14.4 
BRCA1 36 IDC 1.1 10.3 2.3 
BRCA1 41 DCIS 13 1.7 12.4 n.d. 
BRCA1 47 IDC 30 2.8 20.9 21.6b 
10 BRCA1 55 IDC 16 5.4 228.4 27.2 
11 BRCA1 42 IDC 1.8 42.5 4.7 
12 BRCA1 53 IDC 11 4.6 48.3 15.7 
13 BRCA1 52 GRCCC 11 4.2 95.5 14.4 
14 BRCA1 41 IDC 20 1.7 6.7 10.2b 
15 BRCA1 47 IDC 11 2.8 78.3 9.5 

aExcluded were prevalent cancers found within 6 months of RRSO

bPossibly prevalent tumors based on tumor doubling time calculations.

Abbreviations: GRCCC, glycogen rich clear cell carcinoma; IDC, invasive ductal carcinoma; LC, lobular carcinoma; n.d, no data, tumor doubling time was not calculated for DCIS.

Table 3.

Number of women with incident breast cancer expected versus observed

Expected without RRSOaExpected after RRSObObserved
All women    
(N = 162, total follow-up 532 years)    
 Number of women with incident breast cancer 16 8 (range 6–10) 13 
 In 1,000 women years 30 15 24 
BRCA1 mutation    
(N = 104, total follow-up 359 years)    
 Number of women with incident breast cancer 10 5 (range 3–6) 12 
 In 1,000 women years 28 14 33 
BRCA2 mutation    
(N = 58, total follow-up 173 years)    
 Number of women with incident breast cancer 3 (range 2–5) 
 In 1,000 women years 35 17 
Expected without RRSOaExpected after RRSObObserved
All women    
(N = 162, total follow-up 532 years)    
 Number of women with incident breast cancer 16 8 (range 6–10) 13 
 In 1,000 women years 30 15 24 
BRCA1 mutation    
(N = 104, total follow-up 359 years)    
 Number of women with incident breast cancer 10 5 (range 3–6) 12 
 In 1,000 women years 28 14 33 
BRCA2 mutation    
(N = 58, total follow-up 173 years)    
 Number of women with incident breast cancer 3 (range 2–5) 
 In 1,000 women years 35 17 

aEstimates based on the Van der Kolk penetrance curves (3).

bRisk reduction: 50% [BRCA1/2: HR, 0.49 (95% CI 0.37–0.65), BRCA1: HR, 0.47 (95% CI 0.35–0.63), and BRCA2: HR, 0.47 (95% CI 0.26–0.84; ref. 11].

Table 4.

Characteristics of women who did and did not develop incident breast cancer after RRSO

Women with incident breast cancer (n = 13)Women without incident breast cancer (n = 149)
Mutation   
BRCA1 92% (12/13) 62% (92/149) 
BRCA2 8% (1/13) 38% (57/149) 
Age at RRSO in years   
 ≤40 years 54% (7/13) 41% (61/149) 
 >40 years 46% (6/13) 59% (88/149) 
Follow-up after RRSO in months   
 Median (range) 28 (2–218) 27 (7–228) 
Previous breast cancer   
 No 69% (9/13) 77% (115/149) 
 Yesa 31% (4/13) 23% (34/149) 
bEver-use of hormonal replacement therapy   
 No 62% (8/13) 51% (73/142) 
 Yes 38% (5/13) 49% (69/142) 
Women with incident breast cancer (n = 13)Women without incident breast cancer (n = 149)
Mutation   
BRCA1 92% (12/13) 62% (92/149) 
BRCA2 8% (1/13) 38% (57/149) 
Age at RRSO in years   
 ≤40 years 54% (7/13) 41% (61/149) 
 >40 years 46% (6/13) 59% (88/149) 
Follow-up after RRSO in months   
 Median (range) 28 (2–218) 27 (7–228) 
Previous breast cancer   
 No 69% (9/13) 77% (115/149) 
 Yesa 31% (4/13) 23% (34/149) 
bEver-use of hormonal replacement therapy   
 No 62% (8/13) 51% (73/142) 
 Yes 38% (5/13) 49% (69/142) 

aPrevalent and possibly prevalent cancers were considered previous breast cancer.

bHT: Hormonal replacement therapy after RRSO.

Tumor characteristics

Of the 13 incident breast cancers detected after RRSO, 11 (86%) were invasive and 2 (15%) were DCIS (Table 5). In 4 of 11 (36%) invasive cancers, axillary lymph nodes were positive. Histologic grade was higher in breast cancers from BRCA1 mutation carriers than from BRCA2 mutation carriers (70% grade 3 vs. none, respectively). Of the 11 invasive breast cancers, 9 (82%) were ER, PR, and HER2 negative (triple negative), all in BRCA1 mutation carriers.

Table 5.

Characteristics of incident breast cancers detected after RRSO (N = 13)a

N (%)
Mutation  
BRCA1 12/13 (92) 
BRCA2 1/13 (8) 
WHO tumor classification  
 IDC 9/13 (69) 
 GRCCC 1/13 (8) 
 LC 1/13 (8) 
 DCIS 2/13 (15) 
Tumor sizeb  
 ≤10 mm 4/12 (33) 
 10–20 mm 7/12 (58) 
 >20 mm 1/12 (8) 
Histologic gradec  
 Grade 1 1/11 (9) 
 Grade 2 3/11 (27) 
 Grade 3 7/11 (64) 
ER statusc  
 Negative 9/11 (82) 
 Positive 2/11 (18) 
PR statusc  
 Negative 9/11 (82) 
 Positive 2/11 (18) 
HER2 statusc  
 Negative 10/11 (91) 
 Positive 1/11 (9) 
DCIS  
 Negative 7/13 (46) 
 Grade 1 — 
 Grade 2 1/6 (17) 
 Grade 3 5/6 (83) 
Lymph node statusc  
 Negative 7/11 (64) 
 Positive 4/11 (36) 
N (%)
Mutation  
BRCA1 12/13 (92) 
BRCA2 1/13 (8) 
WHO tumor classification  
 IDC 9/13 (69) 
 GRCCC 1/13 (8) 
 LC 1/13 (8) 
 DCIS 2/13 (15) 
Tumor sizeb  
 ≤10 mm 4/12 (33) 
 10–20 mm 7/12 (58) 
 >20 mm 1/12 (8) 
Histologic gradec  
 Grade 1 1/11 (9) 
 Grade 2 3/11 (27) 
 Grade 3 7/11 (64) 
ER statusc  
 Negative 9/11 (82) 
 Positive 2/11 (18) 
PR statusc  
 Negative 9/11 (82) 
 Positive 2/11 (18) 
HER2 statusc  
 Negative 10/11 (91) 
 Positive 1/11 (9) 
DCIS  
 Negative 7/13 (46) 
 Grade 1 — 
 Grade 2 1/6 (17) 
 Grade 3 5/6 (83) 
Lymph node statusc  
 Negative 7/11 (64) 
 Positive 4/11 (36) 

aExcluded were prevalent and possibly prevalent cancers

bTumor size could not be measured in one DCIS case.

cNot determined for DCIS.

Abbreviations: GRCCC, glycogen rich clear cell carcinoma; IDC, invasive ductal carcinoma; LC, lobular carcinoma; WHO, World health organization.

In a consecutive group of 104 BRCA1 and 58 BRCA2 mutation carriers with RRSO at premenopausal age, breast cancer screening at our Family Cancer Clinic revealed 18 breast cancers in 18 women during 532 women-years (34/1,000 women-years), of which, 13 were incident breast cancers (24/1,000 women-years). On the basis of breast cancer incidence curves and a 50% risk reduction associated with RRSO, we expected to find 8 (range 6–10) incident breast cancers (15/1,000 women-years; refs. 3, 11). Several factors may have contributed to this difference in expected and observed breast cancer incidence after RRSO.

An important finding is that 12 incident breast cancers developed in BRCA1 mutation carriers compared with 5 (range 3–6) expected. For BRCA2 mutation carriers, 1 incident breast cancer developed compared with 3 (range 2–5) breast cancers expected. The risk reduction associated with RRSO might be smaller in BRCA1 than in BRCA2 mutation carriers. The same hypothesis was suggested by Shah and colleagues (15); they found 9 new tumors after RRSO in 45 BRCA1 mutation carriers and none in 35 BRCA2 mutation carriers. Kauff and colleagues (24) also showed a significant breast cancer risk reduction for BRCA2 mutation carriers but not for BRCA1 mutation carriers [BRCA1: HR, 0.61 (95% CI, 0.30–122), BRCA2: HR 0.28 (95% CI, 0.08–0.92)] in a large prospective study with 190 BRCA1 and 113 BRCA2 mutation carriers at risk for breast cancer after RRSO.

One explanation for this difference is that the effect of RRSO might be less marked in BRCA1 mutation carriers, because their breast cancers are often ER and PR negative (14, 24). Of the invasive breast cancers found in BRCA1 mutation carriers in this study, 90% were ER and PR negative. Nevertheless, a protective effect of RRSO in BRCA1 mutation carriers has been shown in several studies (12, 13).

Others suggested that RRSO might inhibit breast cancer growth in BRCA1 mutation carriers at tumorigenesis: growth of ER and PR negative cells might be indirectly induced by paracrine signals from ER- and PR-positive cells that are influenced by estrogen and progesterone (15, 25). Thus, breast cancer risk reduction after RRSO may take longer to establish than the duration of follow-up in this study, which may be a second explanation why we saw more breast cancers than expected.

Another explanation for finding more breast cancers than expected may be the intensification of the breast cancer screening regime since 2008, when MRI screening for all BRCA1/2 mutation carriers was introduced at our centre. Van der Kolks study contains information on breast cancer incidence up to March 2008. Before 2008, MRI screening was used in a small selection of women participating in the MRISC study. It is known that after introducing a new effective screening regimen, more breast tumors are found. Warner and colleagues found a higher incidence of breast cancer in the first 3 years after the introduction of MRI screening in BRCA1/2 mutation carriers and an overall higher incidence of DCIS (26). This effect has also been shown in the general population after introduction of the population-based breast cancer screening with mammography (27, 28). This explanation is weakened by the fact that this effect was not seen in BRCA2 mutation carriers.

A fourth explanation might be that RRSO is chosen by women with especially high breast cancer risks. Although eventually RRSO is chosen by almost all mutation carriers at our centre, timing might be affected by family history and previous breast cancers. As can be seen in Table 4, of the women who developed breast cancer after RRSO, 54% were younger than 40 years and 31% had previous breast cancer, compared with 41% and 23% in the women who did not develop breast cancer.

A last explanation might be the use of hormonal replacement therapy after RRSO. In our study population, 47% of the women used hormonal replacement therapy after RRSO and this percentage was not higher in women with incident breast cancer. Although it has been shown that short-term use of hormonal replacement therapy does not negate the effect of RRSO (29) and one study found an inversed relation in hormonal replacement therapy use and breast cancer incidence in BRCA1 mutation carriers (30), hormonal replacement therapy does increase the risk of new and recurrent breast cancer in women with previous breast cancer (31, 32). On the contrary, a higher mortality was seen in women with bilateral oophorectomy before the age of 45 who did not use hormonal replacement therapy, compared with those women who did (33). Theoretically, it is plausible that hormonal replacement therapy use after RRSO partially negates the risk-reducing effect of RRSO, but bias might be introduced if hormonal replacement therapy is more often prescribed to women with less breast cancer in their family, or if survival is shorter in women who do not use hormonal replacement therapy. Our study sample is too small and follow-up to short to draw conclusions on this issue. The effects of hormonal replacement therapy after RRSO on the long-term breast cancer risk and survival should be monitored carefully.

We aimed to study the incidence of breast cancer after RRSO at premenopausal age. The strength of this study is that we used an algorithm that incorporates an estimate of growing time to exclude the effect of prevalent breast cancer on the incidence of new breast cancers after RRSO. Small sample size and short follow-up limit the possibilities to identify risk factors for breast cancer after RRSO. Because menopausal status at RRSO was not known for all women, we chose to include all women with the age at RRSO of 51 years or younger, which can be a limitation. Although this is the mean age of menopause in the Netherlands, some of these women might have been postmenopausal at time of RRSO, either due to natural or chemotherapy-induced menopause. Furthermore, we estimated the amount of breast cancer after RRSO with breast cancer penetrance curves from our own centre. An ideal design would be a randomized controlled trial with a RRSO and a surveillance group. As surveillance is not effective and RRSO is chosen by almost all mutation carriers at our centre, this design would be unethical.

To conclude, the breast cancer incidence after premenopausal RRSO is still high, especially in BRCA1 mutation carriers. We could not confirm the expected risk reduction as described by other authors. As a consequence, after RRSO, continued surveillance with mammography and MRI for breast cancer in BRCA1 and BRCA2 mutation carriers is warranted.

No potential conflicts of interest were disclosed.

Conception and design: I.E. Fakkert, M.J.E. Mourits, J.C. Oosterwijk, G.H. de Bock

Development of methodology: I.E. Fakkert, M.J.E. Mourits, G.H. de Bock

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): I.E. Fakkert, M.J.E. Mourits, L. Jansen, K. Meijer, J.C. Oosterwijk, B. van der Vegt

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): I.E. Fakkert, L. Jansen, M.J.W. Greuter, G.H. de Bock

Writing, review, and/or revision of the manuscript: I.E. Fakkert, M.J.E. Mourits, L. Jansen, D.M. van der Kolk, K. Meijer, J.C. Oosterwijk, B. van der Vegt, M.J.W. Greuter

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): I.E. Fakkert, M.J.E. Mourits, G.H. de Bock

Study supervision: M.J.E. Mourits, M.J.W. Greuter, G.H. de Bock

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1.
Antoniou
A
,
Pharoah
PD
,
Narod
S
,
Risch
HA
,
Eyfjord
JE
,
Loman
N
, et al
Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies
.
Am J Hum Genet
2003
;
72
:
1117
30
.
2.
Chen
S
,
Parmigiani
G
. 
Meta-analysis of BRCA1 and BRCA2 penetrance
.
J Clin Oncol
2007
;
25
:
1329
33
.
3.
van der Kolk
DM
,
de Bock
GH
,
Leegte
BK
,
Schaapveld
M
,
Mourits
MJ
,
de Vries
J
, et al
Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age
.
Breast Cancer Res Treat
2010
;
124
:
643
51
.
4.
Kriege
M
,
Brekelmans
CT
,
Boetes
C
,
Besnard
PE
,
Zonderland
HM
,
Obdeijn
IM
, et al
Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition
.
N Engl J Med
351
:
427
37
.
5.
Leach
MO
,
Boggis
CR
,
Dixon
AK
,
Easton
DF
,
Eeles
RA
,
Evans
DG
, et al
Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS)
.
Lancet
365
:
1769
78
.
6.
Warner
E
,
Plewes
DB
,
Hill
KA
,
Causer
PA
,
Zubovits
JT
,
Jong
RA
, et al
Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination
.
JAMA
2004
;
292
:
1317
25
.
7.
Kuhl
CK
,
Schrading
S
,
Leutner
CC
,
Morakkabati-Spitz
N
,
Wardelmann
E
,
Fimmers
R
, et al
Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer
.
J Clin Oncol
2005
;
23
:
8469
76
.
8.
Hagen
AI
,
Kvistad
KA
,
Maehle
L
,
Holmen
MM
,
Aase
H
,
Styr
B
, et al
Sensitivity of MRI versus conventional screening in the diagnosis of BRCA-associated breast cancer in a national prospective series
.
Breast
2007
;
16
:
367
74
.
9.
Hermsen
BB
,
Olivier
RI
,
Verheijen
RH
,
van Beurden
M
,
de Hulla
JA
,
Massuger
LF
, et al
No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study
.
Br J Cancer
2007
;
96
:
1335
42
.
10.
van der Velde
NM
,
Mourits
MJ
,
Arts
HJ
,
de Vries
J
,
Leegte
BK
,
Dijkhuis
G
, et al
Time to stop ovarian cancer screening in BRCA1/2 mutation carriers?
Int J Cancer
2009
;
124
:
919
23
.
11.
Rebbeck
TR
,
Kauff
ND
,
Domchek
SM
. 
Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers
.
J Natl Cancer Inst
2009
;
101
:
80
7
.
12.
Kramer
JL
,
Velazquez
IA
,
Chen
BE
,
Rosenberg
PS
,
Struewing
JP
,
Greene
MH
. 
Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers
.
J Clin Oncol
2005
;
23
:
8629
35
.
13.
Eisen
A
,
Lubinski
J
,
Klijn
J
,
Moller
P
,
Lynch
HT
,
Offit
K
, et al
Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: an international case-control study
.
J Clin Oncol
2005
;
23
:
7491
6
.
14.
Arnold
AGA
,
Kauff
ND
. 
Prophylactic oophorectomy may differentially reduce breast cancer risk in women with BRCA1 versus BRCA2 mutations
.
Curr Breast Cancer Rep
2009
;
1
:
157
61
.
15.
Shah
P
,
Rosen
M
,
Stopfer
J
,
Siegfried
J
,
Kaltman
R
,
Mason
B
, et al
Prospective study of breast MRI in BRCA1 and BRCA2 mutation carriers: effect of mutation status on cancer incidence
.
Breast Cancer Res Treat
2009
;
118
:
539
46
.
16.
Groeneveld
FP
,
Bareman
FP
,
Barentsen
R
,
Dokter
HJ
,
Drogendijk
AC
,
Hoes
AW
. 
The climacteric and well-being
.
J Psychosom Obstet Gynaecol
1993
;
14
:
127
43
.
17.
Fakkert
IE
,
Jansen
L
,
Meijer
K
,
Kok
T
,
Oosterwijk
JC
,
Mourits
MJ
, et al
Breast cancer screening in BRCA1 and BRCA2 mutation carriers after risk reducing salpingo-oophorectomy
.
Breast Cancer Res Treat
2011
;
129
:
157
64
.
18.
Zonderland
H
,
Wagner
T
,
van Asperen
C
,
Benraadt
J
,
de Bock
GH
,
den Heeten
GJ
, et al
Richtlijn mammacarcinoom 2008 [Internet]
.
Utrecht
:
Kwaliteitsinstituut voor de gezondheidszorg CBO
; 
2008
[cited 2011 dec 13] Available from
: http://www.cbo.nl/Downloads/328/rl_mamma_08.pdf.].
19.
Kenkhuis
MJ
,
de Bock
GH
,
Elferink
PO
,
Arts
HJ
,
Oosterwijk
JC
,
Jansen
L
, et al
Short-term surgical outcome and safety of risk reducing salpingo-oophorectomy in BRCA1/2 mutation carriers
.
Maturitas
2010
;
66
:
310
4
.
20.
Kriege
M
,
Brekelmans
CT
,
Boetes
C
,
Rutgers
EJ
,
Oosterwijk
JC
,
Tollenaar
RA
, et al
MRI screening for breast cancer in women with familial or genetic predisposition: design of the Dutch National Study (MRISC)
.
Fam Cancer
2001
;
1
:
163
8
.
21.
Tilanus-Linthorst
MM
,
Kriege
M
,
Boetes
C
,
Hop
WC
,
Obdeijn
IM
,
Oosterwijk
JC
, et al
Hereditary breast cancer growth rates and its impact on screening policy
.
Eur J Cancer
2005
;
41
:
1610
7
.
22.
Plevritis
SK
,
Kurian
AW
,
Sigal
BM
,
Daniel
BL
,
Ikeda
DM
,
Stockdale
FE
, et al
Cost-effectiveness of screening BRCA1/2 mutation carriers with breast magnetic resonance imaging
.
JAMA
2006
;
295
:
2374
84
.
23.
Liberman
L
,
Mason
G
,
Morris
EA
,
Dershaw
DD
. 
Does size matter? Positive predictive value of MRI-detected breast lesions as a function of lesion size
.
AJR Am J Roentgenol
2006
;
186
:
426
30
.
24.
Kauff
ND
,
Domchek
SM
,
Friebel
TM
,
Robson
ME
,
Lee
J
,
Garber
JE
, et al
Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study
.
J Clin Oncol
2008
;
26
:
1331
7
.
25.
Clarke
RB
. 
Ovarian steroids and the human breast: regulation of stem cells and cell proliferation
.
Maturitas
2006
;
54
:
327
34
.
26.
Warner
E
,
Hill
K
,
Causer
P
,
Plewes
D
,
Jong
R
,
Yaffe
M
, et al
Prospective study of breast cancer incidence in women with a BRCA1 or BRCA2 mutation under surveillance with and without magnetic resonance imaging
.
J Clin Oncol
2011
;
29
:
1664
9
.
27.
Dutch cancer figures, breast cancer incidence in 1989 and 2009 [Internet]
.
The Netherlands Cancer Registry
; 
2011
[cited 2011 Aug 28]. Available from:
http://www.cijfersoverkanker.nl.
28.
Junod
B
,
Zahl
PH
,
Kaplan
RM
,
Olsen
J
,
Greenland
S
. 
An investigation of the apparent breast cancer epidemic in France: screening and incidence trends in birth cohorts
.
BMC Cancer
2011
;
11
:
401
.
29.
Rebbeck
TR
,
Friebel
T
,
Wagner
T
,
Lynch
HT
,
Garber
JE
,
Daly
MB
, et al
Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group
.
J Clin Oncol
2005
;
23
:
7804
10
.
30.
Eisen
A
,
Lubinski
J
,
Gronwald
J
,
Moller
P
,
Lynch
HT
,
Klijn
J
, et al
Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers
.
J Natl Cancer Inst
2008
;
100
:
1361
7
.
31.
Holmberg
L
,
Iversen
OE
,
Rudenstam
CM
,
Kumpulainen
E
,
Jaskiewicz
J
,
Jassem
J
, et al
Increased risk of recurrence after hormone replacement therapy in breast cancer survivors
.
J Natl Cancer Inst
2008
;
100
:
475
82
.
32.
Kenemans
P
,
Bundred
NJ
,
Foidart
JM
,
Kubista
E
,
von Schoultz
B
,
Sismondi
P
, et al
Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial
.
Lancet Oncol
2009
;
10
:
135
46
.
33.
Rocca
WA
,
Grossardt
BR
,
de Andrade
M
,
Malkasian
GD
,
Melton
LJ
 III
. 
Survival patterns after oophorectomy in premenopausal women: a population-based cohort study
.
Lancet Oncol
2006
;
7
:
821
8
.